| Japanese Journal of Clinical Oncology | Pages |
Introduction
Patients And Methods
Results
Discussion
Acknowledgements
References
Second-line Chemotherapy for Relapsed Small Cell Lung Cancer
Between January 1985 and August 1991, 159 patients with small cell lung cancer received first-line chemotherapy and 123 (77%) were responders. Of these, 88 relapsed, the remainder having died of other or unknown diseases or being alive without carrying cancer. The relapsed patients were examined to evaluate the outcome of the treatment for relapsed small cell lung cancer and to identify the factors that would contribute to the response rates and the survival durations. Forty-eight of 88 relapsed patients received second-line chemotherapy. Of the 48, 3 were evaluated as showing a complete response, 13 as partial response, 9 as no change, 15 as progressive disease and 8 as not evaluable. The response rate was 33% (95% confidence interval 20.4-48.4%). The median survival time was 146 days. The duration and rate of response in first-line chemotherapy affected the response rates of the second-line chemotherapy, but without statistical significance (P = 0.058 and 0.067 respectively). Increased response duration, time off chemotherapy and previous response to first-line chemotherapy all had a positive effect on the survival times (P < 0.01). Relapsed small cell lung cancer still shows a response to second-line chemotherapy without lessening survival time, and thus clinical trials of new drugs or combination chemotherapeutic regimens for relapsed small cell lung cancer cases would be reasonably justified. Randomized comparative studies are warranted for determining the benefits of second-line chemotherapy for relapsed small cell lung cancer cases.
INTRODUCTION
Small cell lung cancer (SCLC) is sensitive to chemotherapy and to radiotherapy, although after apparently successful first-line chemotherapy, most patients experience a relapse within two years because of the emergence of drug-resistant cancer cells during the first-line chemotherapy or the existence of such cells before chemotherapy (1 ). It has been reported that second-line chemotherapy in relapsed SCLC usually yields unsuccessful results. Median survival time (MST) is approximately 8-12 weeks (2 ).
In the 1970s, first-line chemotherapy on responding SCLC patients often continued for up to 2 years. However, randomized studies comparing high dose to conventional dose chemotherapy with the same drugs showed that higher doses given for only the first 6-9 weeks produce superior response rates but no change in survival rates (3-5 ). Thus many chemotherapy programs used since the 1980s are intended to be discontinued after 4-6 months. Also the results of several randomized trials that addressed the optimal duration of chemotherapy suggest that there is little role for maintenance chemotherapy (6-9 ). The study by Spiro and colleagues (6 ), in which patients were randomly selected for chemotherapy or for supportive care alone after tumor progression, showed that survival was compromised with supportive care alone in patients who initially received only 4 chemotherapy cycles but not in those who had received 8. These trials suggest that the natural history and the response to chemotherapy of relapsed SCLC in the era when first-line chemotherapy was intensive and of short duration may be different from those in the 1970s. As few reports have evaluated the comprehensive outcome of relapsed SCLC, all patients with SCLC treated in our Institution were analyzed. The purpose of this study was to evaluate the treatment outcome of relapsed SCLC and to identify the factors that would contribute to the response rates in second-line chemotherapy and to survival durations.
Table 1.
| Second-line chemotherapy | ||
| Characteristic | Yes | No |
| No. of patients | 48 | 40 |
| Age, years | ||
| Median | 66 | 67 |
| Range | 36-79 | 37-86 |
| Sex | ||
| Male | 41 | 36 |
| Female | 7 | 4 |
| Performance status | ||
| 0 | 2 | 0 |
| 1 | 18 | 3 |
| 2 | 21 | 11 |
| 3 | 6 | 22 |
| 4 | 1 | 4 |
| Extent of disease | ||
| Limited | 18 | 8 |
| Extensive | 30 | 32 |
| Fires-line chemotherapy | ||
| PVP | 19 | 13 |
| PACE | 10 | 15 |
| CAV/PVP | 9 | 3 |
| CAV | 6 | 5 |
| VAN | 2 | 1 |
| CODE | 2 | |
| VP-16 (po) | 3 | |
PATIENTS AND METHODS
Among 179 patients with histologically or cytologically proven SCLC diagnosed in the National Sanatorium Matsudo Hospital (formerly Institute of National Cancer Center Hospital East) between January 1985 and August 1991, 9 received surgery, 10 received no treatment and 1 received radiotherapy alone. One hundred and fifty nine patients received first-line chemotherapy; of these, 123 (77%) were responders, including 27 (17%) evaluated as showing complete response (CR). Of the responding patients, 18 died of other diseases, 10 died of unknown causes and 7 remained continuously free of disease, leaving 88 patients with relapsed SCLC. All the relapsed patients were analyzed in regard to response to second-line chemotherapy and survival.
Limited disease (LD) was defined as disease confined to one hemithorax, which included bilateral mediastinal and bilateral supraclavicular lymph nodes; any involvement beyond these confines and carcinomatous hydrothorax were defined as extensive disease(ED). Response was classified in accordance with the WHO (World Health Organization) criteria (10 ).
To identify the factors contributing to response rate to second- line chemotherapy and survival, significant differences were assessed for 6 factors including the time since the last chemotherapy (>90, <90days), response duration following first-line chemotherapy (>270, <270days), previous tumor response [CR, partial response (PR)], extent of disease (LD, ED), thoracic radiotherapy (yes, no) and performance status (PS) (0-1, 2-3) using the [chi]2 test for response rate and survival. Response duration was calculated from the day of the observed response until the day of documentation of progression. Survival time from relapse was defined as the number of days from the start of second-line chemotherapy until death in the chemotherapy group, and from progression until death in the non-chemotherapy group. Time off chemotherapy was calculated from the day following completion of first-line chemotherapy until progression.
RESULTS
Patients' characteristics are listed in Table 1 . Of the 88 patients defined as relapsed SCLC cases, 48 received second-line chemotherapy and 40 did not. There was a higher proportion of patients with a good performance status in the chemotherapy group. The median and range of age, male to female ratio, extent of disease and content of first-line chemotherapy did not differ between the two groups. The overall response rate was 33% (95% confidence interval 20.4-48.4%), with the CR rate 6.3% (95% C.I. 1.3-17.2%). The MST was 146 days. Chemotherapeutic regimens for relapsed cases was as follows: cisplatin and etoposide 23 patients; vincristine, adriamycin and nimustine 8; cisplatin, adriamycin, cyclophosphamide and etoposide 7; low dose oral etoposide 3; cyclophosphamide, adriamycin and vincristine 2; cisplatin, vincristine, adriamycin and etoposide 2 and others 3.
Responses were seen only in those patients with PS 0-2. The response rate of the patients with PS 0-1 and PS 0-2 were 45% and 39% respectively.
Various factors other than PS at recurrence which affected the response rate and survival time are listed in Table 2 . The factors contributing significantly to response rate could not be identified but response duration and tumor response to first-line chemotherapy tended to influence the response rate (P = 0.058, P = 0.067 respectively). Survival time was significantly influenced by response duration, time off chemotherapy and tumor response to first-line chemotherapy (P < 0.01 for all three).
DISCUSSION
Salvage chemotherapy for SCLC may be considered for patients who relapsed after responding to first-line chemotherapy and those who failed to respond to the induction regimen. In a study of teniposide, 10 of 24 patients who responded to first-line chemotherapy responded to salvage therapy, whereas none of the 7 patients who failed first-line chemotherapy responded to salvage therapy (11 ). A similar observation was also made in a chronic oral etoposide study, in which 10 of 18 patients who initially responded to first-line chemotherapy also responded to salvage chronic oral etoposide, whereas none of the 4 initially resistant patients responded (12 ). Thus responsiveness to previous first-line chemotherapy is one of the most important factors in predicting the efficacy of salvage therapy.
Several randomized trials failed to show any survival benefit of maintenance chemotherapy in SCLC (6-9 ). The study by Spiro and colleagues (6 ) which was mentioned earlier led to the recommendation of four to six cycles of first-line chemotherapy nd retreatment at the time of relapse. This trial also suggested that treating at relapse did not compromize survival.
Table 2 .
| Factor | CR | PR | NC | PD | NE | Response rate (%) |
P value | MST (days) |
P value | |
| Off chemotherapy (median duration 152.5 days) | >90 | 3 | 10 | 7 | 10 | 5 | 37 | 169 | ||
| <90 | 0 | 3 | 2 | 5 | 3 | 23 | 0.36 | 68 | <0.01 | |
| Duration of response to first-line chemotherapy (median 258 days) | >270 | 1 | 8 | 4 | 4 | 1 | 50 | 227 | ||
| <270 | 2 | 5 | 5 | 11 | 7 | 23 | 0.058 | 88 | <0.01 | |
| Response in first-line chemotherapy | CR | 2 | 5 | 2 | 3 | 1 | 54 | 237 | ||
| PR | 1 | 8 | 7 | 12 | 7 | 26 | 0.067 | 102 | <0.01 | |
| Extent of disease in first-line chemotherapy | LD | 0 | 9 | 5 | 6 | 4 | 38 | 147 | ||
| ED | 3 | 4 | 4 | 9 | 4 | 29 | 0.54 | 134 | NS | |
| Radiotherapy with first-line chemotherapy | Yes | 1 | 6 | 5 | 10 | 2 | 29 | 121 | ||
| No | 2 | 7 | 4 | 5 | 6 | 38 | 0.54 | 160 | NS | |
| Performance status in first-line chemotherapy | 0-1 | 2 | 12 | 7 | 11 | 4 | 39 | 160 | ||
| 2-3 | 1 | 1 | 2 | 4 | 3 | 18 | 0.20 | 91 | NS |
Many trials including testing of new drugs or combination chemotherapy have been completed in patients with relapsed SCLC. As few trials were conducted in a randomized setting, unbiased data on the usefulness of salvage chemotherapy for relapsed SCLC is critically needed. In the present study, all the patients treated at our Institution between January 1985 and August 1991 were analyzed.
Several factors including time off chemotherapy, responsiveness to first-line chemotherapy and the composition of previous therapies have been reported as affecting the activity of second-line chemotherapy (13 ). Evans and colleagues (14 ) reported a response rate of 50% when the time off chemotherapy exceeded 3 months while Batist and colleagues demonstrated a response rate of only 12% when the median time off chemotherapy was <1 month (15 ). In a phase II chronic oral etoposide study, the response rates were 64% and 12.5% with time off chemotherapy >90 days and <90 days respectively (12 ). These studies indicate that time off chemotherapy contributes to the response rate of second-line chemotherapy. In the present study, the response rates were 37% and 23% in the group with time off chemotherapy >90 days and <90 days respectively. Although no significant difference was shown in response rate, there was a statistically significant difference in survival related to the time off chemotherapy. Thus, time off chemotherapy is an important factor that would affect the outcome of relapsed SCLC. The response duration and the response of first-line chemotherapy are also found to be important factors that would affect response and survival.
The present study demonstrated that the PS at recurrence is an important factor for decision making in the treatment of the patients. It is notable that no patients with PS 3 or 4 responded to chemotherapy. It is strongly suggested that patients with poor prognostic factors should not undergo futile treatment.
In conclusion, relapsed SCLC still shows a promise of responding to second-line chemotherapy without lessening survival time, and thus clinical trials of new drugs or combination chemotherapeutic regimen for relapsed SCLC cases would be reasonably justified. Randomized comparative studies are warranted for determining the benefits of second-line chemotherapy for relapsed SCLC cases.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Cancer Research No. 5-41,7-23, 5-S-1, from the Ministry of Health and Welfare, Tokyo, Japan. We thank Dr. Russell F. DeVore for critical review of the manuscript.
References
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Copyright© Japanese Journal of Clinical Oncology, 1997.
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