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Adjuvant or Induction Cisplatin-Based Chemotherapy for Operable Lung Cancer

Adjuvant or Induction Cisplatin-Based Chemotherapy for Operable Lung Cancer

ABSTRACT: ABSTRACTDespite aggressive surgical management, 5-year survival rates of patients with non–small-cell lung cancer (NSCLC) range from 73% for those with pathologic stage IA to 25% for stage IIIA. Given the low survival rate associated with treatment by surgery alone, numerous trials have investigated the use of induction or adjuvant strategies with chemotherapy or thoracic irradiation, either alone or in combination. A meta-analysis published in 1995 showed that cisplatin-based regimens produce the best adjuvant chemotherapy results in NSCLC patients, and this finding has been validated by three large randomized trials. Neoadjuvant chemotherapy offers theoretical advantages over adjuvant chemotherapy, including improved patient compliance, a smaller primary tumor, and pathologic evaluation of treatment efficacy. However, most large randomized trials of neoadjuvant chemotherapy have failed to show statistically significant results. This article reviews the pros and cons of each strategy, current guidelines, and treatment methods that are being explored.

Despite aggressive surgical management, 5-year survival rates of non–small-cell lung cancer (NSCLC) patients range from 73% for those with pathologic stage IA to 25% for those with stage IIIA.[1] Clinical or preoperative staging often underestimates the extent of the disease (particularly if positron-emission tomography and mediastinoscopy are not used), and the estimated survival rates for a given clinical stage are much lower than those for the corresponding surgical/pathologic stage.[1] Given the low survival rate associated with treatment by surgery alone, a number of trials have investigated the use of induction or adjuvant strategies with chemotherapy or thoracic irradiation, either alone or combined.

In an individual data-based (IPD) meta-analysis published in 1995, the use of a cisplatin-based regimen emerged as the best adjuvant (postoperative) chemotherapeutic option, which was subsequently validated by three large randomized trials.[2-5] The meta-analysis was updated 12 years later, confirming a 4% absolute improvement of the 5year survival rate in more than 8,000 patients (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.81–0.93).[6]

Neoadjuvant chemotherapy offers several theoretical advantages over adjuvant chemotherapy, including improved patient compliance, a smaller primary tumor, and pathologic evaluation of treatment efficacy. To date, most of the large randomized trials of preoperative chemotherapy have shown statistically nonsignificant results, with the most recent meta-analysis on 1,507 patients reporting a hazard ratio of 0.88 (95% CI = 0.76–1.01; P = .07).[7]

We will review the pros and cons of each strategy, review current guidelines, and summarize treatment methods that are currently being explored.

Adjuvant Chemotherapy Milestones
The first trials evaluating postoperative adjuvant chemotherapy for NSCLC suggested that alkylating agents and older chemotherapy treatments were detrimental for survival.[2] Randomized trials of postoperative cisplatin-based chemotherapy subsequently failed to show any relevant individual benefit. A meta-analysis based on individual patient data from these studies was published in 1995.[2] Eight trials used total doses of cisplatin between 50 and 240 mg/m² in diverse combinations with doxorubicin, cyclophosphamide, or vindesine. The analysis found that such chemotherapy was associated with a 13% reduction in the risk of death, with an overall hazard ratio of 0.87 (P = .08). The absolute benefit of chemotherapy was 5% at 5 years (95% CI = 1% detriment to 10% benefit), but the results were not statistically significant. Nevertheless, these findings led to adjuvant cisplatin-based chemotherapy trials in completely resected NSCLC.

Adjuvant Lung Project Italy
The Adjuvant Lung Project Italy (ALPI) randomly allocated 1,209 completely resected stage I, II, or IIIA NSCLC patients to observation or three cycles of MVP (mitomycin/vindesine/cisplatin).[8] Radiotherapy was administered at the discretion of the individual participating center. As the recruitment rate declined at the end of the recruiting period, the trial enrolled 93% of the intended sample size (1,300 patients). Of these patients, 13 did not match study criteria, and data corresponding to 108 others were considered nonreliable; these patients were therefore excluded. Of all patients included, 39% had stage I disease, 33% had stage II disease, and 28% had stage IIIA disease. After a median follow-up of 64.5 months, there was no significant difference in overall survival between the two groups (HR = 0.96; 95% CI = 0.81–1.13; P = .589).

Big Lung Trial
The Big Lung Trial (BLT) was a randomized trial from the United Kingdom investigating cisplatin-based chemotherapy in patients with completely resected stage I–III NSCLC.[9] This trial was not sufficiently powered to detect clinically significant differences in survival. The 381 patients were randomly assigned to two groups: surgery alone or two to three cycles of cisplatin-based chemotherapy (with vindesine, mitomycin/ifosfamide, mitomycin/vinblastine, or vinorelbine). Approximately 27% of patients had stage I disease, 38% had stage II, and 34% had stage III. Resection was macroscopically complete in roughly 95% of cases, but microscopically incomplete in 15%. The median follow-up was only 2.9 years and provided no evidence that chemotherapy has a positive effect on overall survival (HR = 1.02; 95% CI = 0.77–1.35; P = .90).

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