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.

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

Coordinating radiation therapy teams and palliative care teams based on patient reported outcomes (PROs) improved outpatient symptom management and decreased end-of-life hospitalizations, as well as costs of care for patients with late-stage cancer, according to interim results from an initiative at the University of Virginia Health System.

Annual Meeting of ASTRO, also showed that rapid palliative radiation therapy with shorter, higher doses of radiotherapy (hypofractionation) led to pain relief from bone metastases within 1 week for a substantial proportion of patients.

The integrated patient care program for patients with advanced cancer undergoing radiotherapy was initiated in 2012 at the University of Virginia Health System. The program used PRO information with the goal of improving patients&rsquo; health, quality of life (QOL), and reducing costs of care, with an emphasis on reducing hospitalizations and improving outpatient management.

&ldquo;This shows that if we listen to our patients carefully, talk to them about their changing medical and emotional needs, and develop rapid and coordinated treatment plans based on their feedback, we can improve their quality of life and reduce the need for hospitalization and symptom management at the end of life,&rdquo; said lead author Paul W. Read, MD, PhD, professor of radiation oncology at the University of Virginia Health System.

This program revealed a need for earlier integration of palliative care into management of patients with advanced-stage cancer. &ldquo;But there are not enough palliative care specialists to go around, so we need to innovate and collaborate,&rdquo; he explained. &ldquo;Our solution is collaborative care with three programs to target patients with the highest symptom burdens.

The three programs are: CARE Track, a data-driven palliative care team that meets weekly and develops coordinated care plans; MY COURSE, a PRO program integrated into electronic health records that triggers email alerts for patients in declining status; and STAD RAD, a same-day highly conformal palliative radiation program with the goal of treating painful bone metastases within 3 to 4 hours.

The program underwent a pilot test in February 2013, and then PRO assessments were taken for all patients starting in October of that year.

The CARE Track program enrolled 646 cancer patients. End-of-life (EOL) care compared data from 368 CARE Track patients with 198 patients not enrolled in the program (the control group). CARE Track patients completed a total of 967 PRO surveys.

Patients enrolled in CARE Track had significantly fewer EOL hospitalizations compared with the control group: in the final 90 days of life, 48.3% were hospitalized compared with 64% of controls (

= .0004). Hospice care was delivered to more CARE Track patients: 69.6% compared with 47% of controls (

<.0001), leading to fewer hospital deaths for patients on CARE Track: 8.4% versus 38.5% (

<.0001). Moreover, CARE Track resulted in a per-patient reduction of $7317 in total costs of care during the last 90 days of life compared with controls (

As part of CARE Track, the multidisciplinary team developed a STAT RAD initiative to improve time to response for initiating pain control in patients with bone metastases. The goal of this workflow effort was to transform a 2-to-3-week treatment program into a 1-day treatment procedure with highly focused radiation treatment to reduce treatment-related toxicity.

The STAT RT pilot trial enrolled 28 patients with 1 to 3 painful bone metastases; 37 target lesions were treated with radiotherapy of 5 to 10 Gy per fraction, for between 2 and 5 fractions (mean of 26.1 Gy in 3.1 fractions).

The International Bone Metastasis Consensus Working Party criteria were used to assess pain response; by 3 weeks, partial or complete pain relief was achieved in 80% to 90% of patients. Using the Functional Assessment of Cancer Therapy (FACT)Bone Pain Scale, QOL was significantly improved 1 to 26 weeks post treatment.

A second clinical trial called STAT RAD is accruing patients to assess another schedule of radiation with the aim of shortening the radiation schedule even further using single fraction STAT RAD, so it can be completed in a single 3- to 4-hour procedure.

&ldquo;Integrating patient surveys to collect patient reported outcomes directly into electronic health records, and incorporating them into routine clinical care can be done in most hospital systems. The concept of Tumor Boards for multispecialty care planning of curative cancer patients is practiced throughout the country, and extending this concept to palliative care management is easy and straightforward. Single fraction radiation therapy for palliation of bone metastases for advanced cancer patients with short life expectancies is an accepted national care guideline and has been studied for decades in clinical trials. Therefore, these programs can all be adopted into clinical practice at most health systems, with minimal cost, training, or education,&rdquo; Read said.

Incrocci  L. Hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year oncologic outcomes of the Dutch randomized phase 3 HYPRO trial. Presented at the 57

Annual Meeting of ASTRO. October 18, 2015. Abstract LBA 6689/LBA 4.

Coordinating radiation therapy teams and palliative care teams based on patient reported outcomes from University of Virginia Health System improved outpatient symptom management and decreased end-of-life hospitalizations, as well as costs of care for patients with late-stage cancer.

Coordination of Care Based on Patient-Reported Outcomes Improves End-of-Life Care and Lowers Costs

Although the drug tasquinimod demonstrated promise in phase II trials, it failed to improve overall survival (OS) in a phase III trial in men with treatment-na&iuml;ve metastatic castration-resistant prostate cancer (mCRPC).

Based on the results, Active Biotech and Ipsen have discontinued development of this agent in prostate cancer, and some experts believe this failure highlights the need for more intelligent clinical trial designs in prostate cancer.

&ldquo;In the phase III trial, although radiographic progression-free survival [rPFS] was longer with tasquinimodsimilar to the phase II results&mdash;this did not translate to an overall survival effect. In fact, survival favored placebo,&rdquo; said lead investigator Michael Carducci, MD, Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center.

&ldquo;We don&rsquo;t know the reasons for the disconnect between the radiographic progression-free survival benefit and lack of a survival benefit,&rdquo; he told attendees at the 2015 European Cancer Congress.

Tasquinimod is an oral therapy that is thought to target the tumor microenvironment. The drug is reported to elicit an immune response, antiangiogenic activity, and antimetastatic activity, but formal discussant of this abstract, Johann De Bono, MD, took issue with the purported mechanism of action &ldquo;We don&rsquo;t really know how this drug works, and that should cause concern,&rdquo; said De Bono.

Carducci explained that in the phase II randomized, double-blind, placebo-controlled trial in a similar patient population, tasquinimod significantly extended radiographic progression-free survival (rPFS) versus placebo: median rPFS was 3.3 months with tasquinimod versus 7.6 weeks with placebo (

&ldquo;The greatest benefit of tasquinimod in the phase II trial was in patients with bone-only metastasis, with a median rPFS of 12.1 months versus 5.4 months for placebo,&rdquo; he said.

The randomized, double-blind, placebo-controlled, phase III study screened 1645 men and enrolled 1245 men with asymptomatic or mildly symptomatic, chemotherapy-na&iuml;ve mCRPC with metastasis confined to the bone. Subjects were randomized in a 1:1 ratio to receive tasquinimod once a day titrated to a dose of 1 mg/day over 4 weeks or placebo and treated until the occurrence of disease progression or unacceptable toxicity.

The study met the primary endpoint, with a significant benefit for tasquinimod in rPFS: 7 months versus 4.4 months for placebo (

<.001). Subgroup analysis showed a benefit across the board for tasquinimod in rPFS.

However, no survival advantage was observed. Median OS was 21.3 months for tasquinimod versus 24 months for placebo, and no significant trends toward benefit for tasquinimod were observed in any subgroup.

More patients assigned to tasquinimod stopped treatment due to adverse events. There were more reports of decreased appetite, nausea, fatigue, and asthenia in the tasquinimod arm, which may have led to higher rates of discontinuation of study drug, Carducci said.

In his discussion, De Bono assured attendees that studying failed trials can lead to success by learning lessons about disease biology, drug pharmacology, and how to design better trials.

First, as mentioned above, he took issue with the mechanism of action of tasquinimod, noting that it is poorly understood.

&ldquo;However, that shouldn&rsquo;t stop going to phase III trials if the drug has significant antitumor activity,&rdquo; commented De Bono.

After reviewing the phase I and II tasquinimod data, he found that the antitumor activity of the drug was &ldquo;modest at best.&rdquo;

&ldquo;It would be more important to analyze the genome of those who were exceptional responders to understand why the drug worked in them,&rdquo; he said.

The disconnect between phase II rPFS and OS in phase III has been seen before in prostate cancer with other drugs, so it shouldn&rsquo;t have been a surprise, he continued.

His main argument was that rPFS is not a good surrogate marker for OS in mCRPC. &ldquo;Results of this trial and other trials show that rPFS is truly not an intermediate endpoint in prostate cancer,&rdquo; he stated. At best there is a poor correlation between rPFS and OS in mCRPC.&rdquo;

&ldquo;Randomized phase II results are overrated in prostate cancer. These trials are misleading us, with a high rate of false positivity. We need to raise the bar in clinical trials,&rdquo; De Bono emphasized.

According to De Bono, the way forward is to understand the genome of prostate cancer patients and target actionable mutations. Also, better surrogate endpoints are needed to accelerate anticancer drug development.

&ldquo;We need better understanding of mCRPC to advance our success in finding effective treatments for this disease,&rdquo; he concluded.

Carducci M, Armstrong A, Pili R, et al. A phase 3, randomized, double-blind, placebo-controlled study of tasquinimod (TASQ) in men with metastatic castrate resistant prostate cancer (mCRPC). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 4BA.

Tasquinimod demonstrated promise in phase II trials but failed to improve overall survival in a phase III trial in  treatment-naive metastatic castration-resistant prostate cancer; some experts believe this failure highlights the need for more intelligent clinical trial designs in prostate cancer.