Quality of life assessment in advanced non-small-cell lung cancer patients undergoing an accelerated radiotherapy regimen: report of ECOG study 4593. Eastern Cooperative Oncology Group.

PURPOSE: To prospectively evaluate the quality of life (QOL) before, at completion, and after therapy for patients receiving an accelerated fractionation schedule of radiotherapy for advanced, unresectable non-small-cell lung cancer in a Phase II multi-institutional trial. METHODS AND MATERIALS: The Functional Assessment of Cancer Therapy-Lung (FACT-L) patient questionnaire was used to score the QOL in patients enrolled in the Eastern Cooperative Oncology Group Phase II trial (ECOG 4593) of hyperfractionated accelerated radiotherapy in non-small-cell lung cancer. Radiotherapy (total dose 57.6 Gy in 36 fractions) was delivered during 15 days, with three radiation fractions given each treatment day. The protocol was activated in 1993, and 30 patients had accrued by November 1995. The FACT-L questionnaire was administered at study entry (baseline), on the last day of radiotherapy (assessment 2), and 4 weeks after therapy (assessment 3). The FACT-L includes scores for physical, functional, emotional, and social well-being (33 items), and a subscale of lung cancer symptoms (10 additional items). The summation of the physical, functional, and lung cancer symptom subscales (21 items) constitutes the Trial Outcome Index (TOI), considered the most clinically relevant outcome measure in lung cancer treatment trials. RESULTS: The FACT-L completion rates at the designated study time points were as follows: baseline, 30 of 30 (100%); assessment 2, 29 (97%) of 30; and assessment 3, 24 (80%) of 30. At treatment completion, statistically significant declines in QOL scores were noted, compared with baseline for physical and functional well-being. Emotional well-being scores improved at both assessment 2 and assessment 3. The physical and functional scores returned approximately to baseline values at assessment 3. The change in TOI score was evaluated as a function of the clinical response to treatment, toxicity grade, and survival; no clear association was noted. A trend for the largest decrease in QOL was noted for patient groups with shorter survival times. The mean change in the TOI score from baseline to assessment 3 was -8.96 for patients surviving < 52 weeks vs. -0.95 for those surviving > 52 weeks. CONCLUSIONS: The FACT-L questionnaire can be successfully administered to non-small-cell lung cancer patients enrolled in a prospective Phase II trial of accelerated radiation fractionation. The decrement in physical and functional QOL during treatment returned to baseline level at 4 weeks after treatment. Emotional well-being improved at all time points. A trend was noted for shorter survival times in patients with the largest negative change in TOI score. These data suggest that the clinical use of hyperfractionated accelerated radiotherapy did not cause a significant, long-term decrease in the QOL of the treated patients, and that it is feasible to perform a QOL study of patients enrolled in such a trial.

A cost-effectiveness and cost-utility analysis of radiosurgery vs. resection for single-brain metastases.

PURPOSE: The median survival of well-selected patients with single-brain metastases treated with whole-brain irradiation and resection or radiosurgery is comparable, although a randomized trial of these two modalities has not been performed. In this era of cost containment, it is imperative that health-care professionals make fiscally prudent decisions. The present environment necessitates a critical appraisal of apparently equi-efficacious therapeutic modalities, and it is within this context that we present a comparison of the actual costs of resection and radiosurgery for brain metastases. METHODS AND MATERIALS: Survival and quality of life outcome data for radiation alone or with surgery were obtained from two randomized trials, and radiosurgical results were obtained from a multiinstitutional analysis that specifically evaluated patients meeting surgical criteria. Only linear accelerator radiosurgery data were considered. Cost analysis was performed from a societal view point, and the following parameters were evaluated: actual cost, cost ratios, cost effectiveness, incremental cost effectiveness, cost utility, incremental cost utility, and national cost burden. The computerized billing records for all patients undergoing resection or radiosurgery for single-brain metastases from January 1989 to July 1994 were reviewed. A total of 46 resections and 135 radiosurgery procedures were performed. During the same time period, 454 patients underwent whole-brain radiation alone. An analysis of the entire bill was performed for each procedure, and each itemized cost was assigned a proportionate figure. The relative cost ratios of resection and radiosurgery were compared using the Wilcoxon rank sum test. Cost effectiveness of each modality, defined as the cost per year of median survival, was evaluated. Incremental cost effectiveness, defined as the additional cost per year of incremental gain in median survival, compared to the next least expensive modality, was also determined. To calculate the societal or national impact of these practices, the proportion of patients potentially eligible for aggressive management was estimated and the financial impact was determined using various utilization ratios for radiosurgery and surgery. RESULTS: Both resection and radiosurgery yielded superior survival and functional independence, compared to whole brain radiotherapy alone, with minor differences in outcome between the two modalities; resection resulted in a 1.8-fold increase in cost, compared to radiosurgery. The latter modality yielded superior cost outcomes on all measures, even when a sensitivity analysis of up to 50% was performed. A reversal estimate indicated that in order for surgery to yield equal cost effectiveness, its cost would have to decrease by 48% or median survival would have to improve by 108%. The average cost per week of survival was $310 for radiotherapy, $524 for resection plus radiation, and $270 for radiosurgery plus radiation. CONCLUSIONS: For selected patients, aggressive strategies such as resection or radiosurgery are warranted, as they result in improved median survival and functional independence. Radiosurgery appears to be the more cost-effective procedure.

Growth inhibition of squamous cell carcinoma xenografts with the polyamine analogue BE 4444.

BACKGROUND: The capacity of radiation to cure advanced head and neck squamous cell carcinoma is compromised by the proliferation of surviving tumor cells during the course of therapy (overall duration, often 7-9 weeks). Antiproliferative agents that inhibit tumor proliferation, even in the absence of direct cytotoxicity, may be useful adjuncts for concurrent use with radiation. Modulation of endogenous polyamine (PA) metabolism has the potential to inhibit cell growth. The PA analogue 1,19-bis(ethylamino)-5,10,15-triazanonadecane (BE 4444) is a synthetic compound that demonstrates antiproliferative effects in human tumor cells. OBJECTIVE: To evaluate the PA analogue BE 4444 for its inhibitory effect on the growth of human squamous cell carcinoma xenografts in nude mice. DESIGN: Xenografts of human squamous cell carcinomas were grown in nude mice; then, BE 4444 was injected intraperitoneally (5 mg/kg) on a twice-daily schedule for 8 days. Tumor growth measurements were performed twice weekly for 8 weeks and compared with those of control mice that were injected with sterile saline solution on the same schedule. The PA levels in the tumor and normal tissue samples were assayed at the completion of treatment. RESULTS: Tumor volume in the BE 4444-treated mice was reduced by 62% compared with tumor volumes in control mice, and the tumor growth rate was reduced by 64%. This growth inhibition was maintained through completion of the experiment. Levels of endogenous PAs were not significantly different from control levels, suggesting that the mechanism of action for BE 4444 is not simply PA biosynthesis inhibition. CONCLUSIONS: The PA analogue BE 4444 is an inhibitor of human squamous cell cancer growth. Further studies are in progress to characterize the potential value of PA analogues as adjuncts to radiation therapy for rapidly proliferating squamous cell carcinoma of the head and neck.

A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis.

PURPOSE: Recent randomized trials of selected patients with single brain metastasis comparing resection followed by whole-brain radiotherapy (WBRT) to WBRT alone have shown a statistically significant survival advantage for surgery and WBRT. A multiinstitutional retrospective study was performed, which identified comparable patients who were treated with stereotactic radiosurgery (RS) and WBRT. METHODS AND MATERIALS: The RS databases of four institutions were reviewed to identify patients who met the following criteria: single-brain metastasis; no prior cranial surgery or WBRT; age > 18 years; surgically resectable lesion; Karnofsky Performance Status (KPS) > or = 70 at time of RS; nonradiosensitive histology. One hundred twenty-two patients were identified who met these criteria. Patients were categorized by: (a) status of the primary, (b) status of non-CNS metastasis, (c) age, (d) baseline KPS (from 70-100), (e) histology, (f) time from diagnosis of primary to the detection of the brain metastasis, (g) gender, and (h) tumor volume. RS was performed with a linear accelerator based technique (peripheral dose range was 10-27 Gy, median was 17 Gy). WBRT was performed in all but five patients who refused WBRT (dose range was 25-40 Gy, median was 37.5 Gy). RESULTS: The median follow-up for all patients was 123 weeks. The overall local control rate (defined as lack of progression in the RS volume) was 86%. Intracranial recurrence outside of the RS volume was seen in 27 patients (22%). The actuarial median survival from date of RS is 56 weeks, and the 1-year and 2-year actuarial survival rates are 53% and 30%. The median duration of functional independence (sustained KPS > or = 70) is 44 weeks. Nineteen of 77 deaths were attributed to CNS progression (25% of all deaths). Multivariate analysis revealed the following factors to be statistically significant predictors of survival: baseline KPS (p < .0001) and absence of other sites of metastasis (p = 0.008). CONCLUSION: The RS in conjunction with WBRT for single brain metastasis can produce substantial functional survival, especially in patients with good performance status and without extracranial metastasis. These results are comparable to recent randomized trials of resection and WBRT. The advantages of RS over surgery in terms of cost, hospitalization, morbidity, and wider applicability strongly suggest that a randomized trial to compare RS with surgery is warranted.