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

Platinum-based regimens remain the standard of care.

Although platinum-based regimens remain the standard of care, the hope is that there may be a role for non-platinum–based chemotherapy for recurrent disease. The platinum response rates in patients with recurrent disease who were previously treated with platinum therapy are relatively low. The largest trials looking at platinum-based therapy are the GOG series.

In GOG 169 and 179, patients who had platinum during their primary treatment and then recurred had response rates as low as 5% with single agent cisplatin to as high as 37% with the platinum-based doublets with topotecan or paclitaxel. In patients who have been treated with platinum previously, non-platinum–based chemotherapy might provide higher response rates.

Mark E. Borowsky

However, at present, outside of a clinical trial, non-platinum–based therapy would not be standard of care for initial treatment of recurrent or metastatic disease. The standard of care would be treatment with cisplatin and paclitaxel or cisplatin and topotecan. Those are the two regimens that stand out, certainly for patients with first recurrence.

Right now, the role of non-platinum–based therapy for recurrent cervical cancer would be in the setting of patients who progress on platinum-based treatments. Patients should be initially treated with platinum-based therapy, and if their disease progresses, then I think there is a role for non-platinum–based therapy.

For first recurrence or the first-line treatment of advanced metastatic disease, the standard of care is still platinum-based doublet therapy.

There have been a number of very small phase-2 trials that looked at the doublet of topotecan and paclitaxel. One was a 13-person trial in patients with recurrent cervical cancer that had seven responders. That is a very good response rate but in a very, very small trial. That doublet is now being compared in GOG 240 with the doublet of cisplatin and paclitaxel with or without bevacizumab in patients with first recurrence of cervical cancer or widely metastatic disease at presentation.

Mark E. Borowsky, MD, is Director of Gynecologic Oncology at the Helen F. Graham Cancer Center in Newark, Del.

New drugs may be needed to overcome resistance to platinum-based chemotherapy.

Based on the five prospective randomized trials that were published in 1999, standard of care for locally advanced cervical cancer is weekly cisplatin with radiation therapy. With a 50% reduction in local failure and a 50% increase in OS, cisplatin plus radiotherapy was a major development in 1999. In the mid-90s, there had been an NCI consensus that there was no role for chemotherapy in locally advanced cervical cancer.

The problem is: What do we do with recurrent or metastatic disease? If the patient has only local recurrence, a pelvic exenteration can be performed and patients can be salvaged. If they have recurrence outside the pelvic area, chemotherapy is basically palliative in nature if patients recur after chemoradiation.

Norman G. Rosenblum

When we initially started looking at patients with recurrent disease, Dr. David Moore at Indiana University compared cisplatin with cisplatin and paclitaxel in patients who had recurrent disease. That study showed the combination had a response rate of 36%, which was better than the 19% response rate for cisplatin alone. However, there was no improved OS.

In 2005, Long and colleagues looked at cisplatin with or without topotecan and demonstrated that there was an overall response rate of 27% and a median OS of 9.4 months for cisplatin and topotecan vs. 6.5 months for cisplatin alone. It was the first study showing a potential survival advantage for the combination, but it was only a few months. Moreover, the response rate was 27% compared with 36% in the Moore study.

Then last year, Monk compared four cisplatin-containing doublets in patients with recurrent cervical cancer and found that nothing produced better outcomes compared with cisplatin and paclitaxel. The response rate in this study was just 29%.

As we have gotten further along, more and more people are being treated with cisplatin-based chemotherapy and radiation. What may be happening now is that patients are developing resistance to the cisplatin-based regimens because we are not getting the same response rates as Dr. Moore. In the future, what can we use? None of the experimental arms of GOG 204 outperformed the reference arm of cisplatin/paclitaxel.

With so many patients getting cisplatin as basic treatment, it is possible patients are developing a resistance to platinum. Maybe we should try something without platinum to overcome the resistance. Bevacizumab (Avastin, Genentech) and pemetrexed (Alimta, Eli Lilly), for instance, have been studied in recurrent disease and patients have responded. Maybe we have to find newer drugs or non-platinum based drugs to treat these patients.

Norman G. Rosenblum, MD, PhD, is Director of the Division of Gynecologic Oncology at Jefferson Medical College of Thomas Jefferson University in Philadelphia.