Chemoradiation for Locally Advanced, Unresectable NSCLC

The article by Drs. Gordon and Vokes provides the reader with a comprehensive overview of the treatment of locally advanced unresectable non–small-cell lung cancer (NSCLC) with chemotherapy and radiation therapy. The authors review pivotal US trials conducted by the Cancer and Leukemia Group B (CALGB) and the Radiation Therapy Oncology Group (RTOG) that demonstrate a modest but reproducible overall survival advantage with induction cisplatin (Platinol)/vinblastine (Velban) chemotherapy followed by thoracic radiotherapy, as compared with radiotherapy alone.[1,2] They update current and recently completed cooperative group trials attempting to optimize chemoradiotherapy approaches to stage III disease.

The authors conclude that patients with advanced NSCLC and a reasonable performance status benefit from potentially curative combinations of chemotherapy and radiotherapy. Outside of the setting of a clinical trial, Drs. Gordon and Vokes favor the use of two cycles of platinum-based induction chemotherapy followed by standard radiation therapy.

Although we agree with the authors’ general conclusions, several issues are worthy of comment. First, the pivotal CALGB and RTOG trials that demonstrate a survival advantage for combined-modality therapy were limited to patients with a reasonable performance status and minimal weight loss. These eligibility criteria eliminated approximately 35% of poor-risk patients with locally advanced NSCLC, who are not likely to tolerate aggressive cisplatin-based combined-modality therapy. When applying the results of these two clinical trials to clinical practice, these eligibility criteria are often overlooked.

As described by the authors, the Southwest Oncology Group (SWOG) recently completed a phase II trial of chemoradiotherapy specifically targeting this poor-risk population.[3] The chemotherapy used in this trial consisted of two cycles of a modified-dose carboplatin (Paraplatin)/etoposide regimen administered concurrently with 61 Gy of thoracic radiotherapy. The median survival of 13 months and 2-year survival rate of over 20% are encouraging in this compromised patient subgroup, and were achieved without treatment-related mortality. The RTOG is now comparing this regimen to radiotherapy alone in a randomized phase III trial.

With respect to good-risk patients, which chemoradiotherapy approaches have the highest likelihood of demonstrating an improvement in survival time after the diagnosis of locally advanced NSCLC? We will discuss two categories of clinical trials that address this question: (1) trials comparing concurrent chemoradiotherapy to sequential chemoradiotherapy, and (2) trials evaluating altered fractionation radiotherapy. Finally, we will preview some novel nonchemotherapeutic anticancer agents that are likely to be integrated into chemoradiotherapy programs in the future.

Concurrent vs Sequential Chemoradiotherapy

Whether concurrent chemoradiotherapy results in a superior therapeutic outcome compared to sequential chemotherapy followed by radiotherapy remains highly controversial. Concurrent chemoradiation has the potential advantages of enhanced local control and the elimination of chemotherapy-resistant but radiation-sensitive tumor clones before the clones metastasize beyond the chest. The major disadvantage of concurrent therapy is the likelihood of increased toxicity, which may limit the dose intensity of chemotherapy or radiotherapy.

Recently, long-term follow-up of a landmark study by the West Japan Lung Cancer Group (WJLCG) directly comparing concurrent chemoradiation to sequential chemoradiation was reported.[4] Patients in both arms of the study received two courses of cisplatin/vindesine (Eldisine)/mitomycin (Mutamycin) and 56 Gy of thoracic radiotherapy. The radiotherapy was delivered as a continuous course in the sequential arm of the trial but as a split-course in the concurrent arm with a 10-day break after the first 28 Gy.

Median survival time was 16.4 months for patients receiving concurrent chemoradiation, significantly better than the median of 13.5 months reported for those receiving chemotherapy followed by radiotherapy (P < .05). The advantage persisted at 5 years, at which point the survival rate in the concurrent arm was 16%, as compared with 9% in the sequential arm. Hematologic and esophageal toxicities occurred more frequently in the concurrent arm but were manageable.

As mentioned by Gordon and Vokes, an RTOG trial comparing concurrent chemoradiation to sequential chemoradiation has recently completed accrual. Survival results are expected to be available in the year 2000. The RTOG trial differed from the Japanese trial in that a cisplatin/vinblastine combination was used instead of cisplatin/vindesine/mitomycin. Also, the thoracic radiotherapy dose for the RTOG trial was 63 Gy in a continuous course for both arms—a more conventional regimen by US standards.

The RTOG trial also has a third arm evaluating cisplatin and oral etoposide administered concurrently with a 1.2-Gy/fraction twice-daily radiotherapy regimen to a total dose of 69.6 Gy. Because of the theoretical advantages of concurrent chemotherapy and the WJLCG results discussed above, nearly all cooperative group trials for locally advanced NSCLC now employ concurrent chemoradiation.

Altered Fractionation Radiation Therapy

Drs. Gordon and Vokes appropriately underscore the potential advantages of hyperfractionated accelerated radiation therapy. Since the completion of the first RTOG trial in patients with NSCLC in the mid-1970s, the standard dose for thoracic radiotherapy has been 60 to 66 Gy in daily 1.8- to 2.0-Gy fractions. This approach has been reported to provide local control rates as low as 15%, even when combined with chemotherapy.[5]

By delivering more frequent radiation treatments, the overall treatment duration can be reduced. This approach theoretically reduces tumor cell repopulation during therapy, believed to be a significant problem in the treatment of NSCLC and other cancers.

The continuous hyperfractionated accelerated radiation therapy (CHART) regimen of Saunders et al delivers 54 Gy at 1.5 Gy/fraction three times daily for 12 consecutive days.[6] When standard chest radiotherapy to 60 Gy was compared to the CHART regimen in patients with stage I-III NSCLC, the 2-year survival rate increased from 20% with standard radiotherapy to 29% with CHART. The incidence of acute esophageal toxicity was higher with the CHART regimen, but the most severe esophagitis occurred after therapy was completed and was manageable with symptomatic medications.

A more practical, 16-day hyperfractionated accelerated regimen that provides continuous therapy except on weekends (HART), which delivers 47.6 Gy, appears to as effective as the original CHART regimen and has been safely employed in a sequential combined-modality program with carboplatin/

paclitaxel (Taxol). The Eastern Cooperative Oncology Group (ECOG) is now conducting a randomized, phase III trial comparing carboplatin/paclitaxel followed by standard daily thoracic irradiation to the same chemotherapy followed by HART. As mentioned above, the RTOG has evaluated twice-daily radiation therapy with concurrent chemotherapy in a recently completed phase III trial. These two trials, if positive, may define a new standard of care for thoracic radiotherapy.

Because of increased toxicity with hyperfractionated accelerated radiation regimens, care should be taken to minimize irradiation of normal tissues, including the esophagus, normal lung, and heart. This is best accomplished with three-dimensional treatment planning systems that are currently gaining widespread acceptance in US radiotherapy centers.

A Look to the Future

Despite recent improvements in the treatment of locally advanced NSCLC, the 5-year survival rate of 10% to 20% seen in selected patients treated aggressively with chemotherapy and radiotherapy remains disappointing. Although ongoing clinical trials with newer chemotherapeutic agents and improved radiotherapy techniques will likely improve on these results, dramatic increases in survival are not expected. Instead, incorporation of novel anticancer agents with unique mechanisms of action may provide the greatest potential for substantially improved survival. Although beyond the scope of the Gordon/Vokes article, several of these agents are under study for NSCLC and deserve mention.

The matrix metalloproteinase inhibitors have been demonstrated to reduce tumor cell invasion, angiogenesis, and metastasis. A phase III intergroup trial (SWOG 9906) is evaluating a twice-daily oral matrix metalloproteinase inhibitor (Bay-12-9566) as maintenance therapy after chemoradiation for stage III NSCLC.

Tirapazamine, a hypoxic cell cytotoxin, will be studied in combination with chemotherapy and radiotherapy in stage III NSCLC.

Other trials will evaluate trastuzumab (Herceptin), a monoclonal antibody directed against a human epidermal growth factor receptor (HER-2/neu). Trastuzumab is approved for the treatment of HER-2/neu–positive breast cancer. Overexpression of HER-2/neu, without gene amplification as occurs in breast cancer, is seen in 20% to 30% of patients with NSCLC.

Lastly, a monoclonal antibody against the vascular endothelial growth factor (anti-VEGF) has shown promise in preliminary studies when combined with chemotherapy.

Summary

In summary, although therapeutic nihilism is no longer justified in NSCLC, we cannot yet declare victory. We agree with Gordon and Vokes that standard treatment in the United States today is platinum-based chemotherapy in combination with thoracic radiotherapy. Unfortunately, this treatment results in a median survival duration of approximately 13 months, and a 5-year survival rate of 10% to 20%.

The good news is that a number of promising new anticancer agents and treatment techniques are available for testing. Well-designed clinical trials will need to determine whether and when these new approaches should be employed in daily practice.

References:

1. Dillman, RO, Herndon J, Seagren SL, et al: Improved survival in stage III non-small-cell lung cancer: Seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst 88:1210-1215, 1996.

2. Sause WT, Scott C, Taylor S, et al: Radiation Therapy Oncology Group (RTOG) 8808 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 87:198-205, 1995.

3. Lau DH, Crowley JJ, Gandara DR, et al: Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small-cell lung cancer. J Clin Oncol 16:3078-3081, 1998.

4. Furuse K, Fukuoka M, Takada Y, et al: A randomized phase III study of concurrent vs sequential thoracic radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable stage III non-small-cell lung cancer: Preliminary analysis (abstract). Proc Am Soc Clin Oncol 16:459a, 1997.

5. LeChevalier T, Arriagada R, Quiox E, et al: Radiotherapy alone vs combined chemotherapy and radiotherapy in non-resectable non-small-cell lung cancer: First analysis of a randomized trial in 353 patients. J Natl Cancer Inst 83:417-423, 1991.

6. Saunders M, Dische S, Barrett A, et al: Continuous hyperfractionated accelerated radiotherapy (CHART) vs conventional radiotherapy in non-small-cell lung cancer: A randomised multicenter trial. Lancet 350:161-165, 1997.