Bonnie Gillis

The explosion of new drugs for the treatment of castration-resistant prostate cancer (CRPC) is a welcome advance, but raises questions about how best to sequence these drugs with standard docetaxel chemotherapy. A subanalysis of the ALSYMPCA trial suggests that chemotherapy can be safely administered after treatment with radium-223 (Xofigo), which is the only approved radiopharmaceutical for patients with metastatic CRPC and bone metastasis.

The study, which was presented at the 2015 European Cancer Congress, was a post-hoc analysis of patients enrolled in ALSYMPCA who received chemotherapy post treatment with radium-223 and post treatment with placebo. Follow-up was 3 years.

&ldquo;This study has some limitations, including the fact that it represents a subset of patients based on postrandomization factors, including study drug treatment with radium-223 or placebo, and randomization of the original study does not ensure comparability of the treatment arms,&rdquo; said lead author Oliver Sartor, MD, Tulane Cancer Center, New Orleans, LA.

&ldquo;Given these limitations, this post-hoc analysis indicates that chemotherapy following radium-223 appears to be safe, with no new hematologic concerns and no new detrimental effects on survival. Patients who were earlier in the course of disease and received all 6 injections of radium-223 were able to receive subsequent chemotherapy. This encouraging finding confirms the flexibility and versatility of radium-223, supporting the safety of administering chemotherapy after radium-223 regardless of prior docetaxel use,&rdquo; Sartor stated.

Of 921 patients enrolled in ALSYMPCA, 206 (22%) received chemotherapy post study: 142 from the radium-223 arm and 64 from the placebo arm. Docetaxel was the most commonly used post-study chemotherapy; 70% of the post-radium-223 arm and 72% of the post-placebo arm were treated with docetaxel. Subgroup analysis was performed according to prior docetaxel use.

Demographic and baseline characteristics were generally well balanced between the treatment arms in the chemotherapy post-study drug subgroups for age, baseline ECOG status, extent of disease, prostatespecific antigen (PSA) levels, and other parameters.

Compared with the original ALSYMPCA population, the chemotherapy post-study subgroup patients were younger, had better ECOG performance status, lower disease volume (number of metastases), and lower total alkaline phosphatase levels and lower PSA levels. Compared with the overall ALSYMPCA population, a greater percentage of patients in the post-study drug subgroup received all 6 planned injections of study drug: for those assigned to radium-223, 63% of the overall ALSYMPCA population and 79% of the chemotherapy post-study subgroup got all 6 injections, and 47% and 58%, respectively, of the placebo group got all 6 planned injections.

In both chemotherapy post-study group arms, median hematologic lab values remained constant from the last measurement before chemotherapy to 18 months after chemotherapy. These hematologic values were similar for patients who received prior docetaxel and no prior docetaxel. No treatment differences in hematologic values were observed within the no-prior and prior docetaxel subgroups.

Decreases from baseline in hemoglobin and neutrophil levels were similar in the two treatment arms. Decreases from baseline in platelets tended to be greater in the radium-223 arm compared with placebo, but this was likely due to radium-223 rather than subsequent chemotherapy, according to Sartor. Decreases in platelets were similar in patients who had prior docetaxel and no prior docetaxel. The rates of grade 3 or 4 hematologic adverse events were generally low, but were somewhat higher in the radium-223 arm compared with the placebo arm.

No significant difference in survival was observed between radium-223 and placebo during or within 30 days of completing chemotherapy. Twenty-nine percent of patients in the radium-223 group and 33% in the placebo group died during and within 30 days of completing chemotherapy. The most common cause of death was prostate cancer (90% in the radium-223 arm and 95% in the placebo arm). Median overall survival (OS) from the start of chemotherapy was 18 months after radium-223 and 15.8 months after placebo, which was not statistically different.

Sartor O, Coleman RE, Nilsson S, et al. 3-year follow-up of chemotherapy following radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients (Pts) with symptomatic bone metastases (Mets) from ALSYMPCA. Presented at: European Cancer Congress 2015; Poster session; Vienna, Austria. Abstract 2510.

Articles

The explosion of new drugs for the treatment of castration-resistant prostate cancer (CRPC) is a welcome advance, but raises questions about how best to sequence these drugs with standard docetaxel chemotherapy.

Chemotherapy Safe After Radium-223 for Men With mCRPC

Hypofractionated radiotherapy can achieve similar cure rates with similar side effects compared with conventional radiotherapy for men with low-risk, early prostate cancer, according to follow-up RTOG 0415 study data presented October 20, 2015, during a scientific session at the 2015 ASTRO Annual Meeting.

Hypofractionated radiotherapy is delivered in larger doses over 5.5 weeks whereas conventional radiotherapy requires 8 weeks of treatment. &ldquo;Results of our study demonstrate that for men with low-risk prostate cancer, hypofractionated radiotherapy offers a shorter, more convenient treatment schedule without compromising cure or causing additional side effects,&rdquo; said lead author W. Robert Lee, MD, professor of radiation oncology at Duke University School of Medicine, Durham, NC.

Senior author of the study, Howard Sandler, MD, professor and chair of radiation oncology at Cedars Sinai Medical Center, Los Angeles, CA, said, &ldquo;This is the first large-scale, randomized study demonstrating the value of a shorter course of radiotherapy for low-risk prostate cancer. The results are not surprising; however, given that studies of the effects of hypofractionated radiation therapy in patients with early-stage breast cancer, which is similar to early-stage prostate cancer, have demonstrated similar outcomes.&rdquo;

The phase III RTOG 0415 study, conducted from April 2006 to December 2009 in the United States and Canada, enrolled 1115 men with low-risk prostate cancer and randomized them to receive either hypofractionated radiotherapy or a conventional radiotherapy schedule. Baseline demographic and disease characteristics were comparable between the two groups. Mean age was about 65 years and pretreatment prostate specific antigen (PSA) score was 5.4 ng/mL.

RTOG 0415 was designed as a noninferiority study for the two techniques, as reflected by a 5-year disease-free survival (DFS) rate not lower by more than 7% compared with conventional radiotherapy.

A total of 1105 men with low-risk prostate cancer were randomized 1:1 to conventional radiotherapy (73.8 Gy in 41 fractions delivered over 8.2 weeks) or hypofractionated radiotherapy (70 Gy in 28 fractions delivered over 5.6 weeks). Low risk was defined as not palpable, PSA <10 ng/mL, or Gleason score of 6 or lower.

At a median follow-up of 5.9 years, DFS rates were similar for both groups of men. In more than 300 men followed for more than 5 years, 82% in the hypofractionated group and 76% in the conventional radiotherapy group were alive with no evidence of disease. This demonstrates noninferiority, Sandler said.

Biochemical recurrence and overall survival also met noninferiority criteria.

Toxicity is important to assess in these men, Sandler continued. Grade 3 or higher gastrointestinal toxicity was slightly higher with hypofractionation: 3% for conventional radiotherapy versus 4.6% for hypofractionation. Grade 3 or higher genitourinary toxicity was 3.5% versus 2.3%, respectively.

&ldquo;These are small absolute differences, with a possible increase in late side effects,&rdquo; Sandler noted. &ldquo;Both techniques are very well tolerated. If there is a difference between them, that difference is very small. Results suggest that this shorter regimen is a treatment regimen that physicians can be comfortable discussing and prescribing for their patients.&rdquo;

&ldquo;Standard radiotherapy for prostate cancer takes 8 to 9 weeks. It is a long time commitment and somewhat daunting to patients. Shorter radiotherapy treatments may be a better way to treat prostate cancer,&rdquo; Sandler said.

During the discussion following this presentation at a press conference, Sandler commented that many patients with low-risk disease, such as those included in this trial are now managed with active surveillance, moving on to treatment if there is an indication that the disease has progressed.

&ldquo;We carefully monitor these patients. Some will progress. I would recommend active surveillance as the first option, and move on to hypofractionated radiotherapy if and when it is needed,&rdquo; he stated.

Lee, RW. NRG Oncology RTOG 0415: A randomized phase III non-inferiority study comparing 2 fractionation schedules in patients with low-risk prostate cancer. Presented at the 2015 ASTRO Annual Meeting: San Antonio, TX; Abstract LBA 6.

Hypofractionated radiotherapy can achieve similar cure rates with similar side effects compared with conventional radiotherapy for men with low-risk, early prostate cancer, according to a recent study.

Prostate Cancer Study Shows Hypofractionation Comparable to Standard Radiation in Low-risk Patients

Accelerated partial breast irradiation (APBI) using multicatheter brachytherapy is as effective as conventional whole breast irradiation (WBI) for selected low-risk patients following breast-conserving surgery, according to a long-term follow-up of a phase III multicenter European noninferiority study. The rates of local control, disease-free survival (DFS), and overall survival (OS) were comparable for both techniques.

This is the first phase III study proving noninferiority of APBI compared with WBI for select patients with early-stage breast cancer. It is also the most comprehensive study to date comparing these techniques. Results were reported at the 57

&ldquo;The results of our study show that, at present, multicatheter brachytherapy is an attractive and viable APBI treatment option for low-risk breast cancer patients after breast conserving surgery,&rdquo; said lead author Vratislav Strnad, MD, PhD, professor of radiation oncology at University Hospital Erlangen, Germany.

&ldquo;The results were not totally surprising, because ... results of several smaller phase II trials showed low recurrence rates after breast-conserving surgery and APBI in comparison to WBI. What is surprising, however, is how clear the results are. Our favorable results are in contrast to the disappointing and controversial results reported from other studies that used other APBI techniques, such as intraoperative and external beam radiation therapy,&rdquo; he said.

Standard WBI uses external beam radiation and treats the entire breast and surrounding chest area for several weeks, followed by a boost of radiation to the tumor bed. Many women choose mastectomy in hopes of avoiding WBI, largely due to the duration of treatment and fears of side effects, Strnad said.

APBI with multicatheter brachytherapy delivers effective radiation dose directly to the tumor, shortening the time of treatment to 4 or 5 days, while limiting side effects of radiation exposure to normal adjacent tissue in the heart, lungs, and skin. The shortened time to treatment with APBI is particularly attractive for elderly patients, working women, and women who have to travel distances to a radiation treatment facility, he explained.

From April 2004 to July of 2009, the multicenter phase III study enrolled 1184 patients from 16 centers in Europe. Patients had early-stage breast cancer (stages 0, I, and IIA), were age 40 years or older, and were treated with breast-conserving surgery.  Patients were randomized to conventional WBI (50 Gy with tumor bed boost of 10 Gy &nbsp;about 7 weeks) or APBI using interstitial multicenter brachytherapy for 5 days. Median age was 62 years, and about 50% of patients were younger than 60 years.

Baseline disease and demographic factors were similar for the two groups. At a median follow-up of 6.6 years, 5-year local recurrence rates were 1.4% for APBI versus 0.9% for WBI; 5-year second primary ipsilateral breast cancers were found in 1.1% versus 0.9%, respectively; 5-year DFS rates were 95% versus 94.5%, respectively; 5-year OS rates were 97.3% versus 95.6%, respectively. Local and regional recurrence rates were similar between the two groups for all age groups and all tumor types independent of the type of subsequent therapies that patients received.

Strnad noted that prior recommendations were for APBI to be used in older patientsthose over age 50 or 60 years, but this study showed excellent results in all age groups, including those aged 40 years and older. Longer study is needed to analyze recurrence rates beyond 5 years in different subgroups based on age, according to Strnad.

Catherine Park, MD, USCF, who moderated the press conference where the data were presented, commented that the patients in this study were highly selected. APBI was studied with several techniques. This study focused on multicatheter brachytherapy to deliver the radiation.

&ldquo;In the US, multicatheter brachytherapy is not widely available. External bean radiation is the most widely used technique for partial breast radiation,&rdquo; she explained.

Strnad V. Accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole breast irradiation for early breast cancer: 5-year results of a randomised phase III trial  Part I: Local control and survival results. Presented at 57

Annual Meeting of ASTRO. October 19, 2015: San Antonio, TX. Abstract LBA 7

A phase III study shows noninferiority of accelerated partial breast irradiation as compared to conventional whole breast irradiation.

Shorter Radiation Technique Comparable to Standard Radiation for Low-Risk Breast Cancer

Hypofractionation, known as delivering higher doses of radiation in fewer fractions, appears to be feasible and non-inferior compared with conventional fractionated radiotherapy, according to 5-year follow-up results of the randomized HYPRO trial, which were reported at the 2015 ASTRO Annual Meeting.

The rates of relapse-free survival (RFS), the primary endpoint of the trial, were comparable in both arms: 80% for hypofractionated radiotherapy versus 77% for conventional fractionated radiotherapy. Acute toxicities were similar, with slightly higher gastrointestinal (GI) toxicities reported in the hypofractionated arm.

&ldquo;Hypofractionated radiotherapy achieved a higher relapse-free survival rate compared with conventional fractionated radiotherapy, but the difference between the two arms was not statistically significantly different. The acute and late toxicity are comparable between the two schedules. At this point, we can say that hypofractionated radiotherapy is safe and of interest to be introduced in the clinic,&rdquo; said lead author Luca Incrocci, MD, Department of Radiation Oncology, Erasmus MC Cancer Institute in Rotterdam, the Netherlands, who reported the results during the meeting.

The study enrolled 820 patients with intermediate- or high-risk prostate cancer (stage T1b to T4) at seven centers in the Netherlands between March 2007 and December 2010. Patients were randomized 1:1 to receive hypofractionated radiotherapy (19 fractions of 3.4 Gy in 6.5 weeks, 3 fractions per week) or conventional fractionated radiotherapy (39 fractions of 2 Gy in 8 weeks, 5 fractions per week).  Both groups had a similar distribution of demographic and disease characteristics. Median age was 71 years (range, 44-85 years).

HYPRO was a non-inferiority trial designed to detect an absolute reduction of 10% in relapse rate at 5 years in the hypofractionated arm.

Patients were stratified into three risk groups according to seminal vesicle involvement. Low-risk patients were excluded, and concomitant hormone therapy was allowed.

At a median follow-up of 5 years, 804 patients were evaluable for RFS. Almost two-thirds of patients were treated with hormonal therapy. A multivariate analysis found that a Gleason score of 7 or lower and use of hormonal therapy for 12 months or longer were each statistically significantly associated with higher RFS.

Overall survival at 5 years was 86% in both arms, though follow-up was too short to detect a survival benefit, Incrocci said.

&ldquo;With new radiation schedules, we need to worry about toxicity,&rdquo; he continued.

Acute GI toxicity (grade 2 or higher) at 120 days was slightly higher in the hypofractionated arm: 31.2% versus 42%, respectively, for an absolute difference of 10.8%. Acute genitourinary (GU) toxicity was 57.8% for the conventional arm versus 60.5% for hypofractionation, an absolute difference of 2.7%. These differences were not statistically significant, Incrocci said.

Unpublished data show no significant difference in late toxicity (GU, GI, and sexual function) between the two arms. Further analysis on the data will be forthcoming, Incrocci added.

Hypofractionation, known as delivering higher doses of radiation in fewer fractions, appears to be feasible and non-inferior compared with conventional fractionated radiotherapy.

Bonnie Gillis | Authors

Articles

Chemotherapy Safe After Radium-223 for Men With mCRPC

Prostate Cancer Study Shows Hypofractionation Comparable to Standard Radiation in Low-risk Patients

Shorter Radiation Technique Comparable to Standard Radiation for Low-Risk Breast Cancer

Hypofractionated Radiotherapy May be Viable in Intermediate- and High-Risk Prostate Cancer