Adjuvant radiotherapy and chemotherapy for stage II or IIIA non-small-cell lung cancer after complete resection. Provincial Lung Cancer Disease Site Group.

GUIDELINE QUESTIONS: 1) Does the use of postoperative, adjuvant radiotherapy or chemotherapy, alone or in combination, improve survival rates among patients with completely resected, pathologically confirmed stage II or IIIA non-small-cell lung cancer (NSCLC)? 2) Does the use of radiotherapy reduce the risk of local recurrence among patients with completely resected stage II or IIIA NSCLC? OBJECTIVE: To make recommendations about the use of postoperative adjuvant radiotherapy and chemotherapy in the treatment of patients with completely resected stage II or IIIA NSCLC. OUTCOMES: Overall survival and disease-free survival are the primary outcomes of interest. A secondary outcome of interest is local disease control. PERSPECTIVES (VALUES): Evidence was collected and reviewed by 4 members of the Lung Cancer Disease Site Group (Lung Cancer DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The evidence-based recommendation resulting from this review was approved by the Lung Cancer DSG, which comprises medical oncologists, radiation oncologists, pathologists, surgeons and a medical sociologist. A community representative was present at 1 meeting during which the recommendation was discussed. QUALITY OF EVIDENCE: One meta-analysis and 22 randomized controlled trials (RCTs) were published between 1962 and 1996. The RCTs compared surgery plus radiotherapy with surgery alone; surgery plus adjuvant chemotherapy with surgery alone; surgery plus radiotherapy with surgery plus both chemotherapy and radiotherapy. Many studies included patients with stage IIIB NSCLC; some included patients with incompletely resected stage I NSCLC or with small cell lung cancer (maximum 10%). Older studies used chemotherapy or radiation that would now be considered inferior according to current standards of practice. BENEFITS: There was no survival benefit with adjuvant radiotherapy alone, although 3 RCTs reported a reduction in the rate of local recurrence among patients treated with adjuvant radiotherapy. The meta-analysis showed that postoperative, cisplatin-based chemotherapy alone reduced the relative risk of death by 13% (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.74 to 1.02); in combination with radiotherapy it resulted in a 6% reduction in the relative risk of death (HR 0.94, 95% CI 0.79 to 1.11). HARMS: Postoperative adjuvant chemotherapy with alkylating agents was found in the meta-analysis to increase the relative risk of death by 15%. A study involving prolonged adjuvant chemotherapy (busulfan or cytoxan daily for 2 years) reported that 4 of 726 patients had hematologic malignancies. In 1 study, only 53% of patients received all 4 cycles of chemotherapy with cyclophosphamide-doxorubicin-cisplatin (CAP); in another, 22% of patients refused therapy with CAP because of nausea and vomiting. PRACTICE GUIDELINE: There is evidence from RCTs that postoperative radiotherapy reduces rates of local recurrence by 11% to 18% (or 1.6 to 19-fold) among patients with completely resected, pathologically confirmed stage II or IIIA NSCLC. Therefore, if the outcome of interest is a reduction in the frequency of local tumour recurrence, radiotherapy is recommended. However, there is no evidence of a survival benefit from postoperative radiotherapy alone. In a meta-analysis, postoperative chemotherapy with or without radiotherapy resulted in a slightly reduced (statistically nonsignificant) risk of death among patients with surgically resected stage II or IIIA NSCLC. The survival benefit was small and achieved only with chemotherapy regimens that produced substantial toxic effects and that are no longer used. Newer chemotherapy regimens are currently being evaluated as adjuvant therapy, but there is insufficient evidence of benefit at this time to recommend them. Therefore, if the outcome of interest is survival, there is insufficient evidence to recommend current chemotherapy regimens with or without radiotherapy as postoperative, adjuvant the

Recent advances in the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), which represents the bulk of primary carcinomas of the lung, is an aggressive malignancy. The majority of patients with NSCLC present with advanced disease, not curable by surgery, at the time of diagnosis. Recent randomized trials have shown an improvement in survival for patients with loco-regional disease treated with combination, platinum-based, chemotherapy and curative irradiation. Similarly, randomized studies of good performance status patients with metastatic disease have documented a survival advantage, albeit a modest advantage, for those receiving chemotherapy. New chemotherapy agents with activity in NSCLC have been studied in phase II trials. These agents need to be evaluated, in loco-regional and metastatic disease, in large randomized phase III trials before conclusions can be drawn about their role in treatment. Novel treatments which among other include gene therapy, anti-angiogenic and anti-metastatic agents are currently being assessed in early phase I and II studies. Gene therapy will likely be combined with standard chemotherapy and radiation in the treatment of NSCLC, whereas anti-angiogenic and anti-metastatic agents may play a role in prevention and maintenance therapy. Finally, regardless of the approach or modality, new interventions will need to be assessed for their impact on overall survival and the quality of life of patients with NSCLC.

Continuous hyperfractionated accelerated radiotherapy in the treatment of carcinoma of the columella and vestibule of the nose.

Twenty-one patients with squamous cell carcinoma of the nasal columella and vestibule were treated at the Mount Vernon Centre for Cancer Treatment between March 1986 and January 1994. Tumours ranged from 15 to 55 mm in maximum dimension (median 25 mm). All patients were treated with radical intent with continuous hyperfractionated accelerated radiotherapy (CHART). This group was analysed with respect to tumour control, tumour cell kinetics and radiation-induced morbidity at a median time to last follow-up of 40 months. Particular attention was paid to the detailed evaluation of late radiation changes. Patients who were still alive were assessed as to the satisfaction with the cosmesis of their treated nose. Four patients had relapse of disease either at the primary site alone (2), in neck nodes (1) or in both regions (1). One patient was successfully salvaged with surgery. Cell kinetic studies showed that cancers at this site may have potential for rapid cellular repopulation similar to cancers developing at other head and neck sites. CHART was well tolerated by patients. Late skin changes were remarkedly slight (despite full skin dose) and overall cosmesis excellent with this radiotherapy schedule.

Tumor cell kinetics, local tumor control, and accelerated radiotherapy: a preliminary report.

The local tumor control achieved in patients treated in a pilot study of continuous, hyperfractionated, accelerated radiotherapy has been related to the tumor cell kinetics evaluated by in vivo administration of bromodeoxyuridine and flow cytometry. In 42 of 50 patients with advanced squamous cell carcinomas in the head and neck region it was possible to sample the primary tumor prior to treatment. In three further cases, involved regional nodes were studied: in the remaining five, tissue was obtained subsequently either from a local recurrence or from a distant metastasis. Successful cell kinetic measurements were made in 38 (90%) of the 42 primary tumors. The median values of the labelling index, the duration of the DNA synthetic phase and, thus, the potential doubling time for all primaries were 7.1%, 9.8 hr, and 3.9 days, respectively. Complete regression was achieved in 28 (74%) of the primary tumors and in 23 (61%) this was maintained to the time of observation for this report. There was no significant influence of any of the cell kinetic parameters upon the immediate or longer term local tumor control. This result is compatible with the overcoming of cellular repopulation by the acceleration of radiotherapy.