Radiation Dose Escalation as Treatment for Clinically Localized Prostate Cancer: Title and subTitle BreakIs More Really Better?

Contemporary management of clinically localized adenocarcinoma of the prostate is based on the concept that destruction of prostate cancer cells by radiation therapy or removal of the prostate by radical prostatectomy will render the patient free of disease. Unfortunately, a number of men with clinically localized prostate cancer have only a temporary decrement in serum levels of prostate-specific antigen (PSA) following radiation or surgery, highlighting the need for more accurate staging and improved treatment.^{1 - 2} Several studies have correlated clinical stage, histological tumor grade, and pretreatment PSA levels with risk of disease recurrence following therapy, and contemporary risk stratification of prostate cancer uses a combination of these measures.³ This stratification schema is critical to the rationale for aggressive local treatment by allowing for selection of patients who are most likely to have localized disease and who will therefore potentially benefit by aggressive unimodal therapies, such as dose-escalated radiation.

The ability to target the prostate with dose-escalated radiation therapy, historically considered as more than approximately 70 Gy, has been constrained by the limited tolerance of the genitourinary tract and rectum.^{4 - 5} The past 2 decades have witnessed the development of innovative radiotherapy techniques such as intensity-modulated radiation therapy, which uses computed tomography (CT)–based targeting, sophisticated beam delivery, and complex treatment-planning assessment tools for enhanced precision. In addition, improvements in patient positioning and identification of prostate motion have created the ability to more accurately deliver radiation to the prostate while minimizing irradiation of surrounding tissues.⁶ Such innovations have resulted in fewer adverse effects at isoeffective dose levels.⁷

An alternative technology with potential for delivering higher doses of radiation with acceptable morbidity is proton-beam radiation, such as that used in the trial by Zietman and colleagues⁸ reported in this issue of JAMA. Proton-beam therapy is capable of penetrating tissues with minimal energy deposition prior to reaching a certain depth (Bragg peak).⁹ Although the physical properties of protons are different from the much more commonly available photon treatment, in general the relative biological effectiveness is similar.¹⁰ As such, the impact and potential applicability of the findings of Zietman et al⁸ reach beyond the 2 centers in the United States that currently offer proton-beam therapy.

Preclinical data suggest higher radiation doses delivered to cancer cells result in greater cell death.¹¹ These findings have led to an interest in the use of escalated doses of radiotherapy not only for prostate cancer but also for many other disease sites. Although early studies demonstrated robust dose-response relationships in the clinical setting,¹² it is possible that a point may be reached beyond which increasing radiation dose will no longer result in improved disease control or clinical benefit.¹³ A number of retrospective, single-institution and prospective, single-arm trials of radiation-dose escalation for prostate cancer have provided mixed results, lending early support to this hypothesis. Certain studies have demonstrated no benefit to higher radiation doses for men with lower-risk disease,¹⁴ whereas others have documented an improvement in biochemical control of disease (ie, no PSA recurrence) for men with lower- and higher-risk disease.¹⁵ As such, randomized clinical trials are necessary to determine more accurately the incremental value of increased doses.

The trial reported by Zietman et al⁸ is pivotal in this regard. This study demonstrates that men with clinically localized prostate cancer do indeed benefit from increased radiation dose delivered to the prostate as evidenced by an increase in freedom from disease recurrence (primarily freedom from PSA recurrence). The enhanced PSA control resulting from higher radiation dose was observed in the entire treatment group, as well as in the subset of men with lower-risk prostate cancer. The latter point is significant and novel and provides support for dose escalation in men with lower-risk disease, in contrast to a previous randomized trial by Pollack et al¹⁶ that suggested that any benefit of dose escalation was most pronounced for patients with higher-risk disease.

In this previous prospectively randomized trial¹⁶ of dose-escalated radiation therapy for men with clinically localized prostate cancer, patients treated with a radiation dose of 78 Gy delivered to the prostate experienced an increased freedom from failure (primarily PSA control) when compared with patients treated with a dose of 70 Gy. This benefit was most pronounced in patients with pretreatment PSA levels greater than 10 ng/mL. Importantly, this trial enrolled a number of patients with high-risk features. Specifically, 30% of enrolled patients had stage T2C to T3 prostate cancer, and 18% of patients had tumors with Gleason score 8 to 10. Both of these factors are known to be associated with more aggressive prostate cancer and are not considered associated with lower-risk disease by any criteria.

An even more recently reported prospective, randomized trial by Dearnaley et al¹⁷ of low- vs high-dose radiation therapy demonstrated no significant increase in freedom from PSA recurrence with higher radiation doses delivered to the prostate. This trial was more complicated, however, in that all patients received neoadjuvant and concomitant hormonal therapy and radiation, a treatment paradigm that has been shown to improve disease response when compared with radiation therapy alone.¹⁸ In addition, patients treated in the high-dose group of the trial by Dearnaley et al¹⁷ received a radiation dose of 74 Gy, a dose that is lower than that used in the study by Pollack et al¹⁶ or in the trial by Zietman et al.⁸ In sum, comparing the results of Zietman et al⁸ with previously reported retrospective and randomized data is challenging and even more difficult when trying to extrapolate the findings to those patients with lower-risk prostate cancer.

Notably, the data in the current study are reported with a median follow-up of 5.5 years. The authors did not report a difference in overall survival associated with the use of higher doses of radiation at that point. Moreover, only 2 deaths related to prostate cancer have occurred in the conventional-dose group and none in the high-dose group. While overall and cause-specific survival are far more clinically important end points than freedom from PSA recurrence, determining ultimate disease control in patients with low-risk prostate cancer is difficult. Many patients with prostate cancer, even those who develop biochemical failure after definitive treatment, die of unrelated causes. Nonetheless, control of serum PSA levels following either radiation or surgery is still important, as those patients with rapidly increasing PSA levels following primary therapy are at high risk for death from prostate cancer.^{19 - 20} Thus, improved freedom from PSA recurrence is of some prognostic usefulness, and it may be that higher radiation doses will eventually translate into a cause-specific survival advantage for these men.

Zietman et al⁸ also address the question of the risks associated with higher radiation doses delivered to the prostate. They report that higher radiation doses are, in fact, associated with a statistically significant increase in grade 2 or greater rectal adverse effects (18%) compared with lower radiation doses (10%) and that the genitourinary tract–related adverse effects seem to continue to accumulate with longer follow-up. These data are not surprising, as similar results were reported in other series in which patients treated with comparable radiation doses experienced a 22% to 26% incidence of radiation-induced grade 2 or greater rectal toxicity.^{16 ,21}

An important question remains: is the relative benefit associated with higher radiation doses worth the increased risks? Based on the study by Zietman et al,⁸ it is possible to now state with more certainty that higher radiation doses can be safely delivered to men with clinically localized prostate cancer and that this increased dose is associated with improved biochemical control of disease. However, whether this increase in PSA control will necessarily translate into improvement in clinically meaningful end points such as longer survival is not yet known. As such, this study has not answered the important question of whether patients should accept the modest but real incremental risk of higher radiation doses for the uncertain ultimate benefit derived. Several other questions also remain unanswered: (1) Would higher radiation doses beyond 79 Gy provide even greater benefit? (2) What is the optimal radiation method of dose escalation? and (3) Given that the addition of androgen suppression to radiotherapy has recently been shown to improve survival in some patients, is dose escalation even the best way to improve radiotherapeutic outcomes in this disease?²² Nevertheless, these randomized trial data support the use of higher radiation doses in men with lower-risk prostate cancer, and these findings will serve as an important foundation for future work.