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9
Induction Therapy for Clinical Stage I Lung Cancer
David C. White and Thomas A. D’Amico
those with completely resected early-stage disease, great efforts have been focused on the develop- ment of effective adjuvant therapies.
While many trials have been performed in an attempt to demonstrate survival benefi t with che- motherapy for NSCLC, only in the past decade has this been fruitful. Two small trials fi rst dem- onstrated signifi cant survival benefi t for induc- tion chemotherapy in stage IIIA NSCLC,6,7 which has remained the standard of care.8 In 1995, a meta-analysis of 52 randomized clinical trials suggested an absolute survival benefi t of approxi- mately 5% at 5 years with adjuvant chemotherapy and surgery compared to surgery alone for NSCLC.9 More recently, three prospective, ran- domized clinical trials demonstrated the benefi t of platinum-based adjuvant therapy in the treat- ment of stage I-IIIA NSCLC following complete surgical resection.10–12 Based on the fact that adju- vant chemotherapy appears to improve survival in early-stage NSCLC, and the known occurrence of distant metastases in this patient population, it seems logical to ask whether induction therapy might prove benefi cial in clinical stage I NSCLC, as it does for stage IIIA disease.
9.1. Induction Therapy for Non-Small Cell Lung Cancer
The potential advantages of induction therapy compared to adjuvant therapy are multiple. First, several trials of adjuvant chemotherapy have been hindered by poor compliance, as patients are either not able or not willing to undergo a full Non-small cell lung cancer (NSCLC) remains a
leading cause of death and will cause approxi- mately 163,500 deaths in the United States in 2005.1 While patients presenting with localized disease have the best chance of being cured, they represent a minority of patients and unfortunately have a signifi cant likelihood of developing recur- rent disease after treatment and ultimately dying of their disease. The 5-year survival for patients presenting with clinical stage I lung cancer ranges from 38% to 61%; for those with pathological stage IA disease, the survival is 67%.2
Despite advances in staging, including the use of high-resolution computed tomography (CT) scanning, the advent of positron emission tomog- raphy (PET) scanning, and more widespread use of mediastinoscopy, the clinical staging of lung cancer remains inadequate. A recent multicenter trial of leading institutions demonstrated that only approximately 62% of patients with clinical stage I NSCLC retained that stage after full surgi- cal staging.3 Thus, a signifi cant percentage of patients with clinical stage I NSCLC cancer may in fact have more advanced disease and could there- fore potentially benefi t from induction therapy. Of patients who are able to undergo complete resec- tion for stage I NSCLC, approximately one-third will develop recurrent disease, and 70% of recur- rences will be distant metastases.4 In addition, retrospective studies have demonstrated that even within stage IA there is a worse prognosis with larger tumor size, suggesting a potential role for additional therapies in even the earliest stages of lung cancer.5 Due to the poor overall prognosis for NSCLC, and the chance of recurrence even among
course of chemotherapy in the postoperative period, and this appears to hold true for patients with stage I and II NSCLC.13 The compliance rates for induction therapy followed by surgery are higher6,7 than for surgery followed by adjuvant chemotherapy.9–12 In addition, preoperative ther- apy may have improved effi cacy due to the intact vascular supply of the tumor, may aid in resect- ability by downsizing the primary tumor, and may provide a better chance of cure by treating micrometastatic disease earlier. Finally, it has been suggested that chemotherapy resistance may be related to genetic changes within the tumor itself, and thus chemotherapy may be more effective when given as early as possible after the disease is diagnosed, while the tumor burden is relatively smaller.14 Potential disadvan- tages of induction therapy include impaired wound healing and increased risk of periopera- tive infections, such as empyema and broncho- pleural fi stula, although these potential disadvantages have not been demonstrated thus far.15
Several trials have been designed in an attempt to assess the risks and benefi ts of induction che- motherapy for resectable NSCLC, and some of these trials have included patients with clinical stage I disease. These trials have focused on che- motherapy, as the use of radiation therapy has been limited largely to an adjuvant role for patients at high risk of recurrence following resection.
Trials of induction radiation therapy demon- strated no survival benefi t in patients with NSCLC.16
9.2. Induction Therapy: Phase II Trials
A small phase II feasibility trial was reported in abstract form at the 2001 American Society of Clinical Oncology (ASCO) annual meeting. This North Central Cancer Treatment Group (NCCTG) study enrolled 52 patients for treatment with three cycles of preoperative carboplatin and pacl- itaxel.17 The majority of patients in this trial were stage I, with 17% having T1 tumors, 71% having T2 tumors, and 12% having T3 tumors. Only 10%
had nodal involvement, and mediastinoscopy was mandated to exclude N2 disease prior to enrollment in the trial. Forty-fi ve of the 52 patients (87%) were able to receive all three cycles of preoperative therapy, and complete resection
was achieved in 36 of 46 patients (78%). Three patients died postoperatively, and 2-year survival was estimated at 73%. Grade 3 neutropenia occurred in 23 patients (44%), while grade 3 thrombocytopenia occurred in 9 (17%). Other complications included diarrhea (1), myalgia (4), hyperglycemia (2), vomiting (2), and dysrhyth- mia (1). The overall response rate to chemother- apy was 59%. These data appear to support the feasibility of induction chemotherapy, although the fi nal results have not been published.
Another important trial was conducted by the Bimodality Lung Oncology Team between 1996 and 1998.18 This was a phase II trial designed to assess the feasibility of preoperative chemother- apy consisting of carboplatin and paclitaxel in patients with early-stage NSCLC (stages IB–IIIA).
Patients with stage IA disease were excluded. A total of 94 patients were enrolled in this multi- center trial and treated with two cycles of pre- operative carboplatin and paclitaxel, followed by surgery, and an additional three cycles of adjuvant chemotherapy. Mediastinoscopy was required in patients with lymph nodes greater than 1cm on chest CT. The primary end points of this trial were recurrence, long-term toxicities, and survival. Forty-two of the 94 patients (44.7%) enrolled were clinical stage IB (T2N0). Impor- tantly, 90 of the 94 patients (96%) were able to receive both preoperative cycles of chemotherapy.
Fifty-six percent of patients had a major radio- graphic response to preoperative therapy, while 34% of patients had stable disease and only 3%
had progression of disease during preoperative chemotherapy. Also, 88 of 94 patients (94%) were able to undergo their planned surgery, and R0 resection was achieved in 81 patients (86%). Inter- estingly, despite aggressive preoperative staging with mediastinoscopy, 36% of patients were found to have more extensive disease at the time of surgery. Forty-three patients (46%) were not able to receive their planned postoperative chemo- therapy for a variety of reasons, including periop- erative complications and delayed recovery in 15 patients, again supporting the concept that pre- operative chemotherapy is tolerated better than postoperative chemotherapy. Only 42 patients (45%) received all three planned postoperative cycles of chemotherapy. Toxicities in the pre- operative chemotherapy group included severe
hypersensitivity to paclitaxel in three patients, severe anemia and thrombocytopenia in one patient each, and grade 3 neutropenia in 35% of patients. One patient died of a cerebrovascular accident after developing severe neutropenia and hyponatremia during induction therapy, and two deaths occurred in the postsurgical setting. Other surgical complications included arrhythmia, wound infection, hemorrhage, and respiratory infection.
In summary, this phase II trial demonstrated that preoperative chemotherapy is well tolerated and feasible prior to resection of early-stage NSCLC. It highlights, once again, the need for improved preoperative staging to better stratify patients. Because of the small number of patients and the variable stage presentations, it is impos- sible to comment specifi cally on the potential benefi ts of chemotherapy for stage I disease based on this trial. In addition, the omission of stage IA patients excludes a signifi cant fraction of patients for whom the risks and benefi ts of induction therapy are unknown. Other phase II trials have evaluated the use of newer chemotherapeutic agents for induction regimens, including gem- citabine, and have found this to be a feasible approach as well.19 (See Table 9.1.)
9.3. Phase III Trials
The most convincing data regarding the effi cacy of induction chemotherapy in clinical stage I NSCLC comes from a randomized phase III trial
conducted in France from 1991–1997 by the French Thoracic Cooperative Group.20 This trial enrolled 373 patients with stage I (excluding T1N0), II, or IIIA NSCLC and randomized them to surgery alone or to induction chemotherapy (two cycles of mitomycin, ifosfamide and cispla- tin given 3 weeks apart) followed by surgery 1 month later. Although this trial included patients with stage II and IIIA disease, 205 of the patients were clinical stage I. It should be noted that medi- astinoscopy was not routinely performed prior to surgery, and treatment of the mediastinal lymph nodes at the time of surgery was left to the sur- geon’s discretion, although it was not different between groups.
Results of this trial demonstrated a nonsignifi - cant trend towards improved survival in the induction therapy group. Specifi cally, there was a numerical absolute survival benefi t of 3.8% at 1 year, 6.9% at 2 years, 10.4% at 3 years, and 8.6%
at 4 years. Median survival improved from 26 months in the surgery arm to 37 months in the induction therapy arm, although this difference was also not statistically signifi cant. (p = 0.15).
Interestingly, the numerical survival benefi t in the induction arm was limited to those patients with stage I or II disease. In addition, there was a statistically signifi cant improvement in disease- free survival in the induction therapy arm.
Disease-free survival increased from 12.9 months in the surgery arm to 26.7 months in the induc- tion therapy arm, with 3-year disease-free sur- vival rates of 44% and 33%, respectively.
TABLE 9.1. Major trials of induction therapy for clinical stage I NSCLC.
Reference No. patients Stage Chemotherapy Control Findings Level of evidence
Marks17 (NCCTG) 52 Ib–IIIa Carboplatin, None Preoperative chemotherapy 2b
paclitaxel × 3 feasible
Pisters18 (BLOT) 94 Ib–IIIa Carboplatin, None Preoperative chemotherapy 2b
paclitaxel × 2 feasible
preop, × 3 postop
Depierre20 (FTCG) 373 Ib–IIIa Mitomycin, Surgery alone Improved disease-free 2b
ifosfamide, survival
cisplatin × 2 cycles
Pisters21 (SWOG 9900) 354 Ib–IIIa Carboplatin, Surgery alone Nonsignificant trend towards 2b paclitaxel × 3 improved overall and
disease-free survival
Abbreviations: BLOT, Bimodality Lung Oncology Team; FTCG, French Thoracic Cooperative Group; NCCTG, North Central Cancer Treatment Group; NSCLC, non-small cell lung cancer; SWOG, Southwest Oncology Group.
However, the use of induction chemotherapy did result in a nonsignifi cant increase in the number of treatment-related deaths after surgery.
In addition, there was a nonsignifi cant increase in perioperative morbidity in the induction therapy arm, including more empyemas and bronchopleural fi stulas.
The correlation between clinical and patho- logical staging in this trial once again demon- strated the inadequacy of clinical staging. Of 82 patients with clinical N0 disease, only 47 (57%) proved to be pathological N0, while 18 were N1, 16 were N2, and 1 was N3. Thus, almost half the patients who were clinical stage I were upstaged at the time of complete surgical staging. Although the results of this trial are limited by the use of subset analysis, and the lack of a statistically sig- nifi cant overall survival benefi t, the data is nev- ertheless intriguing and suggestive of a potential benefi t of induction therapy in clinical stage I NSCLC.
A second phase III trial, a follow-up to the Bimodality Lung Oncology Team phase II study,18 was recently closed. This trial, S9900, was a mul- tigroup phase III trial comparing surgery alone to preoperative chemotherapy followed by surgery for early-stage NSCLC.21 This trial stratifi ed patients with early-stage disease, separating those with IB/IIA disease from those with IIB/
IIIA disease (excluding superior sulcus tumors), and randomizing them to receive three preopera- tive cycles of chemotherapy with paclitaxel and carboplatin followed by surgery, or surgery alone.
The trial was powered to detect a 33% increase over an expected 2.7-year median survival with surgery alone. The planned sample size was 600 patients; however, this study closed to new patient entry after positive results from adjuvant chemo- therapy trials became available.10,12
At the time of closure, 354 patients had been accrued. Results were reported in abstract form at the American Society of Oncology (ASCO) 2005 meeting.21 Seventy percent of the patients were stage IB/IIA. A major radiographic response was observed in 40% of patients, and a nonsig- nifi cant trend towards improved progression- free and overall survival was seen in the induction therapy group, with a 9-month improvement in median progression-free survival and a 5-month increase in median overall survival (42 vs. 37
months) with preoperative chemotherapy (p = 0.26). Overall 2-year survival was 68% in the treatment arm and 64% in the surgery arm (p = 0.47). There were four perioperative deaths in the surgery arm and six in the treatment arm. While the study closed early, this trial supports the fea- sibility of induction therapy, although no conclu- sions can be drawn regarding survival. The investigators concluded that further randomized trials are warranted comparing induction therapy to adjuvant therapy for early-stage NSCLC.
Several additional trials have been performed and are currently being evaluated. One of these was a phase III trial comparing surgery alone to surgery following preoperative gemcitabine–cis- platin in patients with stage IB-IIIA NSCLC.22 Accrual to this trial was stopped early due to pub- lication of data regarding adjuvant therapy;10–12 however, early results suggest feasibility with the use of this regimen.
9.4. Meta-analysis
The evidence regarding induction therapy for early-stage NSCLC has been summarized in a meta-analysis presented at the ASCO meeting in 2005.23 This included clinical trials between 1994 and 2004 on induction therapy for resectable NSCLC. Eight trials were identifi ed, with a total of 1965 patients. The overall survival difference was statistically signifi cant, with an odds ratio of 0.68 for induction therapy. However, when the highest quality trials were grouped separately, this difference was not statistically signifi cant. Of importance, this meta-analysis included patients with a range of clinical stages, not just stage I NSCLC. The authors concluded that additional randomized trials are necessary to determine the effi cacy of induction therapy for early-stage NSCLC.
9.5. Summary
Currently there exists insuffi cient published data to formulate an evidence-based recommendation regarding the use of induction therapy for clini- cal stage I NSCLC. The best evidence that sug- gests a survival benefi t from induction therapy
comes from subset analysis of one randomized, controlled trial that included patients with a range of stages of disease.20 Furthermore, only disease-free survival, and not overall survival, was signifi cantly improved in the induction therapy arm of this trial. Although this is a well- designed randomized, controlled trial, the evi- dence for improved survival is no higher than level 2b given the inclusion of multiple stages.
The other randomized, controlled trial that was designed to assess the benefi t of induction therapy, S9900, closed early due to publication of data demonstrating the benefi t of adjuvant therapy, and this trial once again failed to dem- onstrate statistically signifi cant improvements in overall survival with induction therapy, albeit possibly because of incomplete accrual.21 Although well-intentioned, this trial is under- powered and therefore can only be considered level 2b evidence for the benefi t of induction therapy. The two main cohort studies discussed above, while intriguing, provide at best level 2b evidence for a benefi t from induction therapy.
Furthermore, these trials did not evaluate patients with T1N0 disease, who make up a large portion of patients with clinical stage I disease, and for whom there is essentially no data regarding the utility of induction therapy. Thus, any benefi t from induction therapy in clinical stage I NSCLC must be extrapolated from these trials, and there- fore, a recommendation of grade C is the stron- gest one that can be made for the use of induction therapy in this population. While there is some hope of improved survival with induction therapy, higher grade evidence-based recommendations must await the results of randomized trials focused on clinical stage I disease. These trials must be designed to compare induction therapy followed by surgery with surgery plus adjuvant therapy for early-stage lung cancer. The current standard of care for patients with early stage (I and II) NSCLC is surgery, without induction therapy.8 Patients with pathological stage IB-IIIA should be considered for adjuvant therapy.10–12
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