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.
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.
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.
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.
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.
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.
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 treatment protocols employed at PTC are the same internationally accepted protocols that have achieved treatment success world-wide. Proton therapy clearly demonstrates:
Examples of some publications:
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.
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:
UPENN – http://www.pennprotontherapy.org/cancers-we-treat/
University of Florida – http://www.floridaproton.org/cancers-treated/prostate-cancer
Scripps proton therapy center, San Diego – http://www.scripps.org/services/cancer-care__proton-therapy/conditions-treated__proton-therapy-for-prostate-cancer
Loma Linda Proton therapy center, California – http://www.protons.com/proton-therapy/proton-treatments/prostate-cancer/about-the-prostate.page
University of Florida – http://www.floridaproton.org/cancers-treated/prostate-cancer
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
|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 |
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 |
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 |
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:
|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%|
As evidenced by the data provided in the table, the undesirable effects after photon therapy are significantly higher than after proton radiotherapy.
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.
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.
Interim evaluation at proton therapy center has shown that therapy is highly effective in the key parameter of prostate specific antigen (PSA). PSA levels have steadily declined over time, where the mean values decreased from 5.15 ng/mL to 1.25 ng/mL, 1.11 ng/mL, and 1.04 ng/mL after 12, 18, and 24 months, respectively. These results show very good control of the disease and a low risk of relapse.
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 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%)|
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.
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.
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).
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.
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
Proton radiotherapy allows a significant dose reduction to the critical structures of the head and neck. This involves in particular dose reduction to:
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)
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%)|
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.
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).
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.
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.
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).
The most severe radiotherapy toxicity signs in NSCLC is the radiation pneumonitis, oesophagitis and cardial toxicity.
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%):
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%.
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.
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 |
|Photons||74.0||37 x 2.0 Gy||7.4|
|Photons (locally advanced disease)||67.5 |
|25 x 2,7 Gy |
18 x 3 Gy
|10 x 6 Gy |
10 x 7 Gy
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.
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.
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%)|
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
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.
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.
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 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.
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.
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 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.
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.
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:
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.
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:
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:
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.
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.
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 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.
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.
Determining a target volume during irradiation of the esophagus is based on several specifics:
For these reasons, the target volume in radical radiotherapy should include:
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|
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.
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.
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:
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%)|
|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|
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.
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.
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
Anal tumors are treated with irradiation of 2 volumes using the SIB technique (simultaneous integrated boost) at 2 dose levels:
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:
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)|
|Bulb of penis||Dmean||22.92||44.39|
*A significant portion is included in PTV
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).
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:
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.
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.
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.
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).
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)
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).
The expected effect of proton therapy is relevant to the references from the literature and availability of radiotherapy in the Czech Republic:
|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 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.
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).
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.
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.
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:
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)
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%)|
Comparative dosimetric studies of proton and photon radiotherapy of the pancreatic bed and the draining lymph areas show a clear advantage of protons
|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|
|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|
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.
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.
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.
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.
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.
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).
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 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,
(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%)|
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:
Results of treatment of meningioma:
The results of treatment with low-grade gliomas:
Results of treatment of chordoma and chondrosarcoma:
Results of treatment of other CNS carcinomas:
Proton therapy applied by following the PTC protocol offers:
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.
Scripps proton therapy center, San Diego – http://www.scripps.org/services/cancer-care__proton-therapy/conditions-treated__proton-therapy-for-lymphoma
University of Florida – http://www.floridaproton.org/cancers-treated/hodgkin-lymphoma
Astro, PTCOG, OR PTC
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.
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).
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.
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).
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 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:
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).
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).
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)
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.
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,
(c) DVH (dose-volume histogram)
Treatment protocols of proton therapy for lymphoma: