Kate Johnson

May 31, 2015

CHICAGO, IL — Chemotherapy, which has traditionally been considered a treatment of last resort for prostate cancer, continues to inch closer to the therapeutic frontline, according to new research presented here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

On the heels of several recent trials (CHAARTED and STAMPEDE) suggesting a role for docetaxel chemotherapy in metastatic prostate cancer, a new trial — Radiation Therapy Oncology Group (RTOG) 0521 — now suggests it may have even greater benefit at an earlier stage: in high-risk, localized disease.

"Our study included nonmetastatic, potentially curable prostate cancer," lead investigator Howard M. Sandler, MD, from Cedars-Sinai Medical Center in Los Angeles, California, told Medscape Medical News.

"This is the first study that shows a potential survival benefit to using chemotherapy in this high-risk patient subset, and I think that for the right patient, the right physician, there will be justification — based on these results — for adding adjuvant docetaxel."

His words echoed those of STAMPEDE's lead investigator, Nicholas David James, MD, PhD, from Queen Elizabeth Hospital Birmingham, United Kingdom, who said during the same session that in addition to considering routine docetaxel in the metastatic setting, it should also "be considered for selected men with high-risk nonmetastatic disease," given the "substantial prolongation of failure-free survival" his trial showed in this patient population.

However, although some experts welcome the news of an earlier role for chemotherapy in prostate cancer, concerns about the toxicity of docetaxel and the robustness of the RTOG 0521 results have other experts urging caution.

As discussant for both the STAMPEDE and RTOG 0521 studies, Ian Tannock, MD, PhD, from Princess Margaret Cancer Centre, University of Toronto, Ontario, Canada, added a dissenting voice to the plenary session.

Although a newly published trial, Groupe d'Étude des Tumeurs Uro-Génitales (GETUG) 12, shows no benefit to upfront chemotherapy (hazard ratio [HR], 0.71) in high-risk localized disease, according to relapse-free survival rates ( Lancet Oncol. Published online May 28, 2015), and STAMPEDE shows a strong benefit in this same measure (HR, 0.57), relapse-free survival "does not inevitably mean improved overall survival," Dr Tannock pointed out.

Questioning RTOG's one-sided statistics and failure to meet its prestated criteria for an overall survival benefit, he said, "if there is no effect on overall survival, then chemo delayed is toxicity delayed, and is the preferred strategy."

Although he said his opinion might change with longer follow-up, for the time being, Dr Tannock put a damper on some of the enthusiasm for earlier chemotherapy. He recommends that "men with localized nonmetastatic prostate cancer who are to receive local treatment with radiotherapy should not be offered docetaxel in addition to androgen-deprivation therapy."

Study Details

RTOG 0521 enrolled 563 patients (mean age, 66 years) with high-risk localized prostate cancer. Patients were randomly assigned to receive standard therapy, which consisted of 24 months of androgen suppression and 8 weeks of external radiotherapy, or standard therapy plus chemotherapy, which consisted of six 21-day cycles of docetaxel plus prednisone starting 28 days after radiotherapy.

After a median follow-up of approximately 6 years, the 4-year overall survival rate was significantly higher in the chemotherapy group (93% vs 89%; P = .04; HR, 0.70, although this did not meet the prestated HR goal of 0.49).

Other endpoints such as distant metastasis and disease-free survival were also significantly better in the chemotherapy group compared with the control group.

Although there were more deaths in the control group, the causes of death were "strange," noted Dr Tannock.

There were seven more prostate cancer deaths in the control group, but this was counter-balanced by six deaths in the experimental group resulting from toxicity or unknown causes compared with none in the control group.

Speaking at a press conference, Dr Sandler described docetaxel as "a relatively familiar and well-tolerated systemic chemotherapy regimen." However, toxicity should be the main concern for practicing clinicians considering upfront chemotherapy, another expert told Medscape Medical News.

"Death in the adjuvant setting is sobering," said Marc B. Garnick, MD, professor of medicine at Harvard Medical School in Boston, Massachusetts. "With any adjuvant program comes the balance of risk of relapse vs toxicity of the treatment program. These patients may have been cured with the standard therapy, yet may have been exposed to a fatal outcome in the adjuvant setting."

Cause of Death Androgen Suppression + Radiotherapy (n = 59) Androgen Suppression + Radiotherapy + Chemotherapy (n = 43)
Death resulting from cancer under study 23 16
Death resulting from protocol treatment 0 2
Death resulting from other cause 24 16
Death resulting from secondary primary 12 5
Unknown cause of death 0 4

Dr Granick, who is also editor-in chief of the Harvard Medical School Annual Report on Prostate Diseases, also commented that "wiith the introduction of any new treatment programs, the devil will be in the details."

He added, "While Sandler et al need to be congratulated for carrying out this complicated study, final assessment of its importance will by necessity require details, details, and more details, along with greater follow-up."

He also cautioned that because very few of the data have been published in full-length, peer-reviewed manuscripts, "we are left with many unanswered questions and uncertainties before the touted results can be taken as fact."

Reaction was more positive from Christopher Sweeney, MD, whose CHAARTED study, presented last year at this meeting, helped shape the debate about upfront chemotherapy in prostate cancer.

"It is both reassuring and indeed very encouraging to see the results of RTOG 0521," Dr Sweeney, from the Dana-Farber Cancer Institute in Boston, told Medscape Medical News, emphasizing what he called the "consistency of accumulating evidence" for docetaxel in prostate cancer.

"All in all, we are in the medical profession to decrease the number of people who die of cancer," he said. "Multimodality and multidisciplinary care attacking cancer from different angles has been a winning proposition for many other cancers. It is very, very exciting to see we are starting to see strong and consistent evidence that we are achieving the same with high-risk localized prostate cancer treated with radiation plus testosterone suppression plus docetaxel. These are men who have aggressive prostate cancer, and left untreated, many die of this type of prostate cancer. As such, they need proactive treatment. As these results mature, we will not sit on our laurels but are enthusiastic about assessing the other agents which are active in these earlier settings, either in combination with docetaxel or as alternatives for patients who are not fit for chemotherapy."

ASCO expert Charles J. Ryan, MD, professor of medicine at the University of California, San Francisco, School of Medicine, was also enthusiastic.

"Adjuvant chemotherapy has delivered major survival gains to people with several of the most common types of cancer, and now we're finally seeing the same with prostate cancer. Here we have a powerful new use for a long-established therapy," he said.

In fact, RTOG 0521 is the first prostate cancer study ever to show a benefit for "adjuvant" chemotherapy in the strict definition of the word, he added.

In both CHAARTED and STAMPEDE, the chemotherapy was "not adjuvant as we define it in most cases," he told Medscape Medical News. "Adjuvant applies, typically, to medical therapy added to treatments given with curative intent, and RTOG 0521 used radiation with curative intent."

The RTOG 0521 study received funding from the National Institutes of Health, Sanofi, and AstraZeneca. Dr Sandler reported no conflicts of interest, but several coauthors report relationships with pharmaceutical companies, as detailed in the abstract.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA 5002. Presented May 31, 2015.

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