Is Bevacizumab Truly a New Standard in Cervical Cancer?

Nick Mulcahy

March 25, 2015

Adding bevacizumab (Avastin, Genentech/Roche) to chemotherapy in the treatment of advanced cervical cancer was hailed as practice changing when it showed a survival benefit in a landmark trial.

But questions about the combination and quality of life remain because the addition of bevacizumab increases the toxicity of the treatment.

Now data on quality of life from the landmark Gynecologic Oncology Group (GOG) 240 trial have been published; they appear in the March issue of Lancet Oncology.

These data "show convincingly that quality of not adversely affected by the addition of bevacizumab to existing chemotherapy regimens," writes David Cella, MD, from Northwestern University in Chicago, in an accompanying comment.

As previously reported, adding bevacizumab to chemotherapy in this setting resulted in a 3.7-month improvement in overall survival compared with chemotherapy alone (P = .004).

The quality-of-life study provides a bigger picture of the impact of the targeted therapy on patients, according to the authors, led by Richard Penson, MD, from Massachusetts General Hospital in Boston.

They describe the situation this way: "Although patients living for 3.7 months longer might be another small incremental improvement, if this survival gain is considered in context of a sustained quality of life, the therapeutic effect becomes clinically meaningful."

Long before this quality-of-life study, the uptake of bevacizumab in this setting was rapid, as reported by Medscape Medical News.

The authors explain how that came about.

They report that the bevacizumab plus chemotherapy triplet regimens used in the four-group study were approved by the US Food and Drug Administration for the first-line treatment of metastatic and recurrent cervical cancer, and that both triplets have been designated as category 1 interventions in the National Comprehensive Cancer Network cervical cancer treatment guidelines.

But even with the fast adoption of bevacizumab, should these regimens truly be a new standard in this setting? That question is posed by Dr Cella in his comment.

When addressing such a weighty matter, it is necessary to consider quality of life, patient selection, and cost, he suggests.

Dr Cella says that quality of life is now not a concern, but adds a caveat: this assessment only applies to women who participated in the trial, all of whom had a high performance status (i.e., GOG 0 or 1).

This patient population "is an otherwise healthy group of women with advanced cervical cancer," Dr Cella notes.

But, he asks, "will more symptomatic and more disadvantaged women tolerate treatment in a similar way to those in this study?"

Dr Cella observes that cervical cancer disproportionately affects women in low-income countries, who can be quite ill. It is not known whether women in low-income countries will see the survival benefit seen in GOG 240, which was conducted in the United States and Spain, he says.

Cost is another unknown. "This article does not address the cost-effectiveness of the addition of bevacizumab to doublet chemotherapy in advanced cervical cancer," he writes.

Dr Cella cites a study in which the addition of bevacizumab in this setting is calculated to translate into an incremental cost-effectiveness ratio of $155,000 per quality-adjusted life-year (Gynecol Oncol. 2015;136:43-47). That is "quite high according to accepted standards," he notes.

More research into cost, optimal dose, and different patient populations is needed for bevacizumab to "take its proper place in the advanced cervical cancer armamentarium," Dr Cella concludes.

Dr Penson and his colleagues see things differently.

GOG 240 "established a new standard of care," they write.

However, the authors acknowledge that their study population was limited, and some of that was caused by the addition of bevacizumab to the treatment regimen. For example, they explain, patients needed to have "better renal function than previous studies before enrolment, and [this] excluded patients with a GOG performance status of 2."

There was also another wrinkle in the protocol that might have boosted survival outcomes in the trial, the team reports.

"Investigators were required to medically optimize their patients (address nutritional needs and correct renal dysfunction) in order for them to participate in this trial," they explain.

The authors and Dr Cella acknowledge that GOG 240 was not a typical advanced cervical cancer trial; selection bias was at work.

The median survival in the study population of 17 months considerably exceeds the median of 12 months in patients with advanced cervical cancer enrolled in previous GOG studies, and the median of 7 months or less in the general population affected by advanced cervical cancer, they all observe.

Health-Related Quality of Life

GOG 240 involved 452 patients with pretreated advanced cervical cancer who were treated from 2009 to 2012. Most had recurrent disease (72%), but a minority had persistent disease (11%).

Patients were randomly assigned to one of four treatment groups: topotecan plus paclitaxel with bevacizumab; topotecan plus paclitaxel without bevacizumab; cisplatin plus paclitaxel with bevacizumab; and cisplatin plus paclitaxel without bevacizumab.

Intravenous bevacizumab 15 mg/kg was administered once every 3 weeks at the same time as the chemotherapy until disease progression or unacceptable toxicity occurred.

As previously reported, the addition of bevacizumab to chemotherapy led to more adverse effects.

For example, hypertension of grade 2 or higher was significantly more common in those treated with bevacizumab than in those who were not (25% vs 2%; P < .001), but no patients discontinued bevacizumab because of hypertension, the authors point out.

Also, notably, gastrointestinal or genitourinary fistulas of grade 3 or higher were significantly more common in those treated with bevacizumab than in those who were not (6% vs 0%; P = .002), as were thromboembolic events of grade 3 or higher (8% vs 1%; P = .001).

Health-related quality of life was an exploratory end point of GOG 402.

The primary quality-of-life end point was score on the Functional Assessment of Cancer Therapy–Cervix Trial Outcome Index (FACT-Cx TOI). Participants were assessed before treatment cycles 1, 2, and 5, and at 6 and 9 months after the start of cycle 1.

The authors report that the baseline FACT-Cx TOI scores did not differ significantly between patients who received bevacizumab and those who did not (P = .27).

Overall, FACT-Cx TOI scores were an average of 1.2 points lower (98.75% confidence interval, –4.1 to 1.7; P = .30) in patients who received chemotherapy plus bevacizumab than in those who received chemotherapy alone.

The study was funded by the National Institutes of Health. Dr Cella is a member of the Gynecologic Oncology Group. Dr Penson and 2 of his coauthors report financial relationships with Genentech, the maker of bevacizumab.

Lancet Oncol. 2015;16:241-243, 301-311. Comment, Abstract


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