RTOG 0229: A Phase II Trial of Neoadjuvant Therapy with Concurrent Chemotherapy and Full Dose Radiotherapy (XRT) followed by Resection and Consolidative Therapy for LA-NSCLC
Reviewer: Geoffrey Geiger, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 3 de noviembre del 2010
Authors: M. Suntharalingam, R. Paulus, M. J. Edelman, M. Krasna, W. Burrows, E. Gore, S. S. Yom, H. Choy Institution: University of Maryland School of Medicine, Baltimore, MD; RTOG Statistical Center, Philadelphia, PA; University of Maryland Medical Center, Baltimore, MD; St Joseph's Medical Center, Baltimore, MD; Medical College of Wisconsin, Milwaukee, WI; University of California San Francisco, San Francisco, CA; University of Texas Southwestern Medical School, Dallas, TX
Stage III non-small cell lung cancer (NSCLC) is a common entity with approximately 40,000 patients/year in the United States.
Surgical resection or radiotherapy alone will result in cure in less than 10% of patients.
Recent randomized studies have demonstrated that chemotherapy followed by surgery or chemoradiotherapy without surgery can result in superior survival compared to surgery or radiotherapy alone.
Both strategies, however, have a substantial rate of local relapse as the first site of failure. Therefore, the possibility of improving outcome utilizing trimodality therapy (i.e., chemotherapy, radiotherapy, and surgery) is attractive.
Pulmonary resection following induction therapy with chemotherapy and radiotherapy to 45 Gy has now been well documented to be feasible and safe. Two large prospective cooperative studies, Southwest Oncology Group 8805 and the recent Pancoast Intergroup study (INT 0160), demonstrated the ability to perform either lobectomy or pneumonectomy following neoadjuvant concurrent chemotherapy and radiotherapy in a multi-institutional setting
The recently reported intergroup trial lead by the Radiation Therapy Oncology Group (RTOG), 9309 (INT 0139) comparing concurrent chemoradiation +/- surgery did not show a statistically significant difference between the two arms because of an increase in post-operative mortality associated with the addition of surgery following chemoradiation.
The current study specifically addresses the issue of post-operative complications by employing strict surgical management requirements. It should be noted that the 93-09 survival curves do appear to separate toward a survival advantage for the addition of surgery, even though the results are not statistically significant. This difference would be magnified if the post-operative toxicities were reduced. It also is possible that the survival advantage is not more significant due to the lower dose of radiotherapy used in 93-09 (45 Gy versus 60 Gy in the current proposed study).
In SWOG 8805, the strongest predictor of long term survival after resection was the absence of tumor in mediastinal nodes (three-year survival rates, 44% LN- vs. 18% LN+, p < 0.005). Fifty-three percent of patients with lymph nodes sampled pre-operatively and post-operatively had sterilization of the mediastinal nodes.
In a recent analysis of prognostic factors for long-term survival as reported by Bueno and colleagues, the downstaging of nodal disease was determined to be the best predictor of long-term survival following induction therapy in a series of 103 patients. Patients in whom all nodal disease was eradicated had a five-year survival rate of 35.8% versus patients with persistent N1 or N2 disease who had a five-year survival of only 9% (p <0.023). In that analysis, the majority of patients received chemotherapy alone as induction, and the rate of nodal sterilization was 26% (18/67 pts). A similar rate was seen in CALGB 8935, a prospective study of chemotherapy induction in stage IIIA disease, in which the proven nodal downstaging (of N2 disease) was 22% (10/46 pts)
In this context, RTOG 0229 was designed to be a phase II trimodality study designed to estimate the mediastinal nodal clearance rates with the pre-operative regimen and the rate of complete pathological response after treatment with pre-operative chemotherapy with paclitaxel/carboplatin and high dose radiation for stage III NSCLC. Secondary objectives included estimation of the feasibility of surgical resection following induction chemoradiation, estimation of the disease-free and overall survival with this trimodality approach and estimation of the toxicity of this treatment approach.
Materials and Methods
Study design: Phase I/II.
Eligibility: patients with Stage IIIA (T1-3 N2) or Stage IIIB (N3, excluding supraclavicular involvement) non-small cell lung cancer documented by biopsy or cytology (Pancoast tumors were eligible if pathologic evidence of mediastinal nodal disease was present); Disease had to be measurable; mediastinal lymph nodes had to be proven positive by pathologic review. All patients had to undergo mediastinoscopy, thoracoscopy, Chamberlain procedure, or transbronchial needle aspirate to evaluate extent of nodal involvement. Any lymph node assessed by mediastinoscopy and found to be positive was defined as N2 disease.
Surgeons were required to demonstrate expertise in surgery after chemoXRT.
Induction chemoXRT was delivered to all patients (carboplatin AUC = 2.0, paclitaxel 50 mg/m2 q week x 6, 50.4 Gy to the mediastinum and primary tumor and boost of 10.8 Gy to gross disease [61.2 Gy to known disease]). Intensity-modulated radiation (IMRT) was not allowed.
The mediastinum was reassessed prior to or at the time of resection.
Following completion of either trimodality therapy or chemoradiation (if non-resectable), patients were to receive paclitaxel and carboplatin q 21 days x 2 cycles as consolidation.
Within four to six weeks of surgery, eligible patients were encouraged to participate in RTOG 0214, regarding prophylactic cranial irradiation.
For those patients who choose not to participate, the treating physicians could still opt to offer PCI if the patient was found to be disease free at the completion of surgery. For non-operable patients, PCI was administered within 6 weeks of completion of consolidation chemotherapy if, in the judgment of the treating physician, it was felt to be of potential benefit.
The primary endpoint was mediastinal nodal sterilization (MNS).
Sixty patients were accrued, 57 were eligible.
Patient characteristics: median age 59, 61% M, PS = 0: 77%, N2: 98% N3: 2%. Histology: 51% adenocarcinoma, 19% SCC, 28% NSCLC-NOS, 95% received RT per protocol; 91% received induction chemoXRT as per protocol, 49% with dose modifications.
Grade 3/4 toxicities: hematological 35%, GI 14%, and pulmonary 23%.
43 patients (75%) were evaluable for the primary endpoint:
6 patients were unable to undergo resection.
16 patients had residual mediastinal dz.
27/43 (63%) achieved mediastinal clearance.
The primary endpoint of the study was met (improving MNS from 50 to 70% with power of 80% and significance level of 0.05).
There was a 14% (5/37) incidence of grade 3 postoperative pulmonary complications. There was only one post-op grade 5 toxicity (3%).
Median follow-up was 24 months.
The median OS was 26.6 months (95% CI, 18.1, NR) and median PFS is 12.9 months (8.0, 18.9). The 1 year OS is 77% (95% CI 64%, 86%) and 1 yr PFS 51% (38%, 64%).
Median survival for those clearing their mediastinal disease was 8.8 months (3.4, 19.0) versus 18.9 months (12.9, 37.2) for those who successfully cleared their disease with preoperative chemoradiation.
The brain represented the most common site of failure (19%) followed by the ipsilateral lung (18%) and regional nodes (16%).
This multi-institutional trial confirms the ability of neoadjuvant concurrent chemoXRT to sterilize known mediastinal nodal disease.
The acceptable post-operative complication profile supports the contention that tri-modality therapy remains a viable option for carefully selected NSCLC patients presenting with stage III disease.
This trial is important in the context of a recently reported study, also led by the RTOG (9309/INT 0139), which compared concurrent chemoradiation (cisplatin and etoposide) +/- surgery. This trial did not show a statistically significant difference between the two arms because of an increase in post-operative mortality associated with the addition of surgery following chemoradiation.
In that trial, authors observed increased treatment-related deaths with surgery (8 vs. 2%), particularly when pneumonectomy was required.
There was no significant difference in MS (23.6 vs. 22.2 months, p=0.24), observed, although the data demonstrated a 5-year OS trend in favor of surgery (20 vs. 27%, p=0.1)
Two other trials, CALGB 8935 and Bueno et al., demonstrated that the downstaging of nodal disease was determined to be the best predictor of long-term survival following induction therapy.
In this phase I/II trial, the investigators successfully estimated the mediastinal nodal clearance rates with the pre-operative regimen and the rate of complete pathological response following treatment with pre-operative chemotherapy with paclitaxel/carboplatin and high dose radiation for stage III NSCLC.
They were able to demonstrate that multimodality therapy is feasible with a higher dose of radiation than in RTOG 9309 with surgical techniques designed to decreased perioperative morbidity and mortality. Indeed, only 1 pneumonectomy was required in the set of patients that were able to proceed to resection.
Median survival in this trial for those clearing mediastinal disease was nearly 10 months higher than those that did not.
Unlike RTOG 9309, however, this was not a randomized phase III trial assessing whether patients have superior outcomes if they are able to undergo surgical resection. There are interesting data here suggesting that this chemoradiotherapeutic regimen and dose is relatively well tolerated and only one pneumonectomy was required. The data presented here merit evaluation in a phase III trial to assess whether this radiation dose and preoperative chemotherapy regimen is superior to concurrent chemoradiation alone. The difficulty, however, in performing such a trial is the inadequate definitive dosing delivered to those patients who ultimately are not candidates for resection for whom an interval passes between completion of radiotherapy and receipt of additional therapy, which potentially allows for resistant clonal repopulation.
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