Progress in the Treatment of Early Stage Non-Small Cell Lung CancerMay 31 – June 3, 2003Chicago, ILChandra P. Belani MD Professor of Medicine, University of Pittsburgh School of Medicine and Co-Director, Lung and Thoracic Cancer Program University of Pittsburgh Cancer Institute
Co-Author: Sakkaraiappan Ramalingam MD
Lung cancer continues to be the leading cause of cancer-related mortality in the United States. While non-small cell lung cancer (NSCLC) accounts for about 80% of lung cancers, only 25% of these are candidates for surgical resection at the time of diagnosis. 1 Even after adequate surgical resection, a majority of the patients develop recurrence of disease, necessitating the need for additional therapy. 2 The lung cancer sessions at the 2003 meeting of the American Society of Clinical Oncology highlighted the role of multi-modality management in early stage and locally advanced NSCLC. Currently, there does appear to be a role for systemic therapy both in surgically-resected disease and also in potentially resectable disease.
In the past 3-4 decades, several studies have been performed that have evaluated adjuvant treatments following surgical resection for early stage NSCLC. Following surgical resection, the 5-year survival rates for patients with clinical stages IA, IB, IIA, IIB, and IIIA are 61%, 38%, 34%, 24% and 9%, respectively. The survival rates for the above stages post-surgery (pathologic stage) are 67%, 57%, 55%, 39%, and 25%, respectively. 2 Furthermore, two-thirds of recurrences occur systemically, while local recurrence accounts for the remaining one-third.
While progress has not been substantial, much has been learned about the biology of this disease. The presence of micrometastatic disease at the time of resection is the likely reason for recurrence, despite complete removal of all macroscopic disease. Micrometastases have been detected by methods such as immunohistochemistry and polymerase chain reaction (PCR) in patients with radiologically localized lung cancer. 3 The outcome for patients with micrometastases can only be improved by eradication of all metastatic disease in addition to optimal surgical resection. For this reason, adjuvant therapy is being increasingly used following surgical resection for patients with early stage NSCLC.
Treatment Advances for Resectable NSCLC
The International Adjuvant Lung Trial (IALT): Data from the International Adjuvant Lung Trial (IALT) indicates that adjuvant chemotherapy improved median survival by 6 months in patients with completely resected NSCLC. 4 Patients were randomized to receive 3-4 cycles of Platinol®-based therapy versus observation alone. The Platinol® doses prescribed were 80 mg/m 2 every 3 weeks for 4 cycles or 100 mg/m2 every 4 weeks for 3 or 4 cycles or 120 mg/m 2 every 4 weeks for 3 cycles. The second agent consisted of either etoposide 100 mg/m 2 X 3 days or vinblastine 4 mg/m2 /week, or Navelbine® 30 mg/m2/week or vindesine 3 mg/m2 /week. The primary objective was to detect an increase in survival of 50-55% with adjuvant chemotherapy for patients with completely resected stages I, II and IIIA NSCLC.
The accrual goal was 3300 patients with an interim analysis planned after 320 and 640 deaths. However, the study was closed after 1867 patients were entered due to slow accrual. There were no significant differences in baseline characteristics between the two arms of the trial. The post-operative pathologic stages were as follows: Stage I in 36%, Stage II in 25%, and Stage III in 39%. Disease-free survival and overall survival rate at 5 years were improved by 5% and 4.1% respectively with adjuvant chemotherapy (p values of <0.03 and < 0.003, respectively) (Table 1).
Table 1: IALT Results
Comparison of neoadjuvant approaches prior to surgery as used in the Bimodality Lung Oncology Team (BLOT) Trial to adjuvant therapy post-resection are of utmost importance because results indicate that neoadjuvant or induction therapy appears to be promising. 5 Dr. Pisters updated the data from the BLOT Trial at ASCO this year. Among the 134 patients treated, 51% had a major response and only 5% progressed during induction chemotherapy. Ninety-four percent of the patients underwent complete surgical resection. The surgical mortality was 1%. The 1-, 2-, & 5-year survival rates were 85%, 61%, and 42%, respectively. The patterns of failure were as follows: local: 17%, brain only: 21%, distant: 43%, local and distant: 19%.
Because of continued observations of increased distant failures, attempts are needed to further optimize systemic therapy for all stages of NSCLC. The definitive trial randomizing patients to induction chemotherapy followed by surgery versus surgery alone is currently underway. However, based on the IALT data, accrual may be affected in view of concerns regarding randomization to the surgery alone arm.
The Japanese Adjuvant Therapy Trial: UFT (tegafur and uracil) is an oral fluorinated pyrimidine that has also shown a survival advantage in the adjuvant setting. 6 A previous Japanese study had demonstrated improved survival with adjuvant UFT in early stage resected stages I through IIIA disease. 7 In this confirmatory trial, patients with stage I adenocarcinoma of the lung who had undergone adequate surgical resection were randomized post-resection to UFT or control. Among the 999 patients, there was an absolute benefit in survival of 2.5% on the treatment arm (p= 0.035). The benefit was observed in pathological stage T2 patients (p=0.0051). The results and characteristics are summarized in Table 2.
Table 2: Japanese UFT Adjuvant Study
Because of these results, a shift is occurring in the treatment paradigm such that adjuvant chemotherapy is becoming the new standard. However, more randomized data is necessary for establishing this new standard. Accrual has been completed and results are forthcoming for the randomized trial by the NCIC/ECOG (JBR 10) comparing adjuvant Platinol®/Navelbine® versus observation for stage IB and II NSCLC (N= 482). Unfortunately an ongoing clinical trial by the CALGB/RTOG may be in jeopardy because of ‘no treatment randomization’. This trial is evaluating the efficacy of Paraplatin® plus paclitaxel versus observation as adjuvant therapy for patients with stage IB NSCLC following surgical resection.
A randomized trial that includes a control arm consisting of surgery alone, called the neoadjuvant/adjuvant paclitaxel Paraplatin® trial in early stage NSCLC (NATCH Trial), 8 is currently underway in Spain. Thus far, 255 of the planned 600 patients have been randomized. The preliminary data from 148 patients demonstrated 66% radiographic response with neoadjuvant therapy. Though median survival has not been reached, there was a trend towards lower survival with surgery alone (50% at 30 months versus 90% with neoadjuvant and 80% with adjuvant therapy). It is probable that the ‘surgery alone’ arm may have to be dropped, but the study is still of immense importance as it will address the issue of neoadjuvant versus adjuvant therapy.
These data are of great interest and raise many issues for the future management of patients with NSCLC. For instance: Should all patients with surgically resected NSCLC be considered for adjuvant chemotherapy? If so, should it be Platinol®- based or would any doublet suffice? Will the accrual to neoadjuvant trials in early stage NSCLC (with control arms of surgery alone) be affected? The data are compelling and sufficiently strong in favor of adjuvant chemotherapy. We will have to present these to the patients and suggest that adjuvant chemotherapy does have merit. Future trials will include targeted/selective agents-with platinum combination as the control arm.
Chemoradiation followed by surgery is a viable option and the strategy of chemotherapy alone as induction cannot be discounted. Trials are being planned to compare induction chemotherapy with chemoradiation for patients with stage IIIA (N2) disease. In the future, utilization of gene and protein expression profiles to make treatment decisions would lead to improved outcome for patients with stage N2 NSCLC.
Stage IIIA (N2) Disease: The treatment of patients with ipsilateral mediastinal lymph node (N2) positive NSCLC has long been a subject of controversy. It is clear that N2 disease represents a heterogenous group. The 5-year survival rates following surgical resection with clinical and pathological stage IIIA N2 NSCLC are approximately 13% and 23%, respectively. 2 Furthermore, 30-40% of patients with N2 disease have incomplete resection at the time of surgery. Randomized clinical trials have demonstrated survival benefit with pre-operative chemotherapy for patients with stage IIIA N2 NSCLC. 9,10 However, a phase II study demonstrated a significant impact on survival for N2 disease patients who experience a pathological complete response following pre-operative chemoradiation. 11 This study formed the basis for the Intergroup 0139 (INT 0139) trial.
INT 0139: Dr. Albain reported that the INT 0139 study failed to report a survival advantage with surgery following combined chemoradiation for patients with N2 disease. However, there was a disease-free survival (DFS) advantage. Patients with IIIA NSCLC (N2 positive) were randomized to chemoradiation followed by surgery or chemoradiation alone (figure 1). Although the study dragged on for 10 years to accrue 429 patients, of whom 411 were eligible and 392 analyzed, it was completed as planned.
Figure 1: Intergroup 0139
The results of this trial are detailed in Table 3. It will be difficult to convince the thoracic surgeons not to operate.
Conceptually, the data sheds light on a number of aspects of N2 disease. Since this is a heterogenous group of patients, those that have a complete pathological response in the nodes (N2 to N0) may be the ones who benefit from surgical intervention after combined chemoradiotherapy. In the 46% of patients who had a complete nodal clearance (N2 to N0) the median survival of 36.7 months and 3-year survival of over 50% are in fact provocative. Also, the main challenge will be to convince our thoracic surgeons to stop operating on patients who have persistent disease in the mediastinum after induction therapy. This will remain an issue despite the high mortality rate associated with surgery after combined chemoradiotherapy versus control (7% and 1.6%, respectively). Data from INT 0139 are detailed in Table 3.
Table 3: INT 0139: Toxicities and Efficacy
Combination Chemotherapy: The data from novel and aggressive 2- and 3-drug combinations in stage III NSCLC patients also indicates the efficacy of this treatment approach. The combination of Gemzar®, Platinol® and Taxotere® demonstrated a pre-operative response rate of 51% in 120 patients with stages T1-3N2 and T4N0 NSCLC. 13 Complete resection was achieved in 43 of the 58 patients who underwent thoracotomy and the down-staging rate (N2 to N0) was 37%.
Dr. Antonio presented the results of an Italian neoadjuvant trial which evaluated the Gemzar®-Platinol® doublet in patients with stages III A (N2)/IIIB NSCLC. 14 There was a 68% response rate for all participants. Stable and responding patients subsequently received either surgery plus radiation (n=19), surgery alone (n=8), or radiation alone (n=25). The median overall survival was 20 months.
Advances in Treatment of Locally Advanced Unresectable NSCLC
Clinical trials conducted in the 1970’s established the efficacy of radiation therapy in patients with locally advanced NSCLC. The optimal dose of radiation was determined to be 60 Gy administered in 2Gy/fraction over 6 weeks. 15 Despite undergoing definitive radiation, patients experienced a high incidence of local and distant relapse. This led to the initiation of trials that studied the effect of adding chemotherapy in addition to radiation. Chemotherapy was thought to act in multiple ways that included radiation-sensitization of cancer cells in the field of radiation, as well as a cytotoxic effect on micrometastatic disease.
The Cancer and Leukemia Group B (CALGB) 8433 trial evaluated the utility of addition of induction chemotherapy to patients undergoing radiation therapy for locally advanced NSCLC. 16 The median survival for patients treated with induction chemotherapy with Platinol® and vinblastine followed by radiation was 13.7 months, compared to 9.6 months for patients treated with radiation therapy alone. Subsequently, the RTOG 88-08 trial 17 and the French trial 18 established that the combination of chemotherapy and radiation is superior to radiation alone. In the 1990’s, two large randomized trials demonstrated that chemotherapy with concurrent radiation is superior to sequential administration of chemotherapy and radiation (Table 4). 19, 20 In the West Japan Lung Cancer Group trial, 19 there was no difference in the rate of local relapse in both the groups and distant relapse occurred in a majority of the patients in both arms.
Table 4: Clinical trials in locally advanced NSCLC
RTOG 9410: Updated results from RTOG 9410 indicate that concurrent chemoradiation is the standard of care for patients with locally advanced NSCLC, especially those with a good performance status. The RTOG 9410 trial is a 3-arm, randomized phase III trial that evaluated sequential versus concurrent chemoradiation (Table 5). 21 Sequential therapy (Arm 1) consisted of two cycles of Platinol® and vinblastine, followed by 60 Gy external beam radiation, administered in once-daily fractions, beginning on day 50. In arm 2, the same chemotherapy was administered, while radiation was administered concurrently starting on day 1 of the chemotherapy cycle. Arm 3 underwent hyperfractionated radiation therapy with 69.2 Gy administered as twice-daily fractions. Patients in arm 3 received concurrent chemotherapy that consisted of Platinol® and oral etoposide. A total of 611 patients with unresected stage II/III NSCLC were enrolled between 1994 and 1998.
The median survival was superior for patients who received concurrent chemoradiation (arm 2) compared to the sequential treatment (arm 3) (17.0 versus 14.6 months, p=0.038). Hyperfractionated radiation did not result in improved survival compared to the sequential arm (15.6 months vs 14.6 months). The 4-year survival for patients in the concurrent chemotherapy and daily standard radiation arm was 21% versus 12% with sequential chemotherapy followed by radiation (p=0.046). The incidence of acute toxicity was higher in the concurrent arms; however, late, non-hematological toxicity was identical for patients in all three arms. Results are detailed in table 5.
While concurrent therapy was associated with a higher incidence of acute grade 3 esophagitis (up to 20%), the superior overall outcome is important. The reduction of acute toxicity remains a major goal for further research efforts, but better control of micrometastatic disease must be achieved to build upon the survival benefit achieved with concurrent chemoradiation.
Table 5 : Long-term benefits from RTOG 9410
SWOG 9504: The South West Oncology Group investigators reported impressive results for consolidation chemotherapy following concurrent chemoradiation, which was evaluated in a phase II trial (SWOG 9504). 22 Initial therapy consisted of Platinol® and etoposide with concurrent radiation (61 Gy) followed by three cycles of consolidation chemotherapy with Taxotere®. The non-p53 dependent apoptotic effect of Taxotere®, when administered in sequence with Platinol® therapy (which induces apoptosis in a p53 dependent manner) was postulated to improve disease control. This study enrolled 83 eligible patients and demonstrated a median survival of 26 months and median PFS was 16 months. The 1-, 2-, and 3-year survival rates were 76%, 54%, and 37%, respectively. Treatment was well tolerated with a low incidence of grade 3/4 esophageal toxicity during concurrent chemoradiation (17%). The brain was the most common site of failure, occurring in 51% of the patients and in almost all patients with distant failure. Based on the impressive results noted in the 9504 study, the SWOG investigators have adopted the 9504 regimen as ‘the standard’ in the Intergroup 0023 trial in which the patients are then randomized to Iressa® versus observation.
The Hoosier Oncology Group is currently performing a randomized phase III trial comparing consolidation chemotherapy with Taxotere® following concurrent chemoradiation with concurrent chemoradiation alone.
Is Hyperfractionated Accelerated Radiotherapy (HART) the next step?
Continuous HART (CHART) resulted in a significant improvement in survival time compared to standard thoracic radiation (TRT) for patients with locally advanced unresectable NSCLC (20% versus 29%). 23 TRT was administered at 60 Gy/30 fractions for 42 days and CHART consisted of 54 Gy/36 fractions for 12 consecutive days. Safety results showed a higher degree of esophagitis with CHART. The effect was more pronounced in patients with squamous cell carcinoma.
These results provide a compelling argument in favor of pursuing this strategy further.
ECOG 2597: The Eastern Cooperative Oncology Group’s phase III trial led by Dr. Belani (ECOG 2597) provided provocative results in favor of HART over standard radiation which would have been statistically significant if the study had met its accrual goals. ECOG 2597 compared standard radiation to HART, which consisted of 54.6 Gy/1.5 Gy TID over 2.5 weeks with cord doses separated by 8 hours, no treatment on weekends. Both radiation regimens followed 2 cycles of induction chemotherapy with paclitaxel and Paraplatin® (Figure 2). 24 In order to detect a 50% improvement in median survival from 14 months to 21 months, 294 patients were needed for the experimental arm. The accrual was terminated at 141 patients, of whom 119 were randomized after induction chemotherapy.
Figure 2 : ECOG 2597: Schema
ecco_2003_ecog2597.gif goes here – need to upload
One hundred and twelve patients were evaluable for toxicity and response. The study demonstrated a median survival of 20.3 months for the HART arm as compared to 13.7 months with TRT. The incidence of esophagitis that was greater than or equal to grade 3 was 25% for HART and 14% for the TRT arm. In addition to survival benefit, HART also offers the convenience of shorter duration for the radiation course (2.5 weeks instead of 7 weeks). The results are summarized in table 6.
Table 6: Results for ECOG 2597
Recently, steady progress has been made in the management of patients with locally advanced NSCLC. Local control continues to be a problem with the current radiation techniques. Increasing the dose of radiation with 3D conformal radiotherapy or IMRT with reduction in overall radiated lung volume may allow for improvement in therapeutic index. In addition to optimizing therapeutic modalities currently in use, there is a need to develop newer and novel strategies to build upon the progress already made. The use of molecularly targeted therapies is a major step in this direction.
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