Based on the Surveillance, Epidemiology, and End Registry, the estimated incidence of stage IIIB NSCLC is 17.6%. The anticipated 5-year survival for the vast majority of patients who present with clinical stage IIIB NSCLC is 3% to 7%. In small case series, selected patients with T4, N0-1 disease, solely as the result of satellite tumor nodule(s) within the primary lobe, have been reported to have 5-year survival rates of 20%.[3,4][Level of evidence: 3iiiA]
Forty percent of patients with newly diagnosed non-small cell lung cancer (NSCLC) have stage IV disease. Treatment goals are to prolong survival and control disease-related symptoms. Treatment options include cytotoxic chemotherapy and targeted agents. Factors influencing treatment selection include comorbidity, performance status (PS), histology, and molecular genetic features of the cancer. Radiation therapy and surgery are generally used in selective cases for symptom palliation.
Chemotherapy followed by surgery (for selected patients).
Radiation therapy alone.
For treatment of locally advanced unresectable tumor in patients who are not candidates for chemotherapy.
For patients requiring palliative treatment.
In general, patients with stage IIIB NSCLC do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on the following:
Sites of tumor involvement.
The patient's performance status (PS).
Most patients with excellent PS are candidates for combined modality chemotherapy and radiation therapy with the following exceptions:
Selected patients with T4, N0 disease may be treated with combined modality therapy and surgery similar to patients with superior sulcus tumors.
Sequential or concurrent chemotherapy and radiation therapy
Many randomized studies of patients with unresectable stage III NSCLC show that treatment with preoperative or concurrent cisplatin-based chemotherapy and radiation therapy to the chest is associated with improved survival compared with treatment that uses radiation therapy alone. Although patients with unresectable stage IIIB disease may benefit from radiation therapy, long-term outcomes have generally been poor, often the result of local and systemic relapse. The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials.
Evidence (sequential or concurrent chemotherapy and radiation therapy):
A meta-analysis of patient data from 11 randomized clinical trials showed the following:
Cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[Level of evidence: 1iiA]
A meta-analysis of 13 trials (based on 2,214 evaluable patients) showed the following:
The addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (relative risk [RR], 0.93; 95% confidence interval [CI], 0.88–0.98; P = .01).
For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99; P = .02).
A meta-analysis of individual data from 1,764 patients evaluated nine trials.
The hazard ratio of death among patients treated with radiation therapy and chemotherapy compared with radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years.
The combination of platinum with etoposide seemed more effective than platinum alone. Concomitant platinum-based chemotherapy and radiation therapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.
The results from two randomized trials (including RTOG-9410) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.[8,9,10][Level of evidence: 1iiA]
In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared with chemotherapy followed by continuous daily radiation therapy to 56 Gy.
Five-year overall survival (OS) favored concurrent therapy (27% vs. 9%).
Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.
In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 60 Gy of radiation therapy, concurrent chemotherapy, or concurrent chemotherapy with cisplatin and vinblastine with twice-daily radiation therapy.
Median and 4-year survival were superior in the concurrent chemotherapy with daily radiation therapy arm (17 mo vs. 14.6 mo and 21% vs. 12% for sequential regimen [P = .046]).
Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[Level of evidence: 1iiA]
A meta-analysis of three trials evaluated concurrent versus sequential treatment (711 patients).
The analysis indicated a significant benefit of concurrent versus sequential treatment (RR, 0.86; 95% CI, 0.78–0.95; P = .003). All used cisplatin-based regimens and once-daily radiation therapy.
More deaths (3% overall) were reported in the concurrent arm, but this did not reach statistical significance (RR, 1.60; CI, 0.75–3.44; P = .2).
There was more acute esophagitis (grade 3 or worse) with concurrent treatment (range = 17%–26%) compared with sequential treatment (range = 0%–4%; RR, 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.