- Email: [email protected]
Mortality Related to Neoadjuvant Therapy and Surgery for Stage III Non–Small-Cell Lung Cancer
original contribution Mortality Related to Neoadjuvant Therapy and Surgery for Stage III Non–Small-Cell Lung Cancer Gerald H. Clamon,1 Kalpaj R. Parekh2 Abstract Background: Neoadjuvant chemotherapy alone or with concurrent radiation is often used for stage IIIA non–smallcell lung cancer but is often tried in patients with stage IIIB and at times in patients with stage I or II disease. Newer neoadjuvant regimens would need to be compared with currently used programs to see if they increased toxicity. For such a comparison, a baseline estimate is needed of the mortality of currently used regimens. Patients and Methods: In this review, we searched PubMed and associated references, and data on mortality were identified in 34 publications. Results: The mortality of neoadjuvant chemotherapy or chemotherapy plus radiation has been estimated in 2015 patients was 0.7%, and the postsurgical mortality in 2195 patients was 4.3%. Conclusion: These estimates might provide a benchmark for comparison for innovative trials. Clinical Lung Cancer, Vol. 9, No. 4, 213-216, 2008; DOI: 10.3816/CLC.2008.n.031 Keywords: Bronchial stump dehiscence, Comorbidity index, Concurrent radiation, Lobectomy
Introduction For patients with non–small-cell lung cancer (NSCLC) and stage III (N2 disease), neoadjuvant therapy followed by surgery is one of the standard treatment programs. Neoadjuvant therapy might consist of chemotherapy alone or chemotherapy with concurrent radiation. At this time, it is uncertain if the standard of care should be neoadjuvant therapy followed by surgery or chemotherapy and radiation without surgery. Randomized trials to date have not answered this question. If neoadjuvant therapy followed by surgery were to lead to a marked increase in mortality, the benefit of surgery for the population of patients with stage III disease might be offset by early death. A metaanalysis of all randomized trials of preoperative chemotherapy for stage III NSCLC did not show definitive benefit.1 The mortality associated with neoadjuvant therapy followed by surgery was reported by Martins et al2 to be increased particularly for patients requiring a right pneumonectomy. Mortality for patients with a right pneumonectomy was 23%, 1Department 2Department
of Internal Medicine of Cardiothoracic Surgery University of Iowa College of Medicine, Iowa City Submitted: Sep 14, 2007; Revised: Jan 22, 2008; Accepted: Feb 18, 2008 Address for correspondence: Gerald H. Clamon, MD, Department of Internal Medicine, University of Iowa College of Medicine, 200 Hawkins Dr, Iowa City, Iowa 52242 Fax: 319-353-8377; e-mail: [email protected]
with an overall mortality for all lobectomies and pneumonectomies of 2.4%. Takeda et al3 and Siegenthaler et al4 did not find that induction therapy had a prohibitive effect on surgical complications. Fujita et al5 found that preoperative radiation therapy of > 45 Gy was a risk factor for postoperative complications. Attempts to improve the success of neoadjuvant therapies might increase the mortality of induction therapy or mortality in the postoperative period. Selection of patients and elimination of those who might require a pneumonectomy or those who had significant comorbidities might decrease postoperative complications. To assess the range of acceptable risks for any new trial, it would be important to know the toxicity experienced in previous trials. We had earlier proposed a new trial of intensive neoadjuvant therapy, and reviewers were concerned about how the anticipated toxicity of intensive therapy would compare with the toxicity of previously reported trials. In order to assess the risk in previously published studies, we carried out a review of the data from published trials in which the mortality from the induction therapy or the postoperative mortality was given.
Patients and Methods Using a PubMed search for neoadjuvant therapy and lung cancer, and then searching other literature citations, we were able to find 34 publications in which the mortality of induction therapy and/or postoperative mortality were given. For postoperative mortality, we included deaths ≤ 90 days after
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Mortality and Neoadjuvant Therapy for NSCLC Table 1 Deaths with Induction and Surgery Presented by Trial Study Martins et
Deaths with Induction Deaths with Surgery
al2
Takeda et al3 Siegenthaler et
al4
Fujita et al5 Fischer et
al6
Park et al7 Trodella et
al8
Granetzny et al9 al10
Sonnett et
Albain et al11 al12
Zandwijk et
O'Brien et al13 Van Schil et
al14
Mattson et al15
1 of 30
1 of 22
Not given
5 of 100
0 of 76
1 of 76
Not given
9 of 124
0 of 21
1 of 17
1 of 52
1 of 42
0 of 92
7 of 61
1 of 33
Not given
Not given
0 of 40
2 of 126
8 of 101
0 of 47
0 of 17
0 of 52
1 of 12
0 of 166
5 of 12
2 of 127
0 of 22
al16
0 of 90
2 of 75
Ramnath et al17
0 of 62
4 of 62
1 of 94
2 of 88
1 of 74
2 of 63
0 of 31
0 of 20
0 of 154
Not given
1 of 74
2 of 63
Rosell et al23
0 of 30
2 of 30
al24
3 of 104
2 of 83
Van Kooten et al25
1 of 29
1 of 18
al26
2 of 47
0 of 24
Betticher et
al18
Pisters et
Jaklitsch et al19 Nagai et
al20
Esteban et al21 Sugerbaker et
Rusch et
Pohl et
al22
Wirth et al27
0 of 32
3 of 32
Not given
2 of 70
Bueno et al29
Not given
4 of 103
al30
Not given
1 of 70
Brunelli et
Lorent et
al28
Roberts et al31 Martin et
al32
Lam et al33 Stamatis et
al34
0 of 343
2 of 34
Not given
7 of 297
0 of 29
2 of 25
Not given
18 of 392
surgery, or more if the publication suggested that the mortality was related to therapy rather than progression of the cancer. This report should be considered a review rather than a formal metaanalysis because we are not certain that every published trial has been detected. No study was eliminated from the calculation as long as the data in question could be obtained from the publication. In studies in which a small number of patients with stage I or II disease were included who had neoadjuvant therapy and then surgery, the mortality of the patients with stage I and II disease was included because it was not possible to determine the mortality in that group alone. Including patients with earlier stage of disease might be expected to
214
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alter any estimate of the efficacy of neoadjuvant therapy but would not necessarily be expected to alter the toxicity of the treatment program. Surgical mortality is usually given as 30day mortality. However, in this review, postoperative mortality ≤ 90 days was included in order to capture all toxicity potentially related to the treatment program. For example, some patients suffered bronchial stump dehiscence between 30-90 days after surgery; to not include such deaths would underestimate the risks of surgery after tissue-damaging neoadjuvant therapy.
Results Thirty-four references from 1994 to the present time were found in the literature. The number of patients available for assessment of mortality after induction therapy ranged from 21 to 343 patients, with a mean study size of 74.96 patients. This was based on 25 studies with sufficient data. The number of patients available for assessment of mortality after surgery ranges from 12 to 392 patients, with a mean study sample of 70.8 patients, based on 31 studies with adequate data. The mortality was specified in 25 of the 34 trials, and the total number of patients at risk for death after induction therapy was 2015. There were 16 deaths related to induction therapy, or 0.7%. The surgical mortality was specified in 31 of the 34 trials, and the total number of patients at risk for death after surgery was 2195. There were 94 deaths, or 4.3%. Because any death within 90 days not clearly attributed to progressive cancer was considered treatment or surgically related, the data might overestimate the surgical mortality. The data by trial are presented in Table 1.2-34 There was insufficient detail on mortality in most references to determine how many deaths were a result of lobectomy versus pneumonectomy. Further, the criteria for proceeding to surgery after induction versus holding surgery were rarely provided. In order to include as many studies as possible in which mortality related to the induction therapy was given and mortality after the surgery was given, papers with a small number of patients with stage I and II disease were included. Fujita et al5 included 18 patients who were stage IB, 3 who were stage IIA, and 26 who were stage IIB. Martins et al2 included 9 patients who were stage IB and 7 who were IIB before therapy. Pisters et al18 had 42 patients who were stage IB, 1 who was stage IIA, and 44 who were stage IIB. Ramnath et al17 included 27 patients who had stage IB disease, 2 who had stage IIA disease, and 13 who had IIB. In total, 96 patients with stage I disease and 91 patients with stage II disease are included in this review so that approximately 5% were stage I and 5% were stage II.
Discussion The mortality associated with neoadjuvant chemotherapy or neoadjuvant chemotherapy with concurrent radiation was 0.7%. These trials generally included ≤ 3 cycles of chemotherapy. Patients entered into these trials were screened for the capability of having surgery if they had a response to induction therapy. As a consequence, they might have been
Gerald H. Clamon, Kalpaj R. Parekh healthier than the total population of patients with stage IIIA disease. For example, patients with significant comorbidities such as heart disease or pulmonary function too poor to tolerate surgery would not have been given induction therapy. However, the overall mortality in these trials suggests further intensification of the neoadjuvant therapy might be feasible, given the low mortality of existing regimens. The postoperative mortality of 4.3% in those patients able to undergo induction therapy also reflects the mortality in a selected group of patients. It is quite feasible that, with the elimination of patients needing pneumonectomy or those medically at risk, mortality could be further reduced. Respiratory failure, pneumonia, and pulmonary emboli are generally the reasons for mortality in the postoperative period. Patients with poor pulmonary function, those with significant cardiac disease, and those with poor performance status have generally been excluded from studies of neoadjuvant chemotherapy followed by surgery. The neoadjuvant studies cited in Table 1 did not include any reference to selection using a comorbidity index. Breen et al35 have suggested that using the Charlson Comorbidity Index is helpful in selecting therapy for patients aged > 80 years. For patients with stage III NSCLC treated with radiation alone, the Karnofsky performance score and an index of comorbidity called the Cumulative Illness Rating Scale for Geriatrics were independent predictors of poor outcome.36 It is not known if age alone predicts greater mortality or if age is simply associated with more medical illnesses that decrease the tolerance for therapy. Furthermore, we do not know if patients suffering postoperative infections had suffered more pulmonary infections before surgery or if they were patients who had not quit smoking or not had pulmonary rehabilitation therapy before surgery.
Conclusion This review of the literature suggests that the mortality from combined-modality neoadjuvant therapy (chemotherapy or chemoradiation) and surgery is relatively low, and that innovative trials that might require a greater intensity of neoadjuvant therapy or include new biologic agents should not be precluded from study because the baseline mortality of induction therapy is currently quite low. Exclusion of patients who are at the greatest risk for surgical complications (ie, patients requiring pneumonectomy) might allow more intensive therapy to be given to other patients.
References 1. Nakamura H, Kawasaki N, Taguchi M, et al. Role of preoperative chemotherapy for non-small-cell lung cancer: a meta-analysis. Lung Cancer 2006; 54:325-9. 2. Martins RG, Dienstmann R, de Biasi P, et al. Phase II trial of neoadjuvant chemotherapy using alternative doublets in non-small-cell lung cancer. Clin Lung Cancer 2007; 8:257-63. 3. Takeda S, Maeda J, Okada T, et al. Results of pulmonary resection following neoadjuvant therapy for locally advanced (stage IIIA-IIIB) lung cancer. Eur J Cardiothorac Surg 2006; 30:184-9. 4. Siegenthaler MP, Pisters KM, Merriman KW, et al. Preoperative chemotherapy for lung cancer does not increase surgical morbidity. Ann Thorac Surgery 2001; 71:1105-12. 5. Fujita S, Katakami N, Takahashi Y, et al. Postoperative complications after induction chemoradiotherapy in patients with non-small-cell lung cancer. Eur
J Cardiothorac Surg 2006; 29:896-901. 6. Fischer SA, Soberman M, Randolph P, et al. Phase II trial of concurrent paclitaxel, carboplatin and external-beam radiation followed by surgical resection in locally advanced non-small-cell lung cancer, protocol 99-444. Clin Lung Cancer 2006; 8:56-61. 7. Park BB, Park JO, Kim H, et al. Is trimodality approach better than bimodality in stage IIIA, N2 positive non-small cell lung cancer? Lung Cancer 2006; 53:32330. 8. Trodella L, Granone P, Valente S, et al. Neoadjuvant concurrent radiochemotherapy in locally advanced (IIIA-IIIB) non-small-cell lung cancer: long-term results according to downstaging. Ann Oncol 2004; 15:389-98. 9. Granetzny A, Striehn E, Bosse U, et al. A phase II single institution study of neoadjuvant stage IIIA/B chemotherapy and radiochemotherapy in non-small cell lung cancer. Ann Thorac Surg 2003; 75:1107-12. 10. Sonett JR, Suntharalingam M, Edelman MJ, et al. Pulmonary resection after curative intent radiotherapy (> 59 Gy) and concurrent chemotherapy in nonsmall-cell lung cancer. Ann Thorac Surg 2004; 78:1200-6. 11. Albain KS, Rusch VW, Crowley J, 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; 13:1880-92. 12. Zandwijk NV, Smit EF, Kramer GW, et al. Gemcitabine and cisplatin as induction regiment for patients with biopsy-proven stage IIIA N2 non small cell lung cancer: A phase II study of the European Organization for Research and Treatment of Lung Cancer Cooperative Group (EORTC 08955) J Clin Oncol 2000; 18:2658-64. 13. O’Brien ME, Splinter T, Smith ER, et al. Carboplatin and paclitaxel as an induction regimen for patients with biopsy-proven stage IIIA N2 non-small cell lung cancer: an EORTC phase II study (EORTC 08958). Eur J Cancer 2003; 39:141622. 14. Van Schil P, Van Meerbeeck J, Kramer G, et al. Morbidity and mortality in the surgery arm of EORTC 08941 trial. Eur Respir J 2005; 26:192-7. 15. Mattson KV, Abratt RP, ten Velde G, et al. Docetaxel as neoadjuvant therapy for radically treatable stage III non-small-cell lung cancer: a multinational randomized phase III study. Ann Oncol 2003; 14:116-22. 16. Betticher DC, Schmitz SF, Totsch M, et al. Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non small cell lung cancer: a multi-center phase II trial. J Clin Oncol 2003; 21:1752-9. 17. Ramnath N, Sommers E, Robinson L. Phase II study of neoadjuvant chemotherapy with gemcitabine and vinorelbine in respectable non-small cell lung cancer. Chest 2005; 128:3467-74. 18. Pisters KM, Ginsberg RJ, Giroux DJ, et al. Induction chemotherapy before surgery for early-stage lung cancer: A novel approach.Bimodality Lung Oncology Team. J Thorac Cardiovasc Surg 2000; 119:429-39. 19. Jaklitsch MT, Herndon JE, Decamp MM Jr, et al. Nodal downstaging predicts survival following induction chemotherapy for stage IIIA (N2) non-small cell lung cancer in CALGB protocol 8935. J Surg Oncol 2006; 94:599-606. 20. Nagai K, Tsuchiya R, Mori T, et al. A randomized trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage IIIA N2 non-small cell lung cancer (JCOG 9209). J Thorac Cardiovasc Surg 2003; 125:254-60. 21. Esteban E, de Sande JL, Villanueva N, et al. Cisplatin plus gemcitabine with or without vinorelbine as induction chemotherapy prior to radical locoregional treatment for patients with stage III non-small-cell lung cancer (NSCLC): results of a prospective randomized study. Lung Cancer 2007; 55:173-80. 22. Sugarbaker DJ, Herndon J, Kohman LJ, et al. 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 1995; 109:47385. 23. Rosell R, Gómez-Codina J, Camps C, et al. A randomized trial comparing pre operative chemotherapy plus surgery with surgery alone in patients with nonsmall cell lung cancer. N Engl J Med 1994; 330:153-8. 24. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007; 25:313-8. 25. Van Kooten M, Rosenberg M, Orlando M, et al. Neoadjuvant chemotherapy with gemcitabine and cisplatin in stage IIIA/B non-small cell lung cancer. Invest New Drugs 2002; 20:439-46. 26. Pohl G, Krajnik G, Malayeri R, et al. Induction chemotherapy with the TIP regimen (paclitaxel/ifosfamide/cisplatin) in stage III non-small cell lung cancer. Lung Cancer 2006; 54:63-7. 27. Wirth LJ, Lucca J, Ostler P, et al. Induction docetaxel and carboplatin followed by weekly docetaxel and carboplatin with concurrent radiotherapy, then surgery, in stage III non-small cell lung cancer: a phase I study. Clin Cancer Res 2003; 9:1698-704. 28. Brunelli A, Xiume F, Al Refai M, et al. Gemcitabine-cisplatin chemotherapy before lung resection: a case-matched analysis of early outcome. Ann Thorac Surg 2006; 81:1963-8. 29. Bueno R, Richards WG, Swanson S, et al. Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival. Ann Thorac Surg 2000; 70:1826-31.
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Mortality and Neoadjuvant Therapy for Lung Cancer 30. Lorent N, De Leyn P, Lievens Y, et al. Long-term survival of surgically stage IIIAN2 non-small-cell lung cancer treated with surgical combined modality approach: analysis of a 7-year prospective experience. Ann Oncol 2004; 15:1645-53. 31. Roberts JR, Eustis C, Devore R, et al. Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung cancer. Ann Thorac Surg 2001; 72:885-8. 32. Martin J, Ginsberg RJ, Abolhoda A, et al. Morbidity and mortality after neoadjuvant therapy for lung cancer: the risks of right pneumonectomy. Ann Thorac Surg 2001; 72:1149-54. 33. Lam P, Berman S, Thurer R, et al. Phase II trial of sequential chemotherapy followed by chemoradiation, surgery, and postoperative chemotherapy for the
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treatment of stage IIA/IIIB non-small cell lung cancer. Clin Lung Cancer 2006; 8:122-9. 34. Stamatis G, Eberhard W, Pottgen. Surgery after multimodality treatment for nonsmall-cell lung cancer. Lung Cancer 2004; 45(suppl 2):s107-12. 35. Breen D, Barlési F, Zemerli M, et al. Results and impact of routine assessment of comorbidity in elderly patients with non-small cell lung cancer aged > 80 years. Clin Lung Cancer 2007; 8:331-4. 36. Firat S, Byhardt RW, Gore E. Comorbidity and Karnofsky performance score are independent prognostic factors in stage III non-small cell lung cancer: an institutional analysis of patients treated on four FTOG studies. Int J Radiat Oncol Biol Phys 2002; 54:357-64.
Introduction For patients with non–small-cell lung cancer (NSCLC) and stage III (N2 disease), neoadjuvant therapy followed by surgery is one of the standard treatment programs. Neoadjuvant therapy might consist of chemotherapy alone or chemotherapy with concurrent radiation. At this time, it is uncertain if the standard of care should be neoadjuvant therapy followed by surgery or chemotherapy and radiation without surgery. Randomized trials to date have not answered this question. If neoadjuvant therapy followed by surgery were to lead to a marked increase in mortality, the benefit of surgery for the population of patients with stage III disease might be offset by early death. A metaanalysis of all randomized trials of preoperative chemotherapy for stage III NSCLC did not show definitive benefit.1 The mortality associated with neoadjuvant therapy followed by surgery was reported by Martins et al2 to be increased particularly for patients requiring a right pneumonectomy. Mortality for patients with a right pneumonectomy was 23%, 1Department 2Department
of Internal Medicine of Cardiothoracic Surgery University of Iowa College of Medicine, Iowa City Submitted: Sep 14, 2007; Revised: Jan 22, 2008; Accepted: Feb 18, 2008 Address for correspondence: Gerald H. Clamon, MD, Department of Internal Medicine, University of Iowa College of Medicine, 200 Hawkins Dr, Iowa City, Iowa 52242 Fax: 319-353-8377; e-mail: [email protected]
with an overall mortality for all lobectomies and pneumonectomies of 2.4%. Takeda et al3 and Siegenthaler et al4 did not find that induction therapy had a prohibitive effect on surgical complications. Fujita et al5 found that preoperative radiation therapy of > 45 Gy was a risk factor for postoperative complications. Attempts to improve the success of neoadjuvant therapies might increase the mortality of induction therapy or mortality in the postoperative period. Selection of patients and elimination of those who might require a pneumonectomy or those who had significant comorbidities might decrease postoperative complications. To assess the range of acceptable risks for any new trial, it would be important to know the toxicity experienced in previous trials. We had earlier proposed a new trial of intensive neoadjuvant therapy, and reviewers were concerned about how the anticipated toxicity of intensive therapy would compare with the toxicity of previously reported trials. In order to assess the risk in previously published studies, we carried out a review of the data from published trials in which the mortality from the induction therapy or the postoperative mortality was given.
Patients and Methods Using a PubMed search for neoadjuvant therapy and lung cancer, and then searching other literature citations, we were able to find 34 publications in which the mortality of induction therapy and/or postoperative mortality were given. For postoperative mortality, we included deaths ≤ 90 days after
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Lung Cancer July 2008
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213
Mortality and Neoadjuvant Therapy for NSCLC Table 1 Deaths with Induction and Surgery Presented by Trial Study Martins et
Deaths with Induction Deaths with Surgery
al2
Takeda et al3 Siegenthaler et
al4
Fujita et al5 Fischer et
al6
Park et al7 Trodella et
al8
Granetzny et al9 al10
Sonnett et
Albain et al11 al12
Zandwijk et
O'Brien et al13 Van Schil et
al14
Mattson et al15
1 of 30
1 of 22
Not given
5 of 100
0 of 76
1 of 76
Not given
9 of 124
0 of 21
1 of 17
1 of 52
1 of 42
0 of 92
7 of 61
1 of 33
Not given
Not given
0 of 40
2 of 126
8 of 101
0 of 47
0 of 17
0 of 52
1 of 12
0 of 166
5 of 12
2 of 127
0 of 22
al16
0 of 90
2 of 75
Ramnath et al17
0 of 62
4 of 62
1 of 94
2 of 88
1 of 74
2 of 63
0 of 31
0 of 20
0 of 154
Not given
1 of 74
2 of 63
Rosell et al23
0 of 30
2 of 30
al24
3 of 104
2 of 83
Van Kooten et al25
1 of 29
1 of 18
al26
2 of 47
0 of 24
Betticher et
al18
Pisters et
Jaklitsch et al19 Nagai et
al20
Esteban et al21 Sugerbaker et
Rusch et
Pohl et
al22
Wirth et al27
0 of 32
3 of 32
Not given
2 of 70
Bueno et al29
Not given
4 of 103
al30
Not given
1 of 70
Brunelli et
Lorent et
al28
Roberts et al31 Martin et
al32
Lam et al33 Stamatis et
al34
0 of 343
2 of 34
Not given
7 of 297
0 of 29
2 of 25
Not given
18 of 392
surgery, or more if the publication suggested that the mortality was related to therapy rather than progression of the cancer. This report should be considered a review rather than a formal metaanalysis because we are not certain that every published trial has been detected. No study was eliminated from the calculation as long as the data in question could be obtained from the publication. In studies in which a small number of patients with stage I or II disease were included who had neoadjuvant therapy and then surgery, the mortality of the patients with stage I and II disease was included because it was not possible to determine the mortality in that group alone. Including patients with earlier stage of disease might be expected to
214
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Clinical Lung Cancer July 2008
alter any estimate of the efficacy of neoadjuvant therapy but would not necessarily be expected to alter the toxicity of the treatment program. Surgical mortality is usually given as 30day mortality. However, in this review, postoperative mortality ≤ 90 days was included in order to capture all toxicity potentially related to the treatment program. For example, some patients suffered bronchial stump dehiscence between 30-90 days after surgery; to not include such deaths would underestimate the risks of surgery after tissue-damaging neoadjuvant therapy.
Results Thirty-four references from 1994 to the present time were found in the literature. The number of patients available for assessment of mortality after induction therapy ranged from 21 to 343 patients, with a mean study size of 74.96 patients. This was based on 25 studies with sufficient data. The number of patients available for assessment of mortality after surgery ranges from 12 to 392 patients, with a mean study sample of 70.8 patients, based on 31 studies with adequate data. The mortality was specified in 25 of the 34 trials, and the total number of patients at risk for death after induction therapy was 2015. There were 16 deaths related to induction therapy, or 0.7%. The surgical mortality was specified in 31 of the 34 trials, and the total number of patients at risk for death after surgery was 2195. There were 94 deaths, or 4.3%. Because any death within 90 days not clearly attributed to progressive cancer was considered treatment or surgically related, the data might overestimate the surgical mortality. The data by trial are presented in Table 1.2-34 There was insufficient detail on mortality in most references to determine how many deaths were a result of lobectomy versus pneumonectomy. Further, the criteria for proceeding to surgery after induction versus holding surgery were rarely provided. In order to include as many studies as possible in which mortality related to the induction therapy was given and mortality after the surgery was given, papers with a small number of patients with stage I and II disease were included. Fujita et al5 included 18 patients who were stage IB, 3 who were stage IIA, and 26 who were stage IIB. Martins et al2 included 9 patients who were stage IB and 7 who were IIB before therapy. Pisters et al18 had 42 patients who were stage IB, 1 who was stage IIA, and 44 who were stage IIB. Ramnath et al17 included 27 patients who had stage IB disease, 2 who had stage IIA disease, and 13 who had IIB. In total, 96 patients with stage I disease and 91 patients with stage II disease are included in this review so that approximately 5% were stage I and 5% were stage II.
Discussion The mortality associated with neoadjuvant chemotherapy or neoadjuvant chemotherapy with concurrent radiation was 0.7%. These trials generally included ≤ 3 cycles of chemotherapy. Patients entered into these trials were screened for the capability of having surgery if they had a response to induction therapy. As a consequence, they might have been
Gerald H. Clamon, Kalpaj R. Parekh healthier than the total population of patients with stage IIIA disease. For example, patients with significant comorbidities such as heart disease or pulmonary function too poor to tolerate surgery would not have been given induction therapy. However, the overall mortality in these trials suggests further intensification of the neoadjuvant therapy might be feasible, given the low mortality of existing regimens. The postoperative mortality of 4.3% in those patients able to undergo induction therapy also reflects the mortality in a selected group of patients. It is quite feasible that, with the elimination of patients needing pneumonectomy or those medically at risk, mortality could be further reduced. Respiratory failure, pneumonia, and pulmonary emboli are generally the reasons for mortality in the postoperative period. Patients with poor pulmonary function, those with significant cardiac disease, and those with poor performance status have generally been excluded from studies of neoadjuvant chemotherapy followed by surgery. The neoadjuvant studies cited in Table 1 did not include any reference to selection using a comorbidity index. Breen et al35 have suggested that using the Charlson Comorbidity Index is helpful in selecting therapy for patients aged > 80 years. For patients with stage III NSCLC treated with radiation alone, the Karnofsky performance score and an index of comorbidity called the Cumulative Illness Rating Scale for Geriatrics were independent predictors of poor outcome.36 It is not known if age alone predicts greater mortality or if age is simply associated with more medical illnesses that decrease the tolerance for therapy. Furthermore, we do not know if patients suffering postoperative infections had suffered more pulmonary infections before surgery or if they were patients who had not quit smoking or not had pulmonary rehabilitation therapy before surgery.
Conclusion This review of the literature suggests that the mortality from combined-modality neoadjuvant therapy (chemotherapy or chemoradiation) and surgery is relatively low, and that innovative trials that might require a greater intensity of neoadjuvant therapy or include new biologic agents should not be precluded from study because the baseline mortality of induction therapy is currently quite low. Exclusion of patients who are at the greatest risk for surgical complications (ie, patients requiring pneumonectomy) might allow more intensive therapy to be given to other patients.
References 1. Nakamura H, Kawasaki N, Taguchi M, et al. Role of preoperative chemotherapy for non-small-cell lung cancer: a meta-analysis. Lung Cancer 2006; 54:325-9. 2. Martins RG, Dienstmann R, de Biasi P, et al. Phase II trial of neoadjuvant chemotherapy using alternative doublets in non-small-cell lung cancer. Clin Lung Cancer 2007; 8:257-63. 3. Takeda S, Maeda J, Okada T, et al. Results of pulmonary resection following neoadjuvant therapy for locally advanced (stage IIIA-IIIB) lung cancer. Eur J Cardiothorac Surg 2006; 30:184-9. 4. Siegenthaler MP, Pisters KM, Merriman KW, et al. Preoperative chemotherapy for lung cancer does not increase surgical morbidity. Ann Thorac Surgery 2001; 71:1105-12. 5. Fujita S, Katakami N, Takahashi Y, et al. Postoperative complications after induction chemoradiotherapy in patients with non-small-cell lung cancer. Eur
J Cardiothorac Surg 2006; 29:896-901. 6. Fischer SA, Soberman M, Randolph P, et al. Phase II trial of concurrent paclitaxel, carboplatin and external-beam radiation followed by surgical resection in locally advanced non-small-cell lung cancer, protocol 99-444. Clin Lung Cancer 2006; 8:56-61. 7. Park BB, Park JO, Kim H, et al. Is trimodality approach better than bimodality in stage IIIA, N2 positive non-small cell lung cancer? Lung Cancer 2006; 53:32330. 8. Trodella L, Granone P, Valente S, et al. Neoadjuvant concurrent radiochemotherapy in locally advanced (IIIA-IIIB) non-small-cell lung cancer: long-term results according to downstaging. Ann Oncol 2004; 15:389-98. 9. Granetzny A, Striehn E, Bosse U, et al. A phase II single institution study of neoadjuvant stage IIIA/B chemotherapy and radiochemotherapy in non-small cell lung cancer. Ann Thorac Surg 2003; 75:1107-12. 10. Sonett JR, Suntharalingam M, Edelman MJ, et al. Pulmonary resection after curative intent radiotherapy (> 59 Gy) and concurrent chemotherapy in nonsmall-cell lung cancer. Ann Thorac Surg 2004; 78:1200-6. 11. Albain KS, Rusch VW, Crowley J, 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; 13:1880-92. 12. Zandwijk NV, Smit EF, Kramer GW, et al. Gemcitabine and cisplatin as induction regiment for patients with biopsy-proven stage IIIA N2 non small cell lung cancer: A phase II study of the European Organization for Research and Treatment of Lung Cancer Cooperative Group (EORTC 08955) J Clin Oncol 2000; 18:2658-64. 13. O’Brien ME, Splinter T, Smith ER, et al. Carboplatin and paclitaxel as an induction regimen for patients with biopsy-proven stage IIIA N2 non-small cell lung cancer: an EORTC phase II study (EORTC 08958). Eur J Cancer 2003; 39:141622. 14. Van Schil P, Van Meerbeeck J, Kramer G, et al. Morbidity and mortality in the surgery arm of EORTC 08941 trial. Eur Respir J 2005; 26:192-7. 15. Mattson KV, Abratt RP, ten Velde G, et al. Docetaxel as neoadjuvant therapy for radically treatable stage III non-small-cell lung cancer: a multinational randomized phase III study. Ann Oncol 2003; 14:116-22. 16. Betticher DC, Schmitz SF, Totsch M, et al. Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non small cell lung cancer: a multi-center phase II trial. J Clin Oncol 2003; 21:1752-9. 17. Ramnath N, Sommers E, Robinson L. Phase II study of neoadjuvant chemotherapy with gemcitabine and vinorelbine in respectable non-small cell lung cancer. Chest 2005; 128:3467-74. 18. Pisters KM, Ginsberg RJ, Giroux DJ, et al. Induction chemotherapy before surgery for early-stage lung cancer: A novel approach.Bimodality Lung Oncology Team. J Thorac Cardiovasc Surg 2000; 119:429-39. 19. Jaklitsch MT, Herndon JE, Decamp MM Jr, et al. Nodal downstaging predicts survival following induction chemotherapy for stage IIIA (N2) non-small cell lung cancer in CALGB protocol 8935. J Surg Oncol 2006; 94:599-606. 20. Nagai K, Tsuchiya R, Mori T, et al. A randomized trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage IIIA N2 non-small cell lung cancer (JCOG 9209). J Thorac Cardiovasc Surg 2003; 125:254-60. 21. Esteban E, de Sande JL, Villanueva N, et al. Cisplatin plus gemcitabine with or without vinorelbine as induction chemotherapy prior to radical locoregional treatment for patients with stage III non-small-cell lung cancer (NSCLC): results of a prospective randomized study. Lung Cancer 2007; 55:173-80. 22. Sugarbaker DJ, Herndon J, Kohman LJ, et al. 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 1995; 109:47385. 23. Rosell R, Gómez-Codina J, Camps C, et al. A randomized trial comparing pre operative chemotherapy plus surgery with surgery alone in patients with nonsmall cell lung cancer. N Engl J Med 1994; 330:153-8. 24. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007; 25:313-8. 25. Van Kooten M, Rosenberg M, Orlando M, et al. Neoadjuvant chemotherapy with gemcitabine and cisplatin in stage IIIA/B non-small cell lung cancer. Invest New Drugs 2002; 20:439-46. 26. Pohl G, Krajnik G, Malayeri R, et al. Induction chemotherapy with the TIP regimen (paclitaxel/ifosfamide/cisplatin) in stage III non-small cell lung cancer. Lung Cancer 2006; 54:63-7. 27. Wirth LJ, Lucca J, Ostler P, et al. Induction docetaxel and carboplatin followed by weekly docetaxel and carboplatin with concurrent radiotherapy, then surgery, in stage III non-small cell lung cancer: a phase I study. Clin Cancer Res 2003; 9:1698-704. 28. Brunelli A, Xiume F, Al Refai M, et al. Gemcitabine-cisplatin chemotherapy before lung resection: a case-matched analysis of early outcome. Ann Thorac Surg 2006; 81:1963-8. 29. Bueno R, Richards WG, Swanson S, et al. Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival. Ann Thorac Surg 2000; 70:1826-31.
Clinical Lung Cancer July 2008
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Mortality and Neoadjuvant Therapy for Lung Cancer 30. Lorent N, De Leyn P, Lievens Y, et al. Long-term survival of surgically stage IIIAN2 non-small-cell lung cancer treated with surgical combined modality approach: analysis of a 7-year prospective experience. Ann Oncol 2004; 15:1645-53. 31. Roberts JR, Eustis C, Devore R, et al. Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung cancer. Ann Thorac Surg 2001; 72:885-8. 32. Martin J, Ginsberg RJ, Abolhoda A, et al. Morbidity and mortality after neoadjuvant therapy for lung cancer: the risks of right pneumonectomy. Ann Thorac Surg 2001; 72:1149-54. 33. Lam P, Berman S, Thurer R, et al. Phase II trial of sequential chemotherapy followed by chemoradiation, surgery, and postoperative chemotherapy for the
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treatment of stage IIA/IIIB non-small cell lung cancer. Clin Lung Cancer 2006; 8:122-9. 34. Stamatis G, Eberhard W, Pottgen. Surgery after multimodality treatment for nonsmall-cell lung cancer. Lung Cancer 2004; 45(suppl 2):s107-12. 35. Breen D, Barlési F, Zemerli M, et al. Results and impact of routine assessment of comorbidity in elderly patients with non-small cell lung cancer aged > 80 years. Clin Lung Cancer 2007; 8:331-4. 36. Firat S, Byhardt RW, Gore E. Comorbidity and Karnofsky performance score are independent prognostic factors in stage III non-small cell lung cancer: an institutional analysis of patients treated on four FTOG studies. Int J Radiat Oncol Biol Phys 2002; 54:357-64.