EDITORIAL
Is Proton-beam Therapy Better Than Intensity-modulated Radiation Therapy for Prostate Cancer? Arthur R. Kagan, MD,* Jekwon Yeh, MD,w and Robert J. Schulz, PhDz INTRODUCTION Proton-beam therapy (PBT) was first tried at the Lawrence Berkeley Laboratory in 1954, and subsequently as many as 100,000 patients may have been so treated. Then, as now, its rationale is based entirely upon its unique dose distributions, which permit efficacious tumor doses while delivering smaller doses to surrounding normal tissues than can be achieved with x-rays. These qualities would seem to favor PBT for the treatment of prostate cancer (CaP) by reducing gastrointestinal (GI) and gastrourinary (GU) toxicities and the probability of long-term secondary cancers. However, after 20 years of hospital-based experience, there is a dearth of clinical data to show that the 10-year cause-specific survivals or acute and chronic toxicities for patients who received PBT are in any way superior to those treated by intensity-modulated radiation therapy (IMRT).
TREATMENT DELIVERY When a pencil-shaped, monoenergetic beam of high-energy protons is incident upon a patient, the dose increases monotonically with depth, culminating at the so-called Bragg peak, the depth of which is determined by the beam’s incident energy. Cyclotrons, or some variants, are used to produce monoenergetic beams, for example, of 250 MeV. The first step in planning a treatment is to modulate the energy of the beam so that a succession of Bragg peaks span the distal and proximal depths of the tumor, thus producing what is referred to as a spread-out Bragg peak (SOBP). SOBPs are obtained by interposing a range-shifting, energy-absorbing filter into the primary proton beam. Next, to obtain clinically useful field-size fields, a scattering foil intercepts the energy-modulated pencil beam (it is this scattering foil that emits the neutrons discussed below). Because the range of protons in different tissues is inversely proportional to their densities, and also because tumors may have complex shapes, tissue-compensating filters are designed to make the dose distribution conform to the tumor volume. (Note that the introduction of a tissue-compensating filter will require a redesign of the range-shifting filter.) It is common practice when treating CaP with protons to use opposed lateral fields. Clearly, these fields include the femoral heads and portions of the pelvis. Therefore, patient-specific range-shifting filters, scattering foils, and tissue-compensating filters, for the right-lateral and left-lateral fields, must be designed and fabricated for each field and each patient. Computerized treatment planning for proton-beam therapy (PBT) is similar to that used for intensity-modulated radiation therapy (IMRT), both of which are extensions of 2D treatment planning utilizing CAT scans that began in the 1970s. For at least 50 years, radiographs verifying the positions of treatment fields have been standard practice for x-ray therapy (XRT). The more recent techniques of electronic portal imaging, image-guided therapy, and cone-beam CT improve upon our abilities to match dose distributions with planned treatment volumes, and these devices are often built into modern linear accelerators. Unlike x-rays, proton beams do not exit the patient. Therefore, in vivo confirmation that the beam is aimed at the prostate is not possible. Minor day-to-day angular variations may place the SOBP above or below the prostate. To complicate matters further, it is also not possible to confirm that the SOBP encompasses the prostate. Depending upon the design of the range-shifting and tissue-compensating filters, the SOBP could fall proximal to or distal to the prostate. To account for these kinds of dislocations as well as variations in patient setup or organ movements during the course of treatment, the radiation oncologist has but one option: enlarge the width and breadth of the SOBP, and thereby irradiate more of the rectum and bladder than is desirable. From the *Department of Radiation Oncology, Kaiser Permanente Los Angeles Medical Center, Los Angeles; wCancer Center of Irvine, Irvine, CA; and zDepartment of Therapeutic Radiology, Yale University, New Haven, CT. The authors declare no conflicts of interest. Reprints: Arthur R. Kagan, MD, Department of Radiation Oncology, Kaiser Permanente Los Angeles Medical Center, 4950 Sunset Blvd, Los Angeles, CA 90027. E-mail: [email protected]. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/3706-0525 DOI: 10.1097/COC.0000000000000048
American Journal of Clinical Oncology
Volume 37, Number 6, December 2014
www.amjclinicaloncology.com |
525
American Journal of Clinical Oncology
Editorial
SECONDARY CANCERS The issue of how many more SCs may occur in patients who receive XRT for CaP as compared with those who are treated by other means has undergone a rigorous evaluation by Berrington de Gonzalez et al1 who used SEER data for a 20year period starting from 1973. They found 5548 SCs in 76,363 patients (7.3%) who received XRT as compared with 8023 SCs in 123,800 patients (6.5%) who were treated by other means. After adjusting for patient demographics such as attained age, year of diagnosis, stage, etc., Berrington de Gonzalez reported a relative risk (RR) of 1.26 for developing an SC for those who had XRT compared with those who did not. However, questions arise about these demographic adjustments: have unrecognized critical issues been omitted, and would the use of raw data yield more realistic results? For example, using the raw data of Berrington de Gonzalez yields a considerably smaller RR of 1.12. There were 242,000 newly diagnosed cases of CaP in 2012, about 38% or 92,000 received XRT and 150,000 were treated by other means. Using the data of Berrington de Gonzalez, we should expect a total of 16,400 SCs to develop at some time in the next 20 years, 8700 in the XRT group and 7700 in those treated by other means. Clearly, not all of the 8700 SCs in the XRT group would be caused by x-rays. Indeed, based upon RRs of 1.12 or 1.26, somewhere between 1044 or 2262 SCs can be so attributed. The question now arises as to whether, and to what extent, the currently projected 1000 to 2000 SCs attributed to XRT given in the last year could have been reduced if XRT had been replaced by PBT. At present, this question has no answer. Clearly, the integral dose that results from PBT for CaP is lower than that from IMRT. However, as suggested by Gray2—that lower doses may cause more mutations than higher doses that kill—and by Hall3—that the neutron contamination in passively scattered proton beams may override the leakage and scatter of x-rays from IMRT, it is conceivable that, as currently employed, PBT could result in more SCs than IMRT. As pointed out by Muller et al,4 “Only very large prospective studies which are designed to minimize the influence of possible confounders will be able to address the real risk of prostate irradiation-related cancer induction. The available data are clearly not valid nor helpful for guiding any treatment decision.”
Volume 37, Number 6, December 2014
patient-reported outcomes. Because of the absence of direct patient experience or radiation doses in the SEER data, or small numbers of patient-reported outcomes, the results of each of these studies have significant uncertainties. However, taken as a group, they show no differences between PBT and IMRT but a disadvantage of 3D-CRT compared with these other modalities. The reasons for these similar results may be that patients are malleable, and that the highly consistent, day-to-day positioning required by the precisely defined dose distributions of PBT is not routinely achievable in clinical practice.
CONCLUSIONS The dose distributions of PBT are about as good as it gets. The integral dose from PBT will in most cases be considerably smaller than that from IMRT. However, because of the complexities of PBT treatment planning and delivery, and the absence of any means to verify that the SOBP conforms to the tumor in vivo, the cardinal sin of RT, the geographic miss, may be committed more often than realized. RCTs for tumor-cure probability and secondary cancers present unique problems in terms of follow-up duration. As 10year cause-specific survival is now routinely used to report treatment results for CaP, an RCT comparing PBT with IMRT would have to run at least that long before yielding meaningful results. For SCs, even longer follow-up times would be required, and their very low incidence would require the accrual of very large numbers of patients to achieve statistical significance. Thus, the odds for completing RCTs for either of these endpoints are low, and the results are likely to be of little benefit as newer treatments for CaP over the next 10 to 20 years may overtake both IMRT and PBT. Cutting through the “spin” that has been developed around PBT, what we have is another in a series of ionizing radiations that have been used to treat cancer. Each of these (heavy ions, neutrons, negative pi mesons) have unique dose distributions and/or biological properties; however, none has exceeded x-rays in terms of efficacy, versatility, or cost. With its high operating and capital costs, it would seem reasonable for PBT to be reserved for disease sites such as pediatric malignancies, chondrosarcomas, skull-base tumors, etc., where its unique dose distributions may offer higher probabilities of favorable outcomes compared with XRT. However, current clinical data do not support the notion that the prostate is one of these sites.
CLINICAL TRIALS
REFERENCES
There have been 2 randomized clinical trials (RCTs) for CaP that included PBT; however, both were in conjunction with photon (x-ray) radiation. In both trials, patients had photon radiation to the prostate up to 50.4 Gy. In the PROG 9509 study by Zietman et al,5 patients received proton boosts of either 19.6 or 28.8 Gy before the photon radiation, whereas in the study by Shipley et al6 patients initially received photon radiation up to 50.4 Gy, and then were randomized to either a proton boost of 25.5 Gy or additional photons of 16.8 Gy. Both studies were designed to test the efficacy of dose escalation with protons, and not to compare single-modality PBT with photon therapy. There is currently an RCT underway7 to compare the levels of GI and GU toxicities caused by PBT versus IMRT. Patients are limited to those with low and low-to-intermediate-grade disease; results are expected in a few years. Short of RCTs, there are several retrospective studies8–11 comparing GI and GU toxicities following 3-dimensional conformal (3D-CRT), IMRT, and PBT for prostate cancer. Three of these studies used SEER (billing) data, and the fourth used
1. Berrington de Gonzalez A, Curtis RE, Kry SF, et al. Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries. Lancet Oncol. 2011;12:353–360. 2. Gray LH. A Symposium Considering Radiation Effects in the Cell and Possible Implications for Cancer Therapy, a Collection of Papers. Cellular Radiation Biology. Baltimore: Williams & Wilkins; 1965:8–25. 3. Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Bio Phys. 2006;65:1–7. 4. Muller A, Ganswindt U, Bamberg M, et al. Risk of second malignancies after prostate irradiation? Strahlenther Onkol. 2007;183:605–609. 5. Zietman AL, Bae K, Slater JD, et al. 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;28:1106–1111. 6. Shipley WU, Verhey LJ, Munzenrider JE, et al. 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.
526 | www.amjclinicaloncology.com
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2014 Lippincott Williams & Wilkins
American Journal of Clinical Oncology
Volume 37, Number 6, December 2014
7. Jason Efstathiou, Principal Investigator, Massachusetts General Hospital. “Proton therapy vs. IMRT for low or low-intermediate risk prostate cancer.” Available at: http://clinicaltrials.gov/ct2/ show/NCT01617161. Accessed October 1, 2013. 8. Kim S, Shen S, Moore DF, et al. Late gastrointestinal toxicities following radiation therapy for prostate cancer. Eur Urol. 2011;60:908–916. 9. Sheets N, Goldin G, Meyer A, et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and
r
2014 Lippincott Williams & Wilkins
Editorial
morbidity and disease control in localized prostate cancer. JAMA. 2012;307:1611–1620. 10. Yu JB, Soulos PR, Herrin J, et al. Proton versus intensitymodulated radiotherapy for prostate cancer: patterns of care and early toxicity. J Natl Cancer Inst. 2013;105:25–32. 11. Gray PJ, Paly JJ, Yeap BY, et al. Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. Cancer. 2013; 119:1729–1735. Doi:10.1002/cncr.27956.
www.amjclinicaloncology.com |
527
Is Proton-beam Therapy Better Than Intensity-modulated Radiation Therapy for Prostate Cancer? Arthur R. Kagan, MD,* Jekwon Yeh, MD,w and Robert J. Schulz, PhDz INTRODUCTION Proton-beam therapy (PBT) was first tried at the Lawrence Berkeley Laboratory in 1954, and subsequently as many as 100,000 patients may have been so treated. Then, as now, its rationale is based entirely upon its unique dose distributions, which permit efficacious tumor doses while delivering smaller doses to surrounding normal tissues than can be achieved with x-rays. These qualities would seem to favor PBT for the treatment of prostate cancer (CaP) by reducing gastrointestinal (GI) and gastrourinary (GU) toxicities and the probability of long-term secondary cancers. However, after 20 years of hospital-based experience, there is a dearth of clinical data to show that the 10-year cause-specific survivals or acute and chronic toxicities for patients who received PBT are in any way superior to those treated by intensity-modulated radiation therapy (IMRT).
TREATMENT DELIVERY When a pencil-shaped, monoenergetic beam of high-energy protons is incident upon a patient, the dose increases monotonically with depth, culminating at the so-called Bragg peak, the depth of which is determined by the beam’s incident energy. Cyclotrons, or some variants, are used to produce monoenergetic beams, for example, of 250 MeV. The first step in planning a treatment is to modulate the energy of the beam so that a succession of Bragg peaks span the distal and proximal depths of the tumor, thus producing what is referred to as a spread-out Bragg peak (SOBP). SOBPs are obtained by interposing a range-shifting, energy-absorbing filter into the primary proton beam. Next, to obtain clinically useful field-size fields, a scattering foil intercepts the energy-modulated pencil beam (it is this scattering foil that emits the neutrons discussed below). Because the range of protons in different tissues is inversely proportional to their densities, and also because tumors may have complex shapes, tissue-compensating filters are designed to make the dose distribution conform to the tumor volume. (Note that the introduction of a tissue-compensating filter will require a redesign of the range-shifting filter.) It is common practice when treating CaP with protons to use opposed lateral fields. Clearly, these fields include the femoral heads and portions of the pelvis. Therefore, patient-specific range-shifting filters, scattering foils, and tissue-compensating filters, for the right-lateral and left-lateral fields, must be designed and fabricated for each field and each patient. Computerized treatment planning for proton-beam therapy (PBT) is similar to that used for intensity-modulated radiation therapy (IMRT), both of which are extensions of 2D treatment planning utilizing CAT scans that began in the 1970s. For at least 50 years, radiographs verifying the positions of treatment fields have been standard practice for x-ray therapy (XRT). The more recent techniques of electronic portal imaging, image-guided therapy, and cone-beam CT improve upon our abilities to match dose distributions with planned treatment volumes, and these devices are often built into modern linear accelerators. Unlike x-rays, proton beams do not exit the patient. Therefore, in vivo confirmation that the beam is aimed at the prostate is not possible. Minor day-to-day angular variations may place the SOBP above or below the prostate. To complicate matters further, it is also not possible to confirm that the SOBP encompasses the prostate. Depending upon the design of the range-shifting and tissue-compensating filters, the SOBP could fall proximal to or distal to the prostate. To account for these kinds of dislocations as well as variations in patient setup or organ movements during the course of treatment, the radiation oncologist has but one option: enlarge the width and breadth of the SOBP, and thereby irradiate more of the rectum and bladder than is desirable. From the *Department of Radiation Oncology, Kaiser Permanente Los Angeles Medical Center, Los Angeles; wCancer Center of Irvine, Irvine, CA; and zDepartment of Therapeutic Radiology, Yale University, New Haven, CT. The authors declare no conflicts of interest. Reprints: Arthur R. Kagan, MD, Department of Radiation Oncology, Kaiser Permanente Los Angeles Medical Center, 4950 Sunset Blvd, Los Angeles, CA 90027. E-mail: [email protected]. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/3706-0525 DOI: 10.1097/COC.0000000000000048
American Journal of Clinical Oncology
Volume 37, Number 6, December 2014
www.amjclinicaloncology.com |
525
American Journal of Clinical Oncology
Editorial
SECONDARY CANCERS The issue of how many more SCs may occur in patients who receive XRT for CaP as compared with those who are treated by other means has undergone a rigorous evaluation by Berrington de Gonzalez et al1 who used SEER data for a 20year period starting from 1973. They found 5548 SCs in 76,363 patients (7.3%) who received XRT as compared with 8023 SCs in 123,800 patients (6.5%) who were treated by other means. After adjusting for patient demographics such as attained age, year of diagnosis, stage, etc., Berrington de Gonzalez reported a relative risk (RR) of 1.26 for developing an SC for those who had XRT compared with those who did not. However, questions arise about these demographic adjustments: have unrecognized critical issues been omitted, and would the use of raw data yield more realistic results? For example, using the raw data of Berrington de Gonzalez yields a considerably smaller RR of 1.12. There were 242,000 newly diagnosed cases of CaP in 2012, about 38% or 92,000 received XRT and 150,000 were treated by other means. Using the data of Berrington de Gonzalez, we should expect a total of 16,400 SCs to develop at some time in the next 20 years, 8700 in the XRT group and 7700 in those treated by other means. Clearly, not all of the 8700 SCs in the XRT group would be caused by x-rays. Indeed, based upon RRs of 1.12 or 1.26, somewhere between 1044 or 2262 SCs can be so attributed. The question now arises as to whether, and to what extent, the currently projected 1000 to 2000 SCs attributed to XRT given in the last year could have been reduced if XRT had been replaced by PBT. At present, this question has no answer. Clearly, the integral dose that results from PBT for CaP is lower than that from IMRT. However, as suggested by Gray2—that lower doses may cause more mutations than higher doses that kill—and by Hall3—that the neutron contamination in passively scattered proton beams may override the leakage and scatter of x-rays from IMRT, it is conceivable that, as currently employed, PBT could result in more SCs than IMRT. As pointed out by Muller et al,4 “Only very large prospective studies which are designed to minimize the influence of possible confounders will be able to address the real risk of prostate irradiation-related cancer induction. The available data are clearly not valid nor helpful for guiding any treatment decision.”
Volume 37, Number 6, December 2014
patient-reported outcomes. Because of the absence of direct patient experience or radiation doses in the SEER data, or small numbers of patient-reported outcomes, the results of each of these studies have significant uncertainties. However, taken as a group, they show no differences between PBT and IMRT but a disadvantage of 3D-CRT compared with these other modalities. The reasons for these similar results may be that patients are malleable, and that the highly consistent, day-to-day positioning required by the precisely defined dose distributions of PBT is not routinely achievable in clinical practice.
CONCLUSIONS The dose distributions of PBT are about as good as it gets. The integral dose from PBT will in most cases be considerably smaller than that from IMRT. However, because of the complexities of PBT treatment planning and delivery, and the absence of any means to verify that the SOBP conforms to the tumor in vivo, the cardinal sin of RT, the geographic miss, may be committed more often than realized. RCTs for tumor-cure probability and secondary cancers present unique problems in terms of follow-up duration. As 10year cause-specific survival is now routinely used to report treatment results for CaP, an RCT comparing PBT with IMRT would have to run at least that long before yielding meaningful results. For SCs, even longer follow-up times would be required, and their very low incidence would require the accrual of very large numbers of patients to achieve statistical significance. Thus, the odds for completing RCTs for either of these endpoints are low, and the results are likely to be of little benefit as newer treatments for CaP over the next 10 to 20 years may overtake both IMRT and PBT. Cutting through the “spin” that has been developed around PBT, what we have is another in a series of ionizing radiations that have been used to treat cancer. Each of these (heavy ions, neutrons, negative pi mesons) have unique dose distributions and/or biological properties; however, none has exceeded x-rays in terms of efficacy, versatility, or cost. With its high operating and capital costs, it would seem reasonable for PBT to be reserved for disease sites such as pediatric malignancies, chondrosarcomas, skull-base tumors, etc., where its unique dose distributions may offer higher probabilities of favorable outcomes compared with XRT. However, current clinical data do not support the notion that the prostate is one of these sites.
CLINICAL TRIALS
REFERENCES
There have been 2 randomized clinical trials (RCTs) for CaP that included PBT; however, both were in conjunction with photon (x-ray) radiation. In both trials, patients had photon radiation to the prostate up to 50.4 Gy. In the PROG 9509 study by Zietman et al,5 patients received proton boosts of either 19.6 or 28.8 Gy before the photon radiation, whereas in the study by Shipley et al6 patients initially received photon radiation up to 50.4 Gy, and then were randomized to either a proton boost of 25.5 Gy or additional photons of 16.8 Gy. Both studies were designed to test the efficacy of dose escalation with protons, and not to compare single-modality PBT with photon therapy. There is currently an RCT underway7 to compare the levels of GI and GU toxicities caused by PBT versus IMRT. Patients are limited to those with low and low-to-intermediate-grade disease; results are expected in a few years. Short of RCTs, there are several retrospective studies8–11 comparing GI and GU toxicities following 3-dimensional conformal (3D-CRT), IMRT, and PBT for prostate cancer. Three of these studies used SEER (billing) data, and the fourth used
1. Berrington de Gonzalez A, Curtis RE, Kry SF, et al. Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries. Lancet Oncol. 2011;12:353–360. 2. Gray LH. A Symposium Considering Radiation Effects in the Cell and Possible Implications for Cancer Therapy, a Collection of Papers. Cellular Radiation Biology. Baltimore: Williams & Wilkins; 1965:8–25. 3. Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Bio Phys. 2006;65:1–7. 4. Muller A, Ganswindt U, Bamberg M, et al. Risk of second malignancies after prostate irradiation? Strahlenther Onkol. 2007;183:605–609. 5. Zietman AL, Bae K, Slater JD, et al. 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;28:1106–1111. 6. Shipley WU, Verhey LJ, Munzenrider JE, et al. 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.
526 | www.amjclinicaloncology.com
r
2014 Lippincott Williams & Wilkins
American Journal of Clinical Oncology
Volume 37, Number 6, December 2014
7. Jason Efstathiou, Principal Investigator, Massachusetts General Hospital. “Proton therapy vs. IMRT for low or low-intermediate risk prostate cancer.” Available at: http://clinicaltrials.gov/ct2/ show/NCT01617161. Accessed October 1, 2013. 8. Kim S, Shen S, Moore DF, et al. Late gastrointestinal toxicities following radiation therapy for prostate cancer. Eur Urol. 2011;60:908–916. 9. Sheets N, Goldin G, Meyer A, et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and
r
2014 Lippincott Williams & Wilkins
Editorial
morbidity and disease control in localized prostate cancer. JAMA. 2012;307:1611–1620. 10. Yu JB, Soulos PR, Herrin J, et al. Proton versus intensitymodulated radiotherapy for prostate cancer: patterns of care and early toxicity. J Natl Cancer Inst. 2013;105:25–32. 11. Gray PJ, Paly JJ, Yeap BY, et al. Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. Cancer. 2013; 119:1729–1735. Doi:10.1002/cncr.27956.
www.amjclinicaloncology.com |
527
