- Email: [email protected]
Induction therapy for stage III lung cancer
Lung Cancer (2003) 42, S53—S57
CONFERENCE
Induction therapy for stage III lung cancer KEYWORDS Lung cancer; Stage III; Surgery; Radiation; Chemotherapy; Staging
1. Introduction Treatment of stage III non-small cell lung cancer (NSCLC) is perhaps the most controversial area in lung cancer therapy today. Nowhere else do the three major treatment modalities, surgery, radiation and chemotherapy, all play prominent roles in therapeutic decision making. This paper discusses the historical role of surgery in patients with stage III disease and the recently evolving paradigm of induction therapy preceeding surgical resection in selected patients. First, some general observations regarding surgery as a sole therapy, the important role of clinical staging, inconsistencies in assessing a response to therapy and the surprising mortality and morbidity figures associated with our increasingly aggressive therapies. These observations are a prelude to a surgical perspective of induction therapy. Although initiated as a treatment strategy for stage IIIA disease, induction therapy is now touted as an improved treatment for both stage IIIA and certain stage IIIB lung cancers. Thus, this discussion of induction therapy includes its use in mediastinal nodal disease and extra-pulmonary primary tumor invasion. Surgeons see and experience lung cancer differently than their medical and radiation oncology colleagues. Perhaps it is the in-person visual and tactile perspective that brings an extra dimension to the disease, which is over and above the shadowy appearances seen on X-rays and scans. We are confronted in the operating room with a real-time 0169-5002/$ – see front matter doi:10.1016/j.lungcan.2003.08.012
challenge that pits our surgical skills with the anatomic nuances of a highly invasive and destructive neoplasm. The end results, formerly measured in morbidity, mortality and ultimate cure rate, now also include cost, length of stay and economic measures of case complexity. Often lost in this tour de force is an understanding and appreciation of lung cancer’s complex biology that, unfortunately, is usually the final arbiter of the fate of the patient. In an effort to bring the daunting wonders of lung cancer biology down to a clinically digestible size, consider treatment strategies in relation to two well recognized characteristics, or phenotypes, of the disease: its ability to grow and invade contiguous structures (the invasive phenotype), and its propensity to spread (the metastatic phenotype). Unquestionably more complex and convoluted than presented here, it is enticing to think of each phenotype controlled by its own set of gene mutations, deletions and the like. Therefore, each phenotype represents a separate clinical entity to be addressed.
2. General observations Since we do not do well in curing lung cancer, we might as well spend our time defining it better. And that we have. The result is an ever increasing accuracy in dividing, splitting and sub-splitting characteristics of the disease in an effort to accurately prognosticate, and subsequently treat the
S54 patient. The universally accepted staging system with its imperfect, but practical, lymph node map is the envy of other cancer disease sites. Testing the system with a million or so patients a year also helps. Our staging system categorizes patients based on highly refined, yet imprecise, radiologic and pathologic techniques. We devise and execute our treatment plans based on this inherent imprecision. Molecular-based staging is in its infancy, but may offer a considerable advantage over our present methods. Until then, an integral part of clinical staging is the carefully defined sampling of mediastinal lymph nodes using the mediastinascope. Although CT scanning, and more recently PET scanning, have emerged as valuable tools in evaluating mediastinal involvement, neither possess the positive predictive value to supplant mediastinoscopy as the gold standard for staging the mediastinum [1]. Stages I and II NSCLC are best treated by surgical resection. Few would quibble with that. The recent accent of T3N0 tumors to the surgical perview of stage II reinforces this tenet. But what about stage III? The survival curves neatly divide it into IIIA and IIIB, but, perhaps as important, is the surgical practicality of resecting versus not resecting. As it turns out, if we pick our patients very carefully, two particular situations in stage IIIA are reasonably well treated with surgery alone. The Lung Cancer Study Group (LCSG) showed that patients with nodal metastases only to the ipsilateral low mediastinum have a 5 year survival approaching 40% [2]. Similarly, Patterson, in reviewing the Toronto experience with resection of left sided lung cancers and spread only to the aorto-pulmonary window lymph nodes, found a 42% survival at 5 years [3].
3. The metastatic phenotype But these situations are the exception. Most patients with IIIA disease recur following surgery, although relatively few recur locally, that is, at the operative site. The bulk of patients develop recurrences at a distance from the primary tumor, implying systemic metastasis. This is particularly true for stage IIIA disease, as illustrated by Pisters (Table 1) [4]. Thus, in tumors that have demonstrated the metastatic phenotype by mediastinal nodal involvement, consideration of systemic therapy is appropriate. Additional local therapy to the primary tumor site in the form of external beam radiation also needs to be considered. Post-operative adjuvant chemotherapy is not advantageous for patients with stage IIIA disease. This has most recently been demonstrated in a
Conference
Table 1 NSCLC: Relapse pattern Stage
Chest (%)
Distant (%)
Stage I T1N0 T2N0
10 10
15 30
Stage II T1-2N1
12
40
Stage IIIa N2
15
60
large randomized study reported by Keller [5]. The LCSG showed that adjuvant radiation improved local control, but not overall survival [6]; the PORT meta-analysis suggested that radiation may even be detrimental [7]. Clearly, post-operative treatment is not the answer. Based on experience at other disease sites (namely head and neck malignancies) and a plethora of phase 2 studies, neo-adjuvant, or induction, therapy has come under intense scrutiny for stage IIIA disease. The early trials set the stage for the highly controversial phase 3 studies that were to follow. For instance, for the first time we could actually measure pathologically the response to induction therapy. Since all patients received chemotherapy, radiation, or in some instances, both prior to surgery, the effects of these treatments were documented by examination of the resected specimen. Not only did we find that complete pathologic responders fared the best, but also that the clinical response as measured by preand post-induction therapy CT imaging showed no correlation with the ultimate post-operative pathologic response [8]. A resected tumor that showed no or minimal response to induction therapy radiographically may contain only fibrotic and necrotic material. Conversely, patients with a complete clinical response could have microscopic, or even gross residual tumor at surgery. This remains true today, despite better scanners and new technologies [9]. The consequence of these observations is that patients no longer need a documented radiographic response to induction therapy before, being considered for surgical resection. Only progressive disease contraindicates surgery. Those of us who resected these patients following various induction therapies thought that post-operative mortality was bound to increase. We were wrong. The ‘‘gold standard’’ for mortality figures following resection of 2200 lung cancers by LCSG surgeons was reported by Ginsberg [10]. The results are not appreciably different than 241
Induction therapy for stage III lung cancer
Table 2 Treatment-related mortality Surgery alone (LCSG: 2200 patients) 3% Lobectomy 6% Pneumonectomy Induction therapy (241 pt. In phase II trials) 4.1% All resections
resections reported in eight early phase 2 trials (Table 2). Subsequent phase 3 trials have confirmed the safety of performing these often difficult resections after induction therapy, although the morbidity may be increased in some of the more complex resections [11,12]. The two landmark phase 3 studies of induction therapy were reported by Roth and Rosell [13,14]. Updates of both studies were published in this journal and still show survival advantages for the cohorts that received induction chemotherapy. Despite the small number of patients in each study and apparent inequities between treatment arms, induction therapy became firmly entrenched in the lung oncology community. However, doubts as to its true efficacy remain. Two randomized trials cut short by the publication of the Roth and Rosell studies failed to corroborate the benefit of induction chemotherapy followed by surgery [13,14]. The National Cancer Institute of Canada randomized 31 patients with stage IIIA NSCLC to induction chemotherapy (cisplatin and vinblastine) followed by surgery versus radiation [15]. At 30 months, survival was no different between the two study arms. A trial of 73 patients by the Radiation Therapy Oncology Group compared chemotherapy and surgery with chemotherapy and radiation (64 Gy). Both arms received two cycles of MVP or VP up front. Results at 4 years show no difference in overall survival or local control [16]. More disturbing, however, is a study by the French Thoracic Cooperative Group reported by Depierre [11]. 355 patients with stages IB, II or IIIA NSCLC were randomized to either surgery alone or two to four cycles of MIP followed by surgery. In the entire group, disease free survival was significantly prolonged with induction chemotherapy (13 months versus 27 months), but median survival was not (26 months versus 37 months, P = 0.15). When survival was analyzed by nodal status, the advantage of induction chemotherapy was seen only in the patients with N0 or N1 disease. There was no significant difference in those with N2 disease (RR 1.04, P = 0.85). Although widely practiced, induction chemotherapy and surgery for stage IIIA lung cancer still must
S55 be considered an unproven treatment until further data emerges. That data is close at hand. A number of phase 3 studies are nearing completion or in follow-up. These include the large North American Intergroup study of radiation (45 Gy) plus concurrent PE chemotherapy followed by surgery versus radiation (60 Gy) plus concurrent PE alone. Preliminary results should be available later this year.
4. The invasive phenotype T3 and T4 lung cancers have at least two traits in common–—they invade into structures in close proximity to the lung and this invasion does not necessarily imply the presence of nodal or systemic disease, i.e. the metastatic phenotype. Historically, the major difference between the two has been the ability to surgically resect these tumors in their entirety, T3 representing the resectable tumor and T4 unresectable. With improvements in peri-operative and intra-operative management, better tools and the emergence of highly skilled thoracic surgical oncologists, the line between resectable and unresectable has blurred. The surgical literature is now replete with ever enlarging series of patients undergoing resection of T4 NSCLC. At many centers invasion of the primary tumor into left atrium, superior vena cava, tracheal carina, brachial plexus, subclavian artery or vein and vertebral body are not considered contraindications for resection [17]. Although morbidity and mortality rates are higher than more common lung cancer resections, survival rates are better than expected for stage IIIB disease in general. As with T3 tumors, negative nodes and negative margins are the key survival factors. Perhaps the prototype of a lung cancer that exhibits the invasive phenotype is the superior sulcus, or Pancoast, tumor. This lesion at the apex of the lung tends to invade directly into the myriad of structures encompassed within the thoracic outlet. It has been recognized for years that obtaining adequate surgical margins when resecting these lesions is a difficult and often morbid undertaking. Also recognized, although never put to a comparative trial, is the role of pre-operative radiotherapy in improving local control. Paulson’s report of a 43% 5 year survival rate in 56 patients with node negative superior sulcus tumors resected following radiotherapy (30 Gy) established induction therapy as the standard of care for these challenging tumors [18]. A recent North American Intergroup study further strengthens the role of induction therapy. In a phase 2 study, 111 patients with T3 or T4, N0 or
S56 N1, M0 superior sulcus tumors were treated with 2 cycles of PE and 45 Gy of concurrent radiotherapy [19]. Total of 83 patients who did not progress during induction therapy, went on to surgical resection, with 53 of these patients receiving two more cycles of chemotherapy. The overall survival rate at 2 years is about 55% and the median has not yet been reached. Resected patients did even better, with 70% survival at 2 years and, of particular interest, T3 tumors did no better than T4. The only randomized study never completed by the Lung Cancer Study Group due to poor accrual involved adjuvant radiation for T3 tumors. Resection of T4 lung cancers is less common and even more selective. A phase 3 study of induction therapy in the foreseeable future is highly unlikely. A number of phase 2 studies of T4 tumors resected after induction therapy, however, also report impressive survival rates, especially when N2 nodes are not involved [20—22].
5. Conclusion In NSCLC induction therapy prior to surgery is here to stay. What form it takes, what drugs and dosages to use, whether single modality, concurrent or sequential, are all still to be sorted out. Perhaps even more intriguing is the question of what stage or stages of disease will most benefit from this combination of therapies. At this point in time, the case for induction therapy may actually be stronger when dealing with the invasive phenotype rather than the metastatic phenotype.
References [1] Graeter TP, Hellwig D, Hoffman K, Ukena D, Kirsch CM, Schafers HJ. Mediastinal lymph node staging in suspected lung cancer: comparison of positron emission tomography with F-18-fluorodeoxyglucose and mediastinoscopy. Ann Thorac Surg 2003;75(1):231—6. [2] Thomas PA, Piantadosi S, Mountain CF. The Lung Cancer Study Group. Should subcarinal lymph nodes be routinely examined in patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 1988;95(5):883—7. [3] Patterson GA, Piazza D, Pearson FG, Todd TR, Ginsberg RJ, Goldberg M, et al. Significance of metastatic disease in subaortic lymph nodes. Ann Thorac Surg 1987;43(2):155—9. [4] Pisters K. Multidisciplinary management of early lung cancer. ASCO Annual Meeting 2002. [5] Keller SM, Adak S, Wagner H, Herskovic A, Komaki R, Brooks BJ, et al. for the The Eastern Cooperative Oncology Group. A randomized trial of postoperative adjuvant therapy in patient with completely resected stage II or IIIA non-small-cell lung cancer. N Engl J Med 2000;343(17):1217—22.
Conference [6] Weisenberger TH, Gail M. The Lung Cancer Study Group. Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N Eng J Med 1986;315:1377—81. [7] PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small cell-lung cancer: systemic review and meta-analysis of individual patient data from nine randomized controlled trials. Lancet 1998;352: 257—63. [8] Faber LP, Kittle CF, Warren WH, Bonomi PD, Taylor IV SG, Reddy S, et al. Preoperative chemotherapy and irradiation for stage III non-small cell lung cancer. Ann Thorac Surg 1989;47:669—77. [9] Akhurst T, Downey RJ, Ginsberg MS, Gonen M, Bains M, Korst R, et al. An initial experience with FDG-PET in the imaging of residual disease after induction therapy for lung cancer. Ann Thorac Surg 2002;73(1):259—64. [10] Ginsberg RJ, Hill LD, Eagan RT, Thomas P, Mountain CF, Deslauriers J, et al. Modern thirty-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 1983;86(5):654—8. [11] Depierre A, Milleron B, Moro-Sibilot D, Chevret S, Quoix E, Lebeau B, et al. French Thoracic Cooperative Group. Preoperative chemotherapy followed by surgery compared with primary surgery in respectable stage I (except T1N0), II, and IIIA non-small-cell lung cancer. J Clin Onc 2002;20(1):247—53. [12] Roberts JR, Eustis C, Devore R, Carbone D, Choy H, Johnson D. Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung cancer. Ann Thorac Surg 2001;72:885—8. [13] Roth JA, Atkinson EN, Fossella F, Komaki R, Bernadette RM, Putnam Jr JB, et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in respectable stage IIIA non-small cell lung cancer. Lung Cancer 1998;21(1):1—6. [14] Rosell R, Gomez-Codina J, Camps C, Javier Sanchez J, Maestre J, Padilla J, et al. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer; a 7-year assessment of a randomized controlled trial. Lung Cancer 1999;26(1):7—14. [15] Shepherd FA, Johnston MR, Payne D, Burkes R, Deslauriers J, Cormier Y, et al. Randomized study of chemotherapy and surgery versus radiotherapy for stage IIIA non-small-cell lung cancer: a National Cancer Institute of Canada Clinical Trials Group Study. Br J Cancer 1998;78(5): 683—5. [16] Johnstone DW, Byhardt RW, Ettinger D, Scott CB. Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2002;54(2):365—9. [17] Pastorino U. Extended resections for lung cancer: indications and results. Surg Oncol 2002;11(4):207—16. [18] Paulson DL. Technical considerations in stage III disease: the ‘‘superior sulcus’’ lesion. In: Delarue NC, Eschapasse H, editors. International trends in general surgery. Philadelphia, PA: W.B. Saunders; 1985. p. 121—131. [19] Rusch VW, Giroux DJ, Kraut MR, Crowley J, Hazuka M, Johnson D, et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 2001;121(3):472—83.
Induction therapy for stage III lung cancer [20] Albain KS, Rusch VW, Crowley JJ, Rice TW, Turrisi 3rd AT, Weick JK, et al. 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 1995;13(8):1880—92. [21] Grunenwald DH, Andre F, Pechoux CL, Girard P, Lamer C, Laplache A, et al. Benefit of surgery after chemoradiatiotherapy in stage IIIB (T4 and/or N3) non-small cell lung cancer. J Thorac Cardiovasc Surg 2001;122(4):796—802. [22] Stamatis G, Eberhardt W, Stuben G, Bildat S, Dahler O, Hillejan L. Preoperative chemoradiotherapy and surgery
S57 for selected non-small cell lung cancer IIIB subgroups: long-term results. Ann Thorac Surg 1999;68(4):1144—9.
Michael R. Johnston, (MD, FRCSC) University of Toronto, Toronto General Hospital 200 Elizabeth Street, Suite 10 EN-230 Toronto, Ont., Canada M5G 2C4 Tel.: +1-416-340-3838; fax: +1-416-340-3660 E-mail address: [email protected] (M.R. Johnston)
CONFERENCE
Induction therapy for stage III lung cancer KEYWORDS Lung cancer; Stage III; Surgery; Radiation; Chemotherapy; Staging
1. Introduction Treatment of stage III non-small cell lung cancer (NSCLC) is perhaps the most controversial area in lung cancer therapy today. Nowhere else do the three major treatment modalities, surgery, radiation and chemotherapy, all play prominent roles in therapeutic decision making. This paper discusses the historical role of surgery in patients with stage III disease and the recently evolving paradigm of induction therapy preceeding surgical resection in selected patients. First, some general observations regarding surgery as a sole therapy, the important role of clinical staging, inconsistencies in assessing a response to therapy and the surprising mortality and morbidity figures associated with our increasingly aggressive therapies. These observations are a prelude to a surgical perspective of induction therapy. Although initiated as a treatment strategy for stage IIIA disease, induction therapy is now touted as an improved treatment for both stage IIIA and certain stage IIIB lung cancers. Thus, this discussion of induction therapy includes its use in mediastinal nodal disease and extra-pulmonary primary tumor invasion. Surgeons see and experience lung cancer differently than their medical and radiation oncology colleagues. Perhaps it is the in-person visual and tactile perspective that brings an extra dimension to the disease, which is over and above the shadowy appearances seen on X-rays and scans. We are confronted in the operating room with a real-time 0169-5002/$ – see front matter doi:10.1016/j.lungcan.2003.08.012
challenge that pits our surgical skills with the anatomic nuances of a highly invasive and destructive neoplasm. The end results, formerly measured in morbidity, mortality and ultimate cure rate, now also include cost, length of stay and economic measures of case complexity. Often lost in this tour de force is an understanding and appreciation of lung cancer’s complex biology that, unfortunately, is usually the final arbiter of the fate of the patient. In an effort to bring the daunting wonders of lung cancer biology down to a clinically digestible size, consider treatment strategies in relation to two well recognized characteristics, or phenotypes, of the disease: its ability to grow and invade contiguous structures (the invasive phenotype), and its propensity to spread (the metastatic phenotype). Unquestionably more complex and convoluted than presented here, it is enticing to think of each phenotype controlled by its own set of gene mutations, deletions and the like. Therefore, each phenotype represents a separate clinical entity to be addressed.
2. General observations Since we do not do well in curing lung cancer, we might as well spend our time defining it better. And that we have. The result is an ever increasing accuracy in dividing, splitting and sub-splitting characteristics of the disease in an effort to accurately prognosticate, and subsequently treat the
S54 patient. The universally accepted staging system with its imperfect, but practical, lymph node map is the envy of other cancer disease sites. Testing the system with a million or so patients a year also helps. Our staging system categorizes patients based on highly refined, yet imprecise, radiologic and pathologic techniques. We devise and execute our treatment plans based on this inherent imprecision. Molecular-based staging is in its infancy, but may offer a considerable advantage over our present methods. Until then, an integral part of clinical staging is the carefully defined sampling of mediastinal lymph nodes using the mediastinascope. Although CT scanning, and more recently PET scanning, have emerged as valuable tools in evaluating mediastinal involvement, neither possess the positive predictive value to supplant mediastinoscopy as the gold standard for staging the mediastinum [1]. Stages I and II NSCLC are best treated by surgical resection. Few would quibble with that. The recent accent of T3N0 tumors to the surgical perview of stage II reinforces this tenet. But what about stage III? The survival curves neatly divide it into IIIA and IIIB, but, perhaps as important, is the surgical practicality of resecting versus not resecting. As it turns out, if we pick our patients very carefully, two particular situations in stage IIIA are reasonably well treated with surgery alone. The Lung Cancer Study Group (LCSG) showed that patients with nodal metastases only to the ipsilateral low mediastinum have a 5 year survival approaching 40% [2]. Similarly, Patterson, in reviewing the Toronto experience with resection of left sided lung cancers and spread only to the aorto-pulmonary window lymph nodes, found a 42% survival at 5 years [3].
3. The metastatic phenotype But these situations are the exception. Most patients with IIIA disease recur following surgery, although relatively few recur locally, that is, at the operative site. The bulk of patients develop recurrences at a distance from the primary tumor, implying systemic metastasis. This is particularly true for stage IIIA disease, as illustrated by Pisters (Table 1) [4]. Thus, in tumors that have demonstrated the metastatic phenotype by mediastinal nodal involvement, consideration of systemic therapy is appropriate. Additional local therapy to the primary tumor site in the form of external beam radiation also needs to be considered. Post-operative adjuvant chemotherapy is not advantageous for patients with stage IIIA disease. This has most recently been demonstrated in a
Conference
Table 1 NSCLC: Relapse pattern Stage
Chest (%)
Distant (%)
Stage I T1N0 T2N0
10 10
15 30
Stage II T1-2N1
12
40
Stage IIIa N2
15
60
large randomized study reported by Keller [5]. The LCSG showed that adjuvant radiation improved local control, but not overall survival [6]; the PORT meta-analysis suggested that radiation may even be detrimental [7]. Clearly, post-operative treatment is not the answer. Based on experience at other disease sites (namely head and neck malignancies) and a plethora of phase 2 studies, neo-adjuvant, or induction, therapy has come under intense scrutiny for stage IIIA disease. The early trials set the stage for the highly controversial phase 3 studies that were to follow. For instance, for the first time we could actually measure pathologically the response to induction therapy. Since all patients received chemotherapy, radiation, or in some instances, both prior to surgery, the effects of these treatments were documented by examination of the resected specimen. Not only did we find that complete pathologic responders fared the best, but also that the clinical response as measured by preand post-induction therapy CT imaging showed no correlation with the ultimate post-operative pathologic response [8]. A resected tumor that showed no or minimal response to induction therapy radiographically may contain only fibrotic and necrotic material. Conversely, patients with a complete clinical response could have microscopic, or even gross residual tumor at surgery. This remains true today, despite better scanners and new technologies [9]. The consequence of these observations is that patients no longer need a documented radiographic response to induction therapy before, being considered for surgical resection. Only progressive disease contraindicates surgery. Those of us who resected these patients following various induction therapies thought that post-operative mortality was bound to increase. We were wrong. The ‘‘gold standard’’ for mortality figures following resection of 2200 lung cancers by LCSG surgeons was reported by Ginsberg [10]. The results are not appreciably different than 241
Induction therapy for stage III lung cancer
Table 2 Treatment-related mortality Surgery alone (LCSG: 2200 patients) 3% Lobectomy 6% Pneumonectomy Induction therapy (241 pt. In phase II trials) 4.1% All resections
resections reported in eight early phase 2 trials (Table 2). Subsequent phase 3 trials have confirmed the safety of performing these often difficult resections after induction therapy, although the morbidity may be increased in some of the more complex resections [11,12]. The two landmark phase 3 studies of induction therapy were reported by Roth and Rosell [13,14]. Updates of both studies were published in this journal and still show survival advantages for the cohorts that received induction chemotherapy. Despite the small number of patients in each study and apparent inequities between treatment arms, induction therapy became firmly entrenched in the lung oncology community. However, doubts as to its true efficacy remain. Two randomized trials cut short by the publication of the Roth and Rosell studies failed to corroborate the benefit of induction chemotherapy followed by surgery [13,14]. The National Cancer Institute of Canada randomized 31 patients with stage IIIA NSCLC to induction chemotherapy (cisplatin and vinblastine) followed by surgery versus radiation [15]. At 30 months, survival was no different between the two study arms. A trial of 73 patients by the Radiation Therapy Oncology Group compared chemotherapy and surgery with chemotherapy and radiation (64 Gy). Both arms received two cycles of MVP or VP up front. Results at 4 years show no difference in overall survival or local control [16]. More disturbing, however, is a study by the French Thoracic Cooperative Group reported by Depierre [11]. 355 patients with stages IB, II or IIIA NSCLC were randomized to either surgery alone or two to four cycles of MIP followed by surgery. In the entire group, disease free survival was significantly prolonged with induction chemotherapy (13 months versus 27 months), but median survival was not (26 months versus 37 months, P = 0.15). When survival was analyzed by nodal status, the advantage of induction chemotherapy was seen only in the patients with N0 or N1 disease. There was no significant difference in those with N2 disease (RR 1.04, P = 0.85). Although widely practiced, induction chemotherapy and surgery for stage IIIA lung cancer still must
S55 be considered an unproven treatment until further data emerges. That data is close at hand. A number of phase 3 studies are nearing completion or in follow-up. These include the large North American Intergroup study of radiation (45 Gy) plus concurrent PE chemotherapy followed by surgery versus radiation (60 Gy) plus concurrent PE alone. Preliminary results should be available later this year.
4. The invasive phenotype T3 and T4 lung cancers have at least two traits in common–—they invade into structures in close proximity to the lung and this invasion does not necessarily imply the presence of nodal or systemic disease, i.e. the metastatic phenotype. Historically, the major difference between the two has been the ability to surgically resect these tumors in their entirety, T3 representing the resectable tumor and T4 unresectable. With improvements in peri-operative and intra-operative management, better tools and the emergence of highly skilled thoracic surgical oncologists, the line between resectable and unresectable has blurred. The surgical literature is now replete with ever enlarging series of patients undergoing resection of T4 NSCLC. At many centers invasion of the primary tumor into left atrium, superior vena cava, tracheal carina, brachial plexus, subclavian artery or vein and vertebral body are not considered contraindications for resection [17]. Although morbidity and mortality rates are higher than more common lung cancer resections, survival rates are better than expected for stage IIIB disease in general. As with T3 tumors, negative nodes and negative margins are the key survival factors. Perhaps the prototype of a lung cancer that exhibits the invasive phenotype is the superior sulcus, or Pancoast, tumor. This lesion at the apex of the lung tends to invade directly into the myriad of structures encompassed within the thoracic outlet. It has been recognized for years that obtaining adequate surgical margins when resecting these lesions is a difficult and often morbid undertaking. Also recognized, although never put to a comparative trial, is the role of pre-operative radiotherapy in improving local control. Paulson’s report of a 43% 5 year survival rate in 56 patients with node negative superior sulcus tumors resected following radiotherapy (30 Gy) established induction therapy as the standard of care for these challenging tumors [18]. A recent North American Intergroup study further strengthens the role of induction therapy. In a phase 2 study, 111 patients with T3 or T4, N0 or
S56 N1, M0 superior sulcus tumors were treated with 2 cycles of PE and 45 Gy of concurrent radiotherapy [19]. Total of 83 patients who did not progress during induction therapy, went on to surgical resection, with 53 of these patients receiving two more cycles of chemotherapy. The overall survival rate at 2 years is about 55% and the median has not yet been reached. Resected patients did even better, with 70% survival at 2 years and, of particular interest, T3 tumors did no better than T4. The only randomized study never completed by the Lung Cancer Study Group due to poor accrual involved adjuvant radiation for T3 tumors. Resection of T4 lung cancers is less common and even more selective. A phase 3 study of induction therapy in the foreseeable future is highly unlikely. A number of phase 2 studies of T4 tumors resected after induction therapy, however, also report impressive survival rates, especially when N2 nodes are not involved [20—22].
5. Conclusion In NSCLC induction therapy prior to surgery is here to stay. What form it takes, what drugs and dosages to use, whether single modality, concurrent or sequential, are all still to be sorted out. Perhaps even more intriguing is the question of what stage or stages of disease will most benefit from this combination of therapies. At this point in time, the case for induction therapy may actually be stronger when dealing with the invasive phenotype rather than the metastatic phenotype.
References [1] Graeter TP, Hellwig D, Hoffman K, Ukena D, Kirsch CM, Schafers HJ. Mediastinal lymph node staging in suspected lung cancer: comparison of positron emission tomography with F-18-fluorodeoxyglucose and mediastinoscopy. Ann Thorac Surg 2003;75(1):231—6. [2] Thomas PA, Piantadosi S, Mountain CF. The Lung Cancer Study Group. Should subcarinal lymph nodes be routinely examined in patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 1988;95(5):883—7. [3] Patterson GA, Piazza D, Pearson FG, Todd TR, Ginsberg RJ, Goldberg M, et al. Significance of metastatic disease in subaortic lymph nodes. Ann Thorac Surg 1987;43(2):155—9. [4] Pisters K. Multidisciplinary management of early lung cancer. ASCO Annual Meeting 2002. [5] Keller SM, Adak S, Wagner H, Herskovic A, Komaki R, Brooks BJ, et al. for the The Eastern Cooperative Oncology Group. A randomized trial of postoperative adjuvant therapy in patient with completely resected stage II or IIIA non-small-cell lung cancer. N Engl J Med 2000;343(17):1217—22.
Conference [6] Weisenberger TH, Gail M. The Lung Cancer Study Group. Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N Eng J Med 1986;315:1377—81. [7] PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small cell-lung cancer: systemic review and meta-analysis of individual patient data from nine randomized controlled trials. Lancet 1998;352: 257—63. [8] Faber LP, Kittle CF, Warren WH, Bonomi PD, Taylor IV SG, Reddy S, et al. Preoperative chemotherapy and irradiation for stage III non-small cell lung cancer. Ann Thorac Surg 1989;47:669—77. [9] Akhurst T, Downey RJ, Ginsberg MS, Gonen M, Bains M, Korst R, et al. An initial experience with FDG-PET in the imaging of residual disease after induction therapy for lung cancer. Ann Thorac Surg 2002;73(1):259—64. [10] Ginsberg RJ, Hill LD, Eagan RT, Thomas P, Mountain CF, Deslauriers J, et al. Modern thirty-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 1983;86(5):654—8. [11] Depierre A, Milleron B, Moro-Sibilot D, Chevret S, Quoix E, Lebeau B, et al. French Thoracic Cooperative Group. Preoperative chemotherapy followed by surgery compared with primary surgery in respectable stage I (except T1N0), II, and IIIA non-small-cell lung cancer. J Clin Onc 2002;20(1):247—53. [12] Roberts JR, Eustis C, Devore R, Carbone D, Choy H, Johnson D. Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung cancer. Ann Thorac Surg 2001;72:885—8. [13] Roth JA, Atkinson EN, Fossella F, Komaki R, Bernadette RM, Putnam Jr JB, et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in respectable stage IIIA non-small cell lung cancer. Lung Cancer 1998;21(1):1—6. [14] Rosell R, Gomez-Codina J, Camps C, Javier Sanchez J, Maestre J, Padilla J, et al. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer; a 7-year assessment of a randomized controlled trial. Lung Cancer 1999;26(1):7—14. [15] Shepherd FA, Johnston MR, Payne D, Burkes R, Deslauriers J, Cormier Y, et al. Randomized study of chemotherapy and surgery versus radiotherapy for stage IIIA non-small-cell lung cancer: a National Cancer Institute of Canada Clinical Trials Group Study. Br J Cancer 1998;78(5): 683—5. [16] Johnstone DW, Byhardt RW, Ettinger D, Scott CB. Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2002;54(2):365—9. [17] Pastorino U. Extended resections for lung cancer: indications and results. Surg Oncol 2002;11(4):207—16. [18] Paulson DL. Technical considerations in stage III disease: the ‘‘superior sulcus’’ lesion. In: Delarue NC, Eschapasse H, editors. International trends in general surgery. Philadelphia, PA: W.B. Saunders; 1985. p. 121—131. [19] Rusch VW, Giroux DJ, Kraut MR, Crowley J, Hazuka M, Johnson D, et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 2001;121(3):472—83.
Induction therapy for stage III lung cancer [20] Albain KS, Rusch VW, Crowley JJ, Rice TW, Turrisi 3rd AT, Weick JK, et al. 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 1995;13(8):1880—92. [21] Grunenwald DH, Andre F, Pechoux CL, Girard P, Lamer C, Laplache A, et al. Benefit of surgery after chemoradiatiotherapy in stage IIIB (T4 and/or N3) non-small cell lung cancer. J Thorac Cardiovasc Surg 2001;122(4):796—802. [22] Stamatis G, Eberhardt W, Stuben G, Bildat S, Dahler O, Hillejan L. Preoperative chemoradiotherapy and surgery
S57 for selected non-small cell lung cancer IIIB subgroups: long-term results. Ann Thorac Surg 1999;68(4):1144—9.
Michael R. Johnston, (MD, FRCSC) University of Toronto, Toronto General Hospital 200 Elizabeth Street, Suite 10 EN-230 Toronto, Ont., Canada M5G 2C4 Tel.: +1-416-340-3838; fax: +1-416-340-3660 E-mail address: [email protected] (M.R. Johnston)