Chemoradiation for Locally Advanced, Unresectable NSCLC

Gordon and Vokes present a comprehensive review of the management of locally advanced non-small-cell lung cancer (NSCLC). They summarize historical data on sequential and concurrent chemoradiation, as well as altered radiation fraction schedules with and without chemotherapy. They also discuss the use of new agents in combined-modality therapy.

Sequential Chemoradiation

The authors review three benchmark trials of sequential chemoradiation: the Cancer and Leukemia Group B (CALGB) study by Dillman et al, the intergroup study by Sause et al, and the study by LeChevalier et al from France. These three trials provide the rationale for using combined-modality approaches in patients with locally advanced NSCLC, and argue against the use of radiation therapy alone with curative intent in this disease.

Gordon and Vokes do not discuss why the 5-year survival rate for combined-modality therapy was 17% in the CALGB study but only 8% in the intergroup trial and 6% in the French study. Although survival benefits were seen in all three studies, the benefits of combined-modality therapy become more apparent when highly selected patients with good performance status enter trials, as in the CALGB study.

Concomitant Chemoradiation

The rationale for using concomitant chemoradiation in locally advanced NSCLC is based primarily on the radiation-sensitizing effects of cisplatin-based chemotherapeutic agents demonstrated in concomitant chemoradiation trials. As the authors note, improvement in survival with daily cisplatin (Platinol) was due to improved control of local disease.

Achieving local control is one of the critical issues in improving survival for patients with locally advanced NSCLC. One of the reasons why we should abandon radiation therapy alone in this setting is its high local recurrence rate (80%).[1] We cannot expect to cure locally advanced NSCLC with a local failure rate of 80%. With the cisplatin-based chemoradiation regimen, the local recurrence rate is approximately 50%. Although this recurrence rate is better than has been seen with previous approaches, significant further improvement is needed.

Sequential vs Concomitant Chemoradiation

Two studies have compared sequential vs concomitant chemoradiation therapy in locally advanced NSCLC. A study by Furuse et al, mentioned by Gordon and Vokes, was recently updated at the 1999 American Society of Clinical Oncology (ASCO) meeting. This update showed a statistically significant survival benefit for concomitant therapy, as compared with sequential therapy; median survival and 3- and 5-year survival rates were 16.5 months, 22.3%, and 15.8%, respectively, for the concomitant arm and 13.3 months, 14.7%, and 8.8%, respectively, for the sequential arm (P = .039).[2]

The other study, conducted by the Radiation Therapy Oncology Group (RTOG 9410), also is discussed by the authors. The results of that study should be available sometime next year.

Another trial that is not discussed in this review, CALGB 9130,was conducted by Clamon et al.[3] In this trial, patients with locally advanced NSCLC were randomized to receive either induction chemotherapy followed by radiation therapy alone or induction chemotherapy followed by concomitant carboplatin (Paraplatin) and radiation therapy. A total of 141 patients were randomized to each treatment arm.

The complete response rate was 18% with concurrent carboplatin vs 10% with radiotherapy alone (P = .101). No differences were seen with respect to failure-free survival (10% with carboplatin and 9% with radiotherapy alone) or overall survival (13% with carboplatin and 10% with radiotherapy alone) at 4-year follow-up.

In a recent pattern-of-practice survey,[4] we asked US oncologists what they thought was the best approach for combined chemoradiation in patients with locally advanced NSCLC. As expected, respondents’ recommendations were evenly divided between sequential and concomitant chemoradiation.

Hyperfractionated Radiation With or Without Chemotherapy

Gordon and Vokes also summarize several recent clinical studies with hyperfractionated radiotherapy (with or without chemotherapy). Although we are still awaiting the final results from recent Radiation Therapy Oncology Group (RTOG 9410) and North Central Cancer Treatment Group (NCCTG) trials, there is no clear evidence that hyperfractionation results in any major improvement in survival. However, continuous hyperfractionated accelerated radiotherapy (CHART) appears to produce a 9% survival benefit at 2 years.

Hopefully, an ongoing Eastern Cooperative Oncology Group (ECOG) trial comparing induction chemotherapy followed by hyperfractionated accelerated radiotherapy (HART) to standard radiation therapy will provide definitive answers about the role of hyperfractionated accelerated radiation in locally advanced NSCLC.

New Agents in Combined-Modality Regimens

Several new agents appear to be promising in the treatment of NSCLC and also show radiation-enhancing properties in preclinical studies. These agents are paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), gemcitabine (Gemzar), and irinotecan (Camptosar). The authors review phase I and phase II trials of concomitant chemoradiation regimens that incorporate these agents. Most of these trials provide encouraging data with respect to response and survival but also show increased toxicities.

The optimal agents and schedule to be used with radiation are still under investigation. Due to the remarkable improvement in survival with paclitaxel and carboplatin observed in several phase II trials of concomitant chemoradiotherapy, several cooperative groups are studying this combination in their phase III trials.

Conclusions

The authors provide an excellent review of the management of locally advanced NSCLC. The treatment options for this cancer have rapidly changed from radiation alone to sequential chemoradiation, concomitant chemoradiation therapy, hyperfractionated radiation, continuous hyperfractionated accelerated radiotherapy, and hyperfractionated accelerated radiotherapy. Although all of these treatment options provide some benefit over radiation therapy alone, the best overall treatment strategy remains unclear.

Unfortunately, Gordon and Vokes do not offer their own clear view of future strategies for improving the survival of patients with locally advanced NSCLC. I do agree with the authors about the need for patient participation in ongoing clinical trials to determine the best treatment approaches for this disease.

References:

1. Jeremic B, Shibamoto Y, Acimovic L, et al: Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer. J Clin Oncol 13:452-458, 1995.

2. Furuse K, Fukuoka M, Takada Y, et al: Phase III study of concurrent vs sequential thoracic radiotherapy (TRT) in combination with mitomycin (M), vindesine (V) and cisplatin (P) in unresectable stage III non-small-cell lung cancer (NSCLC): Five-year median follow-up results (abstract). Proc Am Soc Clin Oncol 18:458a, 1999.

3. Clamon G, Herndon J, Cooper R, et al: Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: A phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol 17:(1) 4-11, 1999.

4. Shyr Y, Choy H, Cmelak A, et al: Pattern of practice survey: Non-small-cell lung cancer (NSCLC) in US (abstract). Proc Am Soc Clin Oncol 18(1843):478a, 1999.