Latest proton therapy study shows hypofractionated proton therapy as safe and effective for patients with low-risk prostate cancer

A study published in August 2019 in the International Journal of Particle Therapy by Dr. Slater and his team, highlights the results of their latest phase I/II hypofractionated proton therapy study at Loma Linda University Hospital.

Prostate cancer is the most commonly diagnosed cancer in men, and many of these patients have low-risk, early disease. Prostate cancer at these stages remains highly treatable with local control rates over 90% and very low rates of late morbidity commonly reported for a variety of treatment modalities. The focus then turns to the avoidance of unnecessary negative treatment-related side effects that can occur, particularly through the use of conventional treatments such as surgery and x-ray (conventional) radiotherapy.

Proton radiation therapy has demonstrated itself to be an excellent option for low-risk prostate cancer as it delivers high control rates with very little toxicity. Proton beam thereby enhances the physician’s opportunity to minimise risks for the patient.

Hypofractionation is the process of delivering higher doses of radiation per fraction, but using fewer daily fractions. Doctors and physicists at Loma Linda University have successfully used hypofractionated proton therapy for several diseases, including cancers of the breast, lung, and liver. In each instance, control and survival rates have been maintained and unwelcome side effects have not increased. This experience prompted the medical team at Loma Linda to investigate hypofractionation for prostate cancer.

The purpose of the study was to determine whether a hypofractionated proton radiotherapy regimen can control early-stage prostate cancer while maintaining low rates of side effects similar to results obtained using standard-fraction proton radiotherapy.

A cohort of 146 patients with low-risk prostate cancer (Gleason score 7, prostate-specific antigen 10, tumor stage of T1–T2a) received 20 fractions of proton therapy (3.0 Gy per fraction over 4 weeks). Patients were evaluated at least weekly during treatment, at which time documentation of treatment tolerance and acute reactions was obtained. Follow-up visits were conducted every 3 months for the first 1 years, every 6 months for the next 3 years, then annually. Follow-up visits consisted of history and physical examination, PSA measurements, and evaluation of toxicity.

The 3-year biochemical progression-free survival rate was 99.3%, and the 5-year biochemical progression-free survival was 97.9%.

In conclusion, this study showed that hypofractionated proton therapy (60 Gy in 20 fractions) was safe and effective for patients with low-risk prostate cancer. A prospective multi-institutional randomised study is currently being conducted to confirm these results.

Sources:

Kil WJ, Nichols RC Jr, Hoppe BS, Morris CG, Marcus RB Jr, Mendenhall W, Mendenhall NP, Li Z, Costa JA, Williams CR, Henderson RH. Hypofractionated passively scattered proton radiotherapy for low- and intermediate-risk prostate cancer is not associated with post-treatment testosterone suppression. Acta Oncol. 2013;52:492–7

Mendenhall NP, Hoppe BS, Nichols RC, Mendenhall WM, Morris CG, Li Z, Su Z, Williams CR, Costa J, Henderson RH. Five-year outcomes from 3 prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2014;88:596–602

Mendenhall NP, Li Z, Hoppe BS, Marcus RB Jr, Mendenhall WM, Nichols RC, Morris CG, Williams CR, Costa J, Henderson R. Early outcomes from three prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82:213–21

Shipley WU, Verhey LJ, Munzenrider JE, Suit HD, Urie MM, McManus PL, Young RH, Shipley JW, Zietman AL, Biggs PJ, Heney NM, Goitein M. Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys. 1995;32:3–12

Slater JD, Rossi CJ Jr, Yonemoto LT, Bush DA, Jabola BR, Levy RP, Grove RI, Preston W, Slater JM. Proton therapy for prostate cancer: the initial Loma Linda University experience. Int J Radiat Oncol Biol Phys. 2004;59:348–52

Slater JD, Rossi CJ Jr, Yonemoto LT, Reyes-Molyneux NJ, Bush DA, Antoine JE, Miller DW, Teichman SL, Slater JM. Conformal proton therapy for early-stage prostate cancer. Urology. 1999;53:978–84

Slater JD, Yonemoto LT, Rossi CJ Jr, Reyes-Molyneux NJ, Bush DA, Antoine JE, Loredo LN, Schulte RW, Teichman SL, Slater JM. Conformal proton therapy for prostate carcinoma. Int J Radiat Oncol Biol Phys. 1998;42:299–304

Slater JM, Slater JD, Kang JI, et al. Hypofractionated Proton Therapy in Early Prostate Cancer: Results of a Phase I/II Trial at Loma Linda University. Int J Part Ther. 2019;6(1):1–9. doi:10.14338/IJPT-19-00057

Zietman AL, Bae K, Slater JD, Shipley WU, Efstathiou JA, Coen JJ, Bush DA, Lunt M, Spiegel DY, Skowronski R, Jabola BR, Rossi CJ. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09. J Clin Oncol. 2010;28:1106–11

Proton Therapy for Central Nervous System Leukaemia

The guidelines issued by the International Lymphoma Radiation Oncology Group (ILROG) open up new opportunities for the use of proton radiotherapy in leukaemia.

ILROG’s recommendations newly apply also to patients with initial involvement of CNS (positive finding in the cerebrospinal fluid) or patients with a relapsed disease related to CNS who are planned for allogeneic transplantation or have CNS involvement and do not respond to chemotherapy or biological treatment. If patients diagnosed with leukaemia have infiltration of their central nervous system (CNS) or extramedullary involvement (myelosarcoma) and their attending hematologist-oncologist recommends radiotherapy, proton therapy is a suitable choice. This is confirmed both by the newly updated recommendations of the international expert group ILROG, and dosimetric comparisons of the existing forms of available radiotherapy.

In such cases, proton radiotherapy has substantial benefits when compared with other forms of radiotherapy. These include no radiation strain on organs in front of vertebral bodies and minimal systemic toxicity (reduced occurrence of nausea, vomiting, diarrhoea). Proton radiotherapy is suitable for highly pre-treated patients (patients after a few rounds of chemotherapy) with necessary reduction of the dose to which the lungs, intestinal villi, heart and other organs are exposed.

Interview with Dr Kateřina Dědečková on the possibilities of treatment of hematologic diseases with proton radiotherapy

According to the latest recommendations of the International Lymphoma Radiation Oncology Group (ILROG), radiotherapy is also suitable for some patients diagnosed with leukaemia. Which patients specifically?

ILROG is very active in raising awareness on the benefits of radiation in the treatment of hematological malignancies, i.e. blood tumours. Over the past few years, ILROG has issued recommendations for the use of radiation in most haematologic cancers such as lymphomas, leukemias, myelosarcomas, myelomas, and others. For leukemias, in particular patients with central nervous system (CNS) involvement, it is now recommended to use radiation more frequently and to a greater extent.

Why is it now advisable to irradiate the central nervous system (CNS) also in patients with leukaemia?

The CNS (i.e. brain and spinal cord) is separated from the bloodstream by a safety barrier, called blood–brain barrier (BBB), which prevents materials from the blood from entering the brain. Thus, some molecules, including drugs, reach the CNS with limited or no effect. For this reason, in some cases, the CNS may be a source of disease recurrence because part of the cells escape the effects of chemotherapy or biological therapy, leading to a re-spread of cancer cells in the body.

What benefits do patients have from using proton radiotherapy?

Due to the limited possibilities of systemic treatment, irradiation of the entire CNS area is advantageous. This consists of the irradiation of the brain, spinal cord, spaces where cerebrospinal fluid circulates, and craniospinal axis. The aim is also to get to the hard-to-reach leukaemia cells, as well as those that are no longer sensitive to chemotherapy or biological therapy.

Patients who benefit the most from proton radiotherapy are the ones who, despite intensive systemic treatment, have a positive finding of leukemic cells in the cerebrospinal fluid, a positive cerebrospinal fluid at the time of diagnosis, or leukemic lesions in the brain or spinal cord. Also, patients who are at risk of involvement of the central nervous system future.

Therefore, according to the new recommendations, these patients should preferably be irradiated in the whole area of ​​the craniospinal axis.

Is radiotherapy commonly indicated in these patients or is it a new recommendation?

Previously, because of the high toxicity, it was preferable to irradiate only the skull area. However, thanks to the use of proton radiotherapy instead of classical radiation, it is possible to reduce the adverse effects of treatment that previously impaired quality of life, such as nausea, vomiting, fatigue, swallowing pain, and aphthae in the oral cavity. Therefore, radiotherapy has not been commonly used in these patients and, if so, less extensive exposure has been used, mainly because of concerns about toxicity associated with older exposure techniques, as I have mentioned. Irradiation of the CNS as a risk area has been found to improve the outlook for cure in risk patients. According to the new ILROG recommendation, groups of patients have already been identified who will benefit from the inclusion of craniospinal axis irradiation in their treatment plan.

How does the treatment work?

The patient is placed in supine position with their arms along the body, while the head is fixed with a special thermoplastic mask. A CT scan is done over the entire irradiation range, i.e. the entire head and spine to the coccyx. These CT images then show the areas that are the target of radiation and also the areas that we want to protect from radiation, called organs at risk (OAR). Then, the doctors and physicists collaborate to carefully calculate the irradiation plan. This plan is then checked multiple times, as well as directly in the gantry to confirm its accuracy. Then, the actual treatment begins. Leukaemia is typically treated in 9 to 12 sessions (fractions), applied to the entire craniospinal axis. In some patients, we also irradiate the riskiest areas, such as apparent tumor lesions, up to a total of 15-18 fractions. Irradiation takes place every weekday and may be associated with mild swallowing difficulties, fatigue and a decrease in the number of blood cells.

Is there a difference if a patient is irradiated with photon or proton techniques?

Yes, the difference is that when using proton radiotherapy, the patient is less exposed to radiation. There is less irradiation to the organs in front of the tumor, minimal irradiation to lungs, heart, oesophagus, intestinal loops, kidneys, liver, and bladder, which significantly reduces the possibility of late toxicity of these organs. The patient also better tolerates irradiation of the craniospinal axis.

Do you have any recent experience with this form of treatment? If so, how did the patients tolerate the treatment?

At the Proton Therapy Center in Prague we already have experience with this irradiation technique for hematological malignancies, although there has been a relatively small number of patients (around 10 so far). Our experience so far has so far been very positive, both in terms of toxicity and preliminary treatment outcomes. In some of these patients, radiotherapy was the last treatment option and even here we managed to successfully destroy CNS tumor cells. From our point of view this is a very promising method of treatment, but a longer follow-up of patients and evaluation of a larger group of patients will be required.

Dr Kateřina Dědečková

In 1998-2001 Dr Dědečková worked at the radiotherapy department of the District Hospital in Jičín. Then, from 2001 to 20017, she worked at the Institute of Radiation Oncology of the University Hospital Na Bulovce. In 2009 Dr Dědečková gained specialised competence in the field of radiation oncology. Since 2012, she has been working as a radiation oncologist at the Proton Therapy Center in Prague. Since 2019, Dr Dědečková also leads the interdisciplinary Center of Excellence for Proton Radiotherapy of Malignant Lymphomas at the Proton Center in Prague.

Dr Dědečková specialises in radiation treatment of malignant lymphomas and other hematological tumours, urological tumours and head and neck tumours. She has participated in international clinical trials with independent quality control of radiotherapy (GHSG, ESTRO Equal, QARC) in the treatment of malignant lymphomas and head and neck tumours. Dr Dědečková is a member of the Council of the International Lymphoma Radiation Oncology Group (ILROG) and a member of the Lymphoma Sub-Committee of the Particle Therapy Co-Operative Group (PTCOG). Dr Dědečková publishes professional medical press and lectures at congresses, both domestically and internationally. Dr Dědečková is co-author of the “Diagnostic and Treatment Guidelines in Patients with Malignant Lymphoma” of the Lymphoma Cooperative Group (chapter on lymphoma radiotherapy). Dr Dědečková deals with new techniques of lymphoma radiotherapy, such as proton radiotherapy of mediastinal lymphomas using the pencil beam scanning technique in maximum inhalation.