Radiation for localized prostate cancer

There are numerous radiation modalities for the definitive treatment of localized prostate cancer. 

The selection of the optimal radiation therapy approach depends largely on the appropriate stratification of men with prostate cancer, with greater intensification of treatment and greater integration of multimodality therapies for men with higher-risk disease. 

Hormonal therapy should be selectively deployed based on prognostic information derived from risk group and biologic tumor aggressiveness informed by genomic classifiers. 

Treatment intensification and target volumes are informed by molecular imaging and multiparametric magnetic resonance imaging. 

Most men harbor only localized disease at the time of diagnosis, for which definitive treatment is highly effective.

Evidence-based therapies for localized PCa include both systemic hormonal therapies that suppress androgen activity and local therapies that directly address disease in the prostate, including radical prostatectomy (RP) and definitive radiation therapy (RT).

Treatments for localized PCa are broadly divided  into the definitive setting vs the postoperative setting following radical prostatectomy.

In the definitive treatment setting, these treatments include RT and systemic therapy. 

RT includes external beam RT (EBRT) and brachytherapy (BT), whereas systemic therapy includes first- and second-generation hormonal therapies. 

Postoperative treatments tend to focus on the integration of EBRT with hormonal therapy.

Very–Low-Risk and Low-Risk Prostate Cancer:

Is characterized by low prostate-specific antigen (PSA) values, low PSA density, a low burden of PCa in sampled biopsy cores, an International Society of Urological Pathology (ISUP) grade group of 1, and a low T category. 

The ProtecT trial4 enrolled men predominately in these low-risk groups and demonstrated survival equivalence among active surveillance, definitive therapy with RP, and definitive therapy with RT, although approximately 50% of men who initially chose active surveillance ultimately received treatment, and the rate of metastatic disease was higher in the active surveillance arm.

For low-risk disease, EBRT and BT are both evidence-based options that have  similarly high oncologic endpoints. 

BT leverages implanted radioactive isotopes to precisely deliver radiation to the prostate, with a steep falloff in radiation that limits the dose to surrounding organs at risk. 

Radioisotopes can be inserted through the permanent implantation of low-dose-rate (LDR) seeds or through the surgical implantation of temporary catheters that allow high-dose-rate (HDR) sources to deposit radiation. 

Comparing patient-reported quality-of-life (QOL) outcomes among EBRT, LDR BT, and HDR BT demonstrated that urinary symptom scores in both the short- and long-term were worse with LDR BT.

High-dose-rate approach may be the BT modality of choice for men opting for surgical radiation management with BT, given its more favorable toxicity profile.

EBRT, all men in PCa trials of EBRT received conventionally fractionated RT, in which small doses of radiation from 1.8 to 2.0 Gy per fraction are delivered daily over 8 to 9 weeks. 

PCa biology understanding now is that low alpha/beta ratio of PCa, improved radiobiological responses to ionizing radiation in treatments delivered with larger radiation doses per fraction. 

Studies show that moderately hypofractionated RT using 60 Gy in 20 fractions, or 70 Gy in 28 fractions is noninferior to dose-escalated conventionally fractionated regimens, even in the absence of hormonal therapy.

Ultrahypofractionated RT regimens (stereotactic body RT [SBRT]) limit the delivery of RT to just 5 concentrated sessions rather than the historical 40 to 45 sessions. 

Data demonstrates the noninferiority of SBRT compared with more traditional regimens. 

Given the high radiation doses delivered per treatment, SBRT requires a high degree of targeting accuracy and precision: computed tomography (CT) guidance, magnetic resonance imaging (MRI) guidance.

MRI-guided RT (MRgRT) has superior soft tissue resolution and better visualization/delineation of targets and surrounding critical organs at risk, as well as real-time tracking/gating of the target during delivery.

MRI-guided RT reduces planning margins and eliminate the need for fiducial marker/electromagnetic beacon placement, which requires an invasive procedure. 

MRI-guided RT demonstrate a significant reduction of both physician-scored and patient-reported acute gastrointestinal (GI) and genitourinary (GU) toxicities with MRgRT compared with CT-guided SBRT.

To reduce toxicity from both conventional and hypofractionated approaches involves the insertion of a rectal spacer. 

Rectal spacers consist of an absorbable polyethylene glycol hydrogel that is injected into the perirectal space to temporarily increase the distance between the anterior rectal wall and the prostate. 

A rectal spacer may diminish radiation toxicity, improve patient-reported outcomes, and reduce costs, with minimal risk when deployed in the EBRT and BT settings. 

With regard to late GU toxicity rates and long-term QOL measures, there are no significant differences between SBRT and conventionally fractionated RT.

Intermediate-risk PCa: 

Men with intermediate-risk PCa harbor more aggressive clinical features than the low-risk subset of patients, the same radiotherapeutic principles apply in that conventional fractionation, moderate hypofractionation, and ultrahypofractionation remain oncologically equivalent treatment options. 

There is significant biological heterogeneity within intermediate-risk patients, such that some intermediate-risk patients may benefit from a multimodality addition of hormonal therapies to RT, whereas others might not. 

The appropriate duration of androgen deprivation therapy (ADT) and the subgroups of patients in which ADT is most beneficial remain controversial.

Intermediate-risk disease is also subclassified into men with unfavorable intermediate-risk disease and men with favorable intermediate-risk disease. 

This distinction is made on the basis of the primary pattern of Gleason grading, the presence of multiple intermediate-risk factors, and evidence of 50% or greater involvement of the number of sampled cores. 

Hormonal therapies may be helpful with unfavorable intermediate-risk disease, whereas men with favorable intermediate-risk disease might reasonably be spared hormonal therapies. 

The benefit of 4 months of ADT with RT, reported that ADT for favorable intermediate-risk disease did not reduce distant metastasis (DM), PCa-specific mortality, or all-cause mortality. 

On the other hand, in unfavorable intermediate-risk disease, ADT did improve distant metastases and prostate cancer specific mortality   at 15-year follow-up.

If hormonal therapy is chosen for intermediate-risk disease, multiple studies have demonstrated that the ideal duration of ADT that balances oncologic outcomes and QOL is 4 to 6 months. 

EORTC 22991, a randomized trial of 245 patients, found that 74- or 78-Gy RT in conjunction with 6 months of ADT improved event-free survival vs RT alone. 

The PCS III study also found that 6 months of ADT improved freedom from biochemical failure,25 whereas RTOG 0815 showed decreased rates of the more clinically meaningful endpoint of distant metastases.

Several additional studies also found that extending the duration of ADT did not improve outcomes, particularly when dose-escalated RT is employed.

SANDSTORM, a pooled analysis of 12 randomized trials that demonstrated the superiority of concurrent/adjuvant ADT compared with neoadjuvant/concurrent ADT, specifically with regard to the substantive oncologic outcomes of metastasis-free 

PCa-specific mortality and overall survival.

These benefits were reserved for men receiving prostate-only RT, as no benefit was observed for men who also received whole-pelvis RT. 

A biological explanation for the advantages of concurrent/adjuvant ADT may lie in prolonging the interruption of androgen receptor–mediated DNA repair during a period when repair of RT-induced DNA damage remains relevant.

The addition of hormonal therapies to definitive RT mainly benefits men with unfavorable intermediate-risk disease.

There appears to be a relative benefit to adding ADT of any duration to RT for most men with localized PCa. 

The absolute benefit of ADT does diverge for intermediate-risk vs high-risk patients, with a calculated number needed to treat in order to avert 1 metastatic event at 10 years of 8.4 for high-risk patients vs 18.0 for intermediate-risk patients. 

Molecular positron emission tomography (PET) scans that incorporate PCa-specific radiotracers into the staging workup prior to the pursuit of definitive RT has changed risk stratification, particularly  for patients with unfavorable intermediate-risk and high-risk disease, for whom the superiority of PSMA PET compared with conventional imaging (CT and bone scan).

PET/PSMA study shows enhanced sensitivity (85% vs 38%) and specificity (98% vs 91%) with PSMA PET vs conventional imaging, changes in management are significantly more likely in men who underwent PSMA PET–based staging than in those who underwent conventional staging (28% vs 15%. 

Such changes could include intensification of definitive RT through the addition of pelvic lymph node volumes or an increase in the duration or potency of concomitant hormonal therapies, particularly when disease outside of the prostate was identified with molecular PET. 

High-risk PCa is an aggressive biologic entity that carries a high risk of disease progression following definitive treatment. 

The value of long-term ADT of at least 18 months in duration has consistently improved OS in multiple large, randomized trials.

Although ADT is beneficial, 4 months may not be sufficient to improve OS in men with high-risk disease. 

Data suggest that although 18 months of ADT yields superior oncologic outcomes compared with STADT in high-risk patients, longer durations of LTADT (36 months) might be similar in efficacy to shorter durations of LTADT (18 months) in the modern dose-escalated RT treatment era. 

Other evidence suggests that 18 months may still be insufficient.

Incorporating advanced antiandrogen therapy into the up-front treatment of high-risk PCa in conjunction with EBRT/ADT. 

A meta-analysis of two phase 3 trials from the STAMPEDE platform protocol, 1974 high-risk patients (defined as having node-positive disease or the presence of ≥2 of the following features: T3/T4 disease, Gleason score 8-10, or PSA ≥40 ng/mL) undergoing local therapy predominately with RT were randomized to ADT alone; ADT with abiraterone and prednisone; or ADT with abiraterone, prednisone, and enzalutamide.

At 6 years, the combination arms demonstrated improved metastatic free survival 82% vs 69%, OS, prostate cancer specific biochemical recurrence rates, and PFS when compared with ADT alone. 

No benefit in metastatic disease free survival was seen with the addition of enzalutamide, although side effects were increased. 

These data suggest that the addition of abiraterone and prednisone to ADT and definitive RT should be considered for selected men with high-risk, node-negative disease who meet the STAMPEDE criteria, or men with node-positive disease at diagnosis.

Ongoing studies are employing the Decipher genomic test as a stratification method to inform management of patients with high-risk, localized PCa. 

Elective inclusion of pelvic lymph nodes in the radiation field for patients with intermediate- and high-risk PCa is controversial. 

The rationale for whole-pelvis RT is that the draining pelvic lymph nodes may harbor micrometastatic disease that is insufficiently controlled with ADT alone.

3 randomized clinical trials have failed to demonstrate a conclusive benefit from the addition of whole-pelvis RT to treatment.

The only prospective randomized trial to demonstrate a benefit from whole-pelvis RT has been the POP-RT trial, which limited enrollment to clinically node-negative men with a greater than 20% predicted risk of lymph node involvement by the Roach formula.

Eighty percent of patients had a negative PSMA PET prior to enrollment. 

Additionally, modern RT techniques enabled higher doses of radiation to be delivered to the prostate and pelvic nodes, and long-term ADT was used on all patients. 

This trial not only showed a 5-year absolute improvement of 13.8% in the primary endpoint of biochemical failure-free survival but also a 5-year absolute improvement of 7.1% in the exploratory endpoint of metastatic disease free survival. 

There was a significant increase in cumulative grade 2 or higher late GU toxicity with whole-pelvis RT (20.0% vs 8.9%), whereas grade 2 or higher late GI toxicity was similarly low regardless of whether whole-pelvis RT was delivered. 

The potential gain in outcomes needs to be balanced against an increase in late toxicity. 

There has been interest in focal dose escalation for men with high-risk disease, which can be achieved via BT boosting or by simultaneous integrated external beam boosting. 

At a median follow-up of 6.5 years, men who received a BT boost were twice as likely to be free of biochemical failure (HR, 2.04; P=.004), with 7-year biochemical PFS estimates of 86% vs 75%. 

Prostate BT enables significant escalation in prostate dose, with a sharp falloff to surrounding organs at risk. 

This  benefit was appreciated in both the intermediate-risk and high-risk groups, but no difference in distant metastases or OS was reported. 

The biochemical PFS benefits came at the expense of an increase in grade 3 GI and GU toxicity, and thus the balance between increased toxicity and biochemical control must be weighed individually by patients considering a BT boost. 

However, a further benefit of the BT boost is that it may enable a shorter ADT duration of 12 months for high-risk patients, given findings from a retrospective analysis40 of high-risk patients demonstrating that EBRT/BT may allow for a curtailed duration of ADT without compromising outcomes.

Benefits of BT boost in men at the highest end of the risk spectrum with Gleason 9 or 10 disease were demonstrated in a retrospective analysis of 1809 patients. 

Improvements in PCa-specific survival and distant disease free survival were documented in men who received EBRT/BT/ADT, surpassing the outcomes with RP or EBRT/ADT in this high-risk population.

When comparing patients receiving EBRT/BT with the subgroup of EBRT patients who received optimal-duration ADT (ie, >24 months), the observed PCa-specific survival differences were no longer statistically significant. 

This suggests that if the ADT duration were to be optimized, the outcomes might be equivalent to those with EBRT.

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