Sperling Prostate Center

The PIVOTAL Trial: The Safety of Aggressive Radiation for Prostate Cancer

UPDATE: 9/7/2022
Originally published 4/18/2019

The PIVOTAL trial described below opened in 2011, and completed recruitment in 2013. During the trial, patients with advanced localized prostate cancer (PCa) were assigned to either have IMRT radiation to the whole prostate, or to the whole prostate plus the pelvic lymph nodes. The purpose was to compare how well patients coped in terms of side effects and quality of life, since those with additional radiation to the pelvis were expected to have more side effects. The 2018 publication of results showed that IMRT was generally safe, but the prostate-plus-pelvic patients had more inflammatory bowel disease. Just prior to the results publication, a second trial called PIVOTALboost was approved in 2017, and the first patient was recruited in Jan. 2018. This trial explored focal dose escalation, meaning that tumors <50% of the prostate volume (as identified on MRI) would receive targeted additional radiation. The study design included 4 treatment arms: “A: prostate alone IMRT (control), B: prostate and pelvic IMRT, C: prostate IMRT and prostate boost, D: prostate and pelvic IMRT and prostate boost.”[i] Multiparametric MRI (mpMRI) is a key element in planning the strategy of increasing targeted radiation dose to the prostate in parallel to radiating the pelvic lymph nodes. The authors note, “These treatment escalation strategies need to be balanced against the risk of increased side effects which may occur if radiation dose to normal tissue is increased.”[ii] It will be years before the outcomes of the PIVOTALboost trial are known, but if it succeeds in demonstrated decreased PCa recurrence without harming patient function and quality of life, it will be truly rewarding for the patients and doctors who patiently await results.

Thanks to PSA screening and early detection, most prostate cancer (PCa) is diagnosed while it is still contained in the prostate gland. This implies favorable odds that any whole-gland treatment is potentially curative: radical prostatectomy, beam radiation, brachytherapy (seed implants), cryotherapy (freezing), or HIFU. For patients whose PCa exists as an unifocal disease—that is, an isolated tumor of small size—focal therapy carries the same odds.

Before any treatment decision is made, however, it’s essential to get the most complete cancer profile to determine that true level of risk. Other risk factors include:

  • Age and family history
  • Diagnosis of aggression and disease volume based on mpMRI and biopsy
  • Tumor volume and stage
  • Genomic analysis to rule out gene variants that characterize more lethal cell lines
  • Life expectancy based on overall health and any coexisting conditions.

What if the prostate cancer is high risk?

Unfortunately, not every case of prostate cancer is detected and diagnosed within the most likely window for successful localized treatment. Patients with Gleason score 8-10 PCa (or any primary score of Gleason 5) are at significantly greater risk for PCa spread into the pelvic and groin lymph nodes, and potential remote metastasis which is incurable. This is alarming, but high risk PCa does not rule out an aggressive localized treatment by radical prostatectomy (RP) or radiation therapy (RT). The question then becomes how to boost the probability of successfully vanquishing the cancer—especially using radiation, since no repeat radiation can be done if cancer comes back.

The problem with aggressive radiation therapy (RT)

Traditional external beam radiation has a scatter effect that can lead to early and even late-onset urinary, sexual and bowel toxicity (side effects). The greater the radiation dose, the more toxicity risk. Radiation technology has improved, and a method increasingly used for PCa is called Intensity Modulated Radiation Therapy (IMRT). IMRT is more precise and able to be more focused on the target:

IMRT allows for the radiation dose to conform more precisely to the three-dimensional (3-D) shape of the tumor by modulating—or controlling—the intensity of the radiation beam in multiple small volumes. IMRT also allows higher radiation doses to be focused to regions within the tumor while minimizing the dose to surrounding normal critical structures.[iii]

This sounds encouraging, but when it comes to high risk PCa, the question is raised as to how much anatomy (how big an area) can be safely treated in an effort to prevent recurrence? Since the pelvic lymph nodes are a preferred location for early spread of PCa, it makes logical sense to radiate them as well as the prostate. However, traditional EBRT to such an extent could not avoid affecting bladder, rectum, and bowel. Damage to these last two structures, in particular, would have a negative effect on gastrointestinal function (intestinal digestion and excretion).

PIVOTAL trial demonstrates IMRT safety

Therefore, a clinical trial was designed to compare radiating just the prostate gland with IMRT vs. radiating the prostate plus the lymph nodes to evaluate the rate of side effects of each approach. It’s called the PIVOTAL Trial (Prostate and Pelvic Lymph Node Versus Prostate Only Radiotherapy in Advanced Localised Prostate Cancer). [iv]

The International Journal of Radiation Oncology, Biology, Physics (March, 2019) has now published the results of this Phase II randomized multicenter trial. For the PIVOTAL trial, 124 PCa patients who had received no prior treatment were enrolled, and randomly assigned to have IMRT either just to the gland, or to the gland and the lymph nodes. Both groups received the same radiation dose to the prostate and seminal vesicles, while the lymph node group also received radiation to the nodes.

What did the study find?

The average follow-up was just over three years, more than enough time to track short-, medium- and long-term side effects. At week 6, a larger proportion of the prostate-plus-nodes group had more gastrointestinal distress symptoms such as rectal bleeding or diarrhea than the prostate only group (26% vs. 7%). By week 18, both groups had similar low scores on a questionnaire regarding inflammatory bowel disease; the prostate only group reported 96.7% freedom from side effects, whereas the prostate-plus-nodes group reported 95.2% freedom from side effects.

Based on these and other results, the authors concluded “…that high-dose pelvic lymph node IMRT can be delivered at multiple centers with a modest side effect profile.” This is good news for men with high-risk disease who undergo IMRT to the prostate gland plus lymph nodes as their primary treatment. The broader treatment area gives added insurance against future advancing PCa.

One note of caution: the research team notes that although the PIVOTAL trial demonstrated a favorable safety profile for more extensive IMRT treatment, how well it ultimately controls PCa was not established over three years’ follow-up. Still, the trial report should hearten men with high-risk PCa.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

[i] Syndikus I, Cruickshank C, Staffurth J, et al. PIVOTALboost: A phase III randomised controlled trial of prostate and pelvis versus prostate alone radiotherapy with or without prostate boost (CRUK/16/018). Clin Transl Radiat Oncol. 2020;25:22-28. [ii] Ibid. [iii] https://www.radiologyinfo.org/en/info.cfm?pg=imrt [iv] Int J Radiation Oncol Biol Phys. 2019 Mar; 103(3):605-17.


About Dr. Dan Sperling

Dan Sperling, MD, DABR, is a board certified radiologist who is globally recognized as a leader in multiparametric MRI for the detection and diagnosis of a range of disease conditions. As Medical Director of the Sperling Prostate Center, Sperling Medical Group and Sperling Neurosurgery Associates, he and his team are on the leading edge of significant change in medical practice. He is the co-author of the new patient book Redefining Prostate Cancer, and is a contributing author on over 25 published studies. For more information, contact the Sperling Prostate Center.

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