Irinotecan Active in Platinum-Refractory Cervical Cancer

HOUSTON, Texas—Irinotecan (Camptosar) is active in platinum-refractory cervical cancer and should be tested with cisplatin (Platinol) in randomized trials, declared Claire F. Verschraegen, MD. The use of irinotecan might enable clinicians in developing countries (where radiotherapy equipment is in short supply) to downsize many cervical cancers to resectable size, Dr. Verschraegen added. She is assistant professor in the Division of Cancer Medicine Section of Gynecologic and Medical Therapeutics at the University of Texas M. D. Anderson Cancer Center in Houston, Texas.

In summarizing studies on single-agent irinotecan, Dr. Verschraegen said, "Taken together, there is a 4% complete remission (CR) rate. It is always a little ray of hope to see some complete remissions in patients with recurrent cervical cancer. Partial remissions were 14%, for a total response rate of 18%, so this is a very acceptable drug as a single agent."

Her presentation mainly focused on squamous cell carcinoma and adenocarcinoma. "Cervical cancer usually is very curable if detected early, but once a patient is stage IIB or has nodes involved, the prognosis worsens," she said.

Early Stage Disease

The usual treatment for early stage disease, up to Stage IB1, can be either surgery or radiation therapy. Patients with Stage IIB2 or worse are treated with concurrent chemoradiation. "In developing countries and in Europe there are a number of ongoing studies of neoadjuvant chemotherapy prior to surgery, but this is not a modality routinely used in the United States," Dr. Verschraegen said.

Locoregional recurrences can sometimes be salvaged by using radiation in patients who had prior surgery, or surgery for patients with prior radiotherapy. "If there is a central recurrence the patient may benefit from an exenteration. This is a very tough surgery, but we have patients alive 30 and 40 years later," Dr. Verschraegen said.

Out-of-field recurrences following radiotherapy can sometimes be salvaged with additional radiation with or without chemotherapy. For distant recurrences other than an isolated metastasis, palliative chemotherapy is usually the only option.

Single-Agent Study

An M. D. Anderson phase II study of single-agent irinotecan includes 42 patients with cervical cancer, 88% with prior radiotherapy. Patients were treated with irinotecan at 125 mg/m² every week for 4 weeks, with cycles repeated every 6 weeks. "All the patients were platinum refractory, and I must tell you that if a patient has a platinum-refractory cervical cancer, none of the other single agent drugs yields any response," Dr. Verschraegen said. "The response rate to irinotecan was 21%, so we were very excited when we saw responses in this patient population. The median survival was about 6 months, and the duration of response was about 12 weeks."

With regard to toxicity, Dr. Verschraegen said that 75% of the patients had to be dose reduced from 125 to 100 mg/m² and another 25% had to be dose reduced to 75 mg/m². About 45% of the cycles caused nausea and vomiting of grade 3 or 4, and about 25% caused grade 3 or grade 4 diarrhea. "In a disease that you cannot cure and for which you are going to deliver only palliative treatment, I think that a rate of 25% serious diarrhea requiring hospitalization for rehydration is too high. This regimen was not the optimal one, although we got quite good response rate," Dr. Verschraegen said.

Related Studies

Loyola University researchers repeated this study with the same regimen in 16 platinum-refractory patients. Dr. Verschraegen said that there were no responses in this study but researchers noticed a marked subjective improvement of symptoms in a few patients. "We made the same observation in patients who did not have a partial remission but had stable disease or minor progression. A number of these patients reported that their pain subsided, and they felt much better. I cannot really explain that effect yet," she said.

The Gynecologic Oncology Group (GOG) conducted a related study using the same irinotecan schedule in 54 patients who were mostly chemotherapy naive. The response rate in this trial was 13.3%, including one complete response and 5 partial responses.

Dr. Verschraegen also discussed a European study with the commonly used European irinotecan dosing of 350 mg/m2 every 3 weeks in chemotherapy-naive patients. "The overall response rate was about 16%, but it increased to 24% in patients whose recurrence was in a nonirradiated field. Patients that had recurrence in a previously irradiated field had basically no responses. Median survival was around 6 months," she said.

"Data from all the studies except the one from Loyola are pretty consistent, and the lesson is that finally we have a drug that is active in platinum-refractory cervical cancer."

Preclinical Studies

Preclinical studies from Japan found that the two most effective irinotecan combinations were cisplatin/irinotecan and mitomycin-C (Mutamycin)/irinotecan. Most clinical data on use of irinotecan in combination regimens for cervical cancer also comes from Japan.

In reviewing these studies, the first one Dr. Verschraegen cited included 29 chemotherapy-naive patients with advanced disease, mostly squamous cell carcinoma. Patients were treated with cisplatin 60 mg/m² on day 1 and irinotecan 60 mg/m² on days 1, 8, and 15. Cycles were repeated every 4 weeks. The response rate was about 60%, and overall survival was about 27 months.

A second study looked at the feasibility of using irinotecan/cisplatin as neoadjuvant treatment in 23 previously untreated patients, most with squamous cell histology. "In this untreated population there was an almost 80% remission rate, and by the time of publication, the median survival had not been reached," Dr. Verschraegen said.

Doses were increased to 70 mg/m² for both drugs, but with irinotecan given only on day 1 and day 8 and each cycle repeated after 3 weeks instead of 4. Two courses are given prior to surgery, and two patients who had complete clinical remissions following neoadjuvant treatment also had complete pathological remissions at surgery.

Active in Recurrences

"Irinotecan as a single agent has activity in chemotherapy pretreated recurrent cervical cancer and is especially active in recurrences in non-radiated localization. The combination with cisplatin seems to be very active, and it may be a good idea to determine whether the combination would produce better survival than single-agent treatment in cervical cancer. The GOG is currently studying another topoisomerase-I inhibitor, topotecan (Hycamtin), combined with cisplatin vs cisplatin alone. This combination could be fairly toxic, with a risk of neutropenia and thrombocytopenia, and I would have chosen irinotecan for this type of comparison," Dr. Verschraegen said.

"The combination of cisplatin and irinotecan may also be of use, especially in developing countries that lack optimal radiation facilities and if it permits downsizing the cancer enough to become resectable," she added. "I have treated one case of cervical cancer recurrence in that way and found only microscopic disease after resecting the patient’s only site of disease."