Subsequent trials studied the efficacy of using concurrent chemotherapy and radiation as compared to using the sequential method. In a Japanese phase III study,[26] 320 patients with unresectable stage III disease were randomized to receive either two cycles of cisplatin, vindesine, and mitomycin concurrently with split-course thoracic radiation to 56 Gy, or two cycles of cisplatin, vindesine, and mitomycin followed by a single course of radiation to 56 Gy. The use of concurrent chemotherapy and radiation produced a longer median survival compared to the sequential arm (16.5 vs 13.3 months, P = .03998). The 2-, 3-, 4-, and 5-year survival rates were better in the concurrent group than in the sequential group (34.6%, 22.3%, 16.9%, and 15.8% vs 27.4%, 14.7%, 10.1%, and 8.9%, respectively). This study also demonstrated an increased response rate with concurrent use of chemotherapy and radiation compared to sequential use in patients with unresectable stage III NSCLC.
Induction chemotherapy followed by chemoradiotherapy was compared to chemoradiotherapy alone in the phase III CALGB 39801 trial.[27] A total of 366 patients were randomly assigned to receive either immediate concurrent chemoradiotherapy with weekly carboplatin and paclitaxel during 66 Gy of chest radiation, or two cycles of carboplatin and paclitaxel every 21 days followed by the identical chemoradiotherapy regimen. Survival differences were not statistically significant, with a median survival of 12 months for those who received immediate chemoradiation vs 14 months for those who received induction chemotherapy followed by chemoradiation. This trial demonstrated that the addition of induction chemotherapy prior to concurrent chemoradiation did not provide a survival benefit over concurrent therapy alone. In addition, it showed that induction chemotherapy followed by chemoradiation increased the chance of neutropenia and overall chemotherapy-related toxicity.
The Radiation Therapy Oncology Group (RTOG) 9410 trial[28] was a three-armed study that randomized 610 patients with unresectable stage II and III disease to receive (1) sequential chemotherapy with cisplatin and vinblastine followed by 60 Gy of radiotherapy, (2) concurrent cisplatin and vinblastine with radiation to 60 Gy, or (3) concurrent cisplatin and oral etoposide with hyperfractionated radiation delivered twice daily to a total dose of 69.6 Gy. The acute grade 3/4 nonhematologic toxicity rates were higher for the concurrent therapy arms than for the sequential therapy arm, but late toxicity rates were similar. The median survival was 17 months for concurrent therapy with daily radiotherapy, 15.2 months for concurrent therapy with hyperfractionated radiotherapy, and 14.6 months for sequential therapy, indicating a benefit in median survival for the use of concurrent chemoradiotherapy with daily radiation. The 4-year overall survival data showed similar results: 21% for concurrent therapy with daily radiotherapy, 17% for concurrent therapy with hyperfractionated radiotherapy, and 12% for sequential therapy.
Concurrent chemoradiotherapy is a good option for patients who have unresectable NSCLC without a possibility of resection even after concurrent therapy. The risks involved with the concurrent therapy are increased side effects including esophagitis and pneumonitis. It is important to note that even though concurrent chemoradiotherapy is a sensible option for patients with locally advanced unresectable NSCLC, long-term survival continues to be poor.
Definitive Radiation
Definitive radiation is the final treatment option that is available for patients with locally advanced NSCLC. As mentioned previously, this single modality was the treatment of choice prior to trials that proved the benefit of using both chemotherapy and radiation. Definitive radiation should be offered to patients with locally advanced or unresectable stage III disease and a poor performance status who are unable to tolerate chemotherapy or surgery. The benefit of using radiation under these circumstances would be for palliation and local tumor control. Long-term survival with definitive radiation treatment continues to be poor, with a 5-year survival rate of about 5%[29-31] and patterns of local as well as distant relapse.
The current standard dose of radiation is 60 Gy in 30 daily fractions, after a phase III trial published in 1986[31] evaluated the use of various doses and their associated outcomes. Radiation doses of 40, 50, or 60 Gy were used in 2-Gy daily fractions. A radiation dose of 60 Gy was found to produce the best local control; however, survival was similar in all groups.
Hyperfractionated, accelerated radiation has also been studied, with evidence supporting a marginal benefit for this strategy compared to standard radiation. However, this practice has not been widely adopted, and daily radiation continues to be the standard.[32-35]
Definitive radiation frequently offers palliative support for patients with symptoms related to their tumor and provides some degree of local control. However, it should be offered as an initial treatment option only to patients who are unable to tolerate chemotherapy or surgery, given a median survival of only about 10 months.
Summary
Locally advanced stage III NSCLC is a complex and heterogeneous group of diseases that require a combined-modality approach for optimal treatment.[36-38] The patient’s preferences, age, comorbid conditions, and functional status all need to be taken into consideration before any type of therapy is offered.
Recent studies have indicated histologic variability with regard to chemotherapeutic response in lung cancer patients.[39] Also, novel targeted agents have opened up new possibilities in terms of therapeutic options. Ongoing studies based on these developments and using state-of-the-art methods of radiation and surgery might lead to new treatment strategies, which, in turn, could produce an improved overall survival in patients with this complex disease.
