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Radiotherapy is a treatment in which each case requires individual consideration and careful evaluation of the irradiation method most suitable for the patient. Decisions must not be influenced by statements that the limit dose means a safe dose. Moreover, if there is available a safer treatment proton therapy.

Proton Therapy Center Czech is an advanced clinical centre with the newest and highly exact technology – Pencil Beam Scanning for treatment of tumors of head and neck, brain and CNS, lymphomas, lungs, prostate, breast, pancreas and tumors in children.

Radiation therapy strategies

Target volumes, fractionation and the timing of radiotherapy for individual subgroups of pediatric tumors are specified in the respective pediatric protocols. The rule is that the fractionation, volume and dose are the same as in the case of photon radiation therapy. The advantage of proton therapy is the achievement of greater conformity with the lower integral dose.

Unlike adult patients, it can be generalized that accelerated radiotherapy regimens are not used in pediatric patients and normal fractionation is the standard of treatment.

 

Primary pediatric indications for proton therapy:

  • (referral from a pediatric oncologist is required)

  1. Medulloblastoma: postoperative RT – craniospinal axis + boost to the region of the posterior fossa.
  2. Craniopharyngioma: Postoperative radiotherapy, radical surgical resection contraindicated in the case of recurrence.
  3. Gliomas with a low degree of malignancy: inoperable oligodendroglioma and astrocytomas, radical radiotherapy in the case of impossibility to perform radical resection, postoperative radiotherapy in R1 or R2 resection.
  4. Ependymoma: postoperative radiotherapy, radiotherapy of recurrent tumors to the extent according to the stage of disease.
  5. Germ cell tumors: to the extent according to the relevant protocol (independently or after chemotherapy).
  6. High-grade gliomas: recurrent tumors after previous radiotherapy, primarily in unfavorable locations in selected patients.
  7. Chordomas, chondrosarcomas: postoperative/radical radiotherapy.
  8. Soft tissue sarcomas (in unfavorable locations) – to the extent according to the relevant protocol.
  9. Ewing’s sarcoma (in unfavorable locations– to the extent according to the relevant protocol.
  10. Any other tumors as specified by a multidisciplinary team
    (esthesioneuroblastoma, neuroblastoma, nephroblastoma, malignant lymphomas, and others).

 

Toxicity and risks of current therapy

Late side effects rather than acute side effects are of crucial importance, given the excellent treatment results achieved by complex cancer therapy. The expected side effects of radiotherapy depend on the irradiated area and the dose administered.

The risk of late effects steadily increases with the time interval from completed radiotherapy and does not reach a plateau (see figure, literature reference 4). Once emerged, most of the severe adverse effects are not causally influenced by any treatment, and their prevention is of the utmost importance.

Under certain circumstances, radiotherapy may be completely omitted from treatment (as is the case in most of today’s protocols for ALL treatment) or may be delayed in order to reduce its toxicity. This is the case today for children with tumors of the central nervous system under three years of age. The toxicity of radiotherapy is also reduced by modern irradiation techniques.

 

An overview of the most serious late side effects of conventional radiotherapy:

a) Cardiotoxicity

Cardiotoxicity rarely occurs during radiotherapy. It is usually manifested as pericardial effusion or constrictive pericarditis.

Coronary artery endothelial damage with an increased risk of ischemic heart disease is a more common adverse effect of radiotherapy. Typically, we see this adverse effect in patients treated for mediastinal lymphoma or chest sarcoma.

 

b) Pneumotoxicity

Radiotherapy-induced pneumonitis is associated with high morbidity and mortality. Its incidence is lower in the pediatric population than in adults: the incidence in patients with Hodgkin lymphoma or sarcoma of the chest wall is reported to be 8-9%. Apart from bleomycin-containing chemotherapy regimens, it has been demonstrated to have a growing incidence with increasing V24, as shown below (literature reference 2).

 

 

c) Endocrine side effects

These adverse effects are encountered if a significant radiation dose is delivered to irradiate the hypothalamus, pituitary gland, thyroid gland or gonads, and the hypothalamus is more sensitive to radiation than the pituitary gland.

Growth hormone deficiency (GHD) already occurs with low doses of radiation – its incidence increases with doses higher than 27 Gy delivered to the cranium. Despite the growth hormone treatment, which is now standard treatment in the case of diagnosed deficiency, achieved body height may be lower.

Very common adverse effects are TSH deficiency, increased prolactin levels, deficiency in testosterone production and others.

The relationship of age at the time of radiotherapy, dose delivered to the area of the hypothalamus and pituitary gland, and the incidence of hormonal abnormalities in localized radiation therapy is shown in the graph below (literature reference 3).

                        

Thyroid disorders are common after radiotherapy of the lymph nodes in the neck region (in children with malignant lymphomas) or after spinal radiotherapy in children with tumors of the central nervous system.

 

d) Growth disorders

Hypoplasia or growth disorders of bones and soft tissues may occur in the irradiated field following radiotherapy, depending on the dose. The consequences are asymmetric growth of the irradiated area, scoliosis and lower body height in adulthood.

In addition to growth disorders, the endocrinological abnormalities mentioned above may also contribute to the lower body height.

 

e) Gonadal dysfunction and fertility

Fertility is maintained after irradiation of ovaries with doses up to 2.5 Gy in 52% of pediatric patients, and decreases rapidly with the increasing dose – with doses of 10 Gy, fertility is maintained in only about 3% of patients.

Doses above 10 Gy delivered to the uterus area significantly increase the risk of a stillborn fetus or premature birth. However, the incidence of birth defects in fetuses of mothers receiving anticancer treatment is not different compared to that in the healthy population.

In men, very low doses of 2 to 3 Gy delivered to the testicular area have already been reported to cause permanent azoospermia. Hypoandrogenism is observed during irradiation of the testes in prepubertal boys with doses higher than 24 Gy.

 

f) Impairment of renal function

Radiotherapy to this region at a dose >20 Gy can result in tubular damage and hypertension due to renal artery stenosis.

 

g) Disorders of sensory functions

Cataracts occur after irradiation of the eye lens with very small doses (from 0.8 Gy), and the absence of a threshold dose cannot be ruled out. The risk of retinopathy increases from a dose of 45 Gy and has not been reported at doses below 25 Gy using standard fractionation. In contrast, doses tolerated by the optic nerve and chiasm are higher – the risk of damage at doses lower than 55 Gy is less than 3%.

Hearing impairment occurs as a consequence of ototoxic chemotherapy or radiotherapy, but has also been reported in connection with shunt insertion. Its risk increases with decreasing age at the time of radiotherapy (higher in children below the age of three) and with increasing radiation dose (from doses of 35 to 40 Gy). Following radiotherapy it may emerge with a delay of several years and tends to progress over time in some patients.

Changes or loss of the sense of taste or smell are reported fairly often, but there are no clearly defined threshold doses for the individual sensory functions.

 

h) Disorders of neurocognitive function and psychosocial side effects of therapy

Neurocognitive dysfunction is very common and occurs in up to 40% of patients, since most children are treated with radiation for tumors of the central nervous system. The degree of neurocognitive damage sustained is determined by age at the time of treatment (most severe in children under three years of age) and by any concomitant therapy (neurosurgery or chemotherapy); the radiation dose delivered and the anatomical region of the brain are also of utmost importance. While the hippocampus areas and temporal lobes are considered to be particularly important, recent works show a significant correlation between the doses delivered to the cerebellum and a decrease in cognitive functions.

The figure below shows the correlation between age and the dose delivered to the individual organs and the probability of a decline in cognitive functions (specifically in patients irradiated for medulloblastoma) (literature reference 7).

The impact on specific aspects of the quality of life varies according to the irradiated region of the brain (e.g. irradiation of the temporal lobe affects the emotional aspect more than irradiation of the frontal lobe) and has been found to be dose-dependent. Deterioration of overall physical health has been described in 12-27% of patients, while a decreased social quality of life was observed in 23-37% of patients who underwent CNS irradiation during childhood (literature reference 6).

 

i) Secondary Malignancies

These are a significant aspect of late mortality in pediatric cancer patients. The most common secondary malignant tumors (SMN) are tumors of the central nervous system, breast, thyroid, bone and secondary leukemia.

The appearance of secondary solid tumors after radiation therapy is dose dependent and also dependent upon the age of the child when radiotherapy was carried out. The risk of secondary solid tumors after radiotherapy, in contrast to secondary leukemia, has increased steadily, SMN can appear ten years, twenty years, or more after primary diagnosis (literature 4).

The prognosis of SMN has now greatly improved and in many cases approaches the prognosis of newly diagnosed tumors. Due to this improvement we now encounter ever more frequently a new phenomenon – the development of subsequent (tertiary) malignancies.

 

Literature:

  1. Kepák T., Pozdní následky onkologické léčby v dětském věku – potřeba multidisciplinární spolupráce, dostupné na http://zdravi.euro.cz/clanek/postgradualni-medicina/pozdni-nasledky-onkologicke-lecby-v-detskem-veku-potreba-multidi-414593
  2. Hua Ch., Hoth K. et al. INCIDENCE AND CORRELATES OF RADIATION PNEUMONITIS IN PEDIATRIC PATIENTS WITH PARTIAL LUNG IRRADIATION, Int J Radiat Oncol Biol Phys. 2010 September 1; 78(1): 143–149. doi:10.1016/j.ijrobp.2009.07.1709.
  3. Greenberger B., Pulsifer MB et al. Clinical Outcomes and Late Endocrine, Neurocognitive, and Visual Profiles of Proton Radiation for Pediatric Low-Grade Gliomas. Int J Radiation Oncol Biol Phys, Vol. 89, No. 5, pp. 1060e1068, 2014, http://dx.doi.org/10.1016/j.ijrobp.2014.04.053
  4. Mertens AC, Liu Q et al. Cause-Specific Late Mortality Among 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study. J Natl Cancer Inst 2008;100: 1368 – 1379
  5. Bass JK, Hua Ch-H et al. Hearing Loss in Patients Who Received Cranial Radiation Therapy for Childhood Cancer. J Clin Oncol 34:1248-1255. DOI: 10.1200/JCO.2015.63.6738
  6. Armstrong GT, Jain N. et al. Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies. Neuro-Oncology 12(11):1173–1186, 2010. doi:10.1093/neuonc/noq104
  7. Merchant T, Schreiber JE et al. 1.Critical Combinations of Radiation Dose and Volume Predict Intelligence Quotient and Academic Achievement Scores After Craniospinal Irradiation in Children With Medulloblastoma. Int J Radiation Oncol Biol Phys, Vol 90 , Issue 3 , 554 – 561, http://dx.doi.org/10.1016/j.ijrobp.2014.06.058

 

Possibilities for improving results

Treatment results achieved in pediatric protocols are excellent. Radiotherapy should proceed by minimizing the dose to critical structures while ensuring a sufficient dose to the target volume. One of the ways is the inclusion of proton therapy in the treatment of pediatric patients.

 

The advantages of proton therapy

Protons show the characteristic shape of the depth dose distribution. Unlike photons, which release maximum energy on the surface and their energy decreases with depth, protons release only a small amount of energy as they pass through the tissue. Just before the end of the proton’s trajectory, the tissue absorbs most of the energy, and there is a sharp increase in the dose and its subsequent sharp decrease to zero. This area is called the Bragg peak. The depth at which the Bragg peak occurs is determined by proton energy (the energy is between 70-230 MeV and the maximum depth is about 30 cm).

Proton radiotherapy is associated with the sparing of the tissue “in front of the tumor” (from the perspective of the radiation source) and in particular beyond the tumor. In this way, it is possible to deliver the prescribed dose to the target volume while sparing the healthy tissue (as compared to photon radiation), improve the toxicity, and improve the quality of life of pediatric patients.

 

In particular, it is thought that the percentage of tumors induced by irradiation after proton radiotherapy will drop significantly, since the percentage of irradiated healthy tissue decreases considerably in comparison with photon therapy.

 

For illustration, the figure below compares the dose distribution (protons are above, photons below) for irradiation of the craniospinal axis.

Figure: Comparison of dose distribution for irradiation of the craniospinal axis using proton and photon radiotherapy. Sections of the planning CT show the dose distribution in normal and healthy tissues. Sagittal sections show that with proton radiation therapy, the dose is limited to the core skeleton, while photons also deliver the dose to the mediastinum and heart.

 

The Benefits of Proton Therapy

The treatment protocols employed at PTC are the same internationally accepted protocols that have achieved treatment success world-wide. Proton therapy clearly demonstrates:

 

  • Reduced incidence of secondary malignancies
  • Reduced amount of growth abnormalities
  • Reduced hormonal dysfunction
  • Reduced levels of cognitive impairment
  • Proton therapy reduces the incidence of acute adverse effects such as radiation mucositis, pneumonitis, and gastroenteritis.

 

References

Examples of some publications:

    1. Fuss, M. H., Hug, E. B., Schaefer, B. S., Nevinny-Stickel, M., Miller, D. W., Slater, J. M., et al. (1999). Proton radiation therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standardphoton technique. International Journal of Radiation Oncology, Biology and Physics, 45, 1117-1126.
    2. Kirsch, D. G., & Tarbell N. J. (2004). New technologies in radiation therapy for pediatric brain tumors: the rationale for proton radiation therapy. Pediatric Blood & Cancer, 42, 461-464.
    3. Lee, C. T., Bilton, S. D., Famiglietti, R. M., Riley, B. A., Mahajan, A., Chang, E. L., et al. (2005). Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: How do protons compare with other conformal techniques? International Journal of Radiation Oncology and Biology, 63, 362-372
    4. Merchant, T. E., Hua, C.-H., Shukla, H., Ying, X., Nill, S., & Oelfke, U. (2008). Proton versus photon radiotherapy for common pediatric brain tumors: Comparison of models of dose characteristics and their relationship to cognitive function. Pediatric Blood & Cancer, 51, 110-117
    5. Miralbell, R., Lomax, A., Cella, L., & Schneider, U. (2002). Potential reduction of the incidence of radiation induced second cancers by using proton beams in the treatment of pediatric tumors. International Journal of Radiation Oncology, Biology and Physics, 54, 824-829.
    6. Yuh, G. E., Loredo, L. N., Yonemoto, L. T., Bush, D. A., Shahnazi, K., Preston, W., et al. (2004). Reducing toxicity from craniospinal irradiation: Using proton beams to tread medulloblastoma in young children. Cancer Journal, 10, 386-390.
    7. MacDonald SM, Trofimov A, Safai S, Adams J, Fullerton B, Ebb D, Tarbell NJ, Yock TI. Proton radiotherapy for pediatric central nervous system germ cell tumors: early clinical outcomes. Int J Radiat Oncol Biol Phys. 2011 Jan 1;79(1):121-9. Epub 2010 May 6.
    8. Haibo L., Ding X et al. Supine Craniospianl Irradiation Using a Proton Pencil Beam Scanning Technique Without Match Line Changes for Field Junctions. Int J Radiation Oncol Biol Phys , Volume 90 , Issue 1 , 71 – 78, http://dx.doi.org/10.1016/j.ijrobp.2014.05.029
    9. Grant SR, Grosshans DR et al Proton versusu conventiona radiotherapy for pediatric salivary gland tumors: Acute toxicity and dosimetric characteristics. Radiotherapy and Oncology , Volume 116 , Issue 2 , 309 – 315, http://dx.doi.org/10.1016/j.radonc.2015.07.022
    10. Greenberger B., Pulsifer MB et al. Clinical Outcomes and Late Endocrine, Neurocognitive, and Visual Profiles of Proton Radiation for Pediatric Low-Grade Gliomas. Int J Radiation Oncol Biol Phys, Vol. 89, No. 5, pp. 1060e1068, 2014, http://dx.doi.org/10.1016/j.ijrobp.2014.04.053

     

Radiotherapy is one of the basic methods of prostate cancer treatment. The most modern method is proton, i.e. particle radiotherapy. The distribution of radiation dose in tissues in proton therapy shows many advantages when compared to the techniques of photon therapy. This dosimetric advantage increases with the growing size of the target volume and complexity of shapes in the target volume (for example, irradiation of seminal vesicles or lymph nodes). There is a general rule of dose dependence in radiotherapy – the higher the dose of healthy tissue, the higher the risk of side effects.

 

Use of proton therapy in the treatment of prostate cancer

 

Prostate cancer is the most frequent diagnosis treated in proton centers all over the world. The reason is the high degree of curability, an effort to reduce late, unwanted effects and an emphasis on the quality of patient life.

The indication of proton therapy in the treatment of prostate cancer from the PTC is part of the recommendation “list of indications for proton therapy” as elaborated by the PTC expert committee (including both radiation oncologists and other specialists). It is based on common indications in proton centers throughout the world and recommended by professional organizations dealing with proton radiotherapy (PTCOG, NAPT).

 

The position of proton radiotherapy of prostate cancer in the world:

Proton radiotherapy is a common method in the proton centres all around the world. ASTRO (American Society for Radiation Oncology) supported the use of the proton radiotherapy in the treatment of prostate cancer within clinical trials or registries in 2013 – “While proton beam therapy is not a new technology, its use in the treatment of prostate cancer is evolving. ASTRO strongly supports allowing for coverage with evidence development for patients treated on clinical trials or within prospective registries. ASTRO believes that collecting data in these settings is essential to informing consensus on the role of proton therapy for prostate cancer, especially insofar as it is important to understand how the effectiveness of proton therapy compares to other radiation therapy modalities such as IMRT and brachytherapy.

(https://www.astro.org/News-and-Media/News-Releases/2013/ASTRO-Board-of-Directors-approves-statement-on-use-of-proton-beam-therapy-for-prostate-cancer.aspx). In its model, the same ASTRO committee recommended proton therapy reimbursement from health insurance in 2014 (https://www.astro.org/uploadedFiles/Main_Site/Practice_Management/Reimbursement/ASTRO%20PBT%20Model%20Policy%20FINAL.pdf).

 

All the centres (and these are the leaders of the world of oncology) include it in their basic indications. See, for example:

MD Anderson Cancer Centerhttp://www.mdanderson.org/patient-and-cancer-information/proton-therapy-center/conditions-we-treat/prostate-cancer/index.html

MGH Bostonhttp://www.massgeneral.org/radiationoncology/research/researchlab.aspx?id=1630

UPENN – http://www.pennprotontherapy.org/cancers-we-treat/

University of Floridahttp://www.floridaproton.org/cancers-treated/prostate-cancer

Scripps proton therapy center, San Diegohttp://www.scripps.org/services/cancer-care__proton-therapy/conditions-treated__proton-therapy-for-prostate-cancer

Loma Linda Proton therapy center, Californiahttp://www.protons.com/proton-therapy/proton-treatments/prostate-cancer/about-the-prostate.page

University of Floridahttp://www.floridaproton.org/cancers-treated/prostate-cancer

 

Indication of proton therapy and the tactics of treatment by radiation

Reasons for proton radiotherapy for professionals:

  1. Proton radiotherapy is a highly effective method. The probability of cure measured as
    5-year PSA relapse-free survival according to recent published data for low- and medium-risk prostate cancer is higher than 95%. Such results are usually not achieved using photon techniques or surgeries.
  2. Proton radiotherapy is associated with minimal toxicity. The last published papers on large cohorts found severe treatment toxicity in less than 1% of patients. In comparison with the published data on photon radiotherapy and surgical interventions, this toxicity level is minimal and significantly lower than for the other methods.
  3. Compared with surgical therapy, proton therapy does not lead to urinary incontinence, thus saving the costs spent on managing this issue.
  4. Compared with surgical therapy, proton radiotherapy does not lead to impotence, thus significantly improving the quality of life of patients.
  5. Proton therapy, compared with brachytherapy, has a significantly lower risk of the development of urethral stenosis and impotence.
  6. Proton radiotherapy is a fully outpatient treatment method. In most cases, it does not require sick leave. For low- and intermediate-risk prostate cancer, 5-day stereotactic proton irradiation can be used.

 

Standard procedure for external beam photon radiotherapy is standard fractionation treatment to
a total dose greater than 78 Gy, which means treatment is for 39-42 fractions / 8 weeks. For combination with internal radiation mode is used 25 fractions / 5 weeks of external irradiation in combination with 2 factions of internal irradiation exposure, which is performed under general anaesthesia with hospitalisation.

 

Modes suitable for proton radiotherapy allows increasing single doses per fraction and total dose and shortening the irradiation time in compliance with the same biologically equivalent dose.

 

Comparison modes are shown in Table 1

Table 1: Comparison of the fractionation schedules in the treatment of prostate cancer

 

Regime

 

Dose (Gy)

Number of Fractions / dose per fraction (Gy) Overall duration (weeks)
IMRT PHOTONS 82.0 41 x 2.0 Gy 8
Protons – low-risk carcinoma (current regime) 36,25 5 x 7,25 Gy 2
Protons – medium & high risk (current regime) 63.0 21 x 3.0 Gy 4

 

Proton therapy enables increasing the dose into fractions for maintaining a biologically equivalent dose.

 

Table 2: Recent outcomes of prospective studies

Author Number of patients Mode FU (median) 5year survival without biochemical relapse Toxicity Note
Mendenhall  et al., 2014 (1) 211 (89 low risk, 82 intermediate risk, 40 high risk) 78-82 CGE/  39-41 fr 5,2 y Low risk – 99%

Intermediate risk – 99%

High risk – 76%

CTCEA v.4

(grade 3+)

GI – 0,5%

GU – 1%

High risk in combination with HORT and CHT
Henderson et al., 2015 (2) 228 (122 low risk, 106 intermediate risk) 70 CGE/28 fr or 72.5/ 29 fr 4,9 y Low risk – 99,2%

Intermediate risk – 92,6%

CTCEA v.4

(grade 3+)

GI – 0,9%

GU – 0,9%

Without adjuvant hort
Takagi et al., 2015 (3) 1375 (249 low risk, 602 intermediate risk, 499 high risk) 74 CGE/ 37 fr 5,8 y Low risk – 98,7%

Intermediate risk – 90,8%

High risk – 85,6%

CTCEA v.4

(grade 2+)

GI – 4,1%

GU – 5,4%

Only 4% of patients with adjuvant hort

 

These results are better than the recent work published in the field of the photon radiotherapy. For example, Spratt et al. (4) describe 5-year biochemical relapse-free survival in intermediate-risk prostate cancer treated with either external radiotherapy using the IMRT technique or the combination of IMRT and brachytherapy at the level of approximately 90% for IMRT (81.4% after 7 years) and approximately 95% in the combination of IMRT and BRT (92% after 7 years). Grade 2 toxicity or higher (CTCAE v. 4) reached the following levels at the evaluation after 7 years: GU (genitourinary) – 19.6% for IMRT and 21.2% for the combined treatment; grade 3 GU toxicity was 3.1 and 1.4%, respectively; GI (Gastrointestinal) – grade 2 and above 4.6 and 4.1%, respectively; grade 3 0.4% and 1.4%, respectively.

Odrážka et al. (5) describe 5-year biochemical control of prostate cancer treated with IMRT at the level of 86%, 89% and 82% for low risk, medium risk and high risk, respectively. The late toxicity (RTOG/FC-LENT) grade 2 or higher was: GU and GI 17.7% and 22.4%, respectively.

 

Table 3: Comparison of effectiveness and toxicity of individual radiotherapeutic methods and the treatment of low risk prostate cancer:

Proton therapy IMRT Brachytherapy
Efficacy (5-year disease-free survival) 99% 86-90% 97%
Toxicity – genitourinary, Grade 2 and higher 5% 15-20% 20-30%
Toxicity – gastrointestinary, Grade 2 and higher 4% 15-25% 0-5%
Erectile dysfunction 3% 22% 40%

 

As evidenced by the data provided in the table, the undesirable effects after photon therapy are significantly higher than after proton radiotherapy.

 

Summary

Published results from 2015 for proton radiotherapy indicate 5-10% better survival rate without biochemical relapse and 2-3-fold lower incidence of late adverse events. Since the costs for proton irradiation are comparable to modern photon techniques, this method saves costs for the payers, i.e. the medical insurance companies, due to the much lower costs of complications management.

 

Comparison of the risks of various treatment modalities:  Surgery/Photons/Protons

                                     

The relapse rate (or simply recurrence) of the disease is an important factor in the comparison of various treatment modalities. Even here, proton therapy has convincing results. After surgery (low prostate risk), the disease recurs in 10% of cases, while in other stages of prostate cancer, the risk of cancer recurrence after surgical procedure increases up to 30%. With proton therapy, the recurrence rate is only 1%.

According to recent data from the analysis of the results of proton therapy in PTC patients, it has been demonstrated that 95% of these patients do not suffer from the complications that often plague patients undergoing photon therapy. Since protons do not affect healthy organs, patients do not suffer erectile dysfunction. In contrast, photon therapy causes significant pain and a burning sensation during urination, a weak urinary stream, the frequent urge to have a bowel movement or even diarrhoea and abdominal pain in 30% of patients. Proton therapy, however, keeps these complications to a minimum, which (in terms of numbers) means only 5%. Lower doses of proton radiation on healthy organs significantly reduce the occurrence of complications after proton therapy, which is the main goal of modern cancer treatment.

 

Effectiveness, limits of contemporary radiation therapy technical and biological aspects PTC outcomes

 

Independent monitoring of acute and late unwanted effects of proton radiation in patients with
a malignant prostate tumor was carried out in the Prague based “Proton Therapy Center” (PTC). This evaluation included a total of 86 patients with low risk and medium risk prostate cancer (57 and 29 patients), who finished their treatment before January 2015. The average age of the monitored patients was 63 years. The same radiation regimen was used in all these patients – they were exposed to radiation 5 times (so-called 5 fractions) ranging between 7 and 13 days. None of these patients had undergone any surgical procedure on the prostate before the radiation. At the moment, in all these monitored patients, there is zero activity of their cancer.

 

In more than 50% of the monitored patients, no acute unwanted effects on the urinary system have been determined. The most frequent acute unwanted effects (manifested within 90 days from radiation), which affected the urinary system, included: painful urination, an increased frequency of urination, and a worsened flow of the urine. The only acute unwanted effects of the radiation on the digestive system were tenesmuses (an urge for defecation), which were of mild severity, and only determined in 15% of the patients.

   

* We distinguish unwanted effects of mild/moderate/severe and life threatening unwanted effects

 

In the patients, acute unwanted effects subside within 4 weeks after the termination of radiotherapy. As apparent from the graphs above, 97.7% of patients did not suffer from any unwanted effects on the gastrointestinal system which would require any medication. From the viewpoint of the genitourinary system, 83.7% of the patients were without unwanted effects requiring medication. Other patients suffered from mild problems requiring common medication, for example Algifen. Comparing acute unwanted effects of the treatment as observed in the PTC in Prague with acute unwanted effects of modern techniques of photon treatment from the study by Fang et al. (10), we can see that the proton therapy has, when compared to the photon IMRT treatment, fewer unwanted effects of moderate severity on the urinary system (2.3% vs 13.8%) and also on the digestive system (16.3% vs 28.7%).

 

None of the treated patients required any subsequent oncologic therapy after the termination of the proton therapy.

 

The advantages of proton therapy

The main advantage of proton therapy is significantly improved dose distribution in critical organs. Doses applied to the urinary bladder and the rectum is typically 25%-50% compared to the published doses for modern photon techniques. In the case of radiotherapy of the pelvic nodes, the doses applied to organs of the abdominal cavity reach the level of 5-10% of the prescribed dose. Figure 1 and Table 4 are examples of the irradiation schedule and dose distribution to the various organs.

 

Figure: Example of a plan:

(a) photon IMRT;  (b) proton IMPT;  (c) DVH (dose-volume histograms)

a  b  c

 

Table: Dose for each structure / organ

  IMRT (photon) IMPT (proton)
Target volume Prostate 78 Gy (100%) 78 Gy (100%)
Organs at risk Rectum Dmean 40,2 Gy (51%) 17,5 Gy (18,7%)
Bladder D(50%) 9,5 Gy (12%) 0,9 Gy (1%)

 

Conclusion

Particle radiotherapy in the treatment of prostate cancer achieves the best dose distributions among available radiotherapeutic techniques; prospective non-randomized studies have proven its high effectiveness and very low toxicity, which has also been confirmed in the group of patients treated in the PTC.

 

References:

  1. Hoppe BS, Nichols RC, Henderson RH, Morris CG, Williams CR, Costa J, Marcus RB Jr, Mendenhall WM, Li Z, Mendenhall NP. Erectile function, incontinence, and other quality of life outcomes following proton therapy for prostate cancer in men 60 years old and younger. Cancer. 2012 Jan 17. doi: 10.1002/cncr.27398.
  2. Nichols RC Jr, Morris CG, Hoppe BS, Henderson RH, Marcus RB Jr, Mendenhall WM, Li Z, Williams CR, Costa JA, Mendenhall NP. Proton radiotherapy for prostate cancer is not associated with post-treatment testosterone suppression. Int J Radiat Oncol Biol Phys. 2012 Mar 1;82(3):1222-6.
  3. Widesott L, Pierelli A, Fiorino C, Lomax AJ, Amichetti M, Cozzarini C, Soukup M, Schneider R, Hug E, Di Muzio N, Calandrino R, Schwarz M. Helical tomotherapy vs. intensity-modulated proton therapy for whole pelvis irradiation in high-risk prostate cancer patients: dosimetric, normal tissue complication probability, and generalized equivalent uniform dose analysis.Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1589-600. Epub 2010 Dec 1
  4. Mendenhall NP, Li Z, Hoppe BS, Marcus RB Jr, Mendenhall WM, Nichols RC, Morris CG, Williams CR, Costa J, Henderson R. Early outcomes from three prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2012 Jan 1;82(1):213-21.
  5. Colaco RJ, et al., Rectal Toxicity After Proton Therapy For Prostate Cancer: An Analysis of Outcomes of Prospective Studies Conducted at the University of Florida Proton Therapy Institute. Int J Radiat Oncol Biol Phys. 2014 Nov 5. pii: S0360-3016(14)04060-7;
  6. Mendenhall NP, et al., Five-year outcomes from 3 prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2014 Mar 1;88(3):596-602.;
  7. Henderson RH, et al., Urinary functional outcomes and toxicity five years after proton therapy for low- and intermediate-risk prostate cancer: results of two prospective trials. Acta Oncol. 2013 Apr;52(3):463-9.;
  8. Henderson et al., Five-year outcomes from prospective trial of image-guided accelerated hypofractionated proton therapy for prostate cancer. PTCOG 55, San Diego, USA
  9. Takagi M. et al., Long-term outcome in patients treated with proton therapy for localized prostate cancer. PTCOG 55, San Diego, USA
  10. Spratt et al., Comparison of high-dose (86,4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate risk prostate cancer
  11. Odražka a kol., Five year results of IMRT for prostate cancer – tumor control. Klin Onkol 2013; 26(6):415-20
  12. Sheets NC, Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA. 2012 Apr 18;307(15):1611-20.
  13. Kase Y. et al., A treatment planning comparison of passive-scattering and intensity-modulated proton therapy for typical tumor sites. J Radiat Res. 2012;53(2):272-80. Epub 2011 Dec 1.
  14. Hartsell F. et al., Hypofractionated vs Standard Fractionated Proton Beam Therapy for Early-Stage Prostate Cancer: Interim Results of a Randomized Prospective Trial Oncology (Williston Park). 2015 Apr 21;29(4 Suppl 1).
  15. Chung C. et al., Incidence of second malignancies among patients treated with proton versus photon radiation. Int J Radiat Oncol Biol Phys. 2013 Sep 1;87(1)
  16. FANG, Penny, Rosemarie MICK, Curtiland DEVILLE, et al. A case-matched study of toxicity outcomes after proton therapy and intensity-modulated radiation therapy for prostate cancer.Cancer [online]. 2015, 121(7): 1118-1127 [cit. 2015-12-02]. DOI: 10.1002/cncr.29148. ISSN 0008543x.
  17. McGee L, et al., Outcomes in men with large prostates (≥ 60 cm(3)) treated with definitive proton therapy for prostate cancer. Acta Oncol. 2013 Apr;52(3):470-6.;
  18. Hoppe BS, et al., Erectile function, incontinence, and other quality of life outcomes following proton therapy for prostate cancer in men 60 years old and younger. Cancer. 2012 Sep 15;118(18):4619-26.

 

Head and neck and orofacial tumors

 

Radiation therapy strategies

Radiation therapy or concomitant chemoradiotherapy may be administered with curative intent in most locally or locoregionally advanced ENT and orofacial tumors, either after surgery or as a single modality.

The goal of radiation therapy is to deliver a sufficient tumoricidal dose to the tumor and to the involved lymph nodes, as well as to areas with a risk of subclinical involvement (the area surrounding the tumor, sentinel lymph nodes), while minimizing the dose to the surrounding healthy organs. The tolerance of these healthy tissues to irradiation is very similar to that of tumor cells and therefore any undesirable effects of the radiation therapy in this area are very serious.

 

Limitations of current radiation therapy – technical and biological aspects

Due to the presence of many high-risk structures around the ENT or orofacial tumor with a limited tolerance to ionizing radiation (spinal cord, salivary glands, brain stem, swallowing tract, respiratory tract, mandible, oral cavity, or in some cases, eyes, optic nerves, retina, optic chiasm, brain, with limits of tolerance ranging from 40 to 55 Gy), situations may often occur in which it is not possible to administer a sufficient tumoricidal dose of radiation without increasing the risk of damage to the surrounding healthy tissues. This is especially true for tumors of the paranasal sinuses, nasopharynx and skull base, which are close to the eye or optic tract, or brain stem, for tumors spreading to the areas near the spinal canal with the risk of radiation damage to the spinal cord, and large tumors with the involvement of the lower cervical or upper mediastinal lymph nodes, where there is a risk of damage to the larynx, esophagus, swallowing tract and spinal cord. In some cases, highly radioresistant tumors are present (such as sarcomas, melanomas, adenoid cystic carcinomas) that should be irradiated with a high (>74 Gy) radiation dose and for which it is not possible to administer a sufficient dose of conventional photon radiation therapy due to the proximity of high-risk organs to the target volume. These tumors are considered incurable by radiation therapy.

Another complicated situation may arise in patients with recurrent ENT/orofacial tumors after previous radiotherapy, when it is necessary to repeat the irradiation (reradiation) in a situation where dose limits for high-risk organs have been reached in the previous series of RT (doses delivered to certain organs during the individual RT series are added together over time).

 

Use of proton therapy in the treatment of ENT tumors

ENT tumors are a common diagnosis treated at proton centers around the world. The reason is the complexity of the target volumes, which often do not allow the administration of curative doses while respecting the tolerated doses to critical organs. In addition to increasing curability, the aim is to reduce late adverse effects and emphasize the quality of life of the patients. Indications of proton therapy in the treatment of ENT tumors at the PTC center falls on the “list of indications of proton therapy” as prepared by the PTC board of experts (including both radiation oncologists and other specialists). They are based on usual indications at proton centers in the world and recommended by professional organizations involved in proton radiotherapy.

 

MD Anderson Cancer Centrehttp://www.mdanderson.org/patient-and-cancer-information/proton-therapy-center/conditions-we-treat/head-and-neck-cancers/index.html

Scripps proton therapy center, San Diego – http://www.scripps.org/services/cancer-care__proton-therapy/conditions-treated__proton-therapy-for-head-and-neck-cancers

Loma Linda Proton therapy center, California – http://www.protons.com/proton-therapy/proton-treatments/other-conditions.page?

University of Florida – http://www.floridaproton.org/cancers-treated/head-neck-cancer

 

Indications of proton therapy and strategies of radiation therapy

Proton radiotherapy allows a significant dose reduction to the critical structures of the head and neck. This involves in particular dose reduction to:

  • salivary glands
  • brain stem
  • brain, in particular structures responsible for cognitive functions (hippocampus, periventricular area)
  • the inner ear
  • optic tracts
  • midline structures – constrictors of the pharynx, esophagus, larynx
  • chewing muscles and temporomandibular joint

 

The level of dose reduction is highly individual. Generally, the structures that achieve maximum benefits from proton radiotherapy are those located more distant from the target volume, or the contralateral structures.

 

The printed figures show the different dose of photons and protons to the mentioned organs.

Picture: Example plan: (a) photon IMRT, (b) proton IMPT, (c) DVH (dose-volume histogram)

a   b

c     

 

Table: Structure for individual dose / organs

  IMRT (fotons) IMPT (protons)
Target volume (ethmoidal cavity) 70 Gy (100%) 70 Gy (100%)
Eyes (lens) Dmax 10,11 Gy (14,3%)  1,77 Gy (2,5%)
Brain Stem Dmax 28,6 Gy (40,8%) 0,47 Gy (0,6%)
Chiasma opticum Dmax 46,9 Gy (67%) 44,1 Gy (63%)
Chiasma opticum Dmean 31,5 Gy (45%) 5,0 Gy (7%)

 

Indications treated at PTC in Prague:

  • Paranasal sinus cancer (primary or postoperative radiotherapy)
  • Salivary gland cancer (primary or postoperative radiotherapy)
  • Cancer of the nasopharynx (primary radiochemotherapy)
  • Tonsil cancer – particularly postoperative radiotherapy
  • Benign ENT tumors after exhausting other treatment options.

 

Opportunities for improving treatment outcomes

One of the options for improving the therapeutic profile of treatment for locally and locoregionally advanced malignant tumors of the head and neck is using another type of radiotherapy with a more suitable dose distribution profile.

This option is proton radiotherapy. Proton radiotherapy makes it possible to reduce the risks of RT for healthy tissue and to increase the likelihood of curing the tumor due to the possible increase of the overall dose to the tumor region.

 

The advantages of proton therapy

Proton radiotherapy is the technological advantage in local and locoregional cancer treatment. In conventional photon radiation beam is most of the energy of the beam delivered to the tissues below the body surface and the dose in the tissue decreases with increasing depth. In contrast, protons have quite a different characteristic shape of the depth dose distribution respectively. Depth dose curves depending on so called Bragg curve.

 

The main advantage of proton therapy derived from the Bragg peak allows to deliver a predefined dose with high accuracy anywhere in the body directly into the tumor. Healthy tissue lying in front of tumors (approximately 30% of the absorbed energy protons) is preserved and complete protection of healthy tissue behind the tumor because it does not absorb any energy. It also allows you to increase the dose to the tumor target volume, increasing thereby the likelihood of local disease control. At a given dose unwanted side effects on healthy tissue are reduced.

Proton beams also have a higher biological efficacy than conventional radiation because of their dense ionization. This leads to suppression of the effect of oxygen and increased DNA damage of affected cells. If the damage happens multiple cells stop dividing and die. Radiobiology efficiency of protons is approximately 1.1 xhigher than photons (ie, conventional RT).

 

Advantages of the use of proton therapy:

  • larger investigation surrounding healthy tissue with a reduced risk of toxicity and costs associated with treatment of postirradiation toxicity (artificial nutrition, including the introduction of percutaneous endoscopic gastrostomy, hormone replacement hypofunction during postirradiation pituitary and thyroid gland, treatment of skin defects after RT treatment of xerostomia, which is caused by impaired salivary glands after photon radiotherapy)
  • Reduction of late side effects significantly affecting the quality of life of patients, such as permanent swallowing difficulties and PEG dependence, hearing disorders, radiation-induced cognitive dysfunction, and in some cases xerostomia, which is caused by damage to the salivary glands after radiotherapy.
  • improve local disease control with reduced costs for rescue treatment (chemotherapy, biological targeted biological therapy)

 

Conclusion

Comparison of proton and conventional radiation therapy in the treatment of ENT and orofacial tumors

When comparing conventional and proton RT, there is a clear benefit in reducing the burden on the healthy tissues and increasing the dose delivered to the tumor. This dose reduction is not limited to a single organ. On the contrary, it is a complete reduction of radiation exposure to healthy tissues. The level of this reduction is individual. For example, the dose used to irradiate the brain tissue in patients with tumors of the nasopharynx or paranasal sinuses is usually reduced to 10-20% of the usual dose for intensity-modulate photon radiotherapy (IMRT). The dose reduction to the swallowing path and larynx is usually about 50% for the above diagnoses during irradiation of the bilateral cervical lymph nodes.

In properly selected indications, proton radiotherapy allows the administration of high doses of radiation in combination with chemotherapy, with minimal risk of hospitalization, percutaneous endoscopic gastrostomy and treatment with opioid analgesics. Recently published analyses also suggest that it is also cost effective for healthcare payers.

 

References:

  1. Tokuuye K, Akine Y, Kagei K, Hata M, Hashimoto T, Mizumoto T, Ohshiro Y, Sugahara S, Ohara K, Okumara T, Kusukari J, Yoshida H, Otsuka F. Proton therapy for head and neck malignancies at Tsukuba. Strahlentherapie und OnkologieT 2004; 180(2): 96-101.
  2. Murakami M, Niwa Y, Demizu Y, Miyawaki D, Terashima K, Arimura T, Hishikawa Y. Particle-beam radiation therapy for the tumor of pharyngeal region. IFMBE Proceedings 2009; 25(1): 25-28. (abstrakt)
  3. Chan AV, Liebsch AJ, Deschler DG, Adams JA, Vrishali JV, McIntyre LV, Pommier P, Fabian RL, Busse PM. Proton radiotherapy for T4 nasopharyngeal carcinoma. J Clin Oncol. 2004; 22:5574. (abstrakt)
  4. Lin R, Slater JD, Yonemoto LT, Grove RI, Teichman SL, Watt DK, Slater JM. Nasopharyngeal carcinoma: repeat treatment with conformal proton therapy—dose-volume histogram analysis. Radiology 1999, 213:489–494. (abstrakt)
  5. Slater JD, Yonemoto LT, Mantik DW, Bush DA, Preston W, Grove RI, Miller DW, Slater JM. Proton radiation for treatment of cancer of the oropharynx: early experience at Loma Linda University Medical Center using a concomitant boost technique. Int J Radiat Oncol Biol Phys. 2005; 62(2):494-500.
  6. Chan AW, Pommier P, Deschler DG, Liebsch NJ, McIntyre JF, Adams JA, Lopes VV, Frankenthaler RJ, Fabian RL, Thornton AF. Change in patterns of relapse after combined proton and photon irradiation for locally advanced paranasal sinus cancer. Int J Radiat Oncol Biol Phys. 2004; 60(1):S320. (abstrakt)
  7. Zenda S, Kohno R, Kawashima M, Arahira S, Nishio T, Tahara M, Hayashi R, Kishimoto S, Ogino T. Proton beam therapy for unresectable malignancies of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys. 2011; 81(5):1473-8. (abstrakt)
  8. Zenda S.Proton Beam Therapy for Patients with Malignancies of The Nasal Cavity, Para-nasal Sinuses, and/or Involving the Skull Base: The Analysis of Late Toxicity. ASTRO 2011.
  9. Fitzek MM, Thornton AF, Varvares M, Ancukiewicz M, Mcintyre J, Adams J, Rosenthal S, Joseph M, Amrein P. Neuroendocrine tumors of the sinonasal tract. Results of a prospective study incorporating chemotherapy, surgery, and combined proton-photon radiotherapy. Cancer. 2002; 94(10):2623-34.
  10. Weber DC, Chan AW, Lessell S, McIntyre JF, Goldberg SI, Bussiere MR, Fitzek MM, Thornton AF, Delaney TF. Visual outcome of accelerated fractionated radiation for advanced sinonasal malignancies employing photons/protons. Radiother Oncol 2006, 81:243–249.
  11. Takagi M. et al., Treatment outcomes of particle radiotherapy using protons or carbon ions as a single-modality therapy for adenoid cystic carcinoma of the head and neck. Radiother Oncol. 2014 Dec;113(3):364-70.
  12. Frank SJ et al. Multifield optimization intensity modulated proton therapy for head and neck tumors: a translation to practice., Int J Radiat Oncol Biol Phys. 2014 Jul 15;89(4):846-53.
  13. Patel SH, Wang Z, Wong WW, et al., Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol. 2014 Aug;15(9):1027-38
  14. Verma V, Mishra MV, Mehta MP. A systematic review of the cost and cost-effectiveness studies of proton radiotherapy. Cancer. 2016 Feb 1. doi: 10.1002/cncr.29882. [Epub ahead of print]

 

Non-small cell bronchogenic carcinoma

 

Therapy options and standards

NSCLC therapy depends on the extent of the disease, the general condition of the patient and further diseases. The treatment strategy choice should be based on the decision of a multi-disciplinary team.

 

Effectiveness of the current photon radiotherapy

Local control using conventional radiotherapy is stated in 65-80% of cases. However, stricter criteria will lead to only 15% in the year radiotherapy was ended. Elimination of macroscopic and microscopic tumour signs is described in 20% cases after the dose of 60 Gy and in 64% cases after the dose of 80 Gy Higher local control is reached only using stereotactic radiotherapy – local control is achieved in 95% cases (limited to early stages, T1 or T2 tumours).

 

Toxicity and risks of combined therapy

The most severe radiotherapy toxicity signs in NSCLC is the radiation pneumonitis, oesophagitis and cardial toxicity.

 

a) Pneumonitis

 Clinically significant radiation pneumonitis develops in 5-50% patients treated with pulmonary tumours. Another, quite bid group of patients has subclinical signs of radiation pulmonary damage (determinable in function lung tests, radiologic changes). Pneumonitis is not so common (10-25%) after stereotactic radiotherapy. However, this procedure is associated with higher risk of bronchial stenosis after irradiation of perihilous/central tumours.

The recommended dosage limits for lungs burden (pneumonitis risk ≤20%):

  • V20 ≤ 30-35%
  • MLD (mean lung dose) ≤20-23 Gy

 

b) Oesophagitis

Oesophagitis incidence increases with higher “aggressiveness” of the radiotherapy. Grade 3 and higher acute oesophagitis develops in about 1% patients treated with standard fractionation. In concomitant chemotherapy administration, the incidence reaches the range of 6-24% (gemcitabine regimens with 49% patients), about 20% in hyperfractionated radiotherapy. Patients older than 70 years have higher risk. The recommended dosage limits haven’t been precisely determined, data from clinical trials are not consistent. E.g. RTOG 0617 trial recommends medium dose <34 Gy. Other stated limits reach the level of V50 ≤ 50%, V70 ≤ 40%.

 

c) Cardiotoxicity

Acute toxicity has the character of pericarditis. Usually, it is a temporary affection (however, up to 20% cases may progress to chronic stage).

The late toxicity is of higher severity (it develops months or years after radiotherapy), manifesting as heart ischemia, myocardial infarction or congestive heart failure. The relative risk of ischemic complications is 1.3-3.5. The V25 ≤10% parameter (volume of myocardium irradiated with the dose of 25 Gy in standard fractionation) is associated with cardiac death risk within 15 years of radiotherapy end lower than 1%.

All these adverse effects are associated with further treatment costs. The treatment may be provided for long periods or chronically.

 

Irradiation treatment tactics

The target volume is the primary tumour (tumour bed) and the affected nodes (respective lymphatic area in postoperative radiotherapy). Some authors recommend “prophylactic” irradiation of high-risk lymphatic nodes even in the absence of signs of tumorous affection in this area.
The regimes adequate for proton therapy, mainly in locally advanced NSCLC, allow increasing the individual doses per fraction and decreasing the total irradiation period (the same or higher biologically equivalent dose). The same fractionation regimen may be selected for central and peripheral tumours in early carcinomas due to the dosimetric advantages.

 

Table 1: Comparison of fractionation regimens in the treatment of localised/advanced NSCLC

Regimen Dose (Gy) Number of fractions / dose per fraction (Gy) Total duration
(weeks)
Photons 74.0 37 x 2.0 Gy 7.4
Photons (locally advanced disease) 67.5

54.0

25 x 2,7 Gy

18 x 3 Gy

5

3.5

Protons
(localised tumours)
60.0

70.0

10 x 6 Gy

10 x 7 Gy

2

2

 

Indications for proton therapy

 

  1. T1-2 N0 M0: inoperable patient or the surgery is refused – Accelerated hypofractionated radiotherapy
  2. T1-4 N1 M0: non-resectable disease – Normo-fractionated chemoradiotherapy – Accelerated individual radiotherapy (event. sequences after induction chemotherapy)
  3. T1-4 N2 M0: – Normo-fractionated chemoradiotherapy – Accelerated individual radiotherapy (event. after induction chemotherapy)

 

Proton therapy has the following contraindications: metastatic disease, N3 nodular affection (according to the TNM classification, 7th edition) and T4 tumours due to multiple foci, presence of pacemaker or metal implants. In case of mediastinum irradiation, it is necessary to use controlled breathing to increase the precision of the patient setting with variable target parameter – Dyn ´R. The treatment requires complex training of patients in regular breathing and maintain this breathing.

  

Improving the results

The current unsatisfactory results of radiotherapy require implementation of more aggressive approaches in irradiation treatment – dose escalation, combination or radiotherapy with chemotherapy, amended fractionation regimes. Radiotherapy reaching higher conformity, i.e. proton radiotherapy, allows for more aggressive irradiation regimens with lower doses of radiation for healthy tissues.

Stereotactic irradiation is limited for early stages of diseases. In advanced stages, they are not usable due to the volume range of this method associated with unacceptable toxicity. IGRT respiratory gating radiotherapy with modulated intensity (IMRT) is used for all the stages.

The striving to improve the treatment outcomes with toxicity minimisation lead to the introduction of proton therapy in pulmonary tumours treatment.

 

The following figure and table provide an example of irradiation schedule and dose distribution for individual organs.

Figure 1: Schedule example (a) photon IMRT; (b) proton IMPT; (c) DVH (dose-volume histogram).

The slices in the planning CT scan show the dose distribution in the normal and tumorous tissue. In the proton therapy, only 1/6 of the dose in the tumour is administered to the right lung and the left lung is completely protected before the unwanted radiation.

a   b

c

 

Table 2: Dose for lungs and spinal cord compared with the tumour dose

  3-D RT (photons) IMPT (protons)
Target volume (pulmonary tumour) 74 Gy (100%) 74 Gy (100%)
Lungs (Dmean) 19.7 Gy (26%) 8.8 Gy (11.8%)
Spinal cord (Dmax) 53 Gy (71%) 8.1 Gy (10.9%)

 

Advantages of proton therapy

In PTC, proton therapy is indicated in patients with localised (T1-2 M0) and locally advanced NSCLC in good general condition (ECOG 0-1). The proposed indications are based on published data for proton therapy – similar (identic) treatment results and toxicity profile may be expected.

 

In early carcinoma treated with SBRT, proton therapy enables us to irradiate the target volume with less fields (in comparison with photon IMRT) and decrease the integral dose. Decreasing the integral dose is associated with lower risk of stochastic effects, i.e. lower risk of development of radiation pneumonitis, oesophagitis and secondary tumours. Furthermore, the dose for critical tissues decreases, mainly pulmonary tissue.

 

In locally advanced lung carcinoma, proton therapy is better than the photon therapy. It enables us to accelerate (shorten the total irradiation time), use lower number of treatment fractions (hypofractionation), decrease the total dose with maintaining or decreasing the toxicity (lower load of critical organs in the same dose in comparison with the phototherapy), thus providing higher quality of life for the patients. A further advantage is the lower integral dose when compared with photon irradiation, similarly to the early carcinoma.

 

PTC planes the treatment of early lung carcinoma with fractionated regimen in the pulmonary program – 10 x 6-7 Gy, afterwards acceleration up to 4-5 x 12Gy. Advanced carcinoma requires fractionation 25 x 2.7 Gy for the radiotherapy itself. Concomitant chemotherapy will lead to normofractionation.

 

Similarly to other diagnoses, the available data are acquired using the older, passive double-scattering technique. In PTC, we irradiate the patients using state-to-art scanning technique with pencil beam.

 

The following tables 3 and 4 state a dosimetric study with 7 patients suffering from advanced pulmonary tumours (in one patient with early pulmonary carcinoma. A standard 3D CRT plan was processed for the same volumes and a proton plan with pencil beam scanning. The diameters for individual monitored parameters in 3D CRT and PBS are stated in the respective groups. Figures 3 and 4 show an example of a proton schedule and its comparison with 3D CRT with DVH.

 

Dosimetric data of PTC

Table 3: Average dosimetric parameters of schedules for the treatment of an advanced pulmonary carcinoma (T1-4 N1-3), n=7, dose 74 Gy/37 fr, 5 fractions/day

Monitored parameter 3D CRT IMPT
CTV D99% (Gy) 71.18 72.35
PTV D95% (Gy) 70.28 72.89
mean dose lungs (Gy) 17.51 9.82
Relative lung volume receiving the dose > 5 Gy (%) 56.52 23.83
Relative lung volume receiving the dose > 20 Gy (%) 30.14 18.28
mean dose of heart (Gy) 18.19 5.85
Relative heart volume receiving the dose > 25 Gy (%) 27.8 8.92
Relative heart volume receiving the dose > 40 Gy (%) 19.15 6.81
mean dose oesophagus (Gy) 31.11 23.08
Maximal dose spinal cord  – D5% (Gy) 32.79 22.96

 

Table 4: Dosimetric parameters of the schedule for treatment of early pulmonary carcinoma, 48 Gy/4 fr

Monitored parameter 3D CRT IMPT
CTV D99% (Gy) 47,23 46,77
PTV D95% (Gy) 41,53 45,84
mean dose lungs (Gy) 4,23 2,78
Relative lung volume receiving the dose > 5 Gy (%) 20,61 9,61
mean dose trachea and proximal bronchial structure (Gy) 5,12 1,68
Maximal dose oesophagus (Gy) 13,86 0,15
Maximal dose – spinal cord – D5% (Gy) 7,44 0,0

 

Figure 2a: Example of comparing the dose distribution – early carcinoma; 4×12 Gy, 3D CRT column at the left side, IMPT column at the right side

Figure 2b: Comparing DVH for the situation described above

     

Figure 2c: Example of comparing the dose distribution – advanced carcinoma, 74 Gy, 3D CRT column at the left side, IMPT column at the right side

Figure 2d: Comparing DVH for the situation described above

     

 

Results with proton therapy

It has been demonstrated in patients with non small cell lung cancer (NSCLC) that dose escalation improves local control and survival. Due to the physical properties (Bragg peak), minimization of the output dose occurs, leading to the sparing of critically important tissues such as the heart, esophagus, airways, major vessels, and the spinal cord in comparison with photon radiation therapy. The reduction of toxicity in proton radiotherapy (PRT) leads to the reduced cost of the treatment of side effects, thereby reducing the cost of patient hospitalization. Dose optimization also makes it possible to spare healthy tissue in patients with complicated anatomical situations.

 

It is evident from recent works that proton radiotherapy is effective and safe in patients with centrally located stage I NSCLC. Furthermore, tumors located at the apex of the lung, close to the brachial plexus can be better irradiated by proton radiotherapy while sparing the surrounding healthy tissues. In patients with bilateral early stage NSCLC, better dose distribution is ensured when using proton radiotherapy compared to other therapeutic modalities. Several clinical studies have confirmed that proton radiotherapy ensures the delivery of the appropriate dose even in locally advanced disease. Prospective randomized studies show that improved local control during concomitant chemoradiotherapy improves the overall survival rate.

 

It is possible to conclude that proton radiotherapy ensures excellent dose distribution in patients with early-stage NSCLC, with high local control and survival rate. Patients with early-stage disease, centrally-located tumors or those near the brachial plexus enjoy the greatest benefit from proton RT.

 

Recently published works describe the results ad toxicity of proton therapy:

  1. toxicity: Lopez Guerra JL, Gomez DR, Zhuang Y, et. al. Changes in pulmonary function after three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, or proton beam therapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):e537-43. Epub 2012 Mar 13.
  2. Locally advanced disease: Chang JY, Komaki R, Lu C, Wen HY, Allen PK, Tsao A, Gillin M, Mohan R, Cox JD. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer. Cancer. 2011 Mar 22. doi: 10.1002/cncr.26080. [Epub ahead of print]
  3. toxicity – early carcinoma: Chang JY, Komaki R, Wen HY et al. Toxicity and patterns of failure of adaptive/ablative proton therapy for early-stage, medically inoperable non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1350-7. Epub 2011 Jan 20
  4. early carcinoma: Register SP, Zhang X, Mohan R, Chang JY. Proton stereotactic body radiation therapy for clinically challenging cases of centrally and superiorly located stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2011 Jul 15;80(4):1015-22. Epub 2010 Jul 7.

 

Further literature:

  • Kadoya N. et al. Dose-volume comparison of proton radiotherapy and stereotactic body radiotherapy for non-small-cell lung cancer, Int. J. Radiation Oncology Biol. Phys., Vol. 79, No. 4, pp. 1225–1231, 2011
  • Seco J. et al. Treatment of Non-Small Cell Lung Cancer Patients With Proton Beam-Based Stereotactic Body Radiotherapy: Dosimetric Comparison With Photon Plans Highlights Importance of Range Uncertainty, Int J Radiation Oncol Biol Phys, Vol. 83, No. 1, pp. 354e361, 2012
  • Register SP et al. Proton stereotactic body radiation therapy for clinically challenging cases of centrally and superiorly located stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2011 Jul 15;80(4):1015-22. Epub 2010 Jul 7.
  • Chang JY et al. Toxicity and patterns of failure of adaptive/ablative proton therapy for early-stage, medically inoperable non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1350-7. Epub 2011 Jan 20
  • Zhang X. et al. Intensity-modulated proton therapy reduces the dose to normal tissue compared with intensity-modulated radiation therapy or passive scattering proton therapy and enables individualized radical radiotherapy for extensive stage IIIB non-small-cell lung cancer: a virtual clinical study. Int. J. Radiation Oncology Biol. Phys., Vol. 77, No. 2, pp. 357–366, 2010
  • Guerra JL et al. Changes in pulmonary function after three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, or proton beam therapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 83(4):e537-43 (2012)
  • Nakayama H. et al. Proton Beam Therapy of Stage II and III Non–Small-Cell Lung Cancer. Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 4, pp. 979–984, 2011
  • Kase Y. et al. A Treatment Planning Comparison of Passive-Scattering and Intensity-Modulated Proton Therapyfor Typical Tumor Sites. J. Radiat. Res., 53, 272–280 (2012)
  • Chang JY et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer. Cancer. 2011 Mar 22
  • Koay EJ et al. Adaptive/Nonadaptive Proton Radiation Planning and Outcomes in a Phase II Trial for Locally Advanced Non-small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2012 Apr 27. [Epub ahead of print]

 

According to published results, proton radiotherapy is the leader in compliance with the requirements for dose reduction for both critical organs (heart and lungs). Furthermore, it reduces the risk of secondary malignancies induction due to a significant reduction in the integral dose. Current conventional photon radiotherapy has already hit its physical limit and we do not assume that further technological developments will fundamentally help in further reducing the doses to organs at risk.

 

  • A study conducted at the Memorial Sloan-Kettering Cancer Centre in New York showed that postoperative PROTON RADIOTHERAPY is well tolerated, with acceptable acute dermal toxicity in a group of female patients with non-metastatic breast cancer, with excellent coverage of the target volume including the internal mammary nodes. The integral dose to risk organs (heart, lung and contralateral breast) were significantly lower than the ones expectable from conventional photon radiation therapy.

 

Introduction

Breast cancer is the most common malignancy in women and the second leading cause of death from cancer. The incidence in developed countries annually increases by 1-2%. The increasing incidence is associated with rising mortality, although the curve is not rising so quickly. This fact is explained by improved early diagnosis (screening effect) and more successful treatment.

 

The incidence of breast cancer in the Czech Republic in 2012 was 6,852 cases. Out of these patients, approximately 10% are diagnosed under the age of 45 years and 20% under the age of 50 years. Approximately 75% of women have stage I or II disease at the time of diagnosis, with a long life expectancy.

 

Treatment of breast cancer

Treatment of breast cancer is multidisciplinary and multimodal and in optimal cases centralized in centres of comprehensive cancer care. The management is based on surgery, hormone therapy, chemotherapy, biological therapy, and radiation therapy. With long life expectancy in patients with early stages of breast cancer, late and very late toxicity of treatment are becoming the key factors in the selection of individual modalities. A crucial late side effect common to several modalities (anthracycline chemotherapy agents, biological therapy (trastuzumab) and radiotherapy) is cardiotoxicity.

 

Adjuvant radiotherapy is irreplaceable in the multimodal management of breast cancer because it is proven to reduce the incidence of recurrence after partial excisions, thereby directly affecting the quality of further life of patients. The treatment with ionizing radiation is almost always associated with side effects that appear early (i.e. acute side effects of radiotherapy that occur during treatment and do not pose a major problem, because they are predictable and treatable) and many years after the treatment (i.e. late side effects in the months and years after the treatment and very late side effects occurring in the following decades). The major side effects the women with breast cancer have to face are cardiotoxicity, pneumotoxicity and the increased risk of secondary tumours.

 

The toxicity of radiotherapy

 

  • Cardiotoxicity

Radiation-induced heart disease (RIHD) is one of the most important and best-documented very late effects of radiotherapy. It manifests as accelerated atherosclerosis of heart arteries, pericardial and myocardial fibrosis, conduction disorders and defects of heart valves. The pathology is progressive and is proven to be dose and volume dependent. RIHD pathophysiology is still unclear and the main role is attributed to endothelial dysfunction with a following pro-fibrotic and pro-inflammatory condition, which predisposes the arteries to atherosclerosis and stenoses after the acute phase. Darby et al. (6) demonstrated a linear correlation of the intermediate-dose radiation therapy to the heart and ischemic heart disease occurrence in a large group of patients treated with conventional radiotherapy for breast cancer.

 

The effort to reduce the cardiac dose in young women during the irradiation of the left thoracic wall / breast is common and it is a very hot topic for current radiation oncology. Irradiation techniques in deep inspiration, partial breast irradiation or, increasingly, proton radiotherapy are used.

 

  • Pulmonary toxicity

Virtually no data is published on very late toxicity of breast cancer radiotherapy to the lung tissue. Extrapolation of the experience from other diagnoses with long life expectancy after radiotherapy is showing that an irradiation of significant lung volume is associated with the development of pulmonary fibrosis, which potentiates cardiotoxicity and may be associated with recurrent pneumonia and chronic cough.

 

  • Secondary malignancies

Secondary malignancies are the most feared and the best known very late consequences of radiotherapy. It is likely that not all secondary malignant tumours are induced by the treatment – a part of them may reflect a congenital or acquired higher sensitivity to the formation of a malignancy. However, they are often clearly induced by radiotherapy. Due to the stochastic nature of the effects of ionizing radiation in tumour induction, the most rational way to prevent their formation is minimizing the radiation dose, not just for the critical organs, but also minimizing the integral doses. The issue of long-term effects of modern photon therapy techniques surfaces here, reducing the dose to critical organs at the cost of a significant increase in the integral load with low doses. Proton radiotherapy, which is offered as a possible solution through the reduction of the integral dose, was associated with concerns about the potential negative impact of secondary neutrons.

 

The incidence of secondary malignancies after photon or proton radiotherapy was rated by Chung et al. At the median follow-up duration, secondary malignancy was detected in 5.2% of patients treated with protons and 7.5% of patients treated with photons in a group of 1116 patients. As the authors conclude, the incidence of induced tumours after proton radiotherapy is not higher than after photon therapy. In addition, the pencil beam scanning technology reduces the number of secondary neutrons to levels much lower than for IMRT techniques using higher energies. Based on the above stated data, it seems that modern techniques of photon radiotherapy are not able to address these very late adverse effects due to their physical nature (the doses inducing damage are too low and integral dose increasing is undesirable in the long term). Modern conventional photon therapy does not allow for further significant dose reductions for high-risk organs. Conversely, some modern techniques of photon radiotherapy from multiple fields (such as IMRT, including motion IMRT) can lead to an increase in the volume of tissue irradiated by the dose, although relatively low and insignificant in terms of the development of acute toxicity, but not insignificant in terms of the risk of

late toxicity. Current conventional photon radiotherapy has already hit its physical limit and we do not assume that further technological developments will fundamentally help in further reducing the doses to organs at risk.

 

Proton therapy of breast carcinoma in the proton centre in Prague and in the world

 

According to published results, PROTON RADIOTHERAPY is the leader in terms of compliance with the requirements for dose reduction for both critical organs (heart and lungs). Furthermore, it reduces the risk of secondary malignancies induction due to a significant reduction in the integral dose.

 

Sparing the high-risk organs with excellent coverage of the target volume proven by dosimetric analysis are the main benefits of PROTON RADIOTHERAPY used in other countries. A study conducted at the Memorial Sloan-Kettering Cancer Centre in New York showed that postoperative PROTON RADIOTHERAPY is well tolerated, with acceptable acute dermal toxicity in a group of female patients with non-metastatic breast cancer, with excellent coverage of the target volume including the internal mammary nodes. The integral dose to risk organs (heart, lung and contralateral breast) were significantly lower than the ones expectable from conventional photon radiation therapy. (1)

 

In the left-breast irradiation, the mean dose (Dmean) for the the heart was 0.44Gy (0.1-1.2Gy) and the mean heart volume, which received the dose of 20Gy (V20), was 0.01% (0-2.4%). The mean dose for the lungs was 6 Gy (2.4-10.1Gy), and the dose of 20 Gy (V20) was administered to an average of 12.7% (4.4-22.1%) of the lung volume. (2)

 

A Dutch comparative planning study compared 4 dosimetric plans in 20 female patients – IMPT versus IMRT in controlled inspiration and then during normal breathing. At least 97% of the target volume had to be covered by at least 95% of the dose and the analysed parameters as Dmean, Dmax and V5-30 were evaluated with regard to LAD (left anterior descending coronary artery). This artery has due to its location the largest share in the development of atherosclerosis after left-side radiotherapy for breast cancer (7).  The results showed a statistically significant dose reduction in IMPT for the heart and LAD both when using the controlled inspiration technique and when breathing freely. (3) A better dose distribution of proton radiotherapy was proven by dosimetry studies carried out for APBI (accelerated partial breast irradiation). (5)

 

The published results show that PROTON RADIOTHERAPY is a suitable method in breast cancer management. It achieves the same or better coverage of the target volume in comparison with the modern techniques of photon radiotherapy, with a significant (multiple fold) dose reduction for the heart, coronary arteries, lungs and the integral dose as well.

 

PROTON RADIOTHERAPY indication in the treatment of breast cancer

 

In view of the foregoing, good candidates for proton beam treatment are especially young patients under 45 years of age with left-side breast cancer, where it is necessary to reduce the cardiotoxicity and pneumotoxicity (both of these adverse effects may already be present after systemic chemotherapy (anthracyclines, trastuzumab). Another possible group consists of patients with pre-existing cardiac disease, where radiotherapy may lead to significant worsening of the existing heart disease.

 

Generally, the risk of very late effects of radiotherapy should be considered in all patients irradiated at a relatively low age, with a high chance of long survival. The only currently known prevention of these late side effects is to minimize the dose to critical structures to the lowest achievable level.

 

The patients suitable for PROTON RADIOTHERAPY are the following groups:

  1. Patients with left breast cancer, age <45 years, clinical stage I and II, after partial breast resection, indicated for the adjuvant radiotherapy
  2. Patients with left breast cancer, clinical stage I and II, after partial breast resection, indicated for the adjuvant radiotherapy, with a preexisting serious cardiac disease

 

 

Dosimetric comparison of PROTON and PHOTON radiotherapy

The dosimetric benefits of PROTON radiotherapy can be illustrated by comparing the irradiation plans for adjuvant radiotherapy for breast cancer.

 

The planning was performed for a model patient (data obtained after agreement with TN, a real patient, radiation therapy for breast cancer). The original contouring does not correspond to the contouring standard at PTC. Therefore, the artificial approach to determine the robustness of competing proton plans using the IMPT technique was used. Optimal contouring of the target volume and the irradiation plan from one or two fields is able to provide a robust dose delivery to the target volume (inaccuracies tend to increase the dose in the target volume), while maintaining excellent sparing of critical organs, especially the heart and the lungs. The technique of one direct field, perpendicular to the skin, or the technique of two inclining fields, in case of a larger and more curved target volume, will be used depending on the size of the target volume. The design phase of the plan isn’t more time-consuming than in other diagnoses.

 

Obr.2 – Obrázek protonového plánu, vytvořeného pomocí techniky IMPT a dvou přikloněných polí

Obr.3 – Obrázek fotonového plánu, vytvořeného pomocí techniky 3D CRT – dvě tangenciální pole s klínem. Šipkami jsou označeny místa s největším rozdílem v dávce, zde je zřejmé, že protonový plán je mnohem šetřivější, než fotonový, zejména z pohledu maximální dávky na srdce a rovněž dávky na plíce.

     3 

 

PROTON THERAPY procedure

 

It is vital to ensure the reproducibility of the position of the patient, the shape of the target volume and to reduce the breathing dependent movements of the target volume for the breast cancer PROTON RADIOTHERAPY. These requirements are ensured as follows:

 

The positioning and fixation of the patient

 

Irradiation in the PBS mode requires very precise localisation of the target irradiation volume and also of the tissue lying in front of the target area (in relation to the beam path). After consulting some US Centers performing breast radiotherapy, we found out that their experiences in this field cannot be used because they use passive Double Scattering technique (Florida) or wobbling (Chicago).

The change of the volume position is mainly influenced by the following factors:

 

Respiratory movements

As in other tumours localised in the chest area, it is necessary to use the deep inspiration technique and the SDX Dyn’R system. It is a proven approach with proven efficacy, eliminating the differences in the filling of the lungs during the irradiation. The system will be used as the primary gating device. No specific verification of this system has been performed. Its parameters and performance were examined during the preparation of the program for lung cancer irradiation.

 

Breast shape change due to a settings error

Although the patient’s inspiration is the same (with the accuracy of the Dyn’R system)the breast may have a different shape when compared to the planning CT, as it is a non-fixed and non-fixable body part with generally large variability in shape and behaviour across the population. The VisionRT system will be used due to this very reason to check the settings before the irradiation and monitor them during the irradiation, eventually as a secondary gating device.

 

Dyn’R system

In the PTC, breathing movements are tracked using the Dyn’R device during CT scanning and  irradiation. Held breath in the phase of deep inspiration increases the accuracy of irradiation due to the reduced movement of the target volume. The beam is only activated at this stage (deep inspiration). Therefore, there is no influence of the movement of the target volume caused by respiration.

The system consists of a spirometer, mouthpiece, nose clip (against air passage through other ways than the mouth into the spirometer) and glasses transmitting breath cycle images to the patient and helping him/her to regulate deep breath-hold to individually pre-set limit.

PTC is the first centre in the world using the combination of respiratory monitoring (Dyn’R) and the proton beam for all mediastinum tumours.

 

The estimated number of patients

The indication criterion 1 (patients with left breast cancer, age <45 years, clinical stage I and II, after partial breast resection, indicated for the adjuvant radiotherapy) is met maximally by 250 women per year. Some of these patients will not be indicated for proton radiotherapy for technical reasons. We may assume that approximately 100 to 150 women will be suitable for this treatment in the Czech Republic per year.

 

Indication process for the patients

The multidisciplinary approach to breast cancer treatment requires a very close cooperation with comprehensive cancer centres and established specialised breast centres in the proper selection of patients for proton radiotherapy.

 

Restrictions for the indication, arising from the above stated:

  • A cooperating patient in good condition – the need to use breathing control using Dyn’R
  • The target volume may not be located close to the chest wall, the distance of the target volume to the chest wall at least 1 cm, at least 5 mm from the proximal portions of the ribs as for the direction of the beam – because of the uncertainty of the beam range to prevent the penetration of the proton beam into the lungs and heart irradiation
  • Ideally a younger female patient with smaller breasts (max. size B) for better reproducibility of settings – lower uncertainty during repeated exposures (anticipated fractionation scheme 25 x 2 CGE and 7 x 2 CGE boost)

 

 References:

  • John J.Cuaron et al. : Early Toxicity in Patients Treated with Postoperative Proton Therapy for Locally Advanced Breast Cancer, J of Radiation Oncol Biol Phys, Vol. 92, No.2, pp.284-291, 2015
  • Shannon M. MacDonald et al.: Proton Therapy for Breast Cancer After Mastectomy: Early Outcomes of a Prospective Clinical Trial, Int.J of Radiation Oncol Biol Phys, Vol. 86, No.3, pp.484-490, 2013
  • Mirjam E. Mast et al.: Whole breast proton irradiation for maximal reduction of heart dose in breast cancer patients, Springer Breast Cancer Res Treat (2014) 148:33–39
  • Sigole`ne Galland-Girodet et al.: Long-term Cosmetic Outcomes and Toxicities of Proton Beam Therapy Compared With Photon- Based 3-Dimensional Conformal Accelerated Partial-Breast Irradiation: A Phase 1 Trial, Int J Radiation Oncol Biol Phys, Vol. 90, No. 3, pp. 493e500, 2014
  • Xiaochun Wang et al.: External –Beam Accelerated Partial Breast Irradiation Using Multiple Proton Beam Configurations,, Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 5, pp. 1464–1472, 2011
  • Darby SC et al.: Risk of ischemic heart disease in women after radiotherapy for breast cancer.
    N Engl J Med 2013 368:987-998
  • Nilsson G. Et al.: Distribution of coronary artery stenosis after radiation for breast cancer . J Clin Oncol 30(4): 380-386

 

Carcinoma of the esophagus and gastroesophageal junction

 

Radiation therapy strategies

 

Determining a target volume during irradiation of the esophagus is based on several specifics:

  • Primary tumor (squamous-cell cancer and adenocarcinoma) is predominantly spread via the lymphatic route. Dissemination “per continuitatem” is both longitudinal and radial.
  • In esophageal tumors invading the submucosa, i.e. from stage Ib tumors, the risk of involvement of regional lymph nodes at the time of diagnosis sharply increases to 47% and more.
  • Specific anatomy of lymphatic drainage in the esophageal submucosa, which is not segmental, allows longitudinal spreading over larger distances until tumor cells reach the sentinel lymph node. Tributary areas are large and difficult to define.
  • Some lymphatic vessels drain directly into the thoracic duct without being filtered through a lymph node.
  • Residual involvement of lymph nodes in the resected specimen after neoadjuvant radiotherapy is a predictor of relapse and survival.(1,2) Therefore, the correct inclusion of high-risk nodal regions in the irradiated volume is important for preoperative radiotherapy and independent irradiation of the esophagus.

 

For these reasons, the target volume in radical radiotherapy should include:

  • the primary tumor area (or anastomoses during postoperative irradiation) with areas of potential radial and longitudinal invasion;
  • areas of demonstrably affected lymph nodes;
  • large lymphatic areas at risk of involvement – “elective irradiation of lymphatics”.

 

Elective irradiation of lymphatics is a circumstance at the center of attention when irradiating esophageal tumors.

In clinical studies which demonstrated the efficacy of radiochemotherapy, various areas were included in the elective irradiation of lymphatics. According to the current consensus, it is beneficial to include in the target volume all the areas with a risk higher than 15-20%. The risks of lymph node involvement depending on the site of the primary tumor in the esophagus has been described in several studies based on lymphadenectomy findings.(3,4,5) Marked differences are seen in the quantification of risks. The reported differences suggest some uncertainty in risk classification and the non-homogeneity of clinical trials with respect to study groups, which included mostly squamous-cell carcinoma. In contrast, no clear differences have been demonstrated between adenocarcinoma and squamous-cell carcinoma in the risk of lymphatic area involvement.(6)

 

The proximity of radiosensitive organs such as lungs, heart, spinal cord, liver, kidneys, and potentially thyroid gland, and a complex geometric shape of the irradiated volume markedly complicate the achievement of an effective therapeutic range. The risks of late adverse effects that may result in failure of the respective organs are of vital importance. Limited integral dose or maximum dose to the respective organs (“dose constraints”) are listed in the following table:

 

 

Table: obligatory “dose constraints” for irradiation of esophageal tumors.

Organ Maximum integral dose determined by volume of the irradiated organ Maximum integral dose to the organ determined by its level
Lungs V20Gy < 37% Dmean < 20 Gy
Heart V33Gy < 60%
Spinal cord V5% < 50 Gy
Liver Dmean < 23 Gy
Kidneys Dmedian < 17 Gy
Esophagus outside the irradiated volume Entire circumference below 60 Gy

 

Limitations of current radiation therapy – technical and biological aspects

Standard preoperative irradiation of a localized esophageal cancer up to a total dose of 50 Gy in 25 fractions, including elective irradiation of lymphatics at 15% risk by photon therapy is difficult and requires the IMRT technique. The geometric shape of the irradiated volume is complex and includes multiple concavities. Even with the use of IMRT, it is difficult to adhere to the dose constraints specified in the above table. When increasing the dose up to a total of 70 Gy to the area of confirmed involvement (outside the volumes of elective irradiation), the difficulty is much higher even when using the IMRT technique.

 

Toxicity and risks of current therapy

Radiochemotherapy of esophageal cancer usually has acute and late side effects. The severity of both increases depending on the preoperative approach. The timing of surgery 4 to 6 weeks after the end of radiochemotherapy provides a short time window for the resolution of acute side effects. The risk is a delay of the procedure or permanent inability to undergo the resection procedure. Certain procedures, including thoracotomy and mediastinal lymphadenectomy, are associated with postoperative requirements as to the cardiorespiratory capacity, which may be impaired by the development of chronic toxic effects, with maximum impairment in the postoperative period.

 

When using standard techniques of photon radiotherapy (IMRT, 3DCRT), the risk of any complications is up to 75%. 

 

Acute side effects include in particular transient esophagitis with dysphagia and subsequent impaired nutrition, which may potentially result in refractory cachexia.

Other common side effects are acute dysphagia of varying degrees, mucosal bleeding, leukopenia, and thrombocytopenia. In major studies, any acute toxicity of grade 3-4 was recorded in 50-66% of patients. The main complication that clearly rules out any further surgical procedure is perforation of the esophagus.

 

Chronic side effects most commonly include esophageal stenosis, with a risk of about 60%. Dilation or stent implantation (i.e. after independent radiochemotherapy) is necessary in 15-20% of patients.

Chronic pulmonary side effects have been reported with a risk of about 18% and appear as post-radiation pneumonitis with subsequent development of pulmonary fibrosis and functional limitations. Development of pneumonitis is a serious complication in the postoperative period (after thoracotomy), with potentially fatal consequences.

 

The risk of chronic adverse reactions in particular is clearly related to the adherence to the aforementioned “dose constraints”. Considering the increasing risks, various limiting integral doses can be defined for the respective organs.

 

For example, an increased risk of chronic complications has been reported for the lungs. When the irradiated volume V10Gy exceeds 40% of the lung volume – the risk is 8% compared to 35% (for irradiation of esophageal cancer).

 

A similarly limiting organ is the spinal cord, where the risks are related not only to the integral dose but also to local maxima (“hotspot”). Naturally, no statistics are available for adverse effects such as radiation myelitis.

 

The advantages of proton therapy

Application of proton irradiation in consensual protocol therapy of tumors of the esophagus has been tested at several sites in the world, especially in Japan and the USA. Published data include dozens of treated patients. Ie. publications are phase II trials, rarely at the level of phase III studies.

You can derive some conclusions:

 

  • Proton therapy allows a standard dose of 70 Gy, probably even higher. ( They are referenced as the maximum dose of 98 Gy, median dose 79 Gy in the study (6)).
  • Proton therapy can be safely applied with standard concomitant chemotherapy. (Safety of therapy is documented in a recent, comprehensive study of 62 patients (7)).
  • The outcome of irradiation as compared with photon therapy is similar, but not inferior. Probably is even higher (eg 89% achieving a complete regression, 5-year survival over 20% -30%) (superiority) (6,8,9). Naturally comparison of a randomized study is not available (probably from an ethical point of view will never be).
  • Toxicity of proton radiation is lower. Higher levels of chronic toxicity are only about 10%. Comparative studies of realized irradiation plans are demonstrating at risk organs very significant differences in integral doses(10-13).
  • Proton therapy allows safe elective irradiation of lymphatics at risk even with higher dosages(14).
  • The favorable proton irradiation parameters make it possible to change standard fractionation regimens (hypofractionation, concomitant boost (9), etc.) and safely reduces the total time of irradiation. Secure hyperfractional mode with doses up to 3.6 Gy / fraction has been demonstrated (15).

 

Picture: Example plan: (a) photon IMRT, (b) proton IMPT, (c) DVH (dose-volume histogram)

a b c

These slices of planning CTs show the volume of the dose in the normal tissue in relation to the tumour dose(red). With protons (7b) only about 1/6 of the tumour dose is applied in healthy tissue (spinal cord, mediastinum) with complete sparing of the lungs.

 

Table: Structure for individual dose / organs:

IMRT (fotons) IMPT (protons)
Target volume (tumor of the esophagus) 50 Gy (100%) 50 Gy (100%)
Lung (Dmean)  20,7 Gy (41%)  2,99 Gy (5,9%)
Spinal cord (Dmax) 47,4 Gy (94%) 33,0 Gy (66%)
Heart (Dmean) 29,9 Gy (59,8%) 18,42 Gy (26%)
Liver (Dmean) 21.4 Gy (42%) 2,38 Gy (4.7%)

 

 References:

1. Meredith K.L., Weber J.M., Turaga K.K., Siegel E.M. Pathologic response after neoadjuvant therapy is the major determinant of survival in patients with esophageal cancer. Ann. Surg. Oncol. 2010; 4: 1159-67
2. Chirieac L.R., Swisher S.G., Ajani J.A., Komaki R.R. Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation. Cancer 2005; 103:1347-55
3. Akiyama H. et al. Principles of surgical treatment for carcinoma of the esopahagus: Analysis of lymphnode involvement. Ann. Surg. 1981; 194:438
4. Chen J., Suoyan L., Pan J., Zheng X. et al. The pattern and prevalence of lymphatic spread in thoracic oesophageal squamous cell carcinoma. European  Journal of Cardio-thracic Surgery 2009; 36: 480-486
5. Sharma S. et al. Patterns of lymph-node metastasis in 3-field dissection for carcinoma in the thoracic oesopahgus Surg. Today 1994; 24:410
6. Mizumoto M., Sugahara S., Nakayama H., Hashii H. et al. Clinical results of proton-beam therapy for locoregionally advanced esophageal cancer Strahlenther. Onkol. 2010; 186:482-488
7. Lin S.H., Komaki R., Liao Z., Wei C. et al. Proton beam therapy and concurrent chemotherapy for esophageal cancer Int. J. Radiat. Oncol. Biol. Phys. 2012; 83:345-351
8. Sugahara S., Tokuuye K., Okumura T., Nakahara A. et al. Clinical results of proton beam therapy for cancer of the esophagus Int. J. Radiat. Oncol. Biol. Phys. 2005; 61:76-84
9. Mizumoto M., Sugahara S., Okumura T., Hashimoto T. et al. Hyperfractionated concomitant boost proton beam therapy for esophageal carcinoma Int. J. Radiat. Oncol. Biol. Phys. 2011; 81:e601-606
10. Welsh J., Gomez D., Palmer M.B., Riley B.A. et al. Intensity-modulated proton therapy further reduces normal tissue exposure during definitive therapy for locally advanced distal esophageal tumors: a dosimetric study Int. J. Radiat. Oncol. Biol. Phys. 2011; 81:1336-42
11. Makishima H., Ishikawa H., Toshiyuki T., Hashimoto T. et al. Comparison of adverse effects of proton and X-ray chemoradiotherapy for esophageal cancer using and adaptive dose-volume histogram analysis Journal of Radiation Research 2015; 56:568-576
12. Chang J.Y., Heng Li, Zhu R., Liao Z. et al. Clinical implementation of intensity modulated proton therapy for tharacic malignancies Int. J. Radiat. Oncol. Biol. Phys. 2014; 90:809-818
13. Ishikawa H., Hashimoto T., Moriwaki T., Hyodo I. et al. Proton beam therapy combined with concomitant chemotherapy for esophageal cancer Anticancer Res. 2015; 35:1757-1762
14. Ono T., Nakamura T., Azami Y., Yamaguchi H. et al. Clinical results of proton beam therapy for twenty older patients with esophageal cancer Radiol. Oncol. 2015; 49:371-378
15. Koyama S., Tsujii H. Proton beam therapy with high-dose irradiation for superficial and advanced esophageal carcinomas Clin. Cancer Res. 2003; 9:3571-7


 

Carcinoma of the anus

 

Treatment strategy

Concomitant chemoradiotherapy is a standard modality of anal cancer treatment. The disease has
a high cure rate, thanks to the combination of a large volume irradiated, concomitant chemotherapy and the total dose of radiation. However, the risk of early and late side effects is high. More than one third of patients develop acute toxicity of grade 3 or 4.

 

  • Limitations of current radiation therapy – technical and biological aspects

Currently, patients with carcinoma of the anus are treated with the IMRT technique. A disadvantage of this technique still consists in a high burden to the skin and subcutaneous tissues, the bladder, rectosigmoid colon and loops of the small intestine. Another disadvantage is the high integral dose of radiation delivered using this technique. This results in a high degree of acute toxicity of the treatment, especially acute skin reactions, acute gastrointestinal and genitourinary toxicity, and also hematologic toxicity due to the effects of concomitant chemotherapy. Late side effects are related mainly to fibrotisation of the perianal region, groins and other adjacent tissues. It involves dysfunction of the pelvic floor and sphincters, vaginal stenosis, deformation and dysfunction of external genitalia and obstruction in the groin area.

 

Use of proton therapy in the treatment of anal carcinoma

Treatment of anal tumors has been gradually introduced in proton centers worldwide. The reason is the chance to reduce the integral dose in the entire pelvic area, i.e. the radiation burden to the skin, subcutaneous tissues, bladder, genitalia, rectosigmoid colon and small intestine. Dosimetry studies have been published.

The possibility of reducing toxicity is significant especially in those constellations where the toxicity is a long-term limitation, and where the development of IMRT photon radiotherapy techniques brought only a minor improvement and in some cases even an increase in the integral dose as compared to the previous 3 DCRT techniques.

 

For indications of proton therapy for the treatment of tumors in the anal region, see for example:

 

Scripps proton therapy center, San Diego – http://www.scripps.org/services/cancer-care__proton-therapy/conditions-treated__proton-therapy-for-gastrointestinal-cancers

 

  • Strategies in radiation therapy

Anal tumors are treated with irradiation of 2 volumes using the SIB technique (simultaneous integrated boost) at 2 dose levels:

 

  • The volume of electively irradiated regional lymph nodes in the following groups: perirectal, presacral, external, internal and common iliac, inguinal. This volume of drainage regional lymph nodes creates a large concavity in the central pelvis.
  • The volume of the primary tumor with a margin and the volume of macroscopically visible involvement of the lymph nodes with a margin.

 

The requirements for dose distribution with this technique and the geometric constellation can be optimally managed during proton radiation dosimetry. It offers a significant reduction of doses to the critical structures of the pelvis.

This includes mainly reduction of doses to the following structures:

  • Urinary bladder
  • Small intestine
  • Skin and subcutaneous tissue
  • Vagina
  • Penile bulb
  • Bone marrow of pelvis

 

The following figures and the table provide examples of irradiation schedules and dose distributions in the pelvis using proton and photon radiation therapy.

 

Figure 1:   An example of the treatment plan:  a) Isodose plans for proton radiotherapy IMPT and photon radiotherapy IMRT in 2 CT sections.

   

   

b) Dose-volume histograms (DVH) for IMPT and IMRT.

   

 

Table 1: Specification of doses to the individual structures / organs

Organ at risk Dose specification IMPT dose (Gy) IMRT dose (Gy)
Urinary bladder Dmean 13.95 37.00
Small intestine Dmean 8.55 26.24
Bulb of penis Dmean 22.92 44.39
Dmax 55.52 53.54
Sigmoid colon Dmean 18.47 38.68
Rectum * Dmean 44.00 43.16
Dmax 54.84 54.60

*A significant portion is included in PTV

 

Dosimetry results; advantages

Proton radiotherapy clearly provides a significant benefit for the required doses and irradiated volumes in terms of average organ doses and doses to the designated quantiles according to the required dose constraints. Organ doses can be reduced to less than a half. (Peak doses in the organs are usually given by the usual inclusion of a part of the organ in the irradiated volume, which, for the singular intestine, is a phenomenon compensated by its variable position).

 

Indications of proton radiotherapy under the PTC protocols are as follows:

  • Invasive squamous cell carcinoma of the anus
  • Invasive squamous cell carcinoma of the anus after excision biopsy (non-radical procedure)

 

Clinical manifestation of proton therapy benefits

 

In 6 patients that have been treated so far at PTC Prague, we observed the following advantages compared to our own experience with photon radiation:

  • Proton radiotherapy is carried out on an outpatient basis.
  • It is possible to administer standard concomitant chemotherapy with CDDP+FUon an outpatient basis.
  • Hematologic toxicity was rare, probably due to a genetically based intolerance of 5-FU.
  • The extent of mucosal and skin reactions is smaller and sharply demarcated.
  • No need of opiate analgesia.
  • Acute adverse reactions are fully reversible.
  • Typical chronic adverse reactions have not developed.
  • Complete regression has always been achieved, as expected.

 

Conclusion

 

Advantages of proton radiotherapy versus conventional photon therapy

When comparing conventional and proton RT, a clear profit is seen in reducing the burden of healthy tissues and adherence to the prescribed dose in the target volume at 2 levels.

 

For anal tumors, the advantage of improved conformity and lower integral dose outside the irradiated volume can be used during proton radiation. Biology of anal tumors does not require the advantage of dose escalation. The SIB radiation technique uses, to a certain extent, the advantage of altered fractionation.

 

If significant toxicity is a fundamental problem in the radiotherapy of anal carcinoma with a high curative potential and long-term survival of patients, the proton radiation therapy, with all its benefits, is an optimal solution.

 

References

  • Ojerholm E, Kirk ML, Thompson RF, Zhai H, Metz JM, Both S, Ben-Josef E, Plastaras JP. Pencil-beam scanning proton therapy for anal cancer: a dosimetric comparison with intensity-modulated radiotherapy. Acta Oncol. 2015 Mar 3:1-9. [Epub ahead of print] PubMed PMID: 25734796.
  • Meyer J, Czito B., Yin F.F., Willett C. Advanced radiation therapy technologies in the treatment of rectal nad anal cancer: Intensity modulated photon therapy and proton therapy Clin. Colorectal Cancer 2007; 6:348-356
  • Meyer J.J., Willett C.G., Czito B.G. et al. Emerging role of intensity modulated radiation therapy in anorectal cancer Expert Rev. Anticancer  Ther.  2008; 8:585-593
  • Glynne-Jones R., Lim F. Anal cancer: an examination of radiotherapy strategies, Int J Rad Oncol Biol Phys 2011; 79:1290-1301
  • Lin A., Ben-Josef E., Intensity-modulaed radiation therapy for the treatment of anal cancer, Clin. Colorectal Cancer 2007; 6:716-719
  • Anand A., Bues M., Rule W.G., Keole S.R. et al., Scanning proton beam therapy reduces normal tissue exposure in pelvic radiotherapy for anal cancer, Radiother. Oncol. 2015; 117:505-508
  • Andersen A.G., Casares-Magaz O., Muren L.P., Toftegaard J. et al., A method for evaluation of proton plan robustness towards inter-fractional motion applied to pelvic lymph node irradiation, Acta Oncologica 2015; 54:1643-1650

 


 

Primary hepatocellular carcinoma

 

Radiation therapy strategies

HCC itself is sufficiently radiosensitive, as doses of about 50 Gy can induce its regression. The alleged radioresistance is in fact given by the sensitivity of the surrounding liver tissue, which prevented the delivery of effective doses of radiation by standard techniques used in the previous century. Development of IMRT techniques, stereotactic radiotherapy and helical tomotherapy permit the delivery of radiation to precisely confined one or more tumor foci of a complicated shape (including concavities), while sparing the surrounding normal liver parenchyma. The issue of HCC radiotherapy is mainly related to the technical area and to the availability of sophisticated methodologies. The availability of methodologies intended for the treatment of HCC in the Czech Republic is currently limited. Stereotactic techniques are used at about 5 facilities with one installed “CyberKnife” device and no device for helical tomotherapy. Radiotherapy of HCC can only be indicated marginally in the Czech Republic.

 

No standard is available for radiotherapy dosage. A natural dependence of higher dose and greater effect is obvious, even at doses above 70 Gy. In addition, various sophisticated techniques, including helical tomotherapy, do not adhere to the conventional fractionation of 2 Gy/day(1) and total physical doses cannot be compared. In reproducible studies, doses above 50 Gy were usually applied, and the value of /= 10 Gy is used as a basis to calculate the biological equivalent.(2)

 

Despite current minimal usage, radiation therapy of HCC represents an effective tool for what is still believed to be palliative therapy. The development of application techniques moves radiotherapy to the level of radiosurgery, naturally not to the extent of radical resection, such as lobectomy or segmentectomy, but only to the extent of the resection of individual foci.

 

Limitations of current radiation therapy – technical and biological aspects

 

The main toxicity risk of HCC radiotherapy is Radiation Induced Liver Disease (RILD). This is a limiting factor for the radiation dose and the extent of irradiated volume. Given the risk of side effects, in particular the development of RILD, a simple model was created based on the proportion of retained undamaged liver tissue and also on a functional indocyanine green (ICG) retention test to indicate irradiation of HCC and dose (40 to 60 Gy).(3)

The limitation of HCC radiotherapy is based on the ratio of irradiated and non-irradiated liver tissue (liver tissue tolerance is only up to 30 Gy), i.e. it depends on the mode of application and the type of radiation. The achieved difference in doses delivered to the tumor versus liver tissue must be significant, i.e. 70 Gy vs. 30 Gy.

 

Efficacy of current HCC therapy

  • Resection procedures in HCC result in a five-year survival rate of 30-70%. However, the 5-year recurrence rate reaches 70%.
  • Liver transplantation, if indicated according to Milanese criteria (always in the Czech Republic) results in a 4-year survival rate of 85% and a recurrence-free survival rate of 95%.
  • Combined local ablation techniques (chemoembolization, RFA) can be used to achieve a five-year survival rate of more than 40% (at the cost of significant toxicity); nevertheless, the reported populations were highly non-homogeneous and difficult to compare.
  • Systemic biological therapy achieves a median survival of up to 1 year (in the SHARP trial, which served as a basis for authorization of sorafenib, the median survival rate was 10.7 months).
  • When using radiotherapy with focal administration of doses up to 60-70 Gy, 50% of patients achieved regression of the tumor bed, and an additional 40% of patients achieved stabilization of the disease.(4) The efficacy of local therapy is reflected in the survival parameter, with a median survival rate after radiotherapy close to 24 months.(5)

 

All these data confirm the non-comparability of treatment results and the application of a selection bias (patients are selected for various types of therapy according to the extent of involvement).

 

Toxicity and risks of current therapy

Adverse effects of surgical and conservative modalities are described in the literature and are not limiting. In chemoembolization, the limiting factor is the risk of chemical hepatitis, depending on the material used and the extent of embolization. It has been reported to exceed 50% in extensive procedures.

Other limiting factors are toxicity of biological therapy and its manifestations (hypertension, diarrhea, skin changes). Treatment of HCC is associated with the risk of liver toxicity in the form of drug-induced hepatitis, which exceeds 50%.

 

Acute toxicity of HCC radiotherapy is of little importance and appears with symptoms of acute radiation-induced gastritis and enteritis.

Chronic toxicity includes in particular RILD. (RILD is not a typical “late effect”, as it falls into the “consequential late effects” based on its development).

The interval of RILD development is about 2 weeks to 4 months after irradiation. The high-risk factor for RILD is a previous infection with hepatitis B or antigen-positivity, preexisting cirrhosis of Child-Pugh stage B, and portal vein thrombosis. The risk of developing RILD is proportional to the irradiated volume, i.e. it is proportional to the extent of liver damage. At the same time, it is proportional to the amount of healthy liver tissue exposed to a dose higher than 30 Gy.(6)

 

 The advantages and results of proton therapy

 

Proton irradiation is applied in the treatment of HCC for over 20 years. Maximum experience to a greater extent comes from Japan followed by the USA. The number of treated patients has already reached thousands. Number of printed publications is more than one hundred (Phase III or Phase II studies).

  • Proton radiation can be safely administered in various fractionation regimes from normal fractionation 2 Gy/day following a single 24 Gy irradiation. Most commonly used fractions were within the range of 3-6 Gy. (8,9)
  • The effects of therapy or toxicity are not dependent on the fractionation scheme.(7)
  • Proton radiation can even be applied in various specific situations (thrombosis of the inferior vena cava, localization in the porta hepatis, the presence of refractory ascites, advanced cirrhosis, elderly patients, etc.) (8, 10-13).
  • Proton irradiation can be safely repeated for recurrences in the liver without influencing liver function (Child-Pugh A) (14).
  • The effectiveness of proton irradiation (recurrence-free survival at 5 years over 80%) is the only alternative to surgery (8) ( 5 year survival of 56%) (but there can be no comparisons with the surgical procedure, as it is a selection bias. Indications for the procedure are limited by small and specifically localized findings, while this limitation is not present in proton radiotherapy). (19)
  • The effectiveness of proton irradiation is superior to the photon radiation. Randomized trials are ethically not possible.
  • The efficacy criteria are indicators of survival and progression-free or relapse-free survival. Evaluation of the effect in accordance with the RECIST criteria has not been commonly reported in routine practice, as it is not beneficial.(16)
  • The toxicity of proton radiation is minimal. Acute toxicity rarely reaches grade 3; the dominant types of toxicity are gastrointestinal toxicity (incl. treatable ulcerations) and bleeding. As concerns chronic toxicity, RILD has not been reported in relation to proton radiation therapy.(8)
  • The risk of toxicity increases when exceeding the usual “dose constraint” V30Gy<25%. In proton radiation therapy, this limit is easily observed.(17,18)

 

Benefits of proton therapy applied in the proposed PTC protocol

 

The proposed protocol in PTC:

  • Proton irradiation of localized forms of HCC can be applied radiosurgically 24.00 Gy in one session
  • Normal fractionation 35×2.00 Gy up to 70.00 Gy
  • Hypofractionation in the range of 3-6 Gy / is the most proven up to a total dose of> 70Gy.

 

Conclusion

The expected effect of proton therapy is relevant to the references from the literature and availability of radiotherapy in the Czech Republic:

  • the effectiveness is relevant to the surgical procedure, to the extent of survival parameters, i.e., it is the second most effective modality after transplantation
  • a very favorable toxicity profile
  • variability of fractionation regimens, which can be adapted to different needs
  • availability of radiotherapy for patients with HCC; photon radiation has been used sporadically to date.

 

References:

1. Kim J.S., You C.R., Jang J.W., Bae S. et al., Application of helical tomotherapy for two case sof advanced hepatocellular carcinoma. Korean J. Intern. Med. 2011; 26:201-206
2. Park W.,Lim D.H., Paik S.W. et al., Local radiotherapy for patients with unresectable hepatocellular carcinoma. Int. J. Radiat. Oncol., Biol. Phys. 2005; 61:1143-50
3. Cheng S.H., Lim Z.M., Chuang V.P. et al., A pilot study of free dimensional conformal radiotherapy in unresectable hepatocellular cancer Gastroenterol. Hepatol. 1999; 14:1025-1033
4. Chan L.C., Chiu S.K.W., Chan S.L., Stereotactic radiotherapy for hepatocellular carcinoma: Report of a local single centre experience, Hong Kong Med. J. 2011; 17:112-118
5. Hawkins M.A., Dawson L.A., Radiation therapy for hepatocellular carcinoma: From palliation to cure. Cancer 2006; 106:1653-1663)
6. Kim T.H., Kim D.Y., Park J.W. et al., Dose-volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated with free-dimensional conformal radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 2007; 67:225-231
7. Mizumoto M., Okumura T., Hashimoto T., Fukuda K. et al., Proton beam therapy for hepatocellular carcinoma: a comparison of three treatment protocols Int J Radiat Oncol Biol Phys. 2011; 81:1039-45
8. Nakayama H., Sugahara S., Tokita M., Fukuda K., Proton beam therapy for hepatocellular carcinoma: the University of Tsukuba experience, Cancer. 2009 Dec 1;115(23):5499-506
9. Hata M., Tokuuye K., Sugahara S., Tohno E. et al., Proton irradiation in a single fraction for hepatocellular carcinoma patients with uncontrollable ascites. Technical considerations and results., Strahlenther Onkol. 2007; 183:411-416
10. Mizumoto M., Tokuuye K., Sugahara S., Hata M. et al., Proton beam therapy for hepatocellular carcinoma with inferior vena cava tumor thrombus: report of three cases, Jpn J Clin Oncol. 2007; 37:459-62
11. Mizumoto M., Tokuuye K., Sugahara S., Nakayama H. et al., Proton beam therapy for hepatocellular carcinoma adjacent to the porta hepatis, Int J Radiat Oncol Biol Phys. 2008; 71:462-7
12. Hata M., Tokuuye K., Sugahara S., Fukumitsu N. et al., Proton beam therapy for hepatocellular carcinoma patients with severe cirrhosis, Strahlenther Onkol. 2006; 182:713-20
13. Hata M., Tokuuye K., Sugahara S., Tohno E. et al., Proton beam therapy for aged patients with hepatocellular carcinoma, Int J Radiat Oncol Biol Phys. 2007; 69:805-12
14. Hashimoto T., Tokuuye K., Fukumitsu N., Igaki H., Repeated proton beam therapy for hepatocellular carcinoma, Int J Radiat Oncol Biol Phys. 2006; 65:196-202
15. Skinner H.D., Hong T.S., Krishnan S., Charged-particle therapy for hepatocellular carcinoma, Semin Radiat Oncol. 2011; 21:278-86
16. Bush D.A., Kayali Z., Grove R., Slater J.D., The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma: a phase 2 prospective trial, Cancer 2011; 117:3053-9
17. Kawashima M., Kohno R., Nakachi K., Nishio T. et al., Dose-volume histogram analysis of the safety of proton beam therapy for unresectable hepatocellular carcinoma, Int J Radiat Oncol Biol Phys. 2011; 79:1479-86
18. Li J.M., Yu J.M., Liu S.W., Chen Q. et al., Dose distributions of proton beam therapy for hepatocellular carcinoma: a comparative study of treatment planning with 3D-conformal radiation therapy or intensity-modulated radiation therapy, Zhonghua Yi Xue Za Zhi. 2009; 89:3201-6
19. Sugahara S., Oshiro Y., Nakayama H., Fukuda K., Proton beam therapy for large hepatocellular carcinoma, Int J Radiat Oncol Biol Phys. 2010; 76:460-6
20. Kim J.Y., Lim Y.K., Kim T.H., Cho K.H. et al., Normal liver sparing by proton beam therapy for hepatocellular carcinoma: Comparison with helical intensity modulated radiotherapy and volumetric modulated arc therapy, Acta Oncol. 2015; 54: 1827-32
21. Qi W.X., Fu S., Zhang Q., Guo X.M., Charged particle versus photon therapy for patients with hepatocellular carcinoma: a systematic review and meta-analysis, Radiother. Oncol. 2015; 114:289-295
22. Kalogeridi M.A., Zygogianni A., Kyrgias G., Kouvaris J. et al., Role of radiotherapy in the management of  hepatocellular carcinoma: A systematic review. World Journal of Hepatology 2015; 7:101-102
23. Schlachterman A., Craft W.W. Jr., Hilgenfeldt E., Mitra A. et al., Current and future treatments for hepatocellular carcinoma, World Journal of Gastroenterology 2015; 21:8478-8491

 


 

Pancreatic tumors

 

Pancreatic tumors are treated at proton centers around the world. The reason is a close proximity of critical organs and the tumor that usually does not allow the administration of sufficient doses in photon techniques while respecting the tolerated doses to critical organs. In addition to increasing local control of the disease, the goal is to reduce the long-term adverse effects and improve the quality of life of the patients.

 

Pancreatic tumours have a poor prognosis. However, they say nothing about the survival length of the patients and about any possibility of influencing the course of the disease. The possibilities have been expanding.

In addition, the group of pancreatic tumours is not homogenous at all. About 5% of pancreatic tumours are constituted of neuroendocrine tumours (NET) with a much better prognosis. They require completely different treatments. The majority group of epithelial tumours of the exocrine pancreas also includes less common forms classified in the group of cystic and mucinous tumours of the pancreas. These also have a better prognosis and some are even benign. The questions on the use of radiation therapy do not apply to the NET or cystic tumours.

 

Current treatment options

Surgery has always had a fundamental role in the treatment of localized stages of pancreatic carcinoma – total or partial pancreatectomy. In the cancers of the head of the pancreas, which are the most common ones, duodenectomy is used with the restoration of the continuity of anastomoses (hepatojejuno-, gastrojejuno-, possibly pancreatojejuno- or pancreatogastroanastomosis). Only radical resection is beneficial. R1 and R2 type resections lead to an early disease relapse and have minimal impact on the length of survival1).

 

Clinical studies conducted in the last 20 years have shown a benefit of postoperative chemotherapy and postoperative chemotherapy combined with radiation (GITSG, EORTC and subsequent analyses)2,3). Standard treatments currently based on an international consensus include surgery, radiotherapy and chemotherapy as inseparable modalies4).

 

Conventional radiotherapy options with postoperative irradiation of pancreatic cancer are limited and the risk of adverse effects is high

Postoperative radiation after resection of the pancreas is used to reduce the risk of recurrence of the disease. The target volume includes the pancreatic bed and the draining lymph area. The methodology for determining the lymph areas at risk was published5).

 

The therapeutic margin in postoperative radiotherapy of pancreatic carcinoma is minimal owing to the anatomic arrangement of subhepatic structures and the complex lymphatic drainage in the area.

 

Standard techniques of photon radiation (3D-CRT, IMRT) are associated with a high risk of adverse effects. Acute adverse effects include, in particular, gastrointestinal complications, acute radiation gastritis and enteritis. Adverse effects are common also with respect to the haematopoetic system – leukopenia, thrombocytopenia and after some time anaemia6,7,8,9).

 

 

Chronic adverse effects are based on radiation damage of the liver, kidneys and possibly hollow organs – the stomach and intestines. The statistics of late adverse effects are not complete due to the short survival time of the patients. In addition, radiation doses in the described cohorts do not exceed 50-56 Gy and “dose constraints” are consistently adhered to, reducing the risk.

 

In contrast, the references from the field of stereotactic radiotherapy, IMRT and 3D CRT confirm that a dose escalation in the target volume has a potential to increase the efficiency, also naturally the toxicity10,11). Dosages that are currently used in postoperative and separate (chemo) radiotherapy are submaximal and limited by the radiation toxicity.

 

Proton therapy statistically significantly reduces doses to critical organs

A comparative dosimetric study of proton and photon radiotherapy of the pancreatic beds and the draining lymph areas shows a clear advantage of protons. The reduction of the dose to the liver, kidneys, small intestine, stomach and spinal cord is statistically significant.

In proton radiotherapy, the total dose may be increased and administered even in larger fractions. The total irradiation time is up to 50% shorter.

 

Experience with proton radiotherapy

Radiotherapy with heavy particles, mostly protons, was practically verified in several centres in the US and Japan. Other departments dealt with dose distribution modelling. Published studies include dozens of treated patients. The results can be summarized in the following way:

 

  • The possibility to use a favourable dose distribution and to increase the focal dose for the pancreatic bed up to 70 Gy with the irradiation of all the lymphatics at risk is confirmed12,13,14).
  • A phase I/II clinical study verified the efficacy and safety of the regime of irradiation with gradual increase of the dose per fraction. These favourable results provide a basis for increasing the total dose and shortening the irradiation time15,16).
  • Integral doses in risk areas are significantly lower, by more than 50%, compared with photon irradiation12,17).
  • Proton therapy can be safely combined with standard chemotherapy.
  • The toxicity of proton irradiation is lower as regards acute and chronic adverse effects according to the existing literature.,19,20,21).
  • The efficacy of radiation therapy compared to photon therapy is probably the same (non-inferiority). Comparisons of efficacy in terms of benefits (superiority) is difficult, as it is only possible when including proton therapy into neoadjuvant indications.(22)

 

Proton postoperative radiotherapy in PTC Prague

A technique of postoperative irradiation of the pancreatic bed and of the draining lymph tract has been developed in PTC Prague. The irradiated volume is determined using the RTOG standards23).

 

The Pencil Beam Scanning technology (PBS) has very favourable dosimetric parameters, which are the basis for reducing toxicity.

Postoperative irradiation can be administered in 20 to 25 fractions, with the dose of 2.0–2.5 CGE per fraction.

Postoperative irradiation is always combined with chemotherapy. It is administered in the form of tablets (capecitabine) or an infusion (gemcitabine) during the irradiation therapy. Postoperative irradiation is followed by standard adjuvant chemotherapy.

 

An important principle must be adhered to in postoperative irradiation of the pancreas: Irradiation is not a substitute for postoperative chemotherapy administered at specialised clinical oncology sites. Both modalities are significant, complement one another and enhance the efficacy of treatment.
PTC Prague cooperates with respective surgeons and oncologists to ensure the continuity of all the complementary methodologies.

 

Picture : Example plan: (a) photon IMRT, (b) proton IMPT, (c) DVH (dose-volume histogram)

   b 

These slices of planning CTs show the volume of the dose in the normal healthy tissue in relation to the tumour dose (red). With protons (9b) only about 1/6 of the tumour dose is applied in the healthy tissue especially in the small bowel to avoid severe side effects.

 

Table: Structure for individual dose / organs

IMRT (fotons) IMPT (protons)
Target volume (pancreatic cancer) 50 Gy (100%) 50 Gy (100%)
Liver(Dmean) 33 Gy (66%) 16 Gy (32%)
Right Kidney  (Dmean) 12.8 Gy (25.6%) 3.4 Gy (6,8%)
Left Kidney (Dmean) 9.6   Gy (19.2%) 7.5 Gy (15%)

 

Conclusion

Comparative dosimetric studies of proton and photon radiotherapy of the pancreatic bed and the draining lymph areas show a clear advantage of protons

 

References:

1. Howard T.J., Krug J.E., Yu J., Zyromski N.J. et al., A margin-negative R0 resection accomplished with minimal postoperative complications is the surgeon’s contribution to long-term survival in pancreatic cancer. J. Gastrointest Surg. 2006; 10:1338-45
2. Morganti A.G., Falconi M., van Stiphout R., Mattiucci G-C. et al., Multiinstitutional pooled analysis on adjuvant chemoraditaiton in pancreatic cancer, Int. J. Radiat. Oncol. Biol. Phys. 2014; 90:911-917
3. Garofalo M.C., Regine W.F., Tan M.T., On statistical reanalysis, the EORTC trial is a positive trial for adjuvant chemoradiation in pancreatic cancer, Annals of Surgery  2006; 244:332-333
4. http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
5. Caravatta L., Sallustio G., Pacelli F., Padulla G.D.A. et al., Clinical target volume delinetation uncluding elective nodal irradiation in preoperative and definitive radiotherapy of pancreatic cancer. Radiation Oncology 2012; 7:86
6. Katz H.G.M., Fleming J.B., Lee E.J., Pisters P.W.T., Current status of adjuvant therapy for pancreatic cancer, The Oncologist 2010; 15:1205-1213
7. Le Scodan R., Mornex F., Girard N. Mercier C. et al., Preoperative chemoradiation in potentially resectable pancreatic adenocarcinoma: Feasibility, tratment effect evaluation and prognostic factors, analysis of the SFRO-FFCD 9704 trial and literature review, Ann. Oncol. 2009; 20:1387-1396
8. Leone F., Gatti M., Massucco P., Colombi F.  et al. , Induction gemcitabine and oxaliplatin therapy followed by a twice-weekly infusion of gemcitabine and concurrent external-beam radiation for neoadjuvant treatment of locally advanced pancreatic cancer: A single institutional experience.
9. Blackstock A.W., Tepper J.E., Niedwiecki D., Hollis D.R. et al., Cancer and leukemia group B (CALGB) 89805: phase II chemoradiation trial using gemcitabine in patients with locoregional adenocarcinoma of the pancreas, Int. .J Gastrointest Cancer. 2003;34:107-16
10. Ceha H.M., van Thienhoven G., Gouma D.J., Veenhof C.H.N., Feasibility and efficacy of high dose conformal radiotherapy for patients with locally advanced pancreatic carcinoma, Cancer 2000; 89:2222-2229
11. Wei Q., Yu W., Rosati Lm:, Herman J.M., Advances of stereotactic body radiotherapy in pancreatic cancer, Chinese Journal of Cancer Research 2015; 27:349-357
12. Nichols R.C., Huh S.N., Prado K.L., Yi B.Y. et al. , Protons offer reduced normal-tissue exposure for patients receiving postoperative radiotherapy for resected pancreatic head cancer. Int. J. Radiat. Oncol. Biol. Phys. 2012; 83:158-163
13. Ling. T.C., Slatter J.M., Mifflin R., Nookala P. et al., Evaluation of normal tissue exposure in patients receiving radiotherapy for pancreatic cancer based on RTOG 0848, Journal of Gastrointestinal Oncology 2015; 6:108-114
14. Lee R.Y., Nichols R.C., Huh S.N., Ho M.W. et al., Proton therapy may allow for comprehensive elective nodal coverage for patients receiving neoadjuvant radiotherapy for localized pancreatic head cancers., J. Gastrointest. Oncol. 2013; 4:374-379
15. Bouchard M., Amos R.A., Briere T.M., Beddar S. et al., Dose escalation with proton or photon radiation treatment for pancreatic cancer, Radiother Oncol. 2009; 92:238-43
16. Kozak K.R., Kachnic L.A., Adams J., Crowley E.M., Dosimetric feasibility of hypofractionated proton radiotherapy for neoadjuvant pancreatic cancer treatment, Int J Radiat Oncol Biol Phys. 2007; 68:1557-66
17. Thompson R.F., Mayekar S.U., Zhai H., Both S. et al., A dosimetric comparison of proton and photon therapy in unresectable cancers of the head of pancreas, Medical Physics 2014; 41:081711-1 – 081711-10
18. Takatori K., Terashima K., Yoshida R., Horai A., Upper gastrointestinal complications associated with gemcitabine-concurrent proton radiotherapy for inoperable pancreatic cancer, J. Gatroenterol. 2014; 49 :1074-1080
19. Nichols R.C., Huh S., Li Z., Rutenberg M., Proton therapy for pancreatic cancer, World Journal of Gastrointestinal Oncology 2015; 7:141-147
20. Nichols R.C., Hoppe B.S., Re: Upper gastrointestinal complications associated with gemcitabine-concurrent proton radiotherapy for inoperable pancreatic cancer, J. Gastrointest. Oncol. 2013; 4: E33-E34
21. Nichols R.C., George T.J., Zaiden R.A.  jr., Awad Z.T. et al.¨, Proton therapy with concomitant capcecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity, Acta Oncol. 2013; 52: 498-505
22. Hong T.S., Ryan D.P., Borger D.R., Blaszkowsky L.S.  et al., A phase ½ and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma, Int. J. Radiat. Oncol. Biol. Phys. 2014; 89:830-838
23. https://www.rtog.org/CoreLab/ContouringAtlases/PancreasAtlas.aspx

 

Potential and standards of the therapy

 Surgery is the basic approach to brain cancer treatment. Radicality is the decisive prognostic factor. Histological examination of the tumour is decisive for further treatment, also for non-radical procedures. Stereotactic biopsy is made if the tumour is evidently inoperable.

 

Radiotherapy plays an irreplaceable role in the treatment of CNS cancers. In indicated cases, irradiation improves the results after radical or partial resection or for inoperable tumours.

 

Low grade gliomas

Pilocytic astrocytoma

Complete surgical resection is the basic treatment method.

Radical radiotherapy can be indicated for patients with progressing symptomatology if neurosurgery is contraindicated.

 

Nonpilocytic gliomas (astrocytoma, oligodendroglioma, oligoastrocytoma) Radical radiotherapy is indicated in patients with inoperable tumours. Postoperative radiotherapy is indicated in high-risk patients.

 

  1. First experiences in treatment of low-grade glioma grade I and II with proton therapy. Hauswald H, Rieken S, Ecker S, Kessel KA, Herfarth K, Debus J, Combs SE. Radiat Oncol. 2012 Nov 9;7:189.

 

  1. Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas:preliminary results of radiation therapy oncology group 0424. Fisher BJ, Hu C, Macdonald DR, Lesser GJ, Coons SW, Brachman DG, Ryu S,Werner-Wasik M, Bahary JP, Liu J, Chakravarti A, Mehta M. Int J Radiat Oncol Biol Phys. 2015 Mar 1;91(3):497-504.

 

 

Meningiomas

Radical resection is the method of choice. Radical radiotherapy is indicated in patients with inoperable tumours, particularly if located in the area cerebellopontine angle area, skull base, cavernous sinus and optic nerve sheath.

Postoperative radiotherapy is indicated for nonradical resections of Grade 2-3 meningiomas.

 

Based on published data, Grade 2-3 meningiomas require dose elevation up to 68-72 CGE, which is difficult to attain by photon therapy.

  1. Projected second tumor risk and dose to neurocognitive structures after proton versus photon radiotherapy for benign meningioma. Arvold ND, Niemierko A, Broussard GP, Adams J, Fullerton B, Loeffler JS, Shih HA. Projected second tumor risk and dose to neurocognitive structures after proton versus photon radiotherapy for benign meningioma. Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):e495-500.
  2. A comparison of the dose distributions from three proton treatment planning systems in the planning of meningioma patients with single-field uniform dose pencil beam scanning. Doolan PJ, Alshaikhi J, Rosenberg I, Ainsley CG, Gibson A, D’Souza D, Bentefour el H, Royle G. J Appl Clin Med Phys. 2015 Jan 8;16(1):4996.
  3. Results of fractionated targeted proton beam therapy in the treatment of primary optic nerve sheath meningioma. Moyal L, Vignal-Clermont C, Boissonnet H, Alapetite C. J Fr Ophtalmol. 2014 Apr;37(4):288-95.
  4. Dose escalation with proton radiation therapy for high-grade meningiomas. Chan AW, Bernstein KD, Adams JA, Parambi RJ, Loeffler JS. Technol Cancer Res Treat.2012 Dec;11(6):607-14.
  5. Comparison of intensity modulated radiotherapy (IMRT) with intensity modulated particle therapy (IMPT) using fixed beams or an ion gantry for the treatment of patients with skull base meningiomas. Kosaki K, Ecker S, Habermehl D, Rieken S, Jäkel O, Herfarth K, Debus J, Combs SE. Radiat Oncol. 2012 Mar22;7:44.

 

Pituitary adenomas

For hormonally active adenomas, medication is the basic treatment method.

Radical radiotherapy is indicated if medication has failed and if the tumour is inoperable.

 

For hormonally inactive adenomas, surgical resection is the method of choice. Radical radiotherapy is indicated in patients with inoperable tumours.

Proton therapy makes it possible to achieve high treatment effectiveness and to reduce the exposure of surrounding healthy brain structures, such as the temporal lobe, inner ear, and brain stem, thereby reducing the risk and degree of radiation complications.

 

  1. The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas. Brada M, Rajan B, Traish D, et al. ClinEndocrinol (Oxf) 1993;38:571-578
  2. Fractionated proton beam irradiation of pituitary adenomas.Ronson BB, Schulte RW, Han KP, Loredo LN, Slater JM, Slater JD. Int J RadiatOncolBiolPhys. 2006Feb 1;64(2):425-34.
  3. Proton stereotactic radiosurgery in management of persistent acromegaly. Petit JH, Biller BM, Coen JJ, Swearingen B, Ancukiewicz M, Bussiere M, Chapman P, Klibanski A, Loeffler JS. 2007 Nov-Dec;13(7):726-34.
  4. Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas. Petit JH, Biller BM, Yock TI, Swearingen B, Coen JJ, Chapman P, AncukiewiczM,Bussiere M, Klibanski A, Loeffler JS. J ClinEndocrinolMetab. 2008  Feb;93(2):393-9.

 

Chordomas and chondrosarcomas

Radical resection is the method of choice for skull base tumours. Postoperative radiotherapy is indicated due to frequent local relapse after surgery as well as after complete resection for all types.

Primary radiotherapy for inoperable tumours and for tumours located in the pelvic area.

The dose delivered by conventional radiotherapy, i.e. 50-54 Gy, is insufficient to lead to satisfactory results in the long run. In proton therapy, the dose is increased to 68-72 and 72-74 CGE for chondrosarcomas and chordomas, respectively.

 

Efficiency and limitations of current radiotherapy: technical and biological aspects

The efficiency of CNS cancer therapy is dependent on the biological nature of the disease, radicality of the surgery, and feasibility of safe application of the required radiation dose.

The adverse effects of radiotherapy also depend on the radiation dose delivered.

For some CNS cancer types such as Grade 2-3 meningiomas, chordomas and chondrosarcomas, the efficiency of the treatment increases with increasing radiation dose.  Dose elevation for CNS tumours is often impossible because of the presence of high-risk structures nearby or is difficult to attain by photon therapy because of the inacceptable risk of damage of vital high-risk structures.

 

For skull base tumours, surgical therapy is frequently incomplete.  Proton therapy allows the dose to be increased up to 74-78 Gy, thus contributing to a better local control of the tumour in indicated cases.

 

Over a five-year period, proton therapy provides a 91% success rate for chondrosarcoma, a 65% success rate for chordoma, and a 62-88% success rate for other cases.

 

Acute radiotherapy complications (complications arising during or shortly after the exposure) include nausea, focal alopecia and otitis. The most serious delayed complications include impaired cognitive functions, vision disorders (some of which can be remedied by surgery, e.g. lens replacement, while others are permanent), impaired pituitary function, brain tissue necrosis, increased fractions of deaths due to diseases of cerebrovascular etiology.

 

The number of secondary brain tumours also grows with increasing integral radiation dose. .(Minniti G, Traish D, Ashley S, et al. Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years. J Clin Endocrinol Metab 2005;90:800-804).

 

Potential for result improvements

The interdependences between the radiation dose to which the tumour is exposed and the likelihood of patient recovery from the disease, and between the radiation dose to which the healthy tissue is exposed and the extent of tissue injury, have been clearly demonstrated. A way to improve the treatment results thus consists in application of adequately high doses to the entire tumour (this applies, in particular, to atypical and low-differentiated meningiomas, chordomas and chondrosarcomas) while mitigating the adverse effects by reducing the radiation doses delivered to the critical organs.

 

The benefit of proton therapy

The main advantage of proton therapy is in the appreciably better radiation distribution, owing to which improved treatment results can be achieved while reducing toxicity of the therapy, as described above. Where hypofractionation regimens are applied, patient comfort is improved by shortening the treatment time. The improved dose distribution patterns provide the opportunity to apply higher doses without inducing more severe side effects.

 

Picture : Example plan: (a) photon IMRT, (b) proton IMPT,

      b

(c) DVH (dose-volume histogram)

 

Table: doses to the various structures/organs

IMRT (photons) IMPT (protons)
Target volume (brain tumour) 60 Gy (100%) 60 Gy (100%)
Brain (mean dose) 35.7 Gy (59.5%)  25.9 Gy (43.1%)
Brain stem (mean dose) 18.6 Gy (31%) 5.3 Gy (8.8%)
Right eye (mean dose) 28.3 Gy (47.2%) 9.7 Gy (16.2%)
Chiasma opticum (maximum dose) 49.0 Gy (81.6%) 46.0 Gy (76.6%)

 

Proton therapy results achieved

CNS cancers are the most closely followed cancer types treated by proton therapy. Owing to the higher radiation doses applied to the tumour, the treatment results for Grade 2-3 meningiomas, chordomas and chondrosarcomas attained by proton therapy are superior to those attained by photon therapy. In addition, the adverse effects are milder.

 

Results of treatment of pituitary adenomas:

  • Petit JH, Coen J, Yock T, et al. 2004. Proton radiosurgery in the management of functioning and non-functioning pituitary adenomas: a 10-year experience at the Massachusetts General Hospital. Abstr 1094. 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 3-7, 2004, Atlanta, GA.
  • Ronson BB, Schulte RW, Han KP, et al. Fractionated proton beam irradiation of pituitary adenomas. Int J Radiat Oncol Biol Phys 2006;64:425-434
  • Petit JH, Biller BM, Coen JJ, Swearingen B, Ancukiewicz M, Bussiere M, Chapman P, Klibanski A, Loeffler JS.Proton stereotactic radiosurgery in management of persistent acromegaly. Endocr Pract. 2007 Nov-Dec;13(7):726-34.
  • Petit JH, Biller BM, Yock TI, Swearingen B, Coen JJ, Chapman P, Ancukiewicz M,Bussiere M, Klibanski A, Loeffler JS.  Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas.J Clin Endocrinol Metab. 2008  Feb;93(2):393-9.

 

Results of treatment of meningioma:

  • Weber DC, Schneider R, Goitein G, Koch T, Ares C, Geismar JH, Schertler A, Bolsi A, Hug EB. Spot Scanning-based Proton Therapy for Intracranial Meningioma: Long-term Results from the Paul Scherrer Institute. Int J Radiat Oncol Biol Phys. 2011. (abstrakt)
  • Schneider R. Spot-Scanning based proton radiation therapy for complex benign, atypical, and anaplastic meningiomas: 5 year results from the Paul Scherrer Institute (PSI). ASTRO 2011.
  • Wenkel E, Thornton AF, Finkelstein D, Adams J, Lyons S, De La Monte S, Ojeman RG, Munzenrider JE. Benign meningioma: partially resected, biopsied, and recurrent intracranial tumors treated with combined proton and photon radiotherapy. Int J Radiat Oncol Biol Phys 2000; 48:1363–70
  • Vernimmen FJ, Harris JK, Wilson JA, Melvill R, Smit BJ, Slabbert JP. Stereotactic proton beam therapy of skull base meningiomas. Int J Radiat Oncol Biol Phys 2001; 49:99–105.
  • Arvold ND, Niemierko A, Broussard GP, Adams J, Fullerton B, Loeffler JS, Shih HA. Projected second tumor risk and dose to neurocognitive structures after proton versus photon radiotherapy for benign meningioma. Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):e495-500.
  • Doolan PJ, Alshaikhi J, Rosenberg I, Ainsley CG, Gibson A, D’Souza D, Bentefour el H, Royle G. A comparison of the dose distributions from three proton treatment planning systems in the planning of meningioma patients with single-field uniform dose pencil beam scanning. J Appl Clin Med Phys. 2015 Jan 8;16(1):4996.
  • Moyal L, Vignal-Clermont C, Boissonnet H, Alapetite C. Results of fractionated targeted proton beam therapy in the treatment of primary optic nerve sheath meningioma. J Fr Ophtalmol. 2014 Apr;37(4):288-95.
  • Chan AW, Bernstein KD, Adams JA, Parambi RJ, Loeffler JS. Dose escalation with proton radiation therapy for high-grade meningiomas. Technol Cancer Res Treat.2012 Dec;11(6):607-14.
  • Kosaki K, Ecker S, Habermehl D, Rieken S, Jäkel O, Herfarth K, Debus J, Combs SE. Comparison of intensity modulated radiotherapy (IMRT) with intensity modulated particle therapy (IMPT) using fixed beams or an ion gantry for the treatment of patients with skull base meningiomas.  Radiat Oncol. 2012 Mar22;7:44.

 

The results of treatment with low-grade gliomas:

  • Fitzek MM, Thornton AF, Harsh GT, Rabinov JD, Munzenrider JE, Lev M, Ancukiewicz M, Bussiere M, Hedley-Whyte ET, Hochberg FH, Pardo FS. Dose-escalation with proton/photon irradiation for Daumas-Duport lowergrade glioma: results of an institutional phase I/II trial. Int J Radiat Oncol Biol Phys 2001; 51:131–7.
  • Hauswald H, Rieken S, Ecker S, Kessel KA, Herfarth K, Debus J, Combs SE. First experiences in treatment of low-grade glioma grade I and II with proton therapy. Radiat Oncol. 2012 Nov 9;7:189.
  • Fisher BJ, Hu C, Macdonald DR, Lesser GJ, Coons SW, Brachman DG, Ryu S,Werner-Wasik M, Bahary JP, Liu J, Chakravarti A, Mehta M. Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas:preliminary results of radiation therapy oncology group 0424. Int J Radiat Oncol Biol Phys. 2015 Mar 1;91(3):497-504.

 

Results of treatment of chordoma and chondrosarcoma:

  • Noël G, Feuvret L, Calugaru V, Dhermain F, Mammar H, Haie-Méder C, Ponvert D, Hasboun D, Ferrand R, Nauraye C, Boisserie G, Beaudré A, Gaboriaud G, Mazal A, Habrand JL, Mazeron JJ. Chordomas of the base of the skull and upper cervical spine. One hundred patients irradiated by a 3D conformal technique combining photon and proton beams. Acta Oncol. 2005; 44(7):700-8. (abstract)
  • Berson AM, Castro JR, Petti P, Phillips TL, Gauger GE, Gutin P, Collier JM, Henderson SD, Baken K. Charged particle irradiation of chordoma and chondrosarcoma of the base of skull and cervical spine: the Lawrence Berkeley Laboratory experience. Int J Radiat Oncol Biol Phys 1988; 15:559–65. (abstract)
  • Staab A, Rutz HP, Ares C, Timmermann B, Schneider R, Bolsi A, Albertini F, Lomax A, Goitein G, Hug E. Spot-scanning-based proton therapy for extracranial chordoma. Int J Radiat Oncol Biol Phys. 2011; 81(4):e489-96. (abstract)

 

Results of treatment of other CNS carcinomas:

  • Combs SE, Kessel K, Habermehl D, Haberer T, Jäkel O, Debus J. Proton and carbon ion radiotherapy for primary brain tumors and tumors of the skull base. Acta Oncol. 2013 Oct;52(7):1504-9.
  • M.Desai, R.C.Rockne, A.W. Rademake. Overall Survival (OS) and Toxicity Outcomes Following Large-Volume Re-irradiation Using Proton Therapy (PT) for Recurrent Glioma Int J RadiatOncolBiolPhys. 2014 Sep 1;90(1):S286.
  • Matsuda M, Yamamoto T, Ishikawa E, Nakai K, Zaboronok A, Takano S, MatsumuraA. Br Prognostic factors in glioblastoma multiforme patients receiving high-dose particle radiotherapy or conventional J Radiol. 2011 Dec;84 Spec No 1:S54-60.
  • Brown AP, Barney CL, Grosshans DR, McAleer MF, de Groot JF, PuduvalliVK,Tucker SL, Crawford CN, Khan M, Khatua S, Gilbert MR, Brown PD, Mahajan A. Proton beam craniospinal irradiation reduces acute toxicity for adults with Int J RadiatOncolBiolPhys. 2013 Jun 1;86(2):277-84.
  • Harsh GR, Thornton AF, Chapman PH, Bussiere MR, Rabinov JD, LoefflerJS. Int J RadiatOncolBiolPhys. 2002 Sep 1;54(1):35-44.
  • Weber DC, Chan AW, Bussiere MR, Harsh GR 4th, Ancukiewicz M, Barker FG 2nd,Thornton AT, Martuza RL, Nadol JB Jr, Chapman PH, Loeffler JS. Proton beam radiosurgery for vestibular schwannoma: tumor control and cranial nerve toxicity. 2003 Sep;53(3):577-86; discussion 586-8

 

Expected benefit of proton therapy applied within the proposed protocol

 

Proton therapy applied by following the PTC protocol offers:

  1. Improved treatment results owing to the increased radiation doses applied to chordomas, chondrosarcomas and Grade 2-3 meningiomas without increasing the toxicity of the treatment.
  2. Fewer or less severe long-term adverse effects that require active treatment
  3. Improved patients’ quality of life owing to the less severe and shorter adverse effects and a higher chance for preservation of the quality of life.

 

Use of proton therapy in the treatment of lymphomas

Malignant lymphomas are a common diagnosis treated at proton centers around the world. The reason is the complexity of target volumes, the high curability of the disease and efforts to reduce late adverse effects in view of the expected long-term survival of patients.

 

Justification of the suitability of proton therapy in malignant lymphomas is based on the 2016 NCCN Guidelines as well as on the 2013 Czech Lymphoma Study Group guideline, Diagnostic and Therapeutic Procedures in Patients with Malignant Lymphomas section. Both standards refer to the possibility of using proton radiotherapy depending on clinical situations, particularly where it is necessary to consider the reduction of late adverse effects of radiotherapy.

 

Indications of proton therapy for example, recommended here:

MD Anderson Cancer Centrehttp://www.mdanderson.org/patient-and-cancer-information/proton-therapy-center/conditions-we-treat/lymphomas/index.html

Scripps proton therapy center, San Diegohttp://www.scripps.org/services/cancer-care__proton-therapy/conditions-treated__proton-therapy-for-lymphoma

University of Floridahttp://www.floridaproton.org/cancers-treated/hodgkin-lymphoma

Astro, PTCOG, OR PTC

 

Indication of proton therapy and radiation treatment strategies

 

The issues of radiotherapy for lymphomas

Problems encountered in radiation therapy for lymphomas primarily consist in the necessity of reducing some types of acute toxicity (radiation pneumonitis, radiation myelopathy such as Lhermitte’s syndrome), as it is crucial to reduce late toxicity of RT (cardiotoxicity, valvular defects, risk of secondary malignancies, such as breast cancer, lung cancer, post-radiation fibrosis). Due to
a very good prognosis for patients with lymphomas (especially for patients with Hodgkin’s lymphoma, with up to 80% long-term survival, and those with NHL with up to 60% long-term survival) and the age of disease manifestation, a large percentage of patients can survive long enough to develop late and very late toxicity, which may occur even several decades after the therapy.

Given the presence of many high-risk structures with sensitivity to radiation damage in the area surrounding a lymphoma infiltrate or sites of original lymphoma infiltration, which is even more increased over the previous completed chemotherapy (spinal cord, and in patients with supradiaphragmatic involvement: salivary glands, swallowing tract, respiratory tract, oral cavity, heart, mammary gland; and in patients with subdiaphragmatic involvement, e.g. intestinal loops, kidney, liver, urine, bladder, rectum), it is very important to minimize the dose to these high-risk organs. The problem is not only the exposure of healthy tissues to the borderline (limit) dose, but also the irradiation of a large volume of healthy tissues with lower doses of RT (5-8 Gy/RT series). This low dose usually does not cause any acute or apparent late toxicity, but in long-term survivors, the irradiated tissue may accumulate mutations which can lead to the formation of secondary tumors (e.g. lung tumors, breast tumors, non-Hodgkin lymphoma, gastrointestinal tumors) or
a functional impairment of the organs.

 

In this case, even modern conventional photon therapy provides no options for reducing the doses to organs at risk. Conversely, the use of some modern techniques of multiple-field photon RT (IMRT) can lead to an increase in the volume of tissues irradiated with a low dose and increase the risk of secondary malignancies.

 

Acute and late toxicity of conventional radiotherapy:

  • Acute toxicity: post radiation pneumonitis gr. II and higher: 10-15%, post radiation mucositis gr. II and higher: 10%, dysphagia gr. II and higher: 30%.
  • Late toxicity: post radiation myelopathy of Lhermittov’s syndrome 10%, post radiation hypofunction of the thyroid 30-40%.
  • Very late toxicity: secondary malignity up to 20%, 20 years after conventional radiotherapy, (of which the emergence of breast cancer is an important volume of the mammary gland, that receives the dose of 4Gy and higher; in lung tumours the volume of the lung receiving
    a dose of 5 Gy or higher is the main risk factor), cardiovascular toxicity – in patients after treatment of Hodgkin Lymphoma is 2.2 – which is a 7 times higher risk of the manifestation of cardiovascular disease (conventional radiotherapy to the mediastinum is associated with a higher risk of heart valve impairment, impairment of the coronary arteries and associated ischemic heart disease and congestive heart failure).

 

Due to the very positive prognosis for patients with lymphoma, and an associated long-life expectancy, a significant number of patients after lymphoma treatment have been known to suffer from late radiation therapy toxicity. This toxicity can occur up to several decades after treatment. During the time patients are cured from Hodgkin’s lymphoma and some types of non-Hodgkin’s lymphomas the probability of death from lymphoma is decreased and conversely there is increased risk of death from other types of diseases associated with the toxicity of previous cancer treatment. The dominant causes of deaths associated with late toxicity are cardiovascular diseases and secondary tumours (secondary malignancy).

RT techniques in the treatment of lymphomas

Lymphoma RT is associated with certain specificities compared with RT of most solid (non-haematological) tumours. Lymphoma, as a radiosensitive disease, usually does not require the use of a total radiation dose exceeding the limits of the surrounding tissues.  However, minimizing of exposure of surrounding healthy tissues is essential. Their irradiation is associated with significant limitations for the patient, as the development of acute postradiation toxicity, but may also pose
a risk of late and very late toxicity. Therefore, classical dose limits for risk organs cannot be used in lymphomas as in the RT of the majority of solid tumours.

 

In the last decade, we have seen the spectrum of available RT techniques significantly extended. In the field of photon RT techniques, 3D conformal RT (3D-RT) is commonly available. Advanced techniques include intensity modulated RT (IMRT), volumetric arc RT (VMAT) and helical tomotherapy (HT). As for RT techniques using another source of ionizing radiation, proton RT is available (pencil beam scanning technique). The deep inspiration breath hold technique can be used in patients requiring mediastinal or epigastrial irradiation.

 

Photon techniques

However, photon techniques (IMRT, VMAT, tomotherapy) are considered less useful when compared with the benefits for other malignancies. In addition, the older 3D-CRT still maintains its position. The use of modern techniques should be individualized after considering the potential benefits and risks. The benefits of these highly conformal techniques primarily include the reduction of the volume of tissue exposed to high doses of radiation (i.e. a dose close to the prescribed dose for the target volume).  The disadvantages of these techniques include mainly low-dose bath (i.e. a large volume of tissue irradiated with middle and low doses of radiation, possibly increasing the risk of induction of secondary malignancies and late functional impairment) and a theoretical risk of target volume underdosing in the irradiation of moving targets without the possibility of fixation or tracking (e.g. mediastinal irradiation without gating).

Mediastinal irradiation in the maximum inspiration (deep inspiration breath-hold DIBH)

DIBH in mediastinal lymphoma RT is currently a debated and topical subject. This technique is relatively simple and feasible in most patients with mediastinal lymphomas or the need of radiation of epigastrium. It uses active control of the patient’s breathing. Hence, irradiation is active only in deep inspiration (patients are usually able to maintain this position for 15 to 20 seconds). Centres using DIBH must have the equipment necessary to capture the spirometry curves and must be able to synchronize irradiation with the specified respiratory phase of the patient (irradiation is shut down at the beginning of the patient’s exhalation).  Active breathing control increases the sparing of lung tissue, the heart, and coronary arteries, primarily in upper mediastinal tumours RT. Moreover, it reliably ensures a total fixation of the mediastinum during RT and reduces the risk of missing the target volume.

Proton therapy and current data

Proton radiotherapy is the next logical step in the evolution of radiotherapy, as the standard photon RT has reached its physical limits. Data on the safety of proton RT are long-term, e.g. in paediatric cancer patients. Currently, there are new results of 2 clinical studies of treatment outcomes and toxicity of proton RT in mediastinal lymphomas. The first study by Hoppe et al. published in August 2014 dealing with involved node proton RT in the treatment of Hodgkin lymphoma reports the prospective phase II study results. The available results indicate that it is a safe treatment as regards the undesirable side effects and the treatment outcomes. The study was performed in a cohort of 22 patients with a newly diagnosed Hodgkin’s lymphoma in the period from June 2009 to June 2013. The patients were in the stages I-III. 3 irradiation plans were performed after the completion of chemotherapy – one plan for proton irradiation and 2 plans for photon radiotherapy (3D conformal radiotherapy, IMRT). The optimal chosen plan was the one associated with the dose of 4 Gy and higher in the lowest body volume. 15 patients underwent proton RT. Median follow-up of patients after proton RT was 37 months (26-55 months). The evaluated data indicate 93% survival without a relapse of the disease 3 years after the treatment. None of the patients suffered from a severe acute or late adverse effect (grade III and higher).

 

The second study from Massachusetts General Hospital at Harvard Medical School by Winkfield et al. published in October 2015 deals with the evaluation of the 8-year results of proton RT in mediastinal lymphomas. This is the largest study evaluating the outcomes in 46 patients with HL and NHL (34 HL, 12 NHL). Proton RT significantly reduces the dose for cardiac structures, lungs, spinal cord and the integral dose. It is a very well-tolerated treatment that also provides excellent local control (5-year OS of 98%, 5-year PFS 80%, 5-year TFS 78%).

 

It has been repeatedly demonstrated that proton RT reduces the exposure of healthy surrounding organs (high, medium and low doses) and minimizes the total radiation load of the patient.  The use of the proton RT reduces the risk of acute pulmonary toxicity (a significant reduction of the risk of radiation pneumonitis, particularly in large-scale or repeated irradiation of the lymph system over the diaphragm), the incidence of spinal cord lesions (especially of Lhermitte’s syndrome), sometimes also the incidence of dysphagia and odynophagia, xerostomia, nausea, diarrhoea and fatigue. The reduction of the risk of late and very late toxicity has already been mentioned. Moreover, proton RT often allows repeated irradiation in chemoresistant lymphomas with the possibility of dose escalation (repeated irradiation after TBI, repeated irradiation of the mediastinum or an affection under the diaphragm).

 

Few years ago, prestigious treatment protocols of the American organization the National Comprehensive Cancer Network (NCCN) included a reference to the possible use of proton RT in all the types of lymphomas. The latest version of these prestigious protocols created by globally recognized experts in the treatment of cancer has extended the general recommendations for the proton therapy in the treatment of all types of lymphomas. Proton RT is now considered an advanced RT technique in lymphomas that may offer a clinically significant and substantial advantage in the form of sparing of important high-risk organs. Moreover, these protocols negate the requirement for randomized clinical trials for the proton RT (as a technique with a potential to reduce late and very late toxicity) to be included in the clinical practice. A technique that is associated with clinically significant minimization of the risk of organ exposure, still with maintained irradiation of the target volume, should be considered, regardless of the availability of the randomized clinical trials results. It is very unlikely that we will soon have data that would enable us to quantify the risk of late toxicity after individual advanced RT techniques, since a minimum of 10 years and longer is necessary to evaluate these results. Therefore, the theoretical assumption of surrounding tissue sparing and of good irradiation of the target volume is sufficient for the indication of proton RT.

Proton radiotherapy makes it possible to significantly reduce the dose to critical structures, in particularly in patients with mediastinal involvement. This involves in particular dose reduction to:

  • lung tissue
  • heart muscle
  • heart valves
  • coronary arteries
  • esophagus
  • spinal cord
  • mammary glands

 

The level of dose reduction is highly individual. Generally, the structures that have the maximum benefits from proton radiotherapy are those located further away from the target volume (a typical example is dose reduction to the spinal cord to 0 Gy).

 

Summary of the advantages of proton radiotherapy:

  • Decreased acute toxicity:better sparing of healthy tissue with a lower risk of acute toxicity and associated expenses. associated with post radiation toxicity (corticosteroid therapy and oxygen therapy, or artificial lung ventilation in the case of post radiation pneumonitis, artificial nutrition in case of dysphagia and mucositis, treatment of gastrointestinal issues with the need for rehydration)
  • Decreased late and very late toxicity: greatly improved sparing of healthy tissue from unwanted radiation (due to the accuracy of protons), a lower risk of cardiovascular problems and secondary malignancies leading to an overall obvious improvement in quality of life as well as
    a reduced need for treating complications (collateral damage) arising from treatment-related damage to healthy tissue later in life.
  • Experience of experts from the Proton Center in Prague

 

A total of 53 patients with a lymphoma were treated in the Proton Therapy Center from 4/2013 to 4/2016. 4 further patients with a mediastinal affection are being prepared or actually in treatment. In the above stated group of patients, 46 patients underwent proton RT of an affection located over the diaphragm including the mediastinum. The IS-RT definition of the target volume has been used since 3/2015 (12 patients). Since 4/2015, the maximum inspiration technique (DIBH) has been used in most patients – a total of 10 patients. The proton RT technique used in these patients was pencil beam scanning (PBS). To our knowledge, PTC is one of the first centres, where patients receiving the PBS radiotherapy in deep inspiration (DIBH). None of the patients developed clinically significant toxicity associated with the radiotherapy. None of the 25 evaluable patients (3 years or more after the end of irradiation) suffered from recurrences in the irradiated area or severe postradiation toxicity (grade II and higher).

 

Indications of proton radiotherapy according to PTC protocols:

Hodgkin’s lymphoma:

  • Patients with residual involvement of the mediastinum and subdiaphragmatic region, especially those with grade III to IV Hodgkin’s lymphoma achieving suboptimal response to chemotherapy;
  • Patients with grade I to II disease at a young age (up to 35-40 years of age) with mediastinal involvement.

Lymphomas of all histological subtypes, anatomically located near the structures with limiting toxicity
(ENT, in the proximity of ovaries in women of childbearing age, reradiation of already irradiated areas due to lymphoma or other diagnosis)

 

Non-Hodgkin’s lymphoma:

  • Patients with residual involvement of the mediastinum and subdiaphragmatic region in whom no rescue systemic treatment is indicated.
  • Rare histological subtypes of NHL localized in the ENT area (e.g. NK/T-cell lymphoma), the need for escalation of the radiation dose.

 

Advantages of proton therapy

 

The main advantage of proton therapy is:

  • dose reduction to critical organs, with subsequent reduction of the risk of late and very late undesirable effects.

 

As an example, we can provide links to publications addressing comparative dosimetric parameters of photon and proton plans or provide proof of irradiation plans in each particular case, thus proving the correctness of indications.

 

When comparing IMRT and proton RT of the mediastinum, we can see a clear benefit in reducing the burden on healthy tissues, namely the lungs, mammary glands and body volume. This work demonstrated a dose reduction to the pulmonary parenchyma in patients with mediastinal lymphoma by up to 1/3 or 1/2 compared to conventional photon RT. Dose reduction per body volume in a patient who received the dose of 4 to 30 CGE, was reduced by one half, and the mean dose to mammary glands was also reduced. The dose delivered to the heart, thyroid and salivary glands were comparable when using all three RT techniques. During the irradiation of the mediastinum, a significant sparing of the pulmonary parenchyma, mammary glands, as well as
a lower burden on body tissues due to lower and middle-dose radiation was repeatedly demonstrated. For the heart and other organs at risk, the burden reduction is determined by the location of the volume to be irradiated.

 

Conclusion:

The advantages of using proton radiotherapy in patients with lymphomas should be identical in terms of the prognosis and age of patients as in pediatric patients. Due to this benefit, proton radiation therapy was included in treatment protocols of the National Cancer Comprehensive Network as the radiotherapy of choice for all types of lymphomas.

Problems encountered in radiation therapy for lymphomas consist in the necessity of reducing some types of acute toxicity (radiation pneumonitis, radiation myelopathy such as Lhermitte’s syndrome), and in particular the need to reduce the risk of late toxicity of RT (cardiac toxicity, risk of secondary malignancies such as breast cancer, lung cancer, post-radiation fibrosis).

 

Due to a very good prognosis for patients with lymphomas (Hodgkin’s lymphoma, with long-term survival in up to 80% of patients, and non-Hodgkin’s lymphoma with long-term survival in up to 60% of patients) and the age of disease manifestation, a large percentage of patients can survive long enough to develop late and very late toxicity.

The problem is not only the exposure of healthy tissues to a borderline (threshold) dose, but also the irradiation of the volume of healthy tissue with lower doses of RT (5-8 Gy per RT series) that may contribute to the development of late toxicity.

In this case, even modern photon therapy provides no options for reducing the doses to organs at risk. Conversely, the use of some modern techniques of multiple-field photon RT (IMRT, VMAT) can lead to an increase in the volume of tissues irradiated with a low dose and increase the risk of secondary malignancies. Due to the early age of occurrence and a long estimated survival in a large percentage of patients, the use of proton RT in the treatment of lymphomas offers similar potential as in pediatric patients.

 

Proton RT, in the Czech Republic also available in its most advanced form (pencil beam scanning with DIBH RT), should always be considered in patients requiring mediastinal RT or repeated irradiation.

 

Picture: Example plan: (a) photon IMRT, (b) proton IMPT, 

   b 

(c) DVH (dose-volume histogram)

 

References:

  1. Chera SB, Rodriquez Ch, et al. Dosimetric Comparison of Three Different Involved Nodal Irradiation Techniques for Stage II Hodgkin’s Lymphoma Patients: Conventional Radiotherapy, Intensity-Modulated Radiotherapy, and Three-Dimensional Proton Radiotherapy. International Journal of Radiation Oncology * Biology * Physics, Volume 75, Issue 4, Pages 1173-1180, 15 November 2009
  2. Li J., Dabais B. Rationale for and Preliminary Results of Proton Beam Therapy forMediastinal Lymphoma. International Journal of Radiation Oncology, Biology, Physics. Volume 81, Issue 1, Pages 167-174, 1 September 2011
  3. Hoppe BS, Flampouri S.,et al. Consolidative Involved-Node Proton Therapy for Stage IA-IIIB Mediastinal Hodgkin Lymphoma: Preliminary Dosimetric Outcomes From a Phase II Study. International Journal of Radiation Oncology, Biology, Physics. Volume 83, Issue 1, Pages 260-267, 1 May 2012
  4. Chera BS, Rodriquez Ch., et al. Dosimetric Comparison of Three Different Involved Nodal Irradiation Techniques for Stage II Hodgkin’s Lymphoma Patients: Conventional Radiotherapy, Intensity-Modulated Radiotherapy, and Three-Dimensional Proton Radiotherapy. International Journal of Radiation Oncology, Biology, Physics. Volume 75, Issue 4, Pages 1173-1180, 15 November 2009
  5. Hoppe BS., et al. Effective Dose Reduction to Cardiac Structures Using Protons Compared with 3DCRT and IMRT in Mediastinal Hodgkin Lymphoma. International Journal of Radiation Oncology, Biology, Physics Article in Press, Received 23 October 2011; received in revised form 25 October 2011; accepted 8 December 2011. published online 05 March 2012
  6. Hoppe BS, Flampouri S., et al. Reducing the Dose to the Cardiac Chambers, Valves, and Vessels with Proton Therapy Compared with 3D-CRT and IMRT in Patients with Mediastinal Hodgkin Lymphoma. International Journal of Radiation Oncology, Biology, Physics. Volume 81, Issue 2, Supplement , Page S20, 1 October 2011
  7. Chen Y., Adams J., et al. Preliminary Experience with Proton Radiotherapy in Mediastinal Lymphoma. International Journal of Radiation Oncology, Biology, Physics Volume 78, Issue 3, Supplement , Page S547, 1 November 2010
  8. Crew JB, James JA., et al. Dosimetric Comparison of Uniform Scanning Proton Therapy, Helical Tomotherapy, and Volumetric Modulated Arc Therapy in the Treatment of Bilateral Orbital Lymphoma. International Journal of Radiation Oncology, Biology, Physics. Volume 78, Issue 3, Supplement , Pages S806-S807, 1 November 2010
  9. Rodriguez C., Chera BS., et al. Proton Radiotherapy for Hodgkin’s Lymphoma. International Journal of Radiation Oncology, Biology, Physics.Volume 72, Issue 1, Supplement , Pages S124-S125, 1 September 2008
  10. Chung CS, Yoc T. et al. Proton Radiation Therapy and the Incidence of Secondary Malignancies. International Journal of Radiation Oncology, Biology, Physics. Volume 69, Issue 3, Supplement , Pages S178-S179, 1 November 2007
  11. Andolino DL, Hoene T, Xiao L, Buchsbaum J, Chang AL Dosimetric comparison of involved-field three-dimensional conformal photon radiotherapy and breast-sparing proton therapy for the treatment of Hodgkin’s lymphoma in female pediatric patients. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):e667-71. Epub 2011 Apr 1
  12. Hoppe BS et al., Involved-node proton therapy in combined modality therapy for Hodgkin lymphoma: results of a phase 2 study. Int J Radiat Oncol Biol Phys. 2014 Aug 1;89(5):1053-9.
  13. Zeng, C., et al. Proton Pencil Beam Scanning for Mediastinal Lymphoma: Dosimetric Evaluation and 4-Dimensional Robustness Assessment. International Journal of Radiation Oncology • Biology • Physics , Volume 90, Issue 1, S922
  14. Winkfield KM, et al. Proton Therapy for Mediastinal Lymphomas: An 8-year Single-institution Report. International Journal of Radiation Oncology • Biology • Physics, Vol. 93, Issue 3, E461. Published in issue: November 01 2015
  15. Sachsman S, et al. Proton therapy in the management of non-Hodgkin lymphoma. Leuk Lymphoma. 2015 May. 18:1-5. [Epub ahead of print] PubMed PMID: 25669925.
  16. Plastaras JP, et. Al. Special cases for proton beam radiotherapy: re-irradiation, lymphoma, and breast cancer. Semin Oncol. 2014. Dec;41(6):807-19. doi: 10.1053/ j.seminoncol. 2014.10.001. Epub 2014 Oct 7. Review. PubMed PMID: 25499639.
  17. Lohr F, et al. Novel radiotherapy techniques for involved-field and involved-node treatment of mediastinal Hodgkin lymphoma: when should they be considered and which questions remain open? Strahlenther Onkol. 2014 Oct;190(10):864-6, 868-71. doi: 10.1007/s00066-014-0719-9. Epub 2014 Sep 11. Review. PubMed PMID: 25209551.

 

Treatment protocols of proton therapy for lymphoma:

http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf

http://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf

http://www.postersessiononline.com/173580348_eu/congresos/13icml/aula/-P_174_13icml.pdf

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