Gemcitabine Plus Carboplatin Offers Survival Advantage Over Three-Drug Combination

LONDON, UK—The combination of gemcitabine (Gemzar)/carboplatin (Paraplatin) was found to be better tolerated and associated with longer survival than MIP (mitomycin [Mutamycin], ifosfamide [Ifex], and cisplatin [Platinol]) in patients with advanced non-small-cell lung cancer (NSCLC) in a multicenter phase III European trial (ASCO abstract 1164).

"Most patients presenting with non-small-cell lung cancer have received advanced surgery or radiotherapy," said Robin M Rudd, MD, department of medical oncology at St. Bartholomew’s Hospital, London. "There is evidence of a small survival advantage with cisplatin-based chemotherapy. Our aim was to reduce toxicity from the therapy and hospital admissions, while maintaining response rates and survival in these patients with essentially incurable disease and short life expectancy."

Less Toxic Treatment Sought

The MIP regimen is commonly used in Europe to treat NSCLC. The researchers hypothesized that combination therapy with gemcitabine and carboplatin might be less toxic and confer better quality of life while maintaining the survival advantage of cisplatin. Study endpoints were survival, response rates, toxicity, and quality of life.

Between February 1999 and August 2001, 422 patients were randomized into two study arms. Both received 21-day cycles for up to four courses. Patients in the first arm were given infusions of gemcitabine, 1,200 mg/m², on days 1 and 8 and carboplatin, AUC of 5, on day 1. The control arm received the well-established infusion regimen of mitomycin, 6 mg/m², ifosfamide 3 g/m², and cisplatin 50 mg/m², all on day 1.

Study Population

Researchers enrolled patients who were fit to receive chemotherapy and had histologic confirmation of stage III or IV disease, and a greater than 8-week life expectancy. There was no upper age limit, and the median age was 62. The patients in both arms were well matched for age, sex, and histologic distribution, although there was a small excess of patients with stage IV disease and performance status 0-1 in the gemcitabine and carboplatin arm.

More than 60% of patients in both arms received four courses of chemotherapy. A few received more chemotherapy due to clinical decisions. The main reasons for receiving less were disease progression or toxicity. There were more delays to chemotherapy and more dose modifications—usually omission of the day 8 gemcitabine dose—in the gemcitabine-plus-carboplatin arm, mainly due to hematologic toxicity. With the more frequent administration of chemotherapy in this arm, there were more opportunities for treatment delays and modifications.

The incidence of anemia and neutropenia was similar in the two arms, but there was a significant excess of grade 3/4 thrombocytopenia, which was not associated with symptoms, in the gemcitabine-plus-carboplatin arm. Patients assigned to the MIP arm experienced significantly greater nonhematologic toxicities, including nausea, vomiting, constipation, and alopecia.

Modifications of Therapy

The two arms demonstrated the same response rates (41%) and frequency of stable disease. Clinicians chose whether to use radiotherapy, and there was no significant difference in the two groups in the frequency of such use or disease progression. Radiotherapy to the bone, due to metastases, was given more frequently in the gemcitabine-plus-carboplatin arm. Additional chemotherapy could be given and was administered slightly more often to patients in the gemcitabine-plus-carboplatin cohort.

"Overall survival was significantly better in the gemcitabine/carboplatin arm," Dr. Rudd said. "Immediate follow-up with living patients is just under 1 year. Median survival is 10.2 months in the gemcitabine/carboplatin arm and 6.9 months in the MIP arm. One-year survival is 38% in the gemcitabine/carboplatin arm compared with 28% in the MIP arm. Progression-free survival was slightly but not significantly better in the gemcitabine/carboplatin arm."

Quality-of-Life Differences

Quality of life was assessed through European Organization for Research and Treatment of Cancer (EORTC) questionnaires and diary cards completed daily; the gemcitabine-plus-carboplatin arm showed an advantage with regard to fatigue, nausea and vomiting, and constipation. The only advantage of MIP was a lower incidence of insomnia. The two regimens were equally effective in relieving symptoms of lung cancer, such as cough, shortness of breath, and chest pain. Functional scales and global quality of life improved with gemcitabine plus carboplatin, whereas most of these parameters deteriorated on MIP.

"From these early data, there was a significant survival advantage to gemcitabine/carboplatin therapy compared to MIP," Dr. Rudd said. "There was significantly more hematologic toxicity with gemcitabine/carboplatin, particularly thrombocytopenia, but this was not associated with hospital admissions or fatality. Gemcitabine/carboplatin chemotherapy required fewer hospital admissions for administration, caused less nausea and vomiting, constipation, and alopecia, and was associated with an overall better quality of life. The combination of gemcitabine/carboplatin seems an effective and well-tolerated regimen as an outpatient treatment for advanced non-small-cell lung cancer."