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Small cell lung cancer I–III A: cytoreductive chemotherapy followed by resection with continuation of chemotherapy

Small cell lung cancer I–III A: cytoreductive chemotherapy followed by resection with... Abstract Objectives: To define the place for surgery in combined modality treatment of small cell lung cancer patients. The endpoint was: does complete resection reduce the risk of local failure? Methods: Between November 1981 and June 1996, 75 patients in stage I–III A, many of them with a bulky cN2 tumor at presentation, were exposed to VP-16 based cytoreductive chemotherapy. After three courses of induction treatment, 46 patients underwent thoracotomy and 35 of them had resection. Results: There were two sudden deaths (pulmonary embolism). No other complications were observed. In six cases (6/35=16%), no residual tumor was found in the resected specimen. Four weeks after surgery, chemotherapy was resumed. Three patients experienced local relapse (3/33), among them, the single patient with incomplete resection, and two other patients developed local and distant failure (2/33). Thus, the local relapse rate was 15% (5/33). Eight patients, mainly with chemotherapy induced surgicopathological complete remission (pCR) and with lymph nodes free of tumor in surgical specimens (pN0), are alive, tumor-free, at a median of 136+ months. Two patients died tumor-free at 65 and 147 months. One patient died of unrelated causes at 21 months with no evidence of disease at autopsy. The median survival in the cN0+N1 subsets was 25.09 months, whereas in cN2 disease, this was 13.75 months. There were no long-term survivors among the patients with persistent N2 disease. The median survival in all 35 patients using the Kaplan–Meier method was 18 months; the 5-year tumor-free survival rate was 29% and the 10-year tumor-free survival rate was 23%. Conclusions: Satisfactory local tumor control confirmed the assumption of the study. No residual tumor in the resected specimen (pCR) is the most favorable prognostic factor and determinant of long-term survival. Surgery should not be performed in the patients with persistent N2 disease. Small cell lung cancer, Stage I–III A, Neoadjuvant cytoreductive chemotherapy 1 Introduction At the time of diagnosis, more than 90% of small cell lung cancer (SCLC) patients experience spread to the regional lymph nodes and/or dissemination to distant metastatic sites. Chemotherapy is the cornerstone of management. Potential candidates for surgical resection comprise less than 10% of patients. In 1981, we started the study, aiming to find a place for surgery in combined modality treatment of limited SCLC including patients with locally, far advanced disease. The endpoint was: does complete resection reduce the risk of local failure? Determination of the site of first relapse was essential. Special care was given to the patients’ lifelong follow-up. The protocol was accepted by the Local Ethics Committee. All patients were informed of the potential risk of the proposed treatment. 2 Methods 2.1 Staging Staging on entry included physical examination, radiography, chest CT scan, bronchoscopy, peritoneoscopy, liver scan, bilateral bone marrow trephine biopsy and aspiration, and bone scan [1]. Mediastinoscopy was not a routine procedure. It was applied occasionally, mainly to exclude spread to the opposite side. Subsequently, liver imaging was extended to include abdominal and retroperitoneal US. Supplementary staging included brain, retroperitoneal space and liver CT scans [1]. As the study progressed, thorough staging was performed on entry. After induction chemotherapy, resection and completion of all chemotherapy, re-staging was performed including brain, chest and abdominal CT scans, abdominal US, bilateral bone marrow biopsy and aspiration, and bone scan. 2.2 Patients Inclusion criteria were: untreated patients (including those who underwent exploratory thoracotomy) with histological and/or cytological diagnosis of SCLC (WHO, 1981) confined to the hemithorax of origin, including ipsilateral N2 disease, age of up to 65 years, Karnofsky performance status (KPS) of ≫70, with no diabetes, no bronchoscopical contraindication for surgery, and no medical contraindication for pneumonectomy. There was no patient selection. 2.3 Drugs In 1981, there was no understanding of the risk of pneumonectomy after induction chemotherapy, particularly with intention to continue systemic treatment for up to 1 year. In the regimen developed in 1978–1981 by Heine H. Hansen and his group at the Finsen Institute [2], the doses of three drugs were reduced below levels accepted as the standard at that time: CTX, 700 mg/m2 day 1; VCR, 1.3 mg/m2 day 1; CCNU, 50 mg/m2 day 1; VP-16, 100 mg/m2 days 1–5 orally. 2.4 Treatment Chemotherapy was given every 4 weeks. Clinical and radiological assessment, full blood count and serum biochemistry studies were carried out before every course. The patients with progression after two cycles were re-biopsied and off-study. Re-evaluation after three courses included radiography, bronchoscopy plus cytology and biopsy. The patients who experienced no change (NC) off-study. The patients in complete remission (CR) were kept on chemotherapy. In the early 1980s, performing resection, particularly pneumonectomy, on a patient who had responded completely was deemed unacceptable. The patients with no dissemination and partial remission (PR; even little response) were operated on. Thoracotomy was carried out at 4 weeks after the onset of the third course of treatment. All patients who could be resected were to have primary, hilar and mediastinal disease removed. According to the protocol, the patients were operated on irrespective of N status. In a case of pneumonectomy, the bronchial stump was closed by the original hand suture technique developed by one of us (C.T.) The technique consists of bringing the membranous part of the main bronchus towards the cartilaginous wall on the level of the main carina and reduplicating the bronchus. Then, a reduction of the length of the bronchial stump is performed by excision of the cartilaginous part of it, with preservation of the membranous bronchus as a flap to cover the bronchial stump. The reduplicated bronchial stump is sutured with figure-of-eight stitches [3]. As the study progressed, lymph node removal was extended to non-palpable and non-enlarged nodes of the superior and inferior mediastinum. Postoperative chemotherapy was started 4 weeks after resection. After nine additional courses (a total of 12 cycles) – at 1 year – thorough re-staging was performed. The patients achieving CR received prophylactic cranial irradiation (PCI) [4]. 2.5 Some changes in the study design Since 1987, we modified the treatment protocol. We chose drugs of different and non-overlapping toxicities, with rarely observed pulmonary and cardiac damage and low risk to induce secondary cancer. Etopozid+cisplatin–EP-combination was used in standard doses every 3 weeks. The duration of treatment was shortened to 6 months. The age limit was extended to 70 years. Patients who experienced PR or CR had thoracotomy performed. A schematic study design is shown in Fig. 1 . Four weeks after resection, four additional courses of systemic therapy were started. After the completion of chemotherapy, thorough re-staging was carried out. In the patients achieving CR, PCI was applied, but not as a routine procedure. Fig. 1 Open in new tabDownload slide Schematic diagram of study since 1987. Fig. 1 Open in new tabDownload slide Schematic diagram of study since 1987. In the course of time, an effort was made to confirm N2 disease by transcarinal puncture via bronchoscope. 3 Materials Between November 1981 and June 1996, 75 patients were exposed to induction chemotherapy. The study census is listed in Table 1 . According to the first protocol developed in 1981, the patients with CR were kept on chemotherapy. In one patient, no palpable tumor at exploration indicated CR (early 1980s) and we had refrained from resection. Thirty-five patients underwent resection: 27 pneumonectomies, one bilobectomy, and seven lobectomies. Table 1 Open in new tabDownload slide Study census Table 1 Open in new tabDownload slide Study census The characteristics of resected patients on entry were as follows: the male to female ratio was 30:5; and the age ranged in males from 29 to 67 years (median, 51 years) and in females from 38 to 58 years (median, 48 years). The KPS ratings were: 100%, 12 patients; 90%, 14 patients; and 80%, nine patients. Weight loss was noted in 11 patients (11/35). In 13 patients, the primary tumor was located in the lower lobe (13/35). The tumor size, expressed as the total cross-sectional area on X-ray including CT scan, in two-thirds of the patients exceeded 30 cm2. Table 2 shows the pretreatment diagnosis and histology of the resected specimen after three courses of chemotherapy. Table 2 Open in new tabDownload slide Pretreatment histological and/or cytological diagnosis and histology of the resected specimen in 35 patients Table 2 Open in new tabDownload slide Pretreatment histological and/or cytological diagnosis and histology of the resected specimen in 35 patients 4 Results Table 3 shows TNM subsets, vital status and the results of the treatment. Patients were divided into three subgroups in accordance with the clinical stage of disease on entry. The pathological stage after three courses of chemotherapy and resection is shown in the second column. For every patient, data on the pattern and time of first relapse and survival are given. Survival was calculated from the date of first course of induction chemotherapy. The tumor-free survival is indicated with bold font. Table 3 Open in new tabDownload slide TNM — clinical and pathological subsets, type of failure (local vs. distant), results of the treatment and vital status in 35 patients Table 3 Open in new tabDownload slide TNM — clinical and pathological subsets, type of failure (local vs. distant), results of the treatment and vital status in 35 patients Initial tumor staging and all subsequent re-stagings were according to the new international TNM classification system [5]. Only in one patient did we find pathological stage IIIa disease in the face of clinical stage I. Of the 35 patients who responded to three courses of VP-16 based cytoreductive chemotherapy, followed by resection with continuation of systemic treatment, eight patients are alive and tumor-free at 95–182 months (median, 136+ months; Table 3). Of 11 long-term survivors, four patients (among them, three achieving pCR) were exposed to reduced doses of chemotherapy used in the first phase of the study. It is necessary to point out that according to the protocol, TRT was not employed; however, in three cases, salvage treatment was given. The pattern of failure is shown in Table 4 . Local recurrence developed in three patients at 5, 9 and 16 months, and among them was the only patient with incomplete resection (R2 in the superior vena cava region). One of them (pN1 patient), who relapsed locally at 5 months, obtained salvage TRT and is tumor-free at 122 months. Local and distant failure was observed in two patients. Estimation of the observed overall survival using the Kaplan–Meier method is shown in Fig. 2 . The median survival in all 35 resected patients was 18.47 months. The median survival in the cN0+N1 subsets was 25.09 months, whereas in cN2 disease, this was 13.75 months. Table 4 Open in new tabDownload slide Pattern of failure — site of first relapse in 21 patients Table 4 Open in new tabDownload slide Pattern of failure — site of first relapse in 21 patients Fig. 2 Open in new tabDownload slide Overall survival curves in 35 patients using Kaplan–Meier estimation. The difference in survival rates between cN0+N1 and cN2 subsets using the log rank test is statistically significant (P = 0.039). Fig. 2 Open in new tabDownload slide Overall survival curves in 35 patients using Kaplan–Meier estimation. The difference in survival rates between cN0+N1 and cN2 subsets using the log rank test is statistically significant (P = 0.039). The N status strongly reflected outcome as far as local control was concerned (Fig. 2). The long-term survivors originate mainly from the cN0 and cN1 categories; first of all, those achieving chemotherapy induced complete pathological remission (pCR). The 5-year tumor-free survival rate was 29%, and the 10-year tumor-free survival rate was 23%. 5 Discussion The most frequent site of relapse is the area of the primary tumor or its regional lymph nodes. Clinically, half of patients fail initially at the primary site, and for half of those patients, the primary site may be the only area of failure. Similar results have been found at autopsy. Radiotherapy reduces local recurrence by 50%, but isolated local failure rates are still about 25–30% in most series [6]. The assumption that surgery should improve local control is the end-point of this study. Local tumor control is a basic condition of favorable outcome. There are only a small number of series in which patients with SCLC underwent induction chemotherapy followed by resection, and these patients are often reported together with patients who have had surgery as their initial treatment. Some studies are difficult to review and conclude upon, because of the varying patient eligibility and selection criteria, the disparity in series description, and a lack of uniformity in the course and data on the effect of subsequent management. It is worth noticing that a certain draw-back of these studies is a lack of a routine use of invasive techniques for determining pretreatment N status. Hence in eight, mainly prospective studies, published from 1984 to 1997 [7–14], we found 124 patients who had induction chemotherapy combined with resection and received no adjuvant thoracic irradiation (Table 5 ). The number of courses before thoracotomy ranged from 2 to 6; on average, 2–3 courses resulted in no residual tumor in the resected specimen in 0–25%. Of 124 patients, in 18 patients, no residual tumor was found in the resected specimen (14%). Two postoperative deaths were reported. After resection, in only one study, chemotherapy was not resumed [10]. Table 5 Open in new tabDownload slide Chemotherapy followed by resection and continuation of chemotherapy Table 5 Open in new tabDownload slide Chemotherapy followed by resection and continuation of chemotherapy In seven of these studies, the rate of local failure was 10.7% (12 of 112 patients resected); in one study, the incidence of local failure was not reported [8]. The median survival time was reported in six of eight papers, and ranged from 13 to 61.9 months. The 5-year survival rates, reported in three of eight papers, are as follows: 29 [14], 30.7 [13] and 33% [12]. Ninety-eight patients from six studies [15–20], listed in Table 6 , who received adjuvant radiotherapy of different timings, doses, and fractionations, proceeded, except for one study [6], by resumption of chemotherapy after resection. In the resected specimen, no residual tumor was found in 0–25%; among the 98 patients, no residual tumor was found in 11 cases (11.2%). Two operative deaths were reported. Eight patients experienced local failure (8%). Three additional patients developed local+distant relapse, increasing the local failure rate to 11%. Thus, the incidence of local relapse in the patients who had obtained thoracic irradiation was similar to the group of patients with no adjuvant radiotherapy. Table 6 Open in new tabDownload slide Chemotherapy followed by resection, chemotherapy and adjuvant thoracic radiotherapy Table 6 Open in new tabDownload slide Chemotherapy followed by resection, chemotherapy and adjuvant thoracic radiotherapy The above presented reviews of small groups of patients, who had undergone cytoreductive chemotherapy followed by resection, support the thesis that surgery incorporated in combined modality treatment improves local control. The incidence of local relapse in the quoted literature is within the bounds of 11%. In our series, the local relapse rate was 15% (5/33; Table 5). Considering the fact that many patients had locally far advanced disease, local tumor control is consistent with the aim the study. The results from the only prospective intergroup ECOG and EORTC randomized trial (1983–1989) to determine the benefit of surgical resection of residual disease to patients whose SCLC responded to combination chemotherapy did not indicate any benefit from the addition of surgery to multimodality treatment. Only patients with pure small cell cancers were enrolled in this study; patients with small peripheral nodules were excluded. After five courses of the CAV regimen, followed by resection, chemotherapy was not resumed; all patients received thoracic irradiation. This study concluded that pulmonary resection in 70 patients did not improve the survival rate for patients who responded to chemotherapy for SCLC, nor did it influence the pattern of relapse. The local failure rate was 38% in both arms. The median survival was 12 months for all enrolled patients and 16 months for those who were randomized. Surgical resection and staging did not identify any subsets that appeared to benefit from its addition to therapy [21]. The drawback of this study [21] is that all chemotherapy was delivered before surgical resection, thereby possibly delaying control of the primary tumor [24]. Resection was performed rather late (after five courses of induction chemotherapy), despite evidence suggesting that local treatment should be given early [25]. No resumption of chemotherapy after resection is also an important factor. During surgical maneuvers, many cancer cells are released into the blood stream in the immunocompromised patient. Continuation of chemotherapy after resection, at least three courses, appears indispensable. On the contrary, we do not think thoracic irradiation should be a routine procedure. The results of the only randomized study are a great disappointment. In IIIa disease, surgery is evidently the most controversial, but in earlier stages, resection improves the outcome in many series [6]. The Brompton Group reported the results of surgery in 28 patients who had undergone complete resection without adjuvant treatment (1980–1987). In 12 of these patients (12/28), the tumor was in a central position, and 14 patients required pneumonectomy. The 5-year overall survival for patients in stages I and III was 57.1 and 55.5%, respectively. No patients with stage II survived 5 years. The authors concluded that equally good results can be achieved with operation alone in a carefully selected group of patients [22]. Although it is difficult to follow such an approach, the study has a great cognitive advantage. In fact, discussion should focus not on the value of combined modality treatment, but on the sequence of methods applied. The groups performing up-front surgery argue for an accurate diagnosis and reliable staging of disease based on the examination of the resected specimen, including intrathoracic lymph nodes. Meanwhile, also prior to chemotherapy, adequate staging of the tumor is possible, although this clinical staging may be less accurate/understaged in some cases. Histological or cytological estimation of pretreatment N status is of fundamental value. In cN2 patients achieving a neoadjuvant chemotherapy induced response, successive evaluation of the mediastinum is indispensable. It means that in some cases, invasive procedures must be applied twice. The choice of technique for this evaluation should depend on the experience of the group. In III A down staged cases, resection should be carried out. In persistent N2 disease, surgery is contraindicated. Preoperative chemotherapy enables the evaluation of drug induced response. After an initial resection, no such monitoring is possible. Our policy is to start with cytoreductive chemotherapy. The current review of the available data by Lassen and Hansen and their conclusion that chemotherapy remains the first-line therapy for all patients with SCLC [23] is of great importance. According to our first protocol, the patients achieving cCR after three courses of induction chemotherapy were kept on systemic treatment because in the early 1980s, performing resection on a complete responder was deemed unacceptable. All of our four patients succumbed to local and distant relapse within 6 months. Drug induced clinical complete response is the most promising indication for resection, including the patients who require pneumonectomy. In the patients with complete remission (cCR), no viable cells of SCLC in the resected specimen were found (pCR); however, a pathological complete response (pCR) also occurred in cases not reaching cCR due to some inflammatory and fibrous reaction resembling residual tumor. We did not find any data in the literature indicating that, apart from the distinction of peripheral and central positions of the tumor, the location of the primary lesion in the lung parenchyma was considered in the choice of treatment modality. A tumor in the lower lobe makes the use of radiotherapy very difficult (Turrisi A 3rd, personal communication (T.L.), Colorado Springs, 1994). Is there a place for cytoreductive chemotherapy and surgery in such cases? 6 Conclusions Considering the fact that many patients enrolled in the study had locally far advanced disease, 15% (5/33), the local relapse rate means a satisfactory local tumor control corresponding with the aim of the study. No residual tumor in the resected specimen, particularly in the removed hilar+mediastinal lymph nodes (chemotherapy induced pCR), is the most favorable prognostic factor predicting long-term survival. It is essential to perform histological or cytological N status evaluation in all patients during the pretreatment period and after neoadjuvant chemotherapy in those cN2 patients who achieve response and thus, are potential candidates for surgery. Such evaluation calls for the use of invasive techniques, including mediastinoscopy and re-mediastinoscopy. Surgery should not be performed in the patients with persistent N2 disease. Our data confirm the prognostic importance of staging for SCLC categorized by the TNM system. This study was supported in part by the Bristol Myers Int. Co. The authors wish to thank Professor W. Ruka for statistical analysis and Dr M. Symonides for linguistic help. References [1] Lewiński T. , żulawski M. , Mioduszewska O. , Dziukowa J. , Szymendera J. , Kozlowicz- Gudzińska I. , Smorczewska M. , Kodur E. , Maryniak R. , Pietraszek A. , Kawecki A. . 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Treatment of small cell lung cancer patients , Ann Oncol , 1999 , vol. 10 Suppl 6 (pg. S83 - S91 ) Google Scholar Crossref Search ADS PubMed WorldCat Author notes 1 Dr. Turski died on 2 November 2000 © 2001 Elsevier Science B.V. All rights reserved. Elsevier Science B.V. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Cardio-Thoracic Surgery Oxford University Press

Small cell lung cancer I–III A: cytoreductive chemotherapy followed by resection with continuation of chemotherapy

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Oxford University Press
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© 2001 Elsevier Science B.V. All rights reserved.
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Articles
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1010-7940
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1873-734X
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10.1016/S1010-7940(01)00787-4
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Abstract

Abstract Objectives: To define the place for surgery in combined modality treatment of small cell lung cancer patients. The endpoint was: does complete resection reduce the risk of local failure? Methods: Between November 1981 and June 1996, 75 patients in stage I–III A, many of them with a bulky cN2 tumor at presentation, were exposed to VP-16 based cytoreductive chemotherapy. After three courses of induction treatment, 46 patients underwent thoracotomy and 35 of them had resection. Results: There were two sudden deaths (pulmonary embolism). No other complications were observed. In six cases (6/35=16%), no residual tumor was found in the resected specimen. Four weeks after surgery, chemotherapy was resumed. Three patients experienced local relapse (3/33), among them, the single patient with incomplete resection, and two other patients developed local and distant failure (2/33). Thus, the local relapse rate was 15% (5/33). Eight patients, mainly with chemotherapy induced surgicopathological complete remission (pCR) and with lymph nodes free of tumor in surgical specimens (pN0), are alive, tumor-free, at a median of 136+ months. Two patients died tumor-free at 65 and 147 months. One patient died of unrelated causes at 21 months with no evidence of disease at autopsy. The median survival in the cN0+N1 subsets was 25.09 months, whereas in cN2 disease, this was 13.75 months. There were no long-term survivors among the patients with persistent N2 disease. The median survival in all 35 patients using the Kaplan–Meier method was 18 months; the 5-year tumor-free survival rate was 29% and the 10-year tumor-free survival rate was 23%. Conclusions: Satisfactory local tumor control confirmed the assumption of the study. No residual tumor in the resected specimen (pCR) is the most favorable prognostic factor and determinant of long-term survival. Surgery should not be performed in the patients with persistent N2 disease. Small cell lung cancer, Stage I–III A, Neoadjuvant cytoreductive chemotherapy 1 Introduction At the time of diagnosis, more than 90% of small cell lung cancer (SCLC) patients experience spread to the regional lymph nodes and/or dissemination to distant metastatic sites. Chemotherapy is the cornerstone of management. Potential candidates for surgical resection comprise less than 10% of patients. In 1981, we started the study, aiming to find a place for surgery in combined modality treatment of limited SCLC including patients with locally, far advanced disease. The endpoint was: does complete resection reduce the risk of local failure? Determination of the site of first relapse was essential. Special care was given to the patients’ lifelong follow-up. The protocol was accepted by the Local Ethics Committee. All patients were informed of the potential risk of the proposed treatment. 2 Methods 2.1 Staging Staging on entry included physical examination, radiography, chest CT scan, bronchoscopy, peritoneoscopy, liver scan, bilateral bone marrow trephine biopsy and aspiration, and bone scan [1]. Mediastinoscopy was not a routine procedure. It was applied occasionally, mainly to exclude spread to the opposite side. Subsequently, liver imaging was extended to include abdominal and retroperitoneal US. Supplementary staging included brain, retroperitoneal space and liver CT scans [1]. As the study progressed, thorough staging was performed on entry. After induction chemotherapy, resection and completion of all chemotherapy, re-staging was performed including brain, chest and abdominal CT scans, abdominal US, bilateral bone marrow biopsy and aspiration, and bone scan. 2.2 Patients Inclusion criteria were: untreated patients (including those who underwent exploratory thoracotomy) with histological and/or cytological diagnosis of SCLC (WHO, 1981) confined to the hemithorax of origin, including ipsilateral N2 disease, age of up to 65 years, Karnofsky performance status (KPS) of ≫70, with no diabetes, no bronchoscopical contraindication for surgery, and no medical contraindication for pneumonectomy. There was no patient selection. 2.3 Drugs In 1981, there was no understanding of the risk of pneumonectomy after induction chemotherapy, particularly with intention to continue systemic treatment for up to 1 year. In the regimen developed in 1978–1981 by Heine H. Hansen and his group at the Finsen Institute [2], the doses of three drugs were reduced below levels accepted as the standard at that time: CTX, 700 mg/m2 day 1; VCR, 1.3 mg/m2 day 1; CCNU, 50 mg/m2 day 1; VP-16, 100 mg/m2 days 1–5 orally. 2.4 Treatment Chemotherapy was given every 4 weeks. Clinical and radiological assessment, full blood count and serum biochemistry studies were carried out before every course. The patients with progression after two cycles were re-biopsied and off-study. Re-evaluation after three courses included radiography, bronchoscopy plus cytology and biopsy. The patients who experienced no change (NC) off-study. The patients in complete remission (CR) were kept on chemotherapy. In the early 1980s, performing resection, particularly pneumonectomy, on a patient who had responded completely was deemed unacceptable. The patients with no dissemination and partial remission (PR; even little response) were operated on. Thoracotomy was carried out at 4 weeks after the onset of the third course of treatment. All patients who could be resected were to have primary, hilar and mediastinal disease removed. According to the protocol, the patients were operated on irrespective of N status. In a case of pneumonectomy, the bronchial stump was closed by the original hand suture technique developed by one of us (C.T.) The technique consists of bringing the membranous part of the main bronchus towards the cartilaginous wall on the level of the main carina and reduplicating the bronchus. Then, a reduction of the length of the bronchial stump is performed by excision of the cartilaginous part of it, with preservation of the membranous bronchus as a flap to cover the bronchial stump. The reduplicated bronchial stump is sutured with figure-of-eight stitches [3]. As the study progressed, lymph node removal was extended to non-palpable and non-enlarged nodes of the superior and inferior mediastinum. Postoperative chemotherapy was started 4 weeks after resection. After nine additional courses (a total of 12 cycles) – at 1 year – thorough re-staging was performed. The patients achieving CR received prophylactic cranial irradiation (PCI) [4]. 2.5 Some changes in the study design Since 1987, we modified the treatment protocol. We chose drugs of different and non-overlapping toxicities, with rarely observed pulmonary and cardiac damage and low risk to induce secondary cancer. Etopozid+cisplatin–EP-combination was used in standard doses every 3 weeks. The duration of treatment was shortened to 6 months. The age limit was extended to 70 years. Patients who experienced PR or CR had thoracotomy performed. A schematic study design is shown in Fig. 1 . Four weeks after resection, four additional courses of systemic therapy were started. After the completion of chemotherapy, thorough re-staging was carried out. In the patients achieving CR, PCI was applied, but not as a routine procedure. Fig. 1 Open in new tabDownload slide Schematic diagram of study since 1987. Fig. 1 Open in new tabDownload slide Schematic diagram of study since 1987. In the course of time, an effort was made to confirm N2 disease by transcarinal puncture via bronchoscope. 3 Materials Between November 1981 and June 1996, 75 patients were exposed to induction chemotherapy. The study census is listed in Table 1 . According to the first protocol developed in 1981, the patients with CR were kept on chemotherapy. In one patient, no palpable tumor at exploration indicated CR (early 1980s) and we had refrained from resection. Thirty-five patients underwent resection: 27 pneumonectomies, one bilobectomy, and seven lobectomies. Table 1 Open in new tabDownload slide Study census Table 1 Open in new tabDownload slide Study census The characteristics of resected patients on entry were as follows: the male to female ratio was 30:5; and the age ranged in males from 29 to 67 years (median, 51 years) and in females from 38 to 58 years (median, 48 years). The KPS ratings were: 100%, 12 patients; 90%, 14 patients; and 80%, nine patients. Weight loss was noted in 11 patients (11/35). In 13 patients, the primary tumor was located in the lower lobe (13/35). The tumor size, expressed as the total cross-sectional area on X-ray including CT scan, in two-thirds of the patients exceeded 30 cm2. Table 2 shows the pretreatment diagnosis and histology of the resected specimen after three courses of chemotherapy. Table 2 Open in new tabDownload slide Pretreatment histological and/or cytological diagnosis and histology of the resected specimen in 35 patients Table 2 Open in new tabDownload slide Pretreatment histological and/or cytological diagnosis and histology of the resected specimen in 35 patients 4 Results Table 3 shows TNM subsets, vital status and the results of the treatment. Patients were divided into three subgroups in accordance with the clinical stage of disease on entry. The pathological stage after three courses of chemotherapy and resection is shown in the second column. For every patient, data on the pattern and time of first relapse and survival are given. Survival was calculated from the date of first course of induction chemotherapy. The tumor-free survival is indicated with bold font. Table 3 Open in new tabDownload slide TNM — clinical and pathological subsets, type of failure (local vs. distant), results of the treatment and vital status in 35 patients Table 3 Open in new tabDownload slide TNM — clinical and pathological subsets, type of failure (local vs. distant), results of the treatment and vital status in 35 patients Initial tumor staging and all subsequent re-stagings were according to the new international TNM classification system [5]. Only in one patient did we find pathological stage IIIa disease in the face of clinical stage I. Of the 35 patients who responded to three courses of VP-16 based cytoreductive chemotherapy, followed by resection with continuation of systemic treatment, eight patients are alive and tumor-free at 95–182 months (median, 136+ months; Table 3). Of 11 long-term survivors, four patients (among them, three achieving pCR) were exposed to reduced doses of chemotherapy used in the first phase of the study. It is necessary to point out that according to the protocol, TRT was not employed; however, in three cases, salvage treatment was given. The pattern of failure is shown in Table 4 . Local recurrence developed in three patients at 5, 9 and 16 months, and among them was the only patient with incomplete resection (R2 in the superior vena cava region). One of them (pN1 patient), who relapsed locally at 5 months, obtained salvage TRT and is tumor-free at 122 months. Local and distant failure was observed in two patients. Estimation of the observed overall survival using the Kaplan–Meier method is shown in Fig. 2 . The median survival in all 35 resected patients was 18.47 months. The median survival in the cN0+N1 subsets was 25.09 months, whereas in cN2 disease, this was 13.75 months. Table 4 Open in new tabDownload slide Pattern of failure — site of first relapse in 21 patients Table 4 Open in new tabDownload slide Pattern of failure — site of first relapse in 21 patients Fig. 2 Open in new tabDownload slide Overall survival curves in 35 patients using Kaplan–Meier estimation. The difference in survival rates between cN0+N1 and cN2 subsets using the log rank test is statistically significant (P = 0.039). Fig. 2 Open in new tabDownload slide Overall survival curves in 35 patients using Kaplan–Meier estimation. The difference in survival rates between cN0+N1 and cN2 subsets using the log rank test is statistically significant (P = 0.039). The N status strongly reflected outcome as far as local control was concerned (Fig. 2). The long-term survivors originate mainly from the cN0 and cN1 categories; first of all, those achieving chemotherapy induced complete pathological remission (pCR). The 5-year tumor-free survival rate was 29%, and the 10-year tumor-free survival rate was 23%. 5 Discussion The most frequent site of relapse is the area of the primary tumor or its regional lymph nodes. Clinically, half of patients fail initially at the primary site, and for half of those patients, the primary site may be the only area of failure. Similar results have been found at autopsy. Radiotherapy reduces local recurrence by 50%, but isolated local failure rates are still about 25–30% in most series [6]. The assumption that surgery should improve local control is the end-point of this study. Local tumor control is a basic condition of favorable outcome. There are only a small number of series in which patients with SCLC underwent induction chemotherapy followed by resection, and these patients are often reported together with patients who have had surgery as their initial treatment. Some studies are difficult to review and conclude upon, because of the varying patient eligibility and selection criteria, the disparity in series description, and a lack of uniformity in the course and data on the effect of subsequent management. It is worth noticing that a certain draw-back of these studies is a lack of a routine use of invasive techniques for determining pretreatment N status. Hence in eight, mainly prospective studies, published from 1984 to 1997 [7–14], we found 124 patients who had induction chemotherapy combined with resection and received no adjuvant thoracic irradiation (Table 5 ). The number of courses before thoracotomy ranged from 2 to 6; on average, 2–3 courses resulted in no residual tumor in the resected specimen in 0–25%. Of 124 patients, in 18 patients, no residual tumor was found in the resected specimen (14%). Two postoperative deaths were reported. After resection, in only one study, chemotherapy was not resumed [10]. Table 5 Open in new tabDownload slide Chemotherapy followed by resection and continuation of chemotherapy Table 5 Open in new tabDownload slide Chemotherapy followed by resection and continuation of chemotherapy In seven of these studies, the rate of local failure was 10.7% (12 of 112 patients resected); in one study, the incidence of local failure was not reported [8]. The median survival time was reported in six of eight papers, and ranged from 13 to 61.9 months. The 5-year survival rates, reported in three of eight papers, are as follows: 29 [14], 30.7 [13] and 33% [12]. Ninety-eight patients from six studies [15–20], listed in Table 6 , who received adjuvant radiotherapy of different timings, doses, and fractionations, proceeded, except for one study [6], by resumption of chemotherapy after resection. In the resected specimen, no residual tumor was found in 0–25%; among the 98 patients, no residual tumor was found in 11 cases (11.2%). Two operative deaths were reported. Eight patients experienced local failure (8%). Three additional patients developed local+distant relapse, increasing the local failure rate to 11%. Thus, the incidence of local relapse in the patients who had obtained thoracic irradiation was similar to the group of patients with no adjuvant radiotherapy. Table 6 Open in new tabDownload slide Chemotherapy followed by resection, chemotherapy and adjuvant thoracic radiotherapy Table 6 Open in new tabDownload slide Chemotherapy followed by resection, chemotherapy and adjuvant thoracic radiotherapy The above presented reviews of small groups of patients, who had undergone cytoreductive chemotherapy followed by resection, support the thesis that surgery incorporated in combined modality treatment improves local control. The incidence of local relapse in the quoted literature is within the bounds of 11%. In our series, the local relapse rate was 15% (5/33; Table 5). Considering the fact that many patients had locally far advanced disease, local tumor control is consistent with the aim the study. The results from the only prospective intergroup ECOG and EORTC randomized trial (1983–1989) to determine the benefit of surgical resection of residual disease to patients whose SCLC responded to combination chemotherapy did not indicate any benefit from the addition of surgery to multimodality treatment. Only patients with pure small cell cancers were enrolled in this study; patients with small peripheral nodules were excluded. After five courses of the CAV regimen, followed by resection, chemotherapy was not resumed; all patients received thoracic irradiation. This study concluded that pulmonary resection in 70 patients did not improve the survival rate for patients who responded to chemotherapy for SCLC, nor did it influence the pattern of relapse. The local failure rate was 38% in both arms. The median survival was 12 months for all enrolled patients and 16 months for those who were randomized. Surgical resection and staging did not identify any subsets that appeared to benefit from its addition to therapy [21]. The drawback of this study [21] is that all chemotherapy was delivered before surgical resection, thereby possibly delaying control of the primary tumor [24]. Resection was performed rather late (after five courses of induction chemotherapy), despite evidence suggesting that local treatment should be given early [25]. No resumption of chemotherapy after resection is also an important factor. During surgical maneuvers, many cancer cells are released into the blood stream in the immunocompromised patient. Continuation of chemotherapy after resection, at least three courses, appears indispensable. On the contrary, we do not think thoracic irradiation should be a routine procedure. The results of the only randomized study are a great disappointment. In IIIa disease, surgery is evidently the most controversial, but in earlier stages, resection improves the outcome in many series [6]. The Brompton Group reported the results of surgery in 28 patients who had undergone complete resection without adjuvant treatment (1980–1987). In 12 of these patients (12/28), the tumor was in a central position, and 14 patients required pneumonectomy. The 5-year overall survival for patients in stages I and III was 57.1 and 55.5%, respectively. No patients with stage II survived 5 years. The authors concluded that equally good results can be achieved with operation alone in a carefully selected group of patients [22]. Although it is difficult to follow such an approach, the study has a great cognitive advantage. In fact, discussion should focus not on the value of combined modality treatment, but on the sequence of methods applied. The groups performing up-front surgery argue for an accurate diagnosis and reliable staging of disease based on the examination of the resected specimen, including intrathoracic lymph nodes. Meanwhile, also prior to chemotherapy, adequate staging of the tumor is possible, although this clinical staging may be less accurate/understaged in some cases. Histological or cytological estimation of pretreatment N status is of fundamental value. In cN2 patients achieving a neoadjuvant chemotherapy induced response, successive evaluation of the mediastinum is indispensable. It means that in some cases, invasive procedures must be applied twice. The choice of technique for this evaluation should depend on the experience of the group. In III A down staged cases, resection should be carried out. In persistent N2 disease, surgery is contraindicated. Preoperative chemotherapy enables the evaluation of drug induced response. After an initial resection, no such monitoring is possible. Our policy is to start with cytoreductive chemotherapy. The current review of the available data by Lassen and Hansen and their conclusion that chemotherapy remains the first-line therapy for all patients with SCLC [23] is of great importance. According to our first protocol, the patients achieving cCR after three courses of induction chemotherapy were kept on systemic treatment because in the early 1980s, performing resection on a complete responder was deemed unacceptable. All of our four patients succumbed to local and distant relapse within 6 months. Drug induced clinical complete response is the most promising indication for resection, including the patients who require pneumonectomy. In the patients with complete remission (cCR), no viable cells of SCLC in the resected specimen were found (pCR); however, a pathological complete response (pCR) also occurred in cases not reaching cCR due to some inflammatory and fibrous reaction resembling residual tumor. We did not find any data in the literature indicating that, apart from the distinction of peripheral and central positions of the tumor, the location of the primary lesion in the lung parenchyma was considered in the choice of treatment modality. A tumor in the lower lobe makes the use of radiotherapy very difficult (Turrisi A 3rd, personal communication (T.L.), Colorado Springs, 1994). Is there a place for cytoreductive chemotherapy and surgery in such cases? 6 Conclusions Considering the fact that many patients enrolled in the study had locally far advanced disease, 15% (5/33), the local relapse rate means a satisfactory local tumor control corresponding with the aim of the study. No residual tumor in the resected specimen, particularly in the removed hilar+mediastinal lymph nodes (chemotherapy induced pCR), is the most favorable prognostic factor predicting long-term survival. 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Journal

European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Aug 1, 2001

Keywords: Small cell lung cancer Stage I–III A Neoadjuvant cytoreductive chemotherapy

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