Expert highlights the latest radiotherapy developments in prostate cancer

The history of radiation therapy for men with prostate cancer extends back more than a century, said Walter J. Curran Jr, MD, FACR, FASCO. From those early crude methods, the field has advanced to delivery potentially curative therapies that can be administered in as little as 2 weeks.

Walter J. Curran Jr, MD, FACR, FASCO

Curran, professor emeritus with the Department of Radiation Oncology at Emory University School of Medicine and the 2021 Giants of Cancer Care® award winner for radiation oncology, delivered the Giants of Cancer Care® keynote address during the 15th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies.¹

Work by Marie Sklodowska-Curie in radium led to the development of brachytherapy (BT), the first type of therapeutic radiation. BT was used to treat patients with prostate cancer as early as the 1910s.² Today, physicians have a number of radiotherapeutics to choose from. Curran said the patient’s disease stage and risk determine the optimal treatment.

Since then, external beam radiation (EBRT) has become the primary radiotherapy method for men with prostate cancer. Options also include intensity-modulated radiation therapy (IMRT), 3D-conformal radiation, and proton beam therapy.

In 2016, Curtis Bryant, MD, MPH, and colleagues published results from a review of the medical records of 1327 men with localized prostate cancer who received proton beam therapy treated at the University of Florida from 2006 to 2010. Ninety-eight percent of patients received 78 Gy or higher and 18% received androgen deprivation therapy (ADT).³

At a median follow-up time of 5.5 years, the freedom from biochemical progression (FFBP) rate was 99% for men with low-risk disease. FFBP was 94% for intermediate-risk and 74% for high-risk patients. Furthermore, investigators concluded that incidence of high-grade toxicity was low.

“The bottom line is [proton beam] is an effective means of providing long progression-free survival for men with early-stage prostate cancer,” Curran said. “What remains to be determined is if it superior to IMRT. There are ongoing trials that are exploring that at this point.”

Curran said that data produced in the 1980s and 1990s showed that escalation in total radiation dose was associated with better tumor control. “The problem with that is these now, significantly higher doses in standard fractionation would require 8 to 9 weeks of daily visits to execute, which is a significant time commitment of both centers, as well as patients,” he said. “As the ability to target improved, what we really clearly saw was the idea that perhaps a treatment course could be shortened significantly, and that the term hypofractionation became commonly applied to men with prostate cancer.”

The concept behind hypofractionation, Curran said, is that a short course of highly targeted, high-dose radiation could provide similar results as a longer course of small-dose fractions. Hypofractionated treatment must be as carefully planned as the standard fractionation course.

“What it really requires is a high level of quality of planning technology as well as delivering technology, a tighter margin has to be made around the target area, and that there needs to be that onboard imaging…with a cone-beam CT,” said Curran. “There’s also GPS devices which can be implanted into the prostate, so there's really a full level of certainty as to the location and the delivery of the beam. Because prostate cancer can be slow growing and therefore less radiosensitive than faster-growing malignancies, there are some biologic advantages of large dose per fraction if it can be delivered safely.”

In 8-year follow-up data from the phase 3 CHHiP trial (NCT00392535) published in 2020 (N = 3216), investigators found that a shorter course of radiotherapy administered as 20 treatments over 4 weeks is just as effective and safe as the previous, more conventional 7.5-week treatment.

From October 2002 to June 2011, investigators assigned patients to standard therapy with 74 Gy in 37 fractions or to the experimental arms receiving 60 Gy in 20 fractions or 57 Gy in 19 fractions.

In findings first published in 2016, the proportion of patients who were biochemical or clinical failure free at 5 years was 88.3% (95% CI 86.0%-90.2%) in the 74 Gy group, 90.6% (88.5%-92.3%) in the 60 Gy group, and 85.9% (83.4%-88.0%) in the 57 Gy group.⁴

The follow-up data confirm the 60 Gy schedule is noninferior to the 74 Gy schedule. Eight-year event-free rates were 80.6% among the control group compared with 83.7% in the 60 Gy group, and 78.5% in the 57 Gy group.⁵

A Short Course Option

Curran said that hypofractionation regimens can be delivered in 4 to 5 treatments over 2 weeks, compared with 35 to 40 treatments over as much as 9 weeks for standard fractionation. Curran said physicians can consider single-implant, low-dose BT; high-dose BT, robotic radiation is delivered in 3 to 6 fractions, or significant hypofractionation administered as stereotactic body radiation (SBRT) in 4 to 5 fractions.

SBRT originated as a treatment for lung cancer but is now in use in prostate cancer. The tactic employs highly-precise, high-dose radiation for 1 to 5 fractions, with a sharp drop in dose gradient to reduce risk to nearby tissues.

In one of the largest trials assessing SBRT, 515 patients with organ-confined prostate cancer received a regimen of 5-fraction SBRT at a dose of 35 Gy to 36.25 Gy from 2006 to 2010. According to NCCN criteria, 324 patients were low risk, 153 were intermediate risk, and 38 were high risk.

At a median follow-up of 84 months, the 8-year biochemical disease-free survival (bDFS) rate was 93.6% for low-risk patients, 84.3% for intermediate risk, and 65.0% for and high-risk patients. Overall, 106 favorable intermediate-risk patients had excellent outcomes with no significant difference compared with low-risk patients (7-year bDFS, 95.2% vs 93.2%).⁶

In an analysis of the same patient population, the actuarial 7-year FFBF was 95.8%, 89.3%, and 68.5% for low-, intermediate-, and high-risk groups, respectively (P <.001). No patients experienced acute grade 3/4 acute complications and fewer than 5% of patients had any acute grade 2 urinary or rectal toxicity.⁷

Investigators in the ongoing phase 3 NRG GU-005 trial (NCT03367702) are assessing 5 fractions of 7.25 Gy SBRT for superiority vs 28 fractions of 2.5 Gy IMRT in patients with stage IIA to B prostate cancer (N = 622).⁸ The estimated primary completion date is December 2025.

Going Forward

Curran said that radioligand therapy (RLT) is one of the most promising novel therapies currently under investigation. RLT targets the prostate-specific membrane antigen (PSMA), enabling tumor-specific treatment directed against PSMA-overexpressing prostate cancer cells.

Investigators have developed several PSMA ligands such as PSMA-617 or PSMA-I&T that can be labeled with β‑radiating lutetium-177. These ligands are being employed in compassionate use programs to treat metastatic castration-resistant prostate cancer (mCRPC) and is currently being offered in several nuclear medicine departments throughout Germany.

Findings from several retrospective case series show that RLT is associated with PSA decrease greater than 50% in 30% to 60% of patients with mCRPC.⁹

Investigators in the phase 3 VISION trial (NCT03511664) evaluated the targeted RLT 177Lu-PSMA-617 in patients with progressive PSMA-positive mCRPC. From June 2018 to October 2019, a total of 831 of 1179 screened patients were randomly assigned to 7.4 GBq 177Lu-PSMA-617 every 6 weeks for 4 to 6 cycles plus protocol-permitted standard care (n = 551) or standard care alone (n = 280).

At a median follow-up of 20.9 months, both imaging-based median progression-free survival (8.7 vs 3.4 months; HR, 0.40; 99.2% CI, 0.29-0.57; P <.001) and median overall survival (15.3 vs 11.3 months; HR, 0.62; 95% CI, 0.52-0.74; P < .001) were superior in the experimental group. Furthermore, all the key secondary end points—objective response, disease control, and time to first symptomatic skeletal event or death—significantly favored 177Lu-PSMA-617.¹⁰

In September 2021, the FDA granted a priority review to 177Lu-PSMA-617 for the treatment of mCRPC in the post-androgen receptor pathway inhibition, post–taxane-based chemotherapy setting based on results from VISION. The agency is expected to make a ruling in the first half of 2022.

Further exploration of 177Lu-PSMA-617’s ability to improve outcomes in patients with prostate cancer is currently underway in 2 investigational trials, in which the drug is brought into earlier lines of therapy (NCT04689828; NCT04720157). These studies respectively evaluate 177Lu-PSMA-617 in the pre-taxane setting and the metastatic hormone-sensitive setting.

References

1. Curran W. The contributions of radiation oncology to advances in urologic malignancies. Presented at: 15th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies; March 11-12, 2022; New York, NY.
2. Kułakowski A. The contribution of Marie Skłodowska-Curie to the development of modern oncology. Anal Bioanal Chem. 2011;400(6):1583-1586. doi:10.1007/s00216-011-4712-1.
3. Bryant C, Smith TL, Henderson RH, et al. Five-year biochemical results, toxicity, and patient-reported quality of life after delivery of dose-escalated image guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2016;95(1):422-434. doi: 10.1016/j.ijrobp.2016.02.038.
4. Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17(8):1047-1060. doi:10.1016/S1470-2045(16)30102-4.
5. Dearnaley DP, Griffin C, Syndikus I, et al. Eight-year outcomes of a phase III randomized trial of conventional versus hypofractionated high-dose intensity modulated radiotherapy for prostate cancer (CRUK/06/016): update from the CHHiP trial. J Clin Oncol. 2020,38(suppl 6; abstr 325). doi:DOI: 10.1200/JCO.2020.38.6_suppl.325.
6. Katz A, Formenti SC, Kang J. Predicting biochemical disease-free survival after prostate stereotactic body radiotherapy: risk-stratification and patterns of failure. Front Oncol. 2016;6:168. doi:10.3389/fonc.2016.00168.
7. Katz AJ, Kang J. Quality of life and toxicity after SBRT for organ-confined prostate cancer, a 7-year study. Front Oncol. 2014 Oct 28;4:301. doi:10.3389/fonc.2014.00301.
8. Stereotactic body radiation therapy or intensity-modulated radiation therapy in treating patients with stage IIA-B prostate cancer. Last updated January 21, 2022. Accessed March 16, 2022. https://clinicaltrials.gov/ct2/show/NCT03367702.
9. Heck MM, Retz M, Tauber R, et al. Radionuklidtherapie des Prostatakarzinoms mittels PSMA-Lutetium [PSMA-targeted radioligand therapy in prostate cancer]. Urologe A. 2017;56(1):32-39. doi:10.1007/s00120-016-0274-3.
10. Sartor O, de Bono J, Chi KM, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322.