Platinum-based chemotherapy remains standard of care for advanced cervical cancer

Protocol has not changed for three decades, but biologic drugs may represent a new treatment option.

Cisplatin-based chemotherapy has been the standard of care for metastatic cervical cancer for about 30 years. Unfortunately, only about one-third of patients with cervical cancer will respond to this treatment, and responses usually last fewer than 12 months. Moreover, cisplatin-based chemotherapy is also used in combination with radiation therapy to treat patients with earlier-stage disease, so recurrent disease may be resistant to additional treatment with platinum drugs.

The Gynecologic Oncology Group conducted the GOG 204 trial to compare several cisplatin doublets, looking to find a superior treatment regimen; however, the trial was stopped early when no combination proved superior to the cisplatin/paclitaxel combination.

Maurie Markman, MD
Maurie Markman, MD, from The University of Texas M.D. Anderson Cancer Center, said there is currently no evidence to support using bevacizumab in advanced cervical cancer.

Photo by F. Carter Smith

The follow-up study, GOG 240, will assess the efficacy of bevacizumab (Avastin, Genentech) in these patients, but Maurie Markman, MD, vice president for clinical research at The University of Texas M.D. Anderson Cancer Center and a member of the HemOnc Today Editorial Board, said there is no evidence yet suggesting any benefit associated with the biological agent.

Jonathan Cosin, MD, section director for gynecologic oncology at Washington Hospital Center, said platinum is likely to remain the only option for the foreseeable future.

“Platinum remains the standard of care for advanced, persistent recurrent cervical cancer. I don’t think there is any question platinum is a critical part of the treatment,” Cosin said. “However, obviously, given the results of [GOG 204], as well as general experience with cervical cancer, a disease which does not do well with chemotherapy in general, the search for something better is on. There is no traditional chemotherapy drug that is going to improve on platinum anytime soon — maybe ever.”

Although the best method for treating cervical cancer is still being researched, the cause of most cervical cancers is well known. Some of the experts who spoke to HemOnc Today argued that the focus on cervical cancer should be on screening and prevention, rather than cure.

GOG 204

GOG 204 was a four-arm trial conducted by Bradley J. Monk, MD, of the University of California, Irvine, School of Medicine, and colleagues, in which patients were randomly assigned the standard paclitaxel/cisplatin regimen (n=118), vinorelbine/cisplatin (n=117), gemcitabine/cisplatin (n=119) or topotecan/cisplatin (n=118). Survival was the primary endpoint, with a 33% improvement relative to paclitaxel/cisplatin considered important. Quality-of-life data were prospectively collected.

Median OS for the paclitaxel arm was 12.87 months (95% CI, 10.02-16.76) vs. 9.99 months (OR=1.17; 95% CI, 8.25-12.25) for vinorelbine. Median OS for gemcitabine was 10.28 months (OR=1.43; 95% CI, 7.62-11.60) and 10.25 months for topotecan (OR=1.34; 95% CI, 8.61-11.66).

When compared with paclitaxel/cisplatin, the HR for OS was 1.15 for vinorelbine (95% CI, 0.79-1.67), 1.32 (95% CI, 0.91-1.92) for gemcitabine and 1.26 (95% CI, 0.86-1.82) for topotecan. Researchers said there were no statistically significant differences between the experimental regimens and the paclitaxel/cisplatin arm.

Similarly, PFS was not substantially different between the reference arm and the experimental arms (see chart below).

Cosin said the results were not surprising.

“I can’t imagine anyone is going to suddenly come up with a cytotoxic drug that’s going to be a home run in cervical cancer,” he said. “Looking at GOG 204, there wasn’t a lot of reason to believe one of these arms was going to be a big slam dunk.”

However, Barbara A. Goff, MD, division director of gynecologic oncology with the University of Washington, said there was value in the toxicity and quality-of-life results from that study.

Only 43.1% of patients assigned gemcitabine experienced grade-3 or higher leucopenia, which was one-third to one-half less than what was experienced in the other arms. Roughly 50% of patients in the other arms experienced severe neutropenia compared with just 15% in the gemcitabine arm. Additionally, the rate of grade-2 alopecia was 54% in the paclitaxel arm compared with 26% for topotecan, 9% for vinorelbine and 7% for gemcitabine.

“If a patient has a lot of neuropathy, cisplatin and paclitaxel is probably not the best regimen,” Goff said. “With paclitaxel, the patient has hair loss. Certainly, with gemcitabine and the topotecan/cisplatin, that won’t happen. The results give us options to discuss with the patient, but certainly none of these regimens are better than paclitaxel and cisplatin.”

Jonathan Cosin, MD
Jonathan Cosin

Exploring biologics

Results from phase-2 of a study published last year in the Journal of Clinical Oncology showed that the human anti-CTLA4 monoclonal antibody tremelimumab (Pfizer) produced two complete responses and three partial responses in 84 evaluable patients with advanced cervical cancer. Responses lasted up to 30 months.

In the study, patients were assigned 15 mg/kg tremelimumab every three months or 10 mg/kg every month.

The objective response rate was 9.8% (95% CI, 3%-23%) for the 10 mg/kg arm and 9.3% (95% CI, 3%-22%) for the 15 mg/kg arm. Researchers noted responses in skin, bone, liver, adrenal gland, chest wall, lymph nodes and soft tissues, and neither patient who had complete response had received prior immunotherapy.

Median time to response was 21 weeks, and at the time of publication, two patients who had an objective response had relapsed. Most patients with stable disease progressed by six months.

The only biologic therapy to advance to phase-3 testing has been bevacizumab. Researchers are currently recruiting women with metastatic, recurrent or persistent cervical cancer that cannot be treated with surgery or radiation for GOG 240. Patients will be randomly assigned paclitaxel/cisplatin, paclitaxel/topotecan or either of these combinations with the addition of bevacizumab.

Bevacizumab appeared to demonstrate efficacy in the phase-2 GOG 227-C study. In 227-C, researchers recruited 46 women with persistent or recurrent squamous cell carcinoma of the cervix who had undergone one or two prior cytotoxic regimens, not including prior cisplatin-based chemotherapy concomitantly administered with primary pelvic radiation. Patients were administered 15 mg/kg IV bevacizumab every 21 days with no dose modification unless there was change in body weight of at least 10%.

Eleven patients had complete response with a median PFS of 6.21 months. Median overall PFS was 3.4 months (95% CI, 2.53-4.53). OS for all patients was 7.29 months (95% CI, 6.11-10.41).

Because bevacizumab is a targeted biologic treatment, as opposed to a direct cytotoxic drug that has been shown to have limited efficacy, there is hope that the angiogenic agent may represent a new treatment option. Cosin said he is cautiously optimistic that bevacizumab will be the answer.

Fast Facts

“Bevacizumab is the drug we know the most about, so that’s what makes it the most attractive right now,” he said. “Whether it turns out to be the best drug or if it will be that effective or important at all remains to be seen. There is some early, largely anecdotal, evidence to suggest that it may have some utility, but it needs to be studied.”

Markman agreed with Cosin that more studies of bevacizumab are needed in these patients because there is no current data to support its use.

“There have been some reports that some patients have had some shrinkage of tumor. That in no way, shape or form today constitutes evidence demonstrating clinical benefit,” he said. “Again, bevacizumab is a drug that is not only expensive, but may be toxic in this patient population. We’re dealing with a population at risk for blood clots, that may have poor wound healing due to radiation, that may have problems with bowel on contact with tumor, and we know from experience with several tumor types, including ovarian cancer, that the risk of perforation, wound healing and blood clots can be very much increased with bevacizumab.

“Certainly, this is a drug worthy of testing, and it is being tested,” Markman said. “But to suggest today that we can simply give bevacizumab to patients with advanced cervical cancer and think it will be safe and effective is simply not supported by data and could be potentially dangerous.”

Krishnansu Tewari, MD
Krishnansu Tewari

Krishnansu Tewari, MD, president of the Orange County Obstetrics & Gynecology Society and associate professor of obstetrics/gynecology with the Chao Family Comprehensive Cancer Center at the University of California, Irvine, Medical Center, is the lead investigator for GOG 240. From 1999 to 2000, he said, five phase-3 trials showed that adding platinum to radiation treatment improved PFS, OS and response rates. Accordingly, that treatment has become standard in the developed world. Those patients are now experiencing relapse and, because the treatment potential for chemotherapy has been largely exhausted, physicians need new treatment options.

GOG 240, Tewari said, seeks to determine whether adding bevacizumab to chemotherapy improves outcome, and whether patients who are refractory to cisplatin-based chemoradiation will respond to nonplatinum-based chemotherapy.

“We need to study something besides chemotherapy,” he said. “Studying bevacizumab is ideal because it’s angiogenic. In the phase-2 protocol 227-C, bevacizumab was associated with a response rate of 14%, which is as good as we’ve seen with other chemotherapy regimens.”

Trials and prevention

Until more is known, attention should also be focused on screening and prevention. In the West, cervical cancer is a relatively rare and infrequently fatal disease. However, cervical cancer is annually the second most common malignancy in women worldwide and the third most common cause of cancer-related mortality in women. More than 270,000 deaths were attributed to the disease last year, and three of four diagnoses occur in developing countries. Women who are elderly, economically disadvantaged or have poor health care access are more likely to develop and die from this disease, as noted by Gopal K. Singh, PhD, and colleagues in a study published in the journal Cancer in 2004.

This creates a twofold problem. First, pharmaceutical companies are not inclined to spend much money on drug development when the market in so-called first world countries is small; and second, it is extremely difficult to conduct rigorous trials in developing nations because such countries often lack the necessary medical infrastructure.

There are ways around the problem, including Cooperative Group trials and international trials, but the experts who spoke to HemOnc Today said there is more value in spending money on prevention rather than cure.

“If you think about where you want to put your money, it’s in prevention, screening and early detection. … Cervical cancer is almost 100% preventable,” Goff said.

“We know what causes [cervical cancer],” Tewari said. “We know how to screen for it. We know how to prevent it with HPV vaccines. But not everyone has access to screening programs, not everyone has access to vaccinations. As a result, we see 500,000 new cases every year worldwide.”

A Bulletin of the World Health Organization published in 2001 looked at cervical cancer screening programs in middle- and low-income countries such as Mexico, South Africa and India. Even in the few countries with screening programs, “there are no organized programs and the testing is often of poor quality and performed inadequately and inefficiently among the population,” researchers said. “As a result, there has been a very limited impact on the incidence of cervical cancer, despite the large numbers of cytological smears taken in some countries such as Cuba and Mexico.”

Physicians, however, have had success operating screening programs even among the world’s poorest people. In 2009, Rengaswamy Sankaranarayanan, MD, chief of the cancer screening group for the International Agency for Research on Cancer, and colleagues published results in The New England Journal of Medicine of a cluster-randomized trial conducted in rural India. Sankaranarayanan was one of the authors of the WHO bulletin.

More than 131,740 healthy women in 52 clusters of villages were randomly segregated into four groups of 13 clusters. The average age for all groups was about 39 years, and about 71% of women, overall, had no formal education.

The groups were assigned HPV testing (n=34,126), cytologic testing (n=32,058), visual inspection of the cervix with acetic acid (n=34,074) or to standard care (n=31,488).

Screening was performed by nine auxiliary nurse–midwives who were trained in a three-week course with the use of International Agency for Research on Cancer manuals in the collection of cervical cells for HPV testing and cytologic testing and in performing visual inspection of the cervix with acetic acid and cryotherapy. Nine doctors were trained to supervise the auxiliary nurse–midwives and to perform colposcopy, cryotherapy and the loop electrosurgical excision procedure.

There were 34 cervical cancer-related deaths in the HPV-testing group, as compared with 64 in the control group (HR=0.52; 95% CI, 0.33 to 0.83). “The cumulative incidence of advanced cervical cancer and the cumulative rate of death were lower in the HPV-testing group than in the control group, and the gap widened throughout the follow-up period,” the researchers wrote.

Fast Facts

There were 22 subsequent incident cancers in the HPV-testing group, 27 in the cytologic-testing group and 34 in the visual inspection group. Researchers detected stage I tumors in 60% of patients in the HPV- and cytologic-testing groups compared with 42% in the visual inspection group and 28% in the control group.

“Our study found that a single round of HPV testing was associated with a significant decline in the rate of advanced cervical cancers and associated deaths, as compared with the unscreened control group,” Sankaranarayanan and colleagues concluded. “By contrast, there was no significant reduction in the rate of death in either the cytologic-testing group or the visual inspection of the cervix with acetic acid group, as compared with the control group.”

Tewari said those results were important, but added that the cost and sheer number of screenings necessary mean that eradicating cervical cancer, although possible, is a difficult task.

“That was a huge study, and it showed that HPV-DNA testing significantly reduced mortality from cervical cancer,” he said. “However, that was a funded study, and the world has several billion people in it — 130,000 is just such a small number. I don’t know how to do HPV-DNA testing globally.” – by Jason Harris

POINT/COUNTER
Is there a role for non-platinum–based chemotherapy in recurrent or metastatic cervix cancer?

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