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(Chest. 1999;116:509S-516S.)
© 1999 American College of Chest Physicians

Role of Chemotherapy in Stages I to III Non-small Cell Lung Cancer*

Gary M. Strauss, MD, FCCP

* From the Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA.

Correspondence to: Gary M. Strauss, MD, FCCP, Division of Thoracic Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115


   Abstract
TOP
 Abstract
Introduction
 Ongoing Trials of Adjuvant...
 Role of Induction Chemotherapy...
 Conclusion
 References
 
The management of resectable non-small cell lung cancer (NSCLC) has been the focus of extensive investigation over the last decade. Nonetheless, existing management strategies are suboptimal for all stage groupings. The only exception is complete resection for stage IA NSCLC, in which a cure is achieved in 70 to 85% of patients. A number of studies demonstrate that adjuvant chemotherapy may be associated with some biological effect. Nonetheless, chemotherapy remains experimental and cannot be definitively recommended outside the context of a randomized trial. Radiation therapy appears to be associated with a reduction in local recurrence in stage II NSCLC. With regard to potentially resectable stage IIIA NSCLC, the results of randomized trials support the conclusion that induction chemotherapy followed by resection (with or without postoperative radiation) may enhance survival compared to that achieved with resection alone. Among patients with stage IIIA and IIIB NSCLC who are treated without resection, numerous phase III studies demonstrate that induction chemotherapy with definitive radiation improves outcome when compared to thoracic radiation therapy alone. While there may be an advantage for concurrent chemoradiation compared to sequential therapy, definitive results are not yet available to support this conclusion. While the magnitude of benefit associated with induction chemotherapy or chemoradiation in regionally advanced NSCLC is debatable, the results of multimodality studies provide a basis for optimism that real therapeutic progress is being achieved. Further study of therapeutic strategies that incorporate aggressive systemic treatment and local-regional therapy in stage IIIA and IIIB NSCLC is warranted. Moreover, completion of randomized studies focusing on the role of adjuvant chemotherapy in stage IB and stage II NSCLC should be given priority.


   Introduction
TOP
 Abstract
 Introduction
Ongoing Trials of Adjuvant...
 Role of Induction Chemotherapy...
 Conclusion
 References
 
The treatment of stages I, II, and III non-small cell lung cancer (NSCLC) has evolved significantly over the last decade. The International Staging System for Lung Cancer was introduced in 1986.1 One of its major objectives was to subdivide regionally advanced disease into two groups: one with patients that were potentially resectable (stage IIIA), and another with patients that were categorically unresectable (stage IIIB). In 1997, the International Staging System was revised in several respects (Table 1 ).2 Stage I and II NSCLC was subdivided into stage IA and IB and stages IIA and IIB. This distinction is predominantly based on the size of the primary tumor. Moreover, T3N0 lesions have been reclassified and are no longer considered to be in stage IIIA. These lesions have been downstaged into the new stage IIB category. Based on the 1997 modification, stage IIIA NSCLC is composed of T3N1 and T1-T3N2 lesions. The definition of stage IIIB NSCLC has not been affected by the new revision. Among patients with resected stage I NSCLC, the most common pattern of failure following curative resection is distant metastatic disease.3 4 In stage II NSCLC, distant metastases also are the major failure pattern, although local recurrence is a greater problem in stage I disease.


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  		Table 1. International Staging System for Lung Cancer, 1997 Revision*

 
Because of the major problem with distant recurrence, adjuvant chemotherapy represents the most rational therapeutic strategy to diminish this risk. While numerous adjuvant chemotherapy trials in resectable NSCLC have been conducted over the past several decades, no patient subset has been identified in which an undisputed benefit from adjuvant chemotherapy has been achieved. Accordingly, adjuvant chemotherapy is not mandated as the standard of care for any patients with resected stage I or stage II disease.

Some of the most influential adjuvant chemotherapy trials for resectable NSCLC comes from a series of three studies by the Lung Cancer Study Group (LCSG). In each of these trials, the chemotherapy regimen employed consisted of the combination of cyclophosphamide (Cytoxan; Meade Johnson Laboratories; Evansville, IN), doxorubicin (Adriamycin; Adria Laboratories; Columbus, OH), and cisplatin (CAP). Doses of cisplatin ranged from 40 to 60 mg/m2 per cycle, with treatment cycles repeated every 28 days.5 6

The first study was LCSG-772, which randomized patients with completely resected stage II and III adenocarcinoma and large cell carcinoma to either six cycles of postoperative CAP chemotherapy or to intrapleural administration of bacillus Calmette-Guerin and levamisole.7 One hundred forty-one patients were randomized after complete surgical resection. Forty-five percent of the patients had stage II disease, and 55% had stage III disease. There were significant differences in disease outcome between the groups that favored the CAP arm of the study, which consisted of a 6-month delay in median time to recurrence and a 15% survival advantage at 1 year (77% vs 62%). With a median follow-up of 8.5 years, the survival curves remain separate and continue to favor the CAP treatment. If the 15 patients who were randomized to chemotherapy but did not receive it were excluded from analysis, the differences in survival were statistically significant (p = 0.013). When all treated patients are included, qualitatively similar results are noted, but the survival differences did not reach significance (p > 0.05).

The second LCSG trial (LCSG-791) was for incompletely resected NSCLC of all histologies and included patients with stage I to IIIA disease.8 Incomplete resection was defined as either a tumor in the highest resected mediastinal node or a margin that was positive for tumor. One hundred seventy-two patients were randomized to either postoperative radiation therapy (RT) (40 Gy) or to postoperative RT plus CAP. The group receiving chemotherapy again experienced improvement in the median length of survival (20 months vs 13 months) and the median time to recurrence (14 months vs 8 months). The survival rate 1 year following randomization was 14% better in the adjuvant chemotherapy group than in the group receiving RT alone (68% vs 54%, respectively). The recurrence and survival rate advantages for the group randomized to adjuvant chemotherapy reached statistical significance only during the first year following randomization. The early differences in the treatment groups diminished with the passage of time.

The third LCSG study (LCSG-801) was designed for stage I patients. However, the older American Joint Committee on Cancer staging system was utilized, so that eligible patients had either T2N0 or T1N1 lesions. Patients with T1N0 lesions were not eligible to participate. Eighty-five percent of patients had T2N0 lesions, and 15% had T1N1 tumors. A total of 283 patients were randomized to either four cycles of postoperative CAP therapy or to no adjuvant therapy.9 Prognostic factors utilized to stratify patients prior to randomization included histologic subtype (squamous vs nonsquamous cell tumor), Karnofsky performance status, and WBC count before surgery. Compliance with chemotherapy was a problem, since only 53% of patients received all four cycles of chemotherapy, and only 57% of these received the treatment on schedule. The 5-year survival rate for both groups was 55%, but CAP chemotherapy did not favorably impact on outcomes. Correlation of the results with prognostic variables (including those not used in the stratification procedure) failed to reveal any imbalances that may have contributed to the negative results of this study.

Another trial that has received considerable attention was reported from Finland.10 In this trial, 110 patients with T1N0M0 to T3N0M0 NSCLC tumors were randomized to surgery alone or to surgery followed by adjuvant chemotherapy. Of the 110 patients who were randomized, 99 had stage I disease. Those randomized to chemotherapy received six cycles of CAP chemotherapy (cyclophosphamide, 400 mg/m2; doxorubicin, 40 mg/m2; and cisplatin, 40 mg/m2). Statistically significant advantages favoring the chemotherapy group over the surgery-alone group were observed with respect to the probability of recurrence (31% vs 48%, respectively), 5-year survival rate (67% vs 56%, respectively), and 10-year survival rate (61% vs 48%, respectively). However, substantial imbalances appear to have existed in the study, because those patients randomized to surgery alone underwent pneumonectomy more frequently than patients randomized to postoperative chemotherapy. For this reason, the clinical importance of the survival advantage can be questioned.

A meta-analysis of the use of chemotherapy in treating NSCLC has been published, with data included from 14 randomized trials comparing surgical resection alone to surgery plus adjuvant chemotherapy.11 These trials included a total of 4,357 patients, and 2,574 deaths. Five of the trials evaluated adjuvant chemotherapy that was based on the use of long-term alkylating agent chemotherapy. In these trials, the hazard ratio favored surgery alone, and the risk of death was 15% higher among those randomized to chemotherapy (p = 0.005).

On the other hand, for studies that utilized a cisplatin-based chemotherapy regimen, the hazard ratio estimates favored adjuvant chemotherapy. Overall, there was a 13% reduction in the risk of death among treated patients among these eight trials (p = 0.08). This translated into an absolute 5% improvement in the probability of long-term survival as a result of adjuvant chemotherapy in this trial.


   Ongoing Trials of Adjuvant Chemotherapy in Stages I and II NSCLC
TOP
 Abstract
 Introduction
 Ongoing Trials of Adjuvant...
Role of Induction Chemotherapy...
 Conclusion
 References
 
While conflicting data exist, a number of studies support the conclusion that adjuvant chemotherapy in resectable NSCLC is associated with some biological effect in resectable NSCLC. Nonetheless, chemotherapy remains experimental in all stages at the present time. Adjuvant chemotherapy cannot be recommended outside the context of a clinical trial.12

Two ongoing North American adjuvant chemotherapy trials for stages I and II NSCLC deserve mention. The National Cancer Institute of Canada is conducting a phase III study comparing surgery alone to surgery followed by adjuvant chemotherapy with cisplatin and vinorelbine tartrate (Navelbine; Glaxo Wellcome; Research Triangle, NC) (NCIC BR10). Eligible patients include those with stage I disease (T2N0 tumors), as well as those with stage II disease (T1N1 or T2N1 tumors). Tissue is being collected to facilitate the study of molecular markers on a prospective basis. Moreover, the presence of a ras mutation will be utilized as a stratification factor prior to randomization. Cooperative groups in the United States are planning to cooperate in this study, so it will be conducted as an intergoup study.12

The Cancer and Leukemia Group B (CALGB) is sponsoring an intergroup study in patients with high-risk stage I NSCLC (CALGB 9633). Eligible patients must have T2N0 primary lesions. A total of 500 patients will be randomized to surgery alone or to surgery followed by adjuvant chemotherapy with carboplatin and paclitaxel (Taxol; Bristol-Myers; Wallingford, CT). The rationale for defining "high risk" exclusively on the basis of tumor status was based on the consistency of individual reports indicating that tumor size was an important predictor of outcome in stage I NSCLC (Table 1) . Moreover, it was thought that there was insufficient information at the present time to permit treatment decisions to be based on any constellation of molecular and pathologic prognostic markers.


   Role of Induction Chemotherapy in Stage IIIA and IIIB NSCLC
TOP
 Abstract
 Introduction
 Ongoing Trials of Adjuvant...
 Role of Induction Chemotherapy...
Conclusion
 References
 
The management of regionally advanced NSCLC has evolved rapidly over the last decade. Conceptually, stage IIIA was intended to imply regionally advanced yet potentially resectable disease, while stage IIIB was intended to describe regionally advanced yet categorically unresectable disease.13 14 15 The criteria for resectability have changed somewhat, and these distinctions are not absolute. Moreover, in this era of multimodality therapy surgery may play a cytoreductive role in the management of cancer.

Stage IIIA disease appears to be associated with a better prognosis than stage IIIB disease. For example, according to data presented when the International Staging System for Lung Cancer was introduced, stage IIIA is associated with a median survival time of 12 months and a 5-year survival rate of 15%, while stage IIIB disease is associated with survival time of 8 months and 5-year survival rate of < 5%.

Induction Chemotherapy and Radiation vs Radiation Alone in Stage III NSCLC
The use of systemic chemotherapy prior in "definitive" local-regional therapy (ie, therapy employing radiation, surgery, or both) is generally referred to as "induction chemotherapy" or "neoadjuvant chemotherapy." The term induction chemotherapy will be employed here.

The role of induction chemotherapy combined with thoracic radiation has been extensively investigated in patients with stage III NSCLC. While many phase II studies have been reported, numerous phase III studies also have been completed. Indeed, the role of induction chemotherapy is perhaps better supported by randomized studies in NSCLC than is the case for any other adult solid tumor. There are a number of theoretic advantages for the use of induction chemotherapy.16 These include stage reduction to facilitate improved local control by radiation, surgery, or both. The response rates to identical chemotherapy regimens appear to be higher when utilized for stage III disease than for stage IV disease. Micrometastases are addressed early in the course of treatment. Finally, some studies suggest that induction chemotherapy is better tolerated than chemotherapy administered later in the course of treatment.

Perhaps the most influential phase III trial in stage III NSCLC is CALGB 84–33.17 Eligibility for this trial was limited to patients with prognostically favorable pretreatment characteristics, including favorable performance status (Eastern Cooperative Oncology Group performance status, 0 or 1) and minimal weight loss (< 5% of body weight in the preceding 3 months). Patients were randomized to receive 60 Gy of radiation in 6 weeks or two cycles of induction chemotherapy with cisplatin and vinblastine followed by identical RT.

An update of this trial has been published that includes 7-year follow-up information.18 A total of 78 patients were randomized to chemoradiation, while 77 were randomized to RT alone. The objective response rate was 56% to combined treatment and 43% to RT alone (p = 0.092). The group randomized to induction chemotherapy achieved a significant improvement in median survival compared to the group randomized to RT alone (13.7 vs 9.6 months, respectively; p = 0.012) as well as improvement in the proportion of patients surviving 1, 2, 3, 5, and 7 years (54%, 26%, 24%, 17%, and 13% vs 40%, 13%, 10%, 6%, and 6%, respectively).

The Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group have conducted a confirmatory three-arm trial involving 452 eligible patients who were randomized to the same two treatment arms employed in study CALGB 84–33 as well as in a third arm that included hyperfractionation RT to a total dose of 69.6 Gy.19 The hyperfractionation RT arm had been demonstrated to produce a survival advantage for favorable patients in Radiation Therapy Oncology Group protocol 83–11.20 Preliminary results of the confirmatory trial indicate that the 1-year survival rate and median survival time were superior in the group randomized to receive induction chemotherapy compared to the other two groups (p = 0.03). The 1-year survival rate and median survival time for the three groups are as follows: induction chemotherapy and RT, 60% and 13.8 months, respectively; hyperfractionation RT, 51% and 12.3 months, respectively; and standard RT, 46% and 11.4 months, respectively.

Le Chevalier reported the results of a multicenter French study involving 353 patients who were randomized to 65-Gy radiation or to three cycles of induction chemotherapy employing cisplatin, vindesine, cyclophosphamide, and lomustine given prior to RT followed by three additional cycles of chemotherapy.21 22 The response rate to induction chemotherapy was 27%. One-, 2-, and 3-year survival rates for the combined chemotherapy/RT arm were 50%, 21%, and 11%, respectively, while for the RT-alone arm they were 41%, 14%, and 5%, respectively (p = 0.08). There was a very high rate of local-regional failure in both groups. Local control was 17% in the RT arm and 15% in the combined-modality arm in this trial. However, the distant failure rate was significantly reduced in the combined-modality arm compared to the RT arm (22% vs 46% failure at 1 year, respectively; p < 0.001). With a mean follow-up of 61 months, there was a statistically significant improvement in survival time associated with combined-modality treatment (p < 0.02).

The European Organization for Research and Treatment of Cancer conducted a three-arm study with 331 patients comparing 50-Gy thoracic RT in one arm to two other arms in which concurrent cisplatin and RT were utilized on one of two schedules.23 In one arm, cisplatin was administered daily (6 mg/m2/d) along with radiation, while in the other arm it was administered weekly (30 mg/m2/wk). There was a significant improvement (p = 0.009) in survival rates for daily cisplatin/radiation therapy compared with RT alone (2- and 3-year survival rates, 26% and 16% vs 13% and 2%, respectively). For weekly cisplatin therapy/RT, the survival rate was intermediate (2- and 3-year survival rates, 19% and 13%, respectively) but was not significantly different from either of the other arms. The survival benefit observed with daily cisplatin therapy/RT appeared to be secondary to that with improved local control (p = 0.003).

A meta-analysis has published that included data on 14 randomized trials comparing chemotherapy and RT to RT alone in regionally advanced stage III NSCLC.24 A total of 2,589 patients participated in these trials. Overall, the meta-analysis revealed that the use of combination chemotherapy and RT reduced the risk of death by 12% at 1 year, 13% at 2 years, and 17% at 3 years. This corresponds to a mean gain of life expectancy of about 2 months. Similarly, the magnitude of benefit was independent of whether sequential or concurrent chemotherapy and RT were utilized.

Despite encouraging data on the advantages of combined chemoradiation, many important questions remain unanswered. The optimal induction chemotherapy regimen has not been established. The optimal sequence of chemotherapy and RT remains unknown. The role of hyperfractionation RT has not been established.

Most importantly, the vast majority of patients continue to have recurrences of disease and eventually succumb to metastatic disease, despite the use of chemoradiation for regionally advanced NSCLC. Local-regional recurrence remains a major problem. In study CALGB 84–33, the group treated with chemoradiation had an 80% incidence of local-regional failure, while the group treated with RT alone had a 90% incidence of local-regional failure. Green25 has emphasized that patterns of failure despite induction chemotherapy and RT mandate better control of both macroscopic intrathoracic disease and distant micrometastatic disease in the setting of regionally advanced NSCLC.

Phase II Trials of Induction Chemotherapy, RT, and Surgery
Numerous phase II trials of induction chemotherapy and surgical resection in regionally advanced stage III NSCLC have been conducted. However, these trials vary considerably with respect to many factors. The variability relates to the use of surgical staging of the mediastinum, the delivery of RT with chemotherapy sequentially vs concurrently, the choice and dose of chemotherapeutic agents, RT dose schedules, and definitions of resectable disease. Such inconsistencies have led to considerable difficulties in the interpretation of these trials.

Table 2 lists 11 phase II trials of induction chemotherapy and surgery with or without RT in stage IIIA NSCLC.26 27 28 29 30 31 32 33 34 35 36 (Two trials also included patients with stage IIIB disease.26 36 ) Each of the trials listed utilized a cisplatin-based combination chemotherapy regimen. Seven of the trials used preoperative RT (in six trials, RT was administered concurrently with chemotherapy, and in one trial it was administered sequentially), two trials used only postoperative RT, and two trials did not employ RT at all.


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  		Table 2. Phase II Trials on Induction Chemotherapy and Surgery in Stage IIIA Disease*

 
Overall, response rates to induction therapy were quite impressive, varying from 39 to 77%. Resectability rates exceeded 50% in each of these trials. The highest resectability rate (93%) was noted in a trial that utilized hyperfractionated RT concurrently with induction chemotherapy.31 Many trials report pathologic complete response rates in the range of 10 to 20% following induction chemotherapy. Median survival time and long-term survival rates varied significantly among the trials, but it is clear that a minority of patients had long-term survival and possible cure. Moreover, two multi-institutional trials showed that patients who were found to have negative N2 lymph nodes at the time of resection had a significantly better survival rate than those with persistent N2 positive disease at resection.30 36

None of these trials were designed to evaluate the therapeutic role of surgery in the context of regionally advanced disease, but the addition of surgery to the local-regional treatment regimen almost certainly accomplishes an improvement in local control. Local recurrence has generally been observed in < 50% of patients who undergo trimodality therapy. This contrasts with an 80 to 90% rate of persistent or recurrent local-regional disease among those patients who do not undergo resection.17 21 23 37 Thus, these phase II trials employing chemotherapy, RT, and surgery demonstrate a shift in recurrence patterns from both local and distant to predominantly distant. Furthermore, improved local control rates may result in significant gains in overall survival times as has been demonstrated by the reports of Schaake-Koning et al23 and Jeremic et al.38

Phase III Trials of Induction Chemotherapy and Surgery
Reports of small randomized trials comparing induction chemotherapy followed by surgical resection to resection without systemic treatment have been influential in modifying the perception of the role of chemotherapy in the management of regionally advanced NSCLC.

A study from Barcelona, Spain, randomized patients to an induction chemotherapy regimen of cisplatin, mitomycin C, and ifosfamide followed by resection and postoperative RT (50 Gy) or to resection and the same postoperative RT. There was a dramatic threefold survival advantage for those patients randomized to receive induction chemotherapy.39 In the group randomized to chemotherapy, the median survival time was 26 months, while in the group randomized to surgery plus RT, survival time was 8 months, which was lower than expected (p < 0.001).

In a similar trial conducted at the MD Anderson Cancer Center at the University of Texas, patients were randomized to induction chemotherapy consisting of three cycles of cyclophosphamide, etoposide, and cisplatin followed by resection or to surgical resection alone.40 Of note, RT was given to > 50% of patients in both arms of the study. The group that received chemotherapy achieved an estimated median survival time that was almost sixfold greater than that of patients randomized to surgery alone (64 vs 11 months, respectively; p < 0.008). Similarly, the 3-year survival rate was 56% for the induction chemotherapy group compared with 15% for the surgery-alone group.

While receiving much less attention than the other two trials, a third randomized trial from the National Cancer Institute preceded the other two.41 In this trial, the experimental group was treated with induction cisplatin and etoposide chemotherapy followed by resection and postoperative chemotherapy. The control group underwent immediate surgical resection and postoperative RT (54 to 60 Gy). Patients treated with induction chemotherapy had a superior survival time, but the difference was not statistically significant (28.7 vs 15.6 months, respectively).

A fourth randomized trial that was conducted by the CALGB is not yet fully mature.42 The experimental arm of this study consisted of induction chemotherapy with cisplatin and etoposide for two cycles followed by resection, two additional cycles of chemotherapy, and subsequent RT (54 or 60 Gy). The control arm consisted of preoperative RT (40 Gy), resection, and postoperative RT (to a total dose of 54 or 60 Gy). Preliminary results show that the median overall survival time was 19 months for the group undergoing induction chemotherapy compared with 23 months for the group receiving preoperative RT. While the trend toward reduced survival time in the group receiving induction chemotherapy was not statistically significant, the results of study CALGB 9134 conflict with the results of the other three randomized trials, which suggest a dramatic benefit with the use of induction chemotherapy.

Although three of the four randomized trials showed a survival benefit with the use of induction chemotherapy (including two trials in which the differences were statistically significant), these studies have significant limitations that raise important questions as to whether induction chemotherapy has been proven to be beneficial. One major problem relates to the fact that each of the trials enrolled small numbers of patients (Barcelona trial, 60 patients; MD Anderson Cancer Center trial, 60 patients; National Cancer Institute, 27 patients; and CALGB, 57 patients). The Barcelona and MD Anderson Cancer Center trials were discontinued before the projected accrual goal was reached because of early stopping rules. The highly publicized beneficial effects observed in the Barcelona and MD Anderson Cancer Center trials were most likely responsible for difficulty in accruing patients to study CALGB 9134, leading to its premature closure. Furthermore, the absolute magnitude of the survival differences seen in the MD Anderson Cancer Center and Barcelona trials were far greater than reasonably could be expected from the modestly effective chemotherapy regimens employed. These extreme results should raise caution. A plausible explanation for the magnitude of the differences seen in these studies is that, despite the process of randomization, there may have been an imbalance of prognostic factors between the arms. In the Barcelona study, it was demonstrated that the group of patients randomized to surgery alone included a higher fraction of tumors with the more virulent characteristics of K-ras mutations (42% vs 15%, respectively) and DNA aneuploidy (70% vs 29%, respectively).39 43 Hence, it is possible that an excess of biologically virulent tumors in the group randomized to surgery alone in the Barcelona study is responsible for the observed outcome differences rather than a beneficial effect of the induction chemotherapy itself. While there is no direct evidence for a similar imbalance in the MD Anderson Cancer Center trial, prognostically important molecular markers were not considered in this study. Possibly, an imbalance of some unmeasured prognostic variable might have contributed to the magnitude of the differences seen in this trial.

Cumulatively, these four phase III studies evaluating the role of induction chemotherapy followed by surgery have included a total of only 204 patients. The results are surprising and conflicting. Accordingly, the benefit of induction chemotherapy, although suggested, has not been definitively demonstrated. The 11 phase II studies listed in Table 2 include 781 patients. While the results of these trials vary, there is greater consistency in the results of the phase II trials than of the randomized trials.


   Conclusion
TOP
 Abstract
 Introduction
 Ongoing Trials of Adjuvant...
 Role of Induction Chemotherapy...
 Conclusion
References
 
Despite the limitations of the randomized induction chemotherapy and surgery trials in stage IIIA NSCLC, the results of these trials lend some support to the conclusion that for favorable patients with stage IIIA NSCLC, induction chemotherapy followed by resection (with or without RT) may enhance disease outcome compared with that achieved with resection (with or without RT). While the magnitude of the survival advantages added by chemotherapy are very likely to have been exaggerated, particularly in the MD Anderson Cancer Center trial, numerous phase II trimodality studies support a similar conclusion, though with a modest degree of effectiveness. In addition, these results for induction chemotherapy with surgery are consistent with numerous phase III studies that have demonstrated that induction chemotherapy with definitive RT improves outcome when compared with thoracic RT alone.

Whether induction chemotherapy is now the standard therapy is debatable, but there is a clear suggestion of benefit, and additional clinical trials evaluating this approach will be difficult to accomplish. The role of resection in stage IIIA disease remains unproved, but local control appears improved in multimodality programs that include resection, and patients found to have negative N2 nodes at resection do quite well. A phase III trial designed to evaluate the efficacy of surgical resection in the context of induction chemoradiation in stage IIIA NSCLC is currently ongoing by several cooperative groups under the leadership of the Southwest Oncology Group. Conventional RT approaches are probably not optimal.

The recent results of both phase III and phase II trials provide a basis for optimism that real therapeutic progress is finally being achieved in regionally advanced NSCLC. Further study of therapeutic strategies that incorporate aggressive systemic treatment and maximal local-regional therapy in stage III NSCLC is clearly warranted.


   Footnotes
 
Abbreviations: CALGB = Cancer and Leukemia Group B; CAP = cyclophosphamide, doxorubicin, and cisplatin; LCSG = Lung Cancer Study Group; NSCLC = non-small cell lung cancer; RT = radiation therapy


   References
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 Abstract
 Introduction
 Ongoing Trials of Adjuvant...
 Role of Induction Chemotherapy...
 Conclusion
 References
 

  1. Mountain, CF (1986) A new international staging system for lung cancer. Chest 89(suppl),225S-233S[Free Full Text]
  2. Mountain, CF (1997) Revisions in the International System for Staging Lung Cancer. Chest 111,1710-1717[Abstract/Free Full Text]
  3. Feld, R, Rubenstein, LV, Weisenberger, TH (1984) Sites of recurrence in resected stage I non-small-cell lung cancer: a guide for future studies. J Clin Oncol 2,1352-1358[Abstract]
  4. Immerman, SC, Vanecko, RM, Fry, WA, et al (1981) Site of recurrence in patients with stages I and II carcinoma of the lung resected for cure. Ann Thorac Surg 32,23-27[Abstract]
  5. Lad, TE (1990) Postsurgical adjuvant therapy in stages I, II, and IIIA non-small cell lung cancer. Hematol Oncol Clin North Am 4,1111-1119[ISI][Medline]
  6. Holmes, EC (1993) Postoperative chemotherapy for non-small cell lung cancer. Chest 103(suppl),30S-34S[Abstract/Free Full Text]
  7. Holmes, EC, Gail, M (1986) Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large-cell undifferentiated carcinoma. J Clin Oncol 4,710-715[Abstract/Free Full Text]
  8. Lad, T, Rubinstein, L, Sadeghi, A (1988) The benefit of adjuvant treatment for resected locally advanced non-small-cell lung cancer. J Clin Oncol 6,9-17[Abstract]
  9. Feld, R, Rubinstein, L, Thomas, PA (1993) Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non-small cell lung cancer. J Natl Cancer Inst 85,299-306[Abstract/Free Full Text]
  10. Niranen, A, Niitamo-Korhonen, S, Kouri, M, et al (1992) Adjuvant chemotherapy after radical surgery for non-small-cell lung cancer: a randomized study. J Clin Oncol 10,1927-1932[Abstract]
  11. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 1995; 311:899–911
  12. Feld, R (1996) Chemotherapy as adjuvant therapy for completely resected non-small cell lung cancer: have we made progress? J Clin Oncol 14,1045-1047[Free Full Text]
  13. Mountain, CF (1988) Prognostic implications of the international staging system for lung cancer. Semin Oncol 15,236-245[ISI][Medline]
  14. Mountain, CF (1989) Value of the new TNM staging system for lung cancer. Chest (suppl); 96,47S-49S[Free Full Text]
  15. Mountain, CF, Greenburg, SD, Fraire, AE (1991) Tumor stage in non-small cell carcinoma of the lung. Chest 99,1258-1260[Free Full Text]
  16. Green, MR (1994) Multimodality therapy for solid tumors. N Engl J Med 330,206-207[Free Full Text]
  17. Dillman, RO, Seagren, S, Propert, K, et al (1990) A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small cell lung cancer. N Engl J Med 323,940-945[Abstract]
  18. Dillman, RO, Herndon, J, Seagren, SL, et al (1996) Improved survival in stage III non-small cell lung cancer: seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst 88,1210-1215[Abstract/Free Full Text]
  19. Sause, W, Scott, C, Taylor, S, et al (1995) Radiation Therapy Oncology Group (RTOG) 88–08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small cell lung cancer. J Natl Cancer Inst 87,198-205[Abstract/Free Full Text]
  20. Cox, JD, Azarnia, N, Byhardt, RW, et al (1990) A randomized phase I-II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with > 69.6 Gy in favorable patients with radiation therapy oncology group stage III non-small cell lung carcinoma: report of radiation therapy oncology group 83–11 J Clin Oncol 8,1543-1555[Abstract]
  21. Le Chevalier, T, Arriagada, R, Quoiz, E, et al (1991) Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 83,417-423[Abstract/Free Full Text]
  22. Le Chevalier, T, Arriagada, R, Tarayre, M, et al (1992) Correspondence-significant effect of adjuvant chemotherapy on survival in locally advanced non-small cell lung carcinoma [letter]. J Natl Cancer Inst 84,58[Free Full Text]
  23. Schaake-Koning, C, Van Den Bogaert, W, Dalesio, O, et al (1992) Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 326,524-530[Abstract]
  24. Pritchard, RS, Anthony, SP (1996) Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small cell lung cancer. Ann Intern Med 125,723-729[Abstract/Free Full Text]
  25. Green, MR (1995) Multimodality therapy in unresected stage III non-small cell lung cancer: the American Cooperative Groups’ experience. Lung Cancer 12(suppl 1),S87-S94
  26. Skarin, A, Jochelson, M, Sheldon, T, et al (1989) Neoadjuvant chemotherapy in marginally resectable stage III M0 non-small cell lung cancer: long-term follow-up in 41 patients. J Surg Oncol 40,266-274[ISI][Medline]
  27. Elias, AD, Skarin, AT, Gonin, P, et al (1994) Neoadjuvant treatment of stage IIIA non-small cell lung cancer: long-term results. Am J Clin Oncol 17,26-36[ISI][Medline]
  28. Elias, AD, Skarin, AT, Leong, T, et al (1997) Neoadjuvant therapy for surgically staged IIIA N2 non-small cell lung cancer (NSCLC). Lung Cancer 17,147-161[CrossRef][ISI][Medline]
  29. Strauss, GM, Herndon, JE, Sherman, DD, et al (1992) Neoadjuvant chemotherapy and radiotherapy followed by surgery in stage IIIA non-small cell carcinoma of the lung: report of a Cancer and Leukemia Group B phase II study. J Clin Oncol 10,1237-1244[Abstract/Free Full Text]
  30. Sugarbaker, DJ, Herndon, J, Kohman, LJ, et al (1995) Results of Cancer and Leukemia Group B Protocol 8935: a multiinstitutional phase II trimodality trial for stage IIIA (N2) non-small cell lung cancer. J Thorac Cardiovasc Surg 109,473-485[Abstract/Free Full Text]
  31. Choi, NC, Carey, RW, Daly, W, et al (1997) Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small cell lung cancer. J Clin Oncol 15,712-722[Abstract/Free Full Text]
  32. Martini, N, Kris, M, Fhelinger, B, et al (1993) Preoperative chemotherapy for stage IIIA (N2) lung cancer: the Sloan-Kettering experience with 136 patients. Ann Thorac Surg 55,1365-1374[Abstract]
  33. Burkes, RL, Ginsberg, RJ, Sheperd, FA, et al (1992) Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage III unresectable non-small cell lung cancer: results of a Toronto phase II trial. J Clin Oncol 10,580-586[Abstract/Free Full Text]
  34. Reddy, S, Lee, MS, Bonomi, P, et al (1992) Combined modality therapy for stage III non-small cell lung cancer: results of treatment sand patterns of failure. Int J Radiat Oncol Biol Phys 24,17-32[ISI][Medline]
  35. Weiden, P, Piantadosi, S (1991) Preoperative chemotherapy (cisplatin and flourouracil) and radiation therapy in stage III non-small cell lung cancer: a phase II study of the Lung Cancer Study Group. J Natl Cancer Inst 83,266-272[Abstract/Free Full Text]
  36. Albain, DK, Rusch, VW, Crowley, JJ, et al (1995) Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 13,1880-1892[Abstract/Free Full Text]
  37. Perez, CA, Bauer, M, Edelstein, S, et al (1986) Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int J Radiat Oncol Biol Phys 12,539-547[ISI][Medline]
  38. Jeremic, B, Shibamoto, Y, Acimovic, L, et al (1995) Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small cell lung cancer. J Clin Oncol 13,452-458[Abstract/Free Full Text]
  39. Rosell, R, Gomez-Codina, J, Camps, C, et al (1994) A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer. N Engl J Med 330,153-158[Abstract/Free Full Text]
  40. Roth, JA, Fossella, F, Komaki, R, et al (1994) A randomized trial comparing preoperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small cell lung cancer. J Natl Cancer Inst 86,673-680[Abstract/Free Full Text]
  41. Pass, HI, Pogrebnick, HW, Steinberg, SM, et al (1992) Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 53,992-998[Abstract]
  42. Elias, AD, Herndon, J, Kumar, P, et al (1997) A phase III comparison of "best local-regional therapy" with or without chemotherapy for stage IIIA T1–3N2 non-small cell lung cancer (NSCLC): preliminary results [abstract]. Proc Am Soc Clin Oncol Annu Meet 16,448a
  43. Rosell, A, Font, A, Pitfarre, A, et al (1996) The role of induction (neoadjuvant) chemotherapy in stage IIIA NSCLC. Chest 109(suppl),102S-106S[Medline]
  44. Strauss, GM, Herndon, JE, Sherman, DD, et al (1996) Induction chemoradiation followed by surgery in stage IIIA non-small cell carcinoma of the lung (NSCLC): long term results of Cancer and Leukemia Group B protocol 8634 [abstract]. Proc Am Soc Clin Oncol Annu Meet 15,376
  45. Kumar, P, Herndon, J, Langer, M, et al (1996) Patterns of disease failure after trimodality therapy of non-small cell lung carcinoma pathologic stage IIIA (N2). Cancer 77,2393-2399[CrossRef][ISI][Medline]



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