• Cheng S, Evans WK, Stys-Norman D, Shepherd FA, Lung Cancer Disease Site Group. Chemotherapy for relapsed small cell lung cancer: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Aug 2. 21 p. (Evidence-based series; no. 7-17). [13 references]

Relapsed small cell lung cancer (SCLC)

Assessment of Therapeutic Effectiveness
Treatment

Oncology
Pulmonary Medicine

Physicians

• To evaluate whether chemotherapy improves survival and quality of life in patients with relapsed small cell lung cancer (SCLC)
• To evaluate which single-agent or combination chemotherapy regimen is most effective in the treatment of relapsed SCLC
• To evaluate which patients with relapsed SCLC are most likely to benefit from additional chemotherapy

Adult patients with relapsed small cell lung cancer (SCLC)

1. Retreatment with original regimen that induced initial response (generally etoposide-cisplatin; alternative regimens include cyclophosphamide, doxorubicin, and vincristine (CAV) or carboplatin and etoposide
2. Oral topotecan as an alternative

• Response rate
• Median survival (weeks and overall)
• Toxicity
• Quality of life

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

Six randomized trial met the pre-defined eligibility criteria for this systematic review.

Expert Consensus (Committee)

Not applicable

Systematic Review with Evidence Tables

The data from the randomized trials were not pooled because the chemotherapy regimens used in the trials were different. The Lung Disease Site Group (DSG) will consider pooling the survival data of future fully published randomized trials if the comparison treatments are considered sufficiently homogenous to allow a meaningful evaluation.

Expert Consensus

This evidence-based series was developed by the Lung Disease Site Group (DSG) of Cancer Care Ontario's Program in Evidence-Based Care (PEB). The series is a convenient and up-to-date source of the best available evidence on the use of chemotherapy for relapsed small cell lung cancer, developed through systematic review, evidence synthesis, and input from practitioners in Ontario.

See the original guideline document for a discussion of the evidence used to formulate the recommendations.

Disease Site Group Consensus

Overall, the group was satisfied with the draft recommendations and document. One comment was made about the recommendations being too concise regarding specific treatment regimens for patients who responded to first-line treatment and then relapsed. As the data is limited, the DSG developed a more general statement derived from clinical expertise.

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

Report Approval Panel

Prior to the submission of this evidence-based series report for external review, the report was reviewed and approved by the Program in Evidence-based Care (PEBC) Report Approval Panel, which consists of two members, including an oncologist, with expertise in clinical and methodology issues. The Panel approved the guideline as written, and only editorial changes were made in response to the suggestions of the Panel.

External Review

Feedback was obtained through a mailed survey of 57 practitioners in Ontario, including 34 medical oncologists and 23 radiation oncologists. The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. The survey was mailed out on June 1, 2006. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Lung Disease Site Group (DSG) reviewed the results of the survey.

• The evidence for the clinical benefit of second-line chemotherapy in the treatment of patients with relapsed small cell lung cancer (SCLC) is limited. The selection of patients for treatment with second-line therapy should be dependent on the treatment-free interval, the extent of response to first-line therapy, residual toxicity from first-line therapy, and the performance status of the patient.
• There is insufficient evidence to recommend a specific chemotherapy regimen. However, in the opinion of the Lung Cancer Disease Site Group, patients who relapse three or more months following the completion of first-line chemotherapy may benefit from retreatment with the same regimen that induced their initial response. This would generally mean retreatment with etoposide-cisplatin. Alternative regimens may include cyclophosphamide, doxorubicin, and vincristine (CAV) or carboplatin and etoposide.
• Oral topotecan is a possible alternative for patients who initially responded to chemotherapy and had a response duration of 45 days or longer.
• There is insufficient evidence to determine whether one mode of administration of topotecan is superior to any other mode of administration. Oral administration is more convenient and may be a treatment option for patients not suitable for intravenous therapy. Oral administration is associated with a higher incidence of grade 3/4 diarrhea, whereas intravenous administration may result in a higher frequency of grade 3/4 neutropenia.
• There is currently no standard second-line chemotherapy regimen for patients who fail to respond to or who relapse shortly after first-line therapy. Clinical trials are needed to determine the optimal treatment regimen.

None provided

The recommendations are supported by randomized trials.

• One recent randomized phase II trial showed that chemotherapy consisting of oral topotecan and best supportive care (BSC) extended survival when compared with best supportive care alone [26 versus 14 weeks, hazard ratio (HR), 0.64; 95% confidence interval (CI), 0.45-0.90; p=0.0104] and improved the quality of life for patients who had relapsed, resistant small cell lung cancer (SCLC). The response rate for patients treated with oral topotecan and best supportive care was only 7%.
• One randomized phase II trial comparing cisplatin and etoposide to carboplatin, cisplatin, and etoposide found no significant differences in response rate (p=0.20) or survival (p=0.11).
• One randomized phase III trial that treated patients with cyclophosphamide, doxorubicin, and vincristine (CAV) or topotecan alone reported no significant differences in response rate (p=0.285) or survival (p=0.795).
• One phase III trial randomized patients to either bis-chloro-ethylnitrosourea [BCNU], thiotepa, vincristine, cyclophosphamide (BTOC) or etoposide and cisplatin; no significant differences in response rate (p=0.91) or survival (p=0.15) were found.
• Two randomized trials (phase II and phase III) compared oral to intravenous (IV) administration of topotecan. Response rates were 18.3% and 23.1% for oral administration and 14.8% and 21.9% for intravenous administration. Survival was not significantly different between the modes of administration (hazard ratio, 0.98; 95% confidence interval, 0.77-1.25; and risk ratio, 0.84; 95% confidence interval, 0.53-1.32).

Grade 3/4 neutropenia was the most common toxicity; 33% of patients receiving oral topotecan reported grade 4 neutropenia (see Table 2 in the original guideline document). Diarrhea (6%) and fatigue (4%) were the most commonly reported non-hematological adverse events in this group. In patients receiving best supportive care (BSC) alone, pain (6%), dyspnea (9%), and fatigue (4%) were the most common adverse events. Mortality from all causes 30 days post-randomization was 7% for topotecan and BSC compared to 13% for BSC alone.

Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the evidence-based series is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding their content or use or application and disclaims any for their application or use in any way.

An implementation strategy was not provided.

Living with Illness

Effectiveness

• Cheng S, Evans WK, Stys-Norman D, Shepherd FA, Lung Cancer Disease Site Group. Chemotherapy for relapsed small cell lung cancer: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Aug 2. 21 p. (Evidence-based series; no. 7-17). [13 references]

Not applicable: The guideline was not adapted from another source.

2006 Aug 2

Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]

The Program in Evidence-based Care (PEBC) is a Province of Ontario initiative sponsored by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Cancer Care Ontario
Ontario Ministry of Health and Long-Term Care

Provincial Lung Cancer Disease Site Group

The members of the Lung Disease Site Group (DSG) declared that there were no potential conflicts of interest relating to the topic of this evidence-based series.

None available

This NGC summary was completed by ECRI on October 26, 2006. The information was verified by the guideline developer on November 24, 2006.