ABSTRACT: Inoperable non–small-cell lung cancer has become the domain of combined-modality treatment based on several recent, large, phase III studies. Results of Radiation Therapy Oncology Group (RTOG) phase II studies have suggested improvements in response and short-term survival, using a strategy of intensification of dosing and scheduling of cisplatin-based regimens and either standard or hyperfractionated radiation therapy. However, some trials also have shown higher rates of severe acute toxicity and more frequent severe late toxicity. There appears to be an institutional learning curve in administering these more complex, intense regimens and in effective management of the acute toxicities. As the RTOG institution accrued more cases onto the intensified regimen studies, toxicity management improved, treatment was given with fewer interruptions or dosage reductions, and survival rates improved. Quality-adjusted survival analysis, in which survival time is reduced by the amount of time spent with severe toxicity, shows that the survival gains observed with some concurrent regimens may be negated by time spent with toxicity. Future attempts to optimize combined-modality therapy must take account of toxicity issues in the study design by incorporating less toxic chemotherapy agents, normal tissue protectors, tumor-targeting sensitizing agents, normal tissue-sparing radiation therapy techniques (eg, three-dimensional conformal), and proactive, aggressive management of toxicity. [ONCOLOGY 13(Suppl 5):116-120, 1999]
Surgery alone is the treatment of choice for stage I and II non–small-cell lung cancer (NSCLC), with long-term survival rates as high as 60% to 70%. Stage IIIA patients with limited, nonbulky N2 nodal disease may have a 10% to 15% 5-year survival rate with surgery alone. Bulky IIIA and most IIIB non–small-cell lung cancer has been the domain of radiation therapy alone, until recently with excellent palliative relief of disease-related symptoms (60% to 70%) but disappointing survival results. Reported median survival ranges from 6 to 11 months, with long-term survival rates of 3% to 10%.[1-3] Even with high doses of conventionally fractionated radiation therapy, local failure occurs in 80% of patients, and distant failure also remains frequent. Higher biologic doses of radiation therapy are possible with altered fractionation radiation therapy, but this does not address occult distant metastases; thus, even if local control improves, survival gains are modest.[2,4]
These limitations of radiation therapy alone for unresectable non–small-cell lung cancer have led to numerous clinical trials exploring adjuvant chemotherapy in various strategic associations with radiation therapy.[3-5] Meta-analyses of these trials have confirmed a long-term survival benefit for the addition of adjuvant chemotherapy to radiation therapy, in either sequential, concurrent, or alternating fashion, with median survivals in the range of 13 to 14 months and 5-year survival rates of 15% to 20%.[2,3,5] Consensus statements from several national and international cancer organizations now conclude that combined chemotherapy/radiation therapy is the new “gold standard” for the treatment of inoperable non–small-cell lung cancer.[6-8]
The survival improvement shown with combined chemotherapy/radiation therapy fostered optimism that additional survival gains might be possible by further optimizing the chemotherapy/radiation therapy combination. The possible approaches to optimization are numerous when one considers the nearly infinite ways in which the dose, scheduling, and delivery of each modality could be altered. The strategy chosen by RTOG was that of treatment intensification accomplished by one of two approaches.
The first approach was to use chemotherapy concurrently during radiation therapy as both a cytotoxic (to contribute to tumor cell kill locally and distantly) and as a radiation sensitizer (to enhance radiation tumor cell kill). Concurrent chemotherapy/radiation therapy with and without induction chemotherapy was explored. The second approach was to intensify the radiation therapy by using hyperfractionation, in which the radiation therapy dose is given twice daily to a higher total dose than standard radiation therapy, with each fraction given 6 hours apart to allow normal tissue recovery. These approaches were tested by RTOG in a series of phase II trials. Each has shown favorable results in terms of response and at least short-term survival rates that appear better than those that established induction chemotherapy and radiation therapy as an improvement over radiation therapy alone. As part of the analysis of these trials and while awaiting the results of a phase III RTOG trial (94-10) evaluating sequential vs concurrent chemotherapy and radiation therapy, the observed toxicity was analyzed in detail. The findings of these analyses are summarized.
Speculating that intensification of the local-regional and systemic treatment components could further augment local and distant control, and, thereby, survival, RTOG conducted five phase II trials evaluating three radiation therapy/chemotherapy strategies:
induction chemotherapy followed by standard radiation therapy (ChT ® SRT),
induction ChT followed by concurrent ChT and standard RT (ChT ® ChT/SRT), and
concurrent ChT and hyperfractionated RT (ChT/HfxRT).
To compare the toxicity and survival results for the three strategies, it was decided to pool the data from the five trials according to strategy. Since the objectives of the five phase II trials did not include combining their data, the studies did differ somewhat in eligibility and patient characteristics. Therefore, the studies were analyzed to evaluate the validity of combining and comparing the data. Patient characteristics are shown in Table 1.
All five trials required a Karnofsky performance status of ³ 70%; three trials (N = 147) set no weight loss requirement, and two trials (N = 336) required < 5% weight loss. All five trials used cisplatin-based chemotherapy combined with either vinblastine (Velban) or etoposide (VePesid). Patients staged as IIIA had radiographically evident bulky N2 disease. There were minor differences in chemotherapy type, chemotherapy dose, and radiation therapy dose. Despite the differences noted above, it was concluded that the five studies were similar enough that differences in toxicity, response, failure patterns, and survival according to treatment strategy might still be evident. It should be understood, however, that inferences from pooled data might be weakened by inclusion of patients in some of the trials with less favorable performance and tumor characteristics.
Acute toxicity was defined as that occurring within 90 days from the start of radiation therapy; late toxicities included those occurring > 90 days after the start of radiation therapy.
All three treatment strategies had a similar incidence of grade 4/5 acute toxicity. Significantly more patients treated with ChT/RT had acute nonhematologic toxicity ³ grade 3 (55%) than patients treated with either ChT ® SRT (27%; P < .0001) or ChT ® ChT/SRT (34%; P = .0005). This was due to a significantly higher (P < .0001) incidence of esophagitis ³ grade 3 (34%) for ChT/HfxRT compared to ChT ® SRT (1.3%) or ChT ® ChT/SRT (6%; Figure 1).
Overall grade 4/5 late toxicities also did not differ by strategy. Late nonhematologic toxicities ³ grade 3 were significantly more frequent with ChT ® ChT/SRT (26%; P = .046) and ChT/HfxRT (28%; P = .003), compared to ChT ® SRT (14%; Figure 2). Although there was a trend toward more frequent late esophageal toxicity ³ grade 3 with the two concurrent strategies, late lung toxicity ³ grade 3 was significantly more frequent (P = .033) for ChT ® ChT/SRT (21%) and ChT/HfxRT (20%), compared to ChT ® SRT (10%; Figure 2).
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