Neoadjuvant chemotherapy with or without preoperative irradiation in stage IIIA/N2 non-small cell lung cancer (NSCLC): A randomized phase III trial by the Swiss Group for Clinical Cancer Research (SAKK trial 16/00)
Reporter: Jacob Shabason, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 6 de junio del 2013
Presenter: Miklos Pless, MD Presenter's Affiliation: SAKK Lung Cancer Project Group; Medical Oncology and Tumorcenter Kantonsspital Winterthur, Winterthur, Switzerland. Abstract #: 7503
Standard treatment for stage IIIA (T1-3, N2) Non Small Cell Lung Cancer (NSCLC) includes definitive chemoradiation, neoadjuvant chemotherapy or neoadjuvant chemoradiation, followed by surgical resection.
Thus far, no trial has shown a clear benefit to one approach and it is extremely important to approach each patient differently as Stage IIIA NSCLC can be a very heterogeneous group.
In a previous phase II trial conducted by the authors, the treatment approach of neoadjuvant chemotherapy with cisplatin and docetaxel, followed by surgical resection led to a promising median survival of 33 months.
Prognosis was mainly determined by surgical resection status and nodal downstaging.
Aggressive neoadjuvant therapy may improve the ability to perform a complete R0 resection and downstage a patient’s nodal status.
Radiotherapy plays an important role in many patients with Stage III NSCLC, particularly those treated with definitive chemoradiation, who do not undergo surgery.
As such the authors performed a randomized Phase III trial to determine if aggressive preoperative sequential chemotherapy and radiation followed by surgical resection would improve outcomes as compared to preoperative chemotherapy alone.
Materials and Methods
232 patients with pathologically proven, resectable stage IIIA/N2 NSCLC were enrolled in this multicenter trial and this interim analysis included the first 219 patients.
N2 disease was confirmed by mediastinoscopy, endobronchial ultrasound, or PET scan.
Other inclusion criteria included, age 18-72 years, WHO performance status 0-1, adequate heart, kidney, liver and bone marrow function.
Patients were randomized 1:1 to receive 3 cycles of neoadjuvant chemotherapy (cisplatin 100 mg/m2 and docetaxel 85 mg/m2 d1, q3weeks) followed by accelerated concomitant boost radiation (44 Gy/22 fractions in 3 weeks) or chemotherapy alone.
The primary endpoint was event-free survival (EFS)
Secondary end points include overall survival (OS), post-operative mortality, complete resection rate, objective response rate (ORR) after completion of chemotherapy or chemoradiotherapy and operability.
Twenty-three centers enrolled 232 patients from April 2001 to July 2012 with a median follow up of 36 months.
The median age was 60 years (30-76 years).
Patient characteristics were well balanced between the two arms.
Toxicity to chemotherapy was substantial with significant hematological toxicity, but 91% completed the 3 cycles of neoadjuvant chemotherapy as planned.
85% of patients received radiation as planned.
Deviations in radiation therapy were a result of toxicity (8 patients) or progressive disease (4 patients).
Radiation was generally well tolerated and the major toxicities included:
5 cases (6%) of Grade 3 esophagitis.
2 cases (3%) of Grade 3 skin toxicity.
A total of 82% of the patents underwent a surgical resection.
Patients who underwent an R1 and R2 resection in the control arm were allowed to receive postoperative radiotherapy.
Overall, there were no statistically significant differences in any endpoints between the two arms, as outlined in the table below.
There was a trend towards improved R0 resections in the radiation arm (90% vs. 80%), however this was not statistically significant.
As such, after this interim analysis the trial was closed to accrual due to determined futility of the experimental arm.
CT - RT - Surgery
CT - Surgery
3 cycles of CT given
EFS, median (95% CI)
12.8 mo (CI 8.1, 22.6)
11.8 mo (CI 7.1, 16.1)
Survival, median (95%CI)
27.1 mo (CI 18.8, 42.8)
26.2 mo (CI 21.0, 52.1)
This is the first completed randomized trial that investigated the addition of neoadjuvant radiation to chemotherapy and surgery for the treatment of stage IIIA NSCLC patients.
The addition of radiation did not improve EFS, OS or reduce the local failure rate.
The authors therefore conclude that only one local treatment remains standard of care, and trimodality therapy in these patients should only be performed in the setting for a clinical trial.
Even though this was a negative trial, the survival results are very encouraging compared to historical data with a median survival of 27 months.
Patients with Stage IIIA NSCLC have a high rate of recurrence and therefore improvements in upfront therapy are sorely needed.
The authors present the first randomized phase III trial comparing neoadjuvant sequential chemotherapy and radiation followed by surgical resection, compared to neoadjuvant chemotherapy and surgery alone in the management of stage IIIA NSCLC patients.
From the data presented, there appears to be no benefit to the addition of radiation therapy to this treatment regimen.
However, this trial should not define a new paradigm in the treatment of Stage IIIA NSCLC given that it is a relatively small trial that only analyzed 219 patients and there was a trend towards improved R0 resection in the radiotherapy arm, which is a know positive prognostic marker.
In a similar patient population of stage IIIA (T1-3, N2) NSCLC the Intergroup-0139 trial has shown that neoadjuvant chemoradiotherapy followed by surgical resection compared to definitive chemoradiation leads to improved progression free survival, but not overall survival. However, there was a significant overall survival benefit in the subset of patients who received a lobectomy, as opposed to pneumonectomy.
It would be interesting to see a similar subset analysis in the described SAKK trial, specifically analyzing only patients who under lobectomy.
Overall, future research is needed to help define the ideal treatment approach for patients with Stage IIIA NSCLC.
This is a very diverse group of patients and key areas of future research will be to better define which patients will benefit the most from different therapeutic approaches.
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