Effects of Increased Dose of External Beam Radiation Therapy (EBRT)
There is growing evidence that increasing the dose of EBRT may decrease the rates of biochemical PSA and clinical recurrence in men with early prostate cancer. As a generality, doses of radiation to the prostate have increased from an average of 60 Gy a decade ago, to at least 70Gy today. Overall, results from studies presented at ASTRO involving radiation therapy in the treatment of localized prostate cancer pointed to superior long-term outcomes, mainly measured by disease-free or progression-free survival, with higher doses of radiation therapy – particularly in high-risk patients. Doses are now being escalated to 80 Gy without prohibitive toxicities in some patients. 3D conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) have contributed to the tolerability of increased radiation doses, as the techniques allow for more precise radiation delivery to the prostate while sparing normal tissue. One of the main messages resounding in several presentations at ASTRO 2003 suggested that dose escalation attempts through clinical trials should continue in the future to further improve outcomes of patients. As dose placement becomes more refined and information more extensive, researchers sound hopeful that the precise placement of increasing doses will improve disease and/or progression-free survival while maintaining quality of life in patients with localized prostate cancer.
Dose Escalation of 3D-CRT
Results from data presented at ASTRO demonstrated that higher doses of 3D-CRT provided and maintained superior long-term outcomes without significant increases in grade III or IV toxicities, compared to lower doses of radiation in localized prostate cancer. One issue in dealing with evaluating treatment for localized prostate cancer is that of unusually long follow-up. To appropriately evaluate different treatment outcomes and late toxicities, 10 years of follow-up may be necessary.
Researchers from MSKCC presented long-term results of dose-escalation in 3D-CRT.1 Follow-up at 10 years (minimum follow-up of 5 years) demonstrated a sustained superiority in outcomes of patients treated with high doses, compared to lower doses. Patients in this trial were divided into low, intermediate and high-risk groups. Ten-year PFS was reported as follows: 83% for favorable-risk patients receiving 75.6 Gy, compared to 57% treated with <70.2 Gy; 50% for intermediate-risk patients treated with higher doses, compared to 42% treated with the lower dose; 42% for poor-risk patients treated with higher doses, compared to 24% treated with lower doses. In addition, the authors stated that the “long-term tolerance of 75.6 Gy at 10 years has been excellent with minimal late grade 3 or 4 morbidities”, and suggested that more dose escalation studies should be done to determine the maximal tolerated dose of EBRT.
A second trial presented by Dr. Bey, demonstrated that doses up to 80 Gy are tolerable and achieve superior results, compared to 66 Gy – 77 Gy, in localized prostate cancer.2 Disease-free survival, defined by PSA and clinical failure, increased from 50% to 70% in patients in this trial treated with 77-80 Gy, compared to those treated with lower doses, without prohibitive toxicities. Grade I-II toxicities increased with increased doses; however, grade III toxicities and late urinary complications were equivalent between low and high-dose radiation.
A third clinical trial presented at ASTRO indicated that treating with higher doses of radiation is particularly important in high-risk patients with localized prostate cancer. This trial was a dose-escalation study of 3D-CRT conducted by researchers from Fox Chase Cancer Center, and involved 420 patients with >15% chance of pelvic lymph node involvement.3 Patients received whole pelvic, partial pelvic, or radiation to the prostate only. In addition, some patients were treated with short-term androgen deprivation. Overall, the authors reported that the only treatment variable making a discernable impact on outcomes was the dose of radiation. Field size and androgen deprivation did not appear to affect outcomes in these patients. Disease control was achieved in 48% of patients receiving <73 Gy, 64% of those receiving 73-76.9 Gy, and 74% of those receiving >77 Gy. The authors stated that “The data presented here indicate that doses above 70 Gy are of paramount importance in high-risk patients.”
As retrospective analyses often lend to larger patient populations than that attainable by prospective studies, Dr. Kupelian and colleagues reported outcomes of 4,839 patients with localized prostate cancer treated in nine different institutions between 1994 and 1995.4 Using multivariate analyses accounting for risk factors (PSA, Gleason Score, Clinical Stage), data indicated that patients who received 72 Gy or higher had a better disease-free survival as defined by time to biochemical PSA failure (ASTRO definition) than patients who received lower doses. Specifically, patients who received 60-71 Gy experienced a 5-year PSA-DFS of 63%, compared to 69% for patients receiving 72 Gy or higher.
Intensity Modulated Radiation Therapy (IMRT)
Results from trials evaluating dose-escalation of IMRT also paralleled the theme of improved outcomes with higher radiation doses in the treatment of localized prostate cancer. Furthermore, radiation oncologists are evaluating different fractionation schedules in IMRT, with particular focus on hypofractionation regimens. Hypofractionation scheduling would potentially save extensive time of the patient, healthcare providers, and medical facilities, as well as significantly reduce medical costs resulting from radiation therapy. One clinical trial involving IMRT delivery in 100 patients with localized prostate cancer evaluated 70 Gy in 28, 2.5 Gy fractions, which is equivalent to 83 Gy when compared with standard fractionation for prostate cancer.5Biochemical failure rates were 0% for low-risk patients and 19% for high-risk patients following this delivery schedule. Only one of the 100 patients had grade 3 toxicity. These authors concluded that hypofractionation may be a more feasible method than standard fractionation schedules in the dose-escalation approach in the treatment of localized prostate cancer.
Furthermore, Cheung, et al. from Toronto reported that adding a “boost” of radiation to the prostate utilizing IMRT may also be a feasible way in which to direct a higher dose of radiation therapy to the prostate.6Researchers estimated that this type of hypofractionation technique could deliver 80 Gy to the prostate without prohibitive toxicity. The IMRT boost would be a convenient method to achieve the desired high doses of radiation to the prostate.
Increased Dose of EBR on Toxicity
For the most part, increasing radiation doses has not demonstrated a significant increase in grade III and IV acute toxicities compared to lower doses. Beckendor, et al. from France compared toxicities in over 300 patients randomized to receive 70 Gy vs 80 Gy of 3D-CRT for localized prostate cancer.7 The goal of this study was to detect a 15% difference in disease control but this presentation dealt only with toxicities. No patient in this study received androgen suppression and the median age was 67 years. No differences in acute toxicity were reported and the researchers deemed that side effects were acceptable in both arms. In the discussion surrounding this topic, it is clear that for most centers IMRT is replacing 3D-CRT as the preferred method of treatment, despite the favorable results in this study.
Lebesque, et al. from Holland also reported that side effect profiles remained similar in higher and lower doses of EBRT. This trial involved over 600 men with localized prostate cancer randomized to treatment with either 68 Gy or 78 Gy of conventional EBRT.8 There were no significant differences in side effects between the two doses being evaluated, except a 10% rate of transfusions needed for rectal bleeding in the high-dose group, compared to a 5% rate in the low-dose group.
Researchers affiliated with RTOG evaluated toxicity of a study evaluating dose escalation up to 78 Gy to the prostate.9 In this trial, there was a reported increase in low-grade toxicity with higher doses compared to lower doses. However, the authors stated that “The rate of grade 3+ toxicity from 3D-CRT with 78 Gy in 2.0 fractions remains better than expected compared to historical controls.”
These data suggest that the maximum dose of radiation that can safely be given to patients with prostate cancer using techniques such as IMRT has probably not yet been reached. There is expectation that the higher the dose delivered, the better the cure rate. This may have been reached with low-risk patients where disease control approaches 100%. However, there are still significant failures in the intermediate and high-risk groups of patients, indicating a possibility of improving cure rates with increased radiation doses for these patients.
Zelefsky M, Fuks H, Chan H, et al.Ten-Year Results of Dose Escalation with 3-Dimensional Conformal Radiotherapy for Patients with Clinically Localized Prostate Cancer. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003;57, No.2, Supplement. Abstract number 44:S149. Patients received 64.8 to <70.2 Gy, 70.2 Gy or 75.6 Gy.
Bey P, Carrie C, Ginestet C, et al. French Study of Dose Escalation From 66 to 80 Gy with 3D-CRT in Prostate Cancer: Results at 5 Years. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003;57, No.2, Supplement. Abstract number 1018:S272.
Jacob R, Hanlon AL, Horwitz EM, et al. Role of Prostate Dose Escalation in Patients with >15% Risk of Pelvic Lymph-Node Involvement. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003,57, No.2, Supplement. Abstract number 45:S150.
Kupelian PA, Kuban D, Thames H, et al. Improved Biochemical Relapse-Free Survival with Increased External Radiation Doses in Patients with Localized Prostate Cancer: The Combined Experience of Nine Institutions in Patients Treated in 1994 and 1995. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003;57, No.2, Supplement. Abstract number 1017:S271.
Djemil T, Reddy CA, Willoughby TR, et al, Hypofractionated Intensity-Modulated Radiotherapy (70 Gy at 2.5 Gy Per Fraction) for Localized Prostate Cancer. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003.57; No.2, Supplement. Abstract number 1024:S275.
Cheung P, Morton G, Loblaw A, et al. Hypofractionated IMRT Boost for Prostate Carcinoma With On-Line Targeting of the Prostate Gland: Patients-Specific PTV Margins and Acute Toxicity Results. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003;57, No.2, Supplement. Abstract number 1025:S276.
Beckendorf V, Guerif S, Le Prise E, et al. The French 70 Gy Versus 80 Gy Dose Escalation Trial for Localized Prostate Cancer: Feasibility and Toxicity. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003;57, No.2, Supplement. Abstract number 48:S152.
Lebesque J, Koper P, Slot A, et al. Acute and Late GI and GU Toxicity After Prostate Irradiation to Doses of 68 Gy and 78 Gy; Results of a Randomized Trial. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003;57, No.2, Supplement. Abstract number 47:S152.
Michalski J, Winter K, Purdy JA, et al. Toxicity Following Radiation Therapy for Prostate Cancer on RTOG 9406 Dose Level V. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003;57, No.2, Supplement. Abstract number 46:S151.