Challenging and Changing the Standard of Care for Cervical and Ovarian Cancers 


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We have learned a lot about the role of PARP inhibitors and who may be the best patients in ovarian cancer to receive these therapies.

—Paul Haluska MD, PhD

“It was a very exciting session this year, particularly for cervical cancers,” said Paul Haluska MD, PhD, of the Mayo Clinic, Rochester, Minnesota, in speaking of the 2013 ASCO Annual Meeting’s gynecologic oncology session and the abstracts highlighted recently at Best of ASCO in Chicago. In one study in recurrent cervical cancer, the addition of bevacizumab (Avastin) to chemotherapy has changed the standard of care,1 and, in another study, the results reportedly have “global implications” that could help avoid 22,000 cervical cancer deaths per year in India and over 72,000 deaths from cervical cancer annually in resource-poor countries.2

Dr. Haluska also discussed a number of studies in ovarian cancer from the Annual Meeting and presented subsequently at Best of ASCO.3-6

Improved Outcomes in Advanced Cervical Cancer

Adding bevacizumab (Avastin) to chemotherapy improved outcomes for women with persistent, metastatic, or recurrent cervical cancer treated in a randomized phase III study, and for those with recurrent disease, the improvements were great enough to warrant a change in the standard of care, according to Dr. Haluska.

The 452 patients participating in the four-armed Gynecologic Oncology Group (GOG 240) clinical trial were randomly assigned to treatment with a chemotherapy-alone regimen or to chemotherapy plus bevacizumab at 15 mg/kg. The two chemotherapy regimens tested included (1) cisplatin at 50 mg/m2 plus paclitaxel at 135 to 175 mg/m2 and (2) topotecan at 0.75 mg/m2 on days 1 to 3, plus paclitaxel at 175 mg/m2 on day 1.

“The rationale for the non–platinum-containing regimen is that many patients have previously been treated with a platinum,” Dr. Haluska explained, since chemoradiation with platinum is the standard of care for front-line treatment of locally advanced cervical cancer. “So the question is, after patients have received a platinum, is a non–platinum-containing regimen better? We know that there is activity with topotecan in combination with paclitaxel, which is the justification for these additional arms.”

Little progress has been made over the past 30 years in treating advanced cervical cancer. This coupled with additional data led investigators to conduct this study. They reported no significant differences in survival between the two chemotherapy arms, but the addition of bevacizumab to a chemotherapy regimen “led to a statistically significant and substantial improvement in overall survival,” Dr. Haluska said. Median overall survival was 17.0 months for those in the bevacizumab/chemotherapy arms vs 13.3 months for those receiving chemotherapy only. “If we look at the progression-free survival, this was also statistically significant and improved by addition of bevacizumab, from 5.9 to 8.2 months,” said Dr. Haluska. Adverse events were similar to those seen in other patients receiving bevacizumab, including hypertension, neutropenia, thromboembolisms, and gastrointestinal -perforations.

Standards of Care Vary by Disease Setting

Dr. Haluska acknowledged that chemoradiation remains the standard of care for locally advanced disease. Further, the study suggested that patients with metastatic disease did not benefit as much by the addition of bevacizumab to chemotherapy as patients who had previously been treated for locally advanced disease.

In the setting of recurrent disease, however, Dr. Haluska said bevacizumab/chemotherapy should be the standard of care. “I think the results speak for themselves,” Dr. Haluska said, and “the addition of bevacizumab to chemotherapy yielded statistically significant improvement in progression-free and overall survival rates [in patients with recurrent disease] with no significant effect on quality of life.” Adverse events with the addition of bevacizumab were expected and mostly manageable, according to study investigators.

Dr. Haluska added that bevacizumab as of yet “has no formal labeled indication” for cervical cancer and whether it will be approved for use in this setting is not presently clear.

Global Implications of Cervical Cancer Screening Study

Referring to a study showing that cervical cancer mortality was reduced by 31% among women in India screened with biennial visual inspection with acetic acid or vinegar, Dr. Haluska commented, “While this may have little impact on U.S. care, the global implications are enormous.” An estimated 22,000 lives per year could be saved in India alone and the worldwide benefit could reach 250,000 lives saved per year. “Importantly, the results were not due to overdiagnosis,” Dr. Haluska said, but “clearly the identification of premalignant lesions.”

Maintenance Therapy for Ovarian Cancer

Maintenance therapy for patients with ovarian cancer was tested in two trials, one with the multi-kinase inhibitor pazopanib (Votrient) and the other with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib.

Among 940 patients who had not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancers, those randomized to maintenance therapy with pazopanib for 24 months had a median progression-free survival of 17.9 months vs 12.3 months for those receiving placebo. This difference of 5.6 months was statistically significant, Dr. Haluska reported. “However, overall survival at the first analysis was not statistically significant,” he noted. “So one has to be concerned that in the end, we will not see an overall survival benefit with pazopanib despite the improvement in progression-free survival.”

Pazopanib therapy was “fairly toxic,” Dr. Haluska said, and “this led to a substantial reduction in the dosing of patients after the first cycle.” Side effects included hypertension, neutropenia, some liver toxicities, hand/foot syndrome, and headache.

While patients could have received chemotherapy prior to the trial, those who had received any anti-VEGF therapy, including bevacizumab, were excluded from this trial. “I think that was a mistake, as patients who may have gone into remission with a VEGF-targeted therapy may have been the best patients to receive this therapy. Perhaps they would have the most to gain from pazopanib. Yet we don’t know how well they would have performed with pazopanib because they were not included in the study.”

Dr. Haluska observed that there were parallels between this study with pazopanib and the use of paclitaxel as maintenance therapy. The paclitaxel studies had shown about a 7-month improvement in progression-free survival, but there was no overall survival improvement, and there was toxicity, particularly the possibility of fairly severe neuropathy in about 25% of patients. “My sense is that most physicians in practice are not using paclitaxel as maintenance chemotherapy after remission,” Dr. Haluska said, and “given this data, it is unlikely that pazopanib will be accepted or approved as a maintenance therapy, particularly without any overall survival benefit.”

Relapsed Ovarian Cancer

“We have learned a lot about the role of PARP inhibitors and who may be the best patients in ovarian cancer to receive these therapies,” Dr. Haluska noted. In particular, tumors with homologous recombination repair deficiency “may be most sensitive to PARP inhibition because of their inefficiency at repairing single-strand DNA breaks, leading to cell death. And BRCA1 and BRCA2 mutant tumors are probably the reference gene mutation for demonstrating this,” Dr. Haluska continued.

BRCA-mutated epithelial cancers are very sensitive to PARP inhibition, although these only represent about 10% to 15% of epithelial ovarian cancers.” Other data, however, indicate the percentage of high-grade serous ovarian cancers sensitive to PARP inhibition could be as high as 50%, according to Dr. Haluska.

A previously reported study among women with platinum-sensitive relapsed serous ovarian cancer found that maintenance therapy with olaparib led to significant improvement in progression-free survival. In addition, a preplanned analysis suggested that progression-free survival might be greater, and there might be an overall survival benefit as well, in patients with a known germline BRCA mutation. BRCA mutation was not a requirement for the study and at baseline only about 36% of patients had a known BRCA mutation, “but given this data on the role of BRCA mutations and response to PARP inhibitors, the investigators went back and identified, as best they could, the number of patients that had a germline BRCA mutation and a tumor mutation BRCA,” Dr. Haluska explained.

“They identified a large number of mutations in the tumor as well as germline mutations,” he said. Out of a total of 265 patients in the original study, 136 had a mutation either in the tumor or at the germline level for BRCA. Among these patients, “there was a fairly impressive improvement in progression-free survival” for those who had received olaparib, 11.2 months vs 4.3 months for those receiving placebo. The hazard ratio was .35 for all patients, but this improved to .18 for patients with mutations in BRCA either in the tumor or at the germline level. “This was highly statistically significant,” Dr. Haluska said.

Overall survival in the total patient population was 29.8 months for those receiving olaparib vs 27.8 months for those receiving placebo, with a hazard ratio of 0.88. In the subset of patients with BRCA mutations, “the hazard ratio was a bit better—0.74, or 34.9 vs 31.9 months—but still was not statistically significant as far as overall survival,” Dr. Haluska said.

“Importantly, there is no difference in quality of life in patients receiving olaparib. It is a very tolerable agent,” Dr. Haluska said. “There were no major problems with delivering this therapy in this population. But its benefit may be greatest in the BRCA-mutated population, and we anxiously await the overall survival data to be updated.”

Chemotherapy Schedule in Advanced Ovarian Cancer

The MITO 7 trial5 compared conventional chemotherapy with paclitaxel and carboplatin vs a weekly regimen for 822 women with advanced ovarian cancer. Both study arms performed well and there were no statistically significant differences in progression-free or overall survival, Dr. Haluska said.

“There were differences, however, in the number of people that could complete the six cycles of chemotherapy, favoring the every-3-weeks regimen, though the quality of life in the weekly group was better,” he added. There were more toxicities, specifically neuropathy, hair loss, vomiting, and neutropenia in the every-3-weeks regimen. The quality of life for those patients was “pretty much coincident with the delivery of chemotherapy on an every-3-weekly basis” and the decrease in the quality of life “was statistically significantly different,” he said.

“There was a lot of discussion at ASCO about this study, as well as subsequently, and I think it is important to consider the MITO 7 results in the context of the standards of care established in the Japanese GOG study,” he said. “There is a great difference between weekly and dose-dense. This study, MITO 7, was a weekly treatment; it was not a dose-dense treatment, so the lack of an improvement compared to conventional chemotherapy doesn’t dampen my enthusiasm for dose-dense chemotherapy.”

Dose-dense therapy, such as established in the Japanese GOG study, “is still a standard of care,” he said. “This study was not to confirm those results. We will have further data from the GOG 252 and ICON 8, which will help us verify that the dose-dense strategy benefit that was seen on the Japanese GOG study was not because of some unrealized pharmacogenomics changes or differences in the Japanese population vs the rest of the world,” Dr. Haluska stated.

“The weekly regimen is a reasonable alternative for patients wanting to focus on quality of life,” Dr. Haluska said. The patient should be counseled, however, “that the outcomes might not be [equivalent to standard dosing of chemotherapy]. I wouldn’t advocate this for routine use, but it could be a discussion that you have with your -patients.”

Neoadjuvant Chemotherapy for Ovarian Cancer

The CHORUS trial compared neoadjuvant chemotherapy followed by surgery to upfront surgery followed by chemotherapy among 550 women with newly diagnosed advanced ovarian cancer and found no real differences in progression-free or overall survival.6 “But what was striking about this study was the poor performance of the arms in this study,” Dr. Haluska said, “compared to some of the more contemporary adjuvant chemotherapy trials.”

While median overall survival in these trials was in the 50- to 60-month range, in the CHORUS trial, median overall survival was in the 20- to 30-month range. The underperformance in the neoadjuvant chemotherapy vs adjuvant chemotherapy trials “is really compelling,” Dr. Haluska said.

To determine underlying reasons for these differences, Dr. Haluska reviewed some key predictors of outcome. There were “impressive” differences in performance status, he noted. The number of patients with performance status 0 “was fairly low in the CHORUS study” compared to other contemporary studies and “may explain the poor underperformance of the arms in this study.”

The percentage of optimal debulking was “reasonable” in the CHORUS study and “somewhat comparable, although probably less than most of the studies done with adjuvant chemotherapy,” Dr. Haluska said. There was a wide range in the ability to optimally debulk patients according to the country, with some countries having poor rates of optimal debulking “and that may have affected the outcome,” he added.

“I think it is unlikely that these results really can be generalized to patients who have a good performance status and are good surgical candidates,” Dr. Haluska stated. “In my opinion, upfront surgical debulking followed by chemotherapy is still the standard of care until we can have a trial that has performance of the arms that are comparable to the adjuvant chemotherapy trials.” ■

Disclosure: Dr. Haluska reported no potential conflicts of interest.

Editor’s note: Additional details of these trials were reported in previous issues of The ASCO Post.

References

1. Tewari KS, Sill M, Long HJ, et al: Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group. ASCO Annual Meeting. Abstract 3. Presented June 2, 2013.

2. Shastri SS, Mittra I, Mishra G, et al: Effect of visual inspection with acetic acid screening by primary health workers on cervical cancer mortality. ASCO Annual Meeting. Abstract 2. Presented June 2, 2013.

3. Du Bois A, Floquet A, Kim JW, et al: Randomized, double-blind placebo, phase III trial of pazopanib vs placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Results of an international Intergroup trial (AGO-OVAR16). ASCO Annual Meeting. Abstract LBA5503. Presented June 2, 2013.

4. Ledermann JA, Harter P, Gourley C, et al: Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer and a BRCA mutation. 2013 ASCO Annual Meeting. Abstract 5505. Presented June 1, 2013.

5. Pignata S, Scambia G, Lauria R, et al: A randomized multicenter phase III study comparing weekly versus every 3 weeks carboplatin plus paclitaxel in patients with advanced ovarian cancer: Multicenter Italian Trials in Ovarian Cancer (MITO)-7—European Network of Gynaecological Trial Groups (ENGOT-ov-10) and Gynaecologic Cancer Intergroup (GCIG) trial. 2013 ASCO Annual Meeting. Abstract LBA5501. Presented June 1, 2013.

6. Kehoe S, Hook J, Nankivell M, et al: Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: Results from the MRC CHORUS trial. 2013 ASCO Annual Meeting. Abstract 5500. Presented June 1, 2013.



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