Palliative RT Research in Prostate Cancer: Understanding the Past, Anticipating the Future

We read with interest the comprehensive review by Drs. Boyer, Salama, and Lee in this issue of ONCOLOGY,[1] highlighting the important role radiation therapy (RT) plays in the care of men with advanced-stage prostate cancer. We wish to elaborate on a few of the review’s themes.

With respect to external beam RT (EBRT) for bone metastases, much has been made of the difference between the ~20% retreatment rates following single-fraction (SF) treatments and the ~10% rates following multiple-fraction (MF) treatments in meta-analyses of randomized trials.[2,3] The difference is typically interpreted as evidence that a SF cannot provide as durable a response, making MFs a more appropriate choice for patients with prostate cancer, given their longer expected survival compared with patients who have other types of cancer. This interpretation is inaccurate.

Trials have not provided detailed guidance regarding the circumstances under which retreatment could or should be administered. Thus, it has long been reasonably speculated that the higher retreatment rates documented following SF treatments had more to do with radiation oncologists considering it safer to retreat after a SF than after MFs, owing to the lower cumulative doses administered to sensitive structures. Put simply, the fact that more patients underwent retreatment following SF treatments cannot be taken to mean that they did so because they needed it more.

Convincing support for this assertion comes from an elegant re-analysis[4] of data from the Dutch Bone Metastasis Study (N = 1,157), the largest study ever conducted to evaluate EBRT for bone metastases.[5] Among the 320 patients who lived for at least a year (87% of whom had either prostate or breast cancer), the retreatment rates following SF and MF treatments were indeed different, at 36% and 11%, respectively. However, the mean durations of initial response prior to retreatment were virtually identical at 29 and 30 weeks. Similarly, of the patients with an initial response, 55% and 53% later developed pain progression, and the mean times to that progression were 17 weeks and 18 weeks, respectively.

Radiation oncologists should take away two salient messages from these data. The first is that the pain response produced by a SF is as durable as that produced by MFs, even for patients with prolonged survival following RT. If one factors in the obvious convenience and cost advantages of SF treatments, and remembers that patients with prostate and breast cancers treated with MFs during the Radiation Therapy Oncology Group 9714 trial (n = 898) experienced nearly twice the rate of acute grade 2–4 toxicity compared with patients treated with a SF (17% vs 10%),[6] it should be difficult to rationalize prescribing MFs in the hope of providing more durable pain relief. The second message is that the key to providing long-term pain relief with conventional RT doses is likely retreatment and not dose escalation. Retreatment should be viewed as a safe and valuable tool available for use when needed, and not as an onerous task that, when undertaken, signals failure of RT. Radiation oncologists must remember that the role of conventional RT is to palliate and not to cure, and accept the need to retreat in response to recurrent or progressive pain in the same way they accept the need to adjust or rotate opioids in other settings. Fortunately, the recently published National Cancer Institute of Canada Clinical Trials Group SC20 retreatment trial (N = 850) provides guidance and support for retreatment, since approximately 50% of patients in that trial responded to retreatment with either a SF or MFs.[7]

Moving forward, perhaps no recent development in the use of RT in metastatic prostate cancer has captured greater attention than the use of radium-223 in metastatic castration-resistant prostate cancer (mCRPC). Unlike the radionuclides used before it, radium-223 is principally an emitter of alpha particles, whose short range and greater biologic effectiveness offer a therapeutic ratio that is substantially improved over that of beta particles. It is the first bone-targeted therapy that has improved overall survival and significantly altered the natural history of mCRPC.[8] While amelioration of bone pain and prolonged freedom from skeletal-related events were also observed in the landmark Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial,[8] what was perhaps most striking was radium-223’s benign toxicity profile.

The optimal place for radium-223 in the increasingly crowded therapeutic landscape of metastatic prostate cancer remains to be defined. While the ALSYMPCA trial enrolled patients with mCRPC who were previously treated with or were unfit for chemotherapy, radium-223 will likely soon be studied in the castration-sensitive setting, where it may have a longer absolute impact on survival. Further, as radium-223 targets only bony metastatic disease, its use in combination with agents that also treat soft-tissue disease is of interest. A recently launched phase III trial will evaluate the addition of radium-223 to abiraterone in asymptomatic or mildly symptomatic bone-predominant mCRPC.[9] Such a combination is particularly attractive given the minimal overlap of the agents’ toxicities.

The treatment of oligometastatic disease with ablative local RT has been less well studied in prostate cancer than in other solid tumors. Boyer, Salama, and Lee correctly identify the relatively sparse related literature on this subject, which consists of small, retrospective, single-institution studies. Given the relatively indolent natural history of metastatic prostate cancer compared with that of other metastatic solid tumors, there is a rationale for evaluating ablative RT directed against bone and nodal oligometastases in randomized trials. A randomized phase II trial underway in Belgium will assess whether ablative RT in the setting of limited-volume metastatic disease can permit deferral of androgen deprivation therapy and its attendant side effects.[10] Beyond measures of efficacy, it will be important for this trial to carefully collect data on treatment-related adverse effects, specifically rates of fracture.

Finally, what of palliative RT directed to the primary tumor itself? Boyer, Salama, and Lee nicely summarize the literature on use of RT in relieving obstructive symptoms and controlling bleeding. While treating and forestalling symptomatic local disease progression remains a worthwhile goal in itself, a number of investigators have put forward a more provocative hypothesis: that local therapy directed against the primary tumor might retard the progression of distant metastatic disease and thereby improve survival.[11] Three large-scale European randomized trials in metastatic prostate cancer are testing this hypothesis, with overall survival as the primary endpoint. In each trial, patients presenting with metastatic prostate cancer are randomized to receive the current standard of androgen deprivation therapy with or without radical-dose RT directed to the prostate gland.[12-14] Within a few years, we will know whether this bold hypothesis remains a fanciful notion or a practice-changing fact.

Financial Disclosure:Dr. Morgan is a consultant to, and receives honoraria from, Janssen, Inc. Dr. Dennis has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this commentary.

References:

1. Boyer MJ, Salama JK, Lee WR. Palliative radiotherapy for prostate cancer. Oncology (Williston Park). 2014;28:306-12.

2. Wu JS, Wong R, Johnston M, et al. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys. 2003;55:594-605.

3. Chow E, Zeng L, Salvo N, et al. Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol). 2012;24:112-24.

4. van der Linden YM, Steenland E, van Houwelingen HC, et al. Patients with a favourable prognosis are equally palliated with single and multiple fraction radiotherapy: results on survival in the Dutch Bone Metastasis Study. Radiother Oncol. 2006;78:245-53.

5. Steenland E, Leer JW, van Houwelingen H, et al. The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiother Oncol. 1999;52:101-9.

6. Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005;97:798-804.

7. Chow E, van der Linden YM, Roos D, et al. Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial. Lancet Oncol. 2014;15:164-71.

8. Parker C, Nolsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213-23.

9. US National Institutes of Health. NCT02043678: Radium-223 dichloride and abiraterone acetate compared to placebo and abiraterone acetate for men with cancer of the prostate when medical or surgical castration does not work and when the cancer has spread to the bone, has not been treated with chemotherapy and is causing no or only mild symptoms. Available from: http://clinicaltrials.gov/show/NCT02043678. Accessed March 12, 2014.

10. US National Institutes of Health. NCT01558427: Non-systemic treatment for patients with low-volume metastatic prostate cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT01558427. Accessed March 12, 2014.

11. Morgan SC, Parker C. Local treatment of metastatic cancer-killing the seed or disturbing the soil? Nat Rev Clin Oncol. 2011;8:504-6.

12. ISRCTN06890529. A randomised study about the effect on survival of hormonal therapy plus local external radiation therapy in patients with primary diagnosed metastasized (M+) prostate cancer. Available from: http://www.controlled-trials.com/ISRCTN06890529. Accessed March 12, 2014.

13. US National Institutes of Health. NCT00268476: STAMPEDE: systemic therapy in advancing or metastatic prostate cancer: evaluation of drug efficacy: a multi-stage multi-arm randomised controlled trial. Available from: http://clinicaltrials.gov/show/NCT00268476. Accessed March 12, 2014.

14. US National Institutes of Health. NCT01957436: A phase III of ADT +/− local RT +/− abiraterone acetate in metastatic hormone-naïve prostate cancer. (PEACE1). Available from: http://clinicaltrials.gov/show/NCT01957436. Accessed March 12, 2014.