The History of Proton Therapy in Prostate Cancer
Proton therapy as a conformal boost after conventional radiation therapy
Prior to 3D imaging and 3DCRT, radiation doses for prostate cancer were limited to 70 Gy or less because of the morbidity associated with high integral doses to large volumes of the bladder and rectum.[17-19] During this era, surgery was the preferred treatment for prostate cancer because of relatively high probabilities of tumor recurrence with radiation as well as high morbidity rates.[18,20] PT was available only in physics research centers, which provided a beam of protons emanating from a fixed beam line, generally of limited energies insufficient for penetration to deep-seated tumors. The initial studies of PT in prostate cancer came from Massachusetts General Hospital and used a 160-MeV proton beam from the Harvard cyclotron. In their first published study, Shipley et al reported on 17 patients treated with conventional megavoltage X-rays to between 48 and 50 Gy followed by a proton boost applied through a perineal field to a final dose of 70 to 76.5 Gy/CGE. Although one patient relapsed 18 months after therapy, the remaining patients did well. A follow-up study by the Massachusetts General Hospital group compared two cohorts of patients: one treated with megavoltage X-rays alone to 67 Gy and the other treated with 50 Gy of XRT followed by a proton boost of 20 to 26.5 CGE. Despite higher doses in the PT cohort, no significant difference was found regarding GU or GI toxicity between the two groups. Following the phase I/II study, Massachusetts General Hospital conducted the first phase III PT study randomly assigning patients with stage T3-4 prostate cancer to treatment with either high-dose radiation with 75.6 CGE (via 50.4 Gy X-rays and 25.2-CGE proton boost; n = 103) or with 67.2 Gy X-rays (n = 99). After a median follow-up of 5 years, no significant differences were found in overall survival or disease-specific survival. However, patients with poorly differentiated prostate cancer (Gleason score ≥ 7) had better local control (LC) with high-dose radiotherapy (5-year LC, 94% vs 64%; P = .0014). Also, there was a trend toward improved LC with high-dose radiation for the cohort as a whole (5-year LC, 92% vs 80%; P = .089), and GU and GI toxicity were not significantly different.
Proton therapy as sole treatment for prostate cancer
In 1991, Loma Linda University Medical Center opened the first clinically dedicated PT facility with higher-energy (250-MeV) protons and a gantry system similar to those available for conventional XRT, thereby permitting PT delivery to deep-seated tumors and from any angle. Loma Linda University conducted a phase I/II study using a higher-energy proton beam that allowed the delivery of PT via lateral fields through the hip, instead of the perineal approach used at Massachusetts General Hospital (Figure 3). The study included 104 patients treated with 45 Gy of X-rays and a 30-CGE boost with PT. With a median follow-up of 20 months, no grade 3 or 4 morbidity was observed and only 12% of patients had a grade 1 or 2 late morbidity (8% rectal and 4% urinary). Two-year local disease control rates were encouraging, with only 2.8% developing progression. In a follow-up report on 319 patients (median follow-up, 43 months) who were treated with PT to 74 to 75 CGE either as a boost following conventional radiation therapy (n = 93) or as sole treatment (n = 226), the 5-year biochemical failure–free survival (BFFS) in the entire cohort was 88%, with no Radiation Therapy Oncology Group (RTOG) grade 3 or 4 GU or GI toxicities. Importantly, this was the first study to report long-term outcomes of patients who were treated solely with PT. In the most recent update of the Loma Linda University experience, Slater et al reported on 1,255 patients (median follow-up, 63 months) who were treated either with protons alone (n = 524) or with a proton boost (n = 731) to total doses of 74 to 75 CGE; 5-year BFFS was 75%, and the rate of late grade 3+ GU or GI toxicities was < 1%.
Proton therapy as a means for dose escalation: Proton Radiation Oncology Group trial 95-09
Considering the promising data emerging from Massachusetts General Hospital and Loma Linda University, a collaboration called Proton Radiation Oncology Group (PROG) developed between the two institutions, supported by the American College of Radiology (ACR). The first trial, PROG 95-05, conducted from 1996 to 1999, randomly assigned 393 men with T1b-2b prostate cancer and a prostate-specific antigen (PSA) level < 15 ng/mL to receive treatment with either low-dose (70.2 Gy/CGE) or high-dose (79.2 Gy/CGE) radiation. The radiation was comprised of a proton “boost” with either 19.8 CGE or 28.8 CGE via opposed lateral 250-mV proton beams at Loma Linda University or via a single en-face 160-mV proton beam through the perineum at Massachusetts General Hospital, followed by 50.4 Gy with 3DCRT. The goal of the study was not to compare protons with X-rays, but to determine whether dose escalation with PT would improve outcomes. In the first outcome report, which had a median follow-up of 5.5 years, Zietman et al reported a statistically significant improvement in 5-year BFFS in the high-dose arm of 80.4% compared with 61.4% in the low-dose arm. Although the study appeared to be positive, demonstrating the feasibility of dose escalation with PT and improved disease control with dose escalation, critics of the study pointed out that both treatment arms did rather poorly compared with other contemporary studies of radiation therapy in prostate cancer. On re-evaluation of the data, Zietman et al identified a considerable statistical error in the initial report. The updated outcomes demonstrated a 5-year BFFS of 91.3% with high-dose therapy compared with 78.8% for low-dose therapy (P < .001), which translated to a 59% reduction in the risk of failure. These BFFS rates were much higher than in the initial evaluation, and similar to those in other published studies. In the most recent update, the group reported 10-year BFFS rates of 83.3% and 67.6% for high-dose and low-dose radiotherapy, respectively. The BFFS in patients with low-risk disease was 93% at 10 years. Importantly, the study demonstrated extremely low rates of grade > 3 GU (2%) and GI (1%) toxicity, even in the high-dose arm.
Contemporary Proton Therapy for Prostate Cancer
Over the last decade, more proton centers have been built in the United States and abroad. PT for prostate cancer has been investigated at these newer centers using treatment guidelines similar to those used at Loma Linda University, with PT for the entire course of treatment to maximize the dosimetric benefit of PT over X-ray radiation.
The University of Florida Proton Therapy Institute recently reported the early outcomes of 211 patients enrolled in one of three treatment protocols, including a low-risk protocol delivering 78 CGE at 2 CGE per fraction, an intermediate-risk protocol of dose escalation from 78 CGE to 82 CGE at 2 CGE per fraction, and a high-risk protocol of 78 CGE at 2 CGE per fraction with concomitant docetaxel(Drug information on docetaxel) (Taxotere) followed by androgen deprivation therapy. With a minimum follow-up of 2 years, the grade > 3 GU toxicity rate was 1.9% and the grade > 3 GI toxicity rate was < 0.5%. Two studies out of Japan have also published early outcomes for PT for prostate cancer. Mayahara et al reported on 287 patients treated to 74 CGE with 190- to 230-MeV protons using opposed lateral fields; the rate of grade > 3 GU toxicity in this study was 1%, and the rate of grade > 3 GI toxicity was 0%. Nihei et al reported on a multi-institutional phase II study from Japan in which 74 CGE was delivered in 37 fractions in 151 patients. With a median follow-up of 43 months, only 1% of patients developed grade > 3 GU toxicity, and 0% developed late grade > 3 GI toxicity. These studies, which are reported in the Table, confirm the safety of PT for prostate cancer over the first 4 years following treatment; however, longer follow-up is needed to confirm the low rate of late toxicity and long-term efficacy of the treatment (and the high rate of BFFS). Interestingly, Massachusetts General Hospital and Loma Linda University have reported a smaller series of patients treated with PT alone to 82 CGE, with a slightly higher rate of toxicity than observed in the University of Florida Proton Therapy Institute series with the same dose and dose per fraction.
Cost-Effectiveness of Proton Therapy
Although the benefits to patients of reduced radiation-dose exposure with PT are quite obvious, concerns still exist regarding whether these dosimetric benefits are cost-effective. In a study by Konski et al, the cost-effectiveness of PT was compared to that of IMRT with the assumption that PT could deliver a 10-Gy higher dose than IMRT, resulting in a 10% improvement in 5-year BFFS compared with IMRT. However, despite the improvement in BFFS, the resulting cost of PT for a 60-year-old man was $65,000, compared with $40,000 for IMRT, which would result in a cost-effectiveness of $56,000 per quality-adjusted life year (QALY). When compared to the commonly accepted standard of $50,000 per QALY, the value for PT indicated that it was not cost-effective. Although this study reaches some intriguing conclusions, the results are based on models and do not take into consideration a number of critical factors. First, Peeters et al have predicted that PT may allow for hypofractionation, which would reduce the treatment costs of this therapy. Studies currently investigating hypofractionation with PT are ongoing at both Loma Linda University and the University of Florida Proton Therapy Institute. Second, a reduction in significant rectal and urinary toxicity afforded by PT will have a positive impact on overall costs of care in prostate cancer patients. Finally, the dose escalation and dose intensification via hypofractionation permitted by PT may result in increased cure rates, particularly in intermediate- and high-risk prostate cancer patients, which may also translate into reduced costs of care.
A Randomized Study Comparing Photons and Protons?
There has already been a great deal of discussion in the literature regarding the feasibility of a randomized study comparing PT and IMRT for prostate cancer, which is an issue beyond the scope of this review.[35-38] It is unclear how much dose escalation and dose intensification the improved dose distribution from PT will permit. Thus, at this point in time, the degree of benefit achievable with PT is unknown, so it seems premature to commit significant resources to a randomized trial testing a mature technology against an immature technology. Funds and research resources would be better spent at this point in developing PT and in determining how best to maximize its benefits.
PT is a promising treatment option for prostate cancer patients. Studies have already demonstrated extremely low rates of grade > 3 GU and GI toxicities and extremely high disease control, presumably related to improved radiation dose distributions over what can be achieved with IMRT. More follow-up is needed to confirm the promising early results. A reduction in the integral dose to the body with PT compared to XRT may have other important implications in the future, including a decrease in secondary-malignancy risks.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.