Invasion of the chest wall (American Joint Committee on Cancer stage T3) is a poor prognostic factor observed in approximately 5% of newly diagnosed NSCLC patients. There are no randomized data specifically examining the role of PORT in patients with the chest wall invasion, but several notable retrospective series have evaluated the risk of local recurrence with and without PORT. Deeper invasion is associated with an increasing risk of positive margins after resection,34 a known risk factor for local recurrence.35 This association confounds the analysis of advanced T stage as a potential indicator for PORT, as many reports do not separately examine the potential benefit of PORT in patients who undergo an en bloc, complete resection as opposed to R1 or R2 resections.
Collectively, the retrospective series examining PORT in T3 patients suggests that local failure is a significant risk and that adjuvant treatment will reduce this risk. Advanced T stage is associated with a higher risk of positive surgical margins; however it seems that much of the observed risk is driven by patients with significant local residual disease. Patients who undergo en bloc, margin-negative resection of T3 tumors do not seem to be at increased risk of recurrence locally, and there is no demonstrable benefit to PORT in that group (Table 3).
The potential benefit of postoperative chemotherapy with or without PORT has been evaluated in a number of randomized trials using regimens based on 5-FU, alkylating agents, and platinum combinations. The Non-small Cell Lung Cancer Collaborative Group40 published a meta-analysis in 1995 evaluating the effect of chemotherapy on NSCLC, which included 14 trials and 4357 patients. Five trials used alkylating agents, 8 used cisplatin-containing regimen, and 3 used tegafur or tegafur-uracil (UFT). The investigators noted a significantly decreased survival in the studies using alkylating agents (P=0.005) and no change with 5-FU regimens. Platinum-based chemotherapy produced a nonsignificant improvement in survival rate of 5% at 5 years (P=0.08). Hamada et al41 reported a meta-analysis of studies from Japan using UFT regimens given postoperatively. The study population comprised mainly stage I patients. The results showed improved 5-year and 7-year survival rates in a Japanese patient population, but the study's relevance to non-Japanese populations has been questioned.42 Most recent European and North American studies have focused on platinum-based combination regimens.
A number of randomized trials since the 1995 meta-analysis have examined the efficacy of adjuvant platinum-based chemotherapy compared with observation. Three of the trials showed no significant benefit. In a Japan Clinical Oncology group study, Tada et al43 reported on 119 pN2 patients, comparing cisplatin and vindesine to no further treatment after resection. The 5-year overall survival rates were 28.2% in the treated group and 36.1% in the control group (P=0.89). The Adjuvant Lung Project Italy trial44 compared cisplatin, vindesine, and mitomycin C (MVP) for 3 cycles versus no further treatment after resection in stage I, II, and IIIA patients. There was no difference in disease-free or overall survival between the 2 groups, although there was a nonsignificant trend towards improved overall survival in the subset of stage II patients. The Big Lung Trial45 included 384 patients treated with 1 of 4 platinum-based chemotherapy regimens after surgical resection. There was no difference in overall survival compared with observation.
In contrast, a number of more recent trials have demonstrated a significant improvement in recurrence-free or overall survival. The International Adjuvant Lung Cancer Trial (IALT)46 compared no further treatment to 1 of 4 schedules of cisplatin and either vinorelbine, vindesine, vinblastine, or etoposide in 1867 completely resected patients with stage I to III NSCLC. There was a 5.1% (P<0.03) and a 4.1% (P<0.003) increase in disease-free and overall 5-year survival rates, respectively, and the greatest survival benefit was noted in stage III patients. The North American Intergroup trial (JBR-10)47,48 included 482 patients with stage IB and II NSCLC randomized to observation or to adjuvant chemotherapy with vinorelbine and cisplatin after complete resection. The 5-year survival rate improved from 54% to 69% (P=0.03) with adjuvant chemotherapy. In a more recent update, the survival advantage held up at 7 years.49 A planned subgroup analysis indicated that the therapeutic advantage was almost exclusively confined to the patients with stage II disease and that the benefit for stage IB patients was present only in those whose primary tumors measured >4 cm, but was not statistically significant.
For patients with stage II or III NSCLC who undergo complete resection, multiple randomized trials and 2 meta-analyses have demonstrated a significant improvement in overall survival with the addition of adjuvant cisplatin-based chemotherapy. For patients without nodal disease but with tumors >4 cm, a survival benefit was evident in a subset analysis of the CALGB 9633 trial, and consideration should be given to treating selected stage IB patients based on these criteria.
The value of combining PORT sequentially or concurrently with postoperative chemotherapy is less well defined. Two of the positive postoperative chemotherapy trials, IALT and ANITA, allowed PORT in a nonrandomized manner.46,52 The radiotherapy in these studies was given after the chemotherapy. The interaction between PORT and adjuvant chemotherapy in the ANITA trial has been examined in a separate publication.54 In the trial, PORT was recommended, but not mandatory, for node-positive patients, and was administered after systemic therapy. In a post hoc subset analysis, patients with N2 disease who received PORT (in addition to chemotherapy) had better overall survival than those who did not receive PORT, whereas no benefit was observed for PORT in patients with resected N1 disease who had received chemotherapy.
Several prospective studies have examined PORT with concurrent chemotherapy. The Radiation Therapy Oncology Group 970524 was a single-arm phase II trial of 88 resected stage II and IIIA patients treated with concurrent radiotherapy and carboplatin and paclitaxel. The toxicities were considered acceptable, and the survival was favorable when compared with the ECOG 3590 (median survival times of 56.3 mo vs. 33.7 mo, respectively). The local failure rates were similar between the studies. In a phase II study conducted at the Fox Chase Cancer Center25 42 patients with stage II or III NSCLC were treated with PORT and concurrent carboplatin and paclitaxel after gross total resection. The radiation dose was 50.4 Gy in 28 fractions, with a boost of 10.8 Gy for extranodal extension or 16.2 Gy for involved margins. Five of 42 patients developed grade 3 esophagitis, and 3 developed grade 3 pneumonitis. Locoregional control was 88% at 5 years.
Several randomized studies have evaluated PORT with or without chemotherapy, although all of these were older efforts. The LCSG 791 trial55 compared radiotherapy (split course) to the same radiotherapy concurrently with cyclophosphamide, doxorubicin, and cisplatin (CAP) in patients with NSCLC who had incomplete resections (positive margins or involvement of the most proximal lymph node in the mediastinum). There was an improvement in recurrence-free survival in the chemotherapy arm, but overall survival was not increased. Pisters and Le Chevalier56 compared postoperative vindesine, platinum, and mediastinal radiotherapy to mediastinal radiotherapy alone in 72 patients with stage III disease (28 of whom were incompletely resected). There was no difference in recurrence-free or overall survival rates. Dautzenberg et al57 reported on 267 patients (259 with stage II or III disease) who in a randomized trial received either radiotherapy of 60 Gy to the mediastinum or CAP and vincristine and lomustine for 3 cycles, then the same radiotherapy. There was no difference in disease-free or overall survival rates. Keller et al23 in a report of an intergroup trial (ECOG 3590), showed that 4 cycles of cisplatin and VP-16, 2 given concurrently with PORT and 2 given after the conclusion of PORT, did not increase survival when compared with PORT alone.
PORT seems to increase local control in patients who have also received chemotherapy, and is reasonable to consider in patients who have mediastinal nodal involvement and who are felt to be at high risk of local recurrence. Studies that included PORT sequentially with chemotherapy typically sequenced the systemic therapy first, due to the survival benefit associated with adjuvant chemotherapy in patients with nodal disease found at surgery. Sequential therapy is better supported by the data for routine adjuvant therapy. For patients at the highest risk of local/regional recurrence (eg, a positive surgical margin), concurrent therapy may be appropriate, extrapolating from studies demonstrating a benefit to concurrent chemoradiotherapy in patients with gross unresectable disease.58 To date, however, there has been no formal phase III trial evaluating the role of PORT in the modern therapeutic era, nor has any trial compared concurrent chemotherapy and PORT to sequential chemotherapy and PORT.
For patients with stage II or III NSCLC, multiple randomized trials and 2 meta-analyses have demonstrated a significant improvement in overall survival with the addition of adjuvant cisplatin-based chemotherapy after resection. For patients without nodal disease, but with tumors >4 cm, a survival benefit was evident in a subset analysis of the CALGB 9633 trial, and consideration should be given to treating selected stage IB patients with adjuvant chemotherapy based on these criteria.
The role of postoperative radiation remains controversial. For patients with completely resected T1-2, N0-N1 NSCLC, there is little evidence to suggest a benefit to PORT. For patients with N2 disease, it is reasonable to discuss the potential risks and benefits of PORT after completion of adjuvant chemotherapy. Patients with positive surgical margins and selected patients with T3 tumors may also benefit from PORT. To date, however, no prospective phase III trial has yet demonstrated a survival advantage for the use of PORT in resected stage IIIa patients (Table 4).
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