Madison, Wis—Chemotherapy for advanced lung cancer has taken a few more steps forward, two recent studies show. However, their results also suggest that we may have reached the limit of what chemotherapy can do for patients with this deadly disease.

One of the studies compared several experimental chemotherapies to a standard regimen for patients with advanced non–small-cell lung cancer.[1] It found that one-year survival was 33%—10% to 20% higher than had been achieved with older forms of chemotherapy, lead author Joan H. Schiller, MD, told PULMONARY REVIEWS. Furthermore, “survival was not significantly different with any of the regimens we studied,” said Dr. Schiller, a Professor of Medical Oncology at the University of Wisconsin in Madison.

In the other study, a phase III trial of patients with advanced small-cell lung cancer, median survival was 12.8 months among those treated with irinotecan (a topoisomerase I inhibitor) plus cisplatin, versus only 9.4 months among those given standard therapy.[2] The two groups’ one-year survival rates were 58% and 38%, respectively.

Although these results are encouraging, they suggest that chemotherapy-induced improvements in survival among patients with advanced lung cancer may be plateauing, argued Desmond N. Carney, MD, PhD, in an editorial. “It is clear that new approaches are required,” stated Dr. Carney, a Consultant Medical Oncologist at Mater Misericordiae Hospital in Dublin, Ireland.[3]

NON–SMALL-CELL LUNG CANCER

Dr. Schiller’s study included 1,207 patients with stage IIIB, stage IV, or recurrent non– small-cell lung cancer. Most had a performance status of 0 or 1, indicating that they were not yet severely impaired. All patients were randomized to standard chemotherapy or one of three experimental protocols:

• Standard chemotherapy: Paclitaxel (135 mg/m2) was given every three weeks for 24 hours each time, followed immediately by administration of cisplatin (75 mg/m2).

•Gemcitabine: 1,000 mg/m2 of this agent was delivered on days 1, 8, and 15 of a four-week cycle. On the first day of each cycle, gemcitabine was combined with cisplatin (100 mg/m2).

•Docetaxel: Every three weeks, 75 mg/m2 of this drug was given in combination with cisplatin.

•Carboplatin: This drug’s dose was calculated to produce an area under the concentration–time curve of 6.0 mg/mL/min. It was given every three weeks, preceded by paclitaxel (225 mg/m2).

Study enrollment occurred between October 1996 and May 1999. As of May 1, 2001, 1,074 of the patients had died.

When the results were being analyzed, 52 patients were discovered to have received chemotherapy before study entry; they were withdrawn from the analysis. Of the 1,155 remaining patients, 19% were found to have had a partial or complete response to chemotherapy; response rates were similar among the four treatment groups.

The median time to disease progression was 3.6 months. Only the gemcitabine regimen appeared to significantly prolong time to disease progression (to 4.2 months).

Median survival was 7.9 months, and the two-year survival rate was 11%. Neither median survival, one-year mortality, nor two-year mortality differed significantly among the treatment groups. However, median survival was found to be inversely related to functional impairment. It fell from 10.8 months among patients with a performance status of 0 to 3.9 months among those with a performance status of 2.

Although the overall rate of toxic effects was similar in the four treatment groups, it was lowest in the patients given carboplatin and paclitaxel. Severe renal toxicity occurred more often in the patients given gemcitabine than in those receiving the other regimens.

“There is a benefit to chemotherapy, albeit a modest one, in advanced lung cancer patients who have a relatively good performance status,” Dr. Schiller said. Based on these results, the Eastern Cooperative Oncology Group, which conducted this study, has chosen carboplatin and paclitaxel as its reference regimen for future trials of non– small-cell lung cancer chemotherapy.

SMALL–CELL LUNG CANCER

In the other study, patients with advanced metastatic small-cell lung cancer were randomized to receive either irinotecan plus cisplatin or standard therapy (etoposide plus cisplatin). The trial, which was planned to include 230 patients, was stopped after only 154 patients were enrolled because an interim analysis showed significantly better survival with irinotecan and cisplatin.

The patients had extensive small-cell lung cancer, as defined by distant metastasis, contralateral hilar-node metastasis, or both. Like the patients in the previous study, most had relatively good performance status; all had adequate organ function.

The irinotecan group underwent four 4-week treatment cycles, receiving 60 mg/m2 of irinotecan on days 1, 8, and 15 of each cycle; in addition, 60 mg/m2 of cisplatin was given on day 1. The other group received four 3-week cycles; they were given 100 mg/m2 of etoposide on days 1, 2, and 3 and 80 mg/m2 of cisplatin on day 1 of each cycle.

In both groups, dosing and treatment schedules were sometimes altered to alleviate toxicity; only 29% of those given irinotecan and 38% of those receiving etoposide were able to complete their treatments as originally scheduled. Nevertheless, about 70% of patients in both groups received all four cycles of chemotherapy.

A partial or complete response to treatment was seen in 84% of the irinotecan group and 68% of the etoposide group. Two-year survival was 20% and 5%, respectively. The study authors calculated that the relative risk of death was 40%

The median duration of survival without disease progression was 6.9 months in the the patients given irinotecan and 4.8 months in those receiving etoposide. In addition, the relative risk of disease progression was 39% lower in the irinotecan group. The authors acknowledged, however, that these progression-free survival estimates may be biased, mainly because disease progression was not monitored continuously.

Severe or life-threatening diarrhea occurred in 16% of the irinotecan-treated patients but in none of those receiving etoposide. In contrast, severe neutropenia, leukopenia, and thrombocytopenia were all markedly more common in the etoposide group. Rates of nausea, vomiting, and other non-hematologic toxic effects were not significantly different between the groups.

TIME FOR A NEW APPROACH

Although this trial’s findings must be confirmed, they seem to indicate an advance in chemotherapy for extensive small-cell lung cancer, stressed Dr. Carney in his editorial. Nevertheless, most patients in both studies were dead at two-year follow-up, he noted. In fact, added Dr. Carney, the results of the Schiller study “confirm that the benefits of combination chemotherapy among the fittest patients with advanced non–small-cell lung cancer are marginal.”

Dr. Carney said that current combination chemotherapies for advanced lung cancer are nonspecific, nonselective, and toxic; new ones are unlikely to substantially improve survival. Thus, he called for new approaches to advanced lung cancer, including prevention, early detection, and novel treatments, such as monoclonal antibodies.

—Timothy Begany

References
1. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non–small-cell lung cancer. N Engl J Med. 2002;346:92-98.
2. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002;346:85-91.
3. Carney DN. Lung cancer—time to move on from chemotherapy. N Engl J Med. 2002;346:126-128.