Eur J Cardiothorac Surg 2004;26:183-188
© 2004 Elsevier Science NL
A retrospective comparative study of surgery followed by chemotherapy vs. non-surgical management in limited-disease small cell lung cancer
Andrzej Badzioa,
Krzysztof Kurowskib,
Hanna Karnicka-Mlodkowskac,
Jacek Jassema*
a Department of Oncology and Radiotherapy, Medical University of Gda
sk, ul. Debinki 7, 80-211 Gdask, Poland
b Department of Thoracic Surgery, Medical University of Gdask, Gdask, Poland
c Department of Chemotherapy, PCK Maritime Hospital, Gdynia, Poland
Received 7 January 2004;
received in revised form 8 April 2004;
accepted 13 April 2004.
* Corresponding author. Tel./fax: +45-58-3492270
e-mail: jjassem{at}amg.gda.pl
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Abstract
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Objective: The role of surgery in limited SCLC is still a matter of controversy. Even though the response rates to chemotherapy are very high, prognosis of SCLC patients has remained poor with a median survival of only 12–14 months for limited disease. High incidence of local relapses after chemotherapy in limited-stage SCLC led to reassessment of the role of local treatment in the multimodality management of this tumor. Methods: We performed retrospective comparative analysis of survival in a series of 134 limited-stage SCLC patients treated between 1984 and 1996 with either complete resection followed by chemotherapy (67 patients), or with conventional non-surgical management (67 patients). In all patients who underwent resection, the diagnosis of SCLC was established only postoperatively. The control (non-surgical) group was selected using ‘pair-matched case-control’ methodology, out of 176 limited-stage patients potentially suitable for surgery (i.e. with no pleural effusion or other local advancement, no supraclavicular lymph node involvement and good performance status), but treated without resection. The major prognostic factors were well balanced between these two groups. Total series included 109 males and 25 females, 20 patients with T1 and 114 patients with T2 disease, 51 N0, 43 N1 and 40 N2 disease. Results: Median survival in patients treated with and without surgery was 22 months and 11 months, respectively, (P<0.001). The two-year and five-year survival probabilities were 43 and 27%, respectively, in the surgical group, and 17 and 4%, respectively, in the non-surgical group. Subset analysis confirmed significantly longer survival with surgery in all T and N categories, except for N2 disease. Local relapse occurred in 15 and 55% of patients treated with and without surgery, respectively, (P<0.001). Distant relapse probabilities were similar in both groups (36 and 40%, respectively). The most common site of metastases in the entire series was brain, followed by liver, lymph nodes, bone, lung and skin. Conclusions: Our results suggest a possible role of surgery in limited-stage SCLC. Thus, a randomised study addressing this issue seems to be justified.
Key Words: Small cell lung cancer • Limited disease • Surgery • Local control • Comparative study
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1. Introduction
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Small cell lung cancer (SCLC) represents approximately one-quarter of all bronchogenic neoplasms and is characterised by rapid growth and early dissemination. Surgery used to be a standard management of patients with limited disease until the late 1960s, but treatment results were very poor due to high incidence of metastases [1]. Surgical treatment for SCLC was generally abandoned after the study of the British Medical Council had showed that fewer than 2% of patients survived more then two years after the resection [2]. Subsequently, after cyclophosphamide and a number of other drugs had been found to improve survival in SCLC, chemotherapy became the mainstay of SCLC treatment [3,4]. However, even though the response rates to chemotherapy are very high, prognosis of SCLC patients has remained poor with a median survival of only 12–14 months for limited disease. High incidence of local relapses after chemotherapy in limited-stage SCLC led to reassessment of the role of local treatment in the multimodality management of this tumor. Radiation therapy has been proved to prolong survival in limited-stage SCLC patients [5]. The role of surgery remains uncertain, but some authors have reported 5-year survival rates of 30–40% in very limited-stage patients treated with chemotherapy combined with resection. To assess the role of surgery in SCLC we performed a retrospective analysis of survival in two pair-matched groups of limited stage patients, of which one was managed with complete pulmonary resection followed by chemotherapy, and the other with conventional non-surgical approach.
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2. Material and methods
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2.1. Patient selection
Between 1984 and 1996, 76 SCLC patients were treated with surgery at the Thoracic Surgery Department of the Medical University of Gdansk Poland. In all instances thoracotomy was performed due to difficulties in obtaining a representative tumor sample for definitive histopathological diagnosis. The diagnosis of SCLC in this group was established only after the resection, based on the examination of surgical specimen. The group managed with surgery was highly selected with regard to disease stage and general status. Major indications for surgery were standard for lung cancer, i.e. clinical stage I–IIIA and good performance status. In all patients resection was followed by standard chemotherapy.
In order to assess the role of surgery in the treatment of limited-stage SCLC, treatment outcome in this group of patients was compared with that of patients managed with conventional non-surgical approaches. To secure a relatively reliable comparative analysis between patients treated with and without surgery, we performed matched case-control procedure, i.e. from the group of patients treated with conventional approaches we selected cases with similar favourable prognostic factors matching those in the surgical group. First, from a total of 469 patients treated with non-surgical approaches, we selected 243 limited-stage cases defined as the disease confined to one hemithorax and ipsilateral supraclavicular nodes. Then, the patients with supraclavicular nodal involvement, pleural effusion or low performance status were excluded, leaving a group of 176 patients potentially suitable for surgery. Out of a total of 76 operated patients, in 7 data obtained before surgery, were insufficient for reliable clinical staging, and these patients were excluded from further analysis. Each patient from the surgical group was then pair-matched to a patient from the non-surgical group, taking into account the most important prognostic factors: performance status, clinical T stage, clinical N stage and sex. Patients from both groups for whom no comparable control case could be found were then excluded from further analysis. As a result of this process, a group of 134 patients was selected for comparative analysis; 67 treated with resection and chemotherapy and 67 managed with conservative approach only. These groups were well balanced for major prognostic factors: clinical T and N stage, performance status and sex, (Table 1)
and the only difference was related to age (the means of 57 and 54 years in patients treated with and without surgery, respectively).
2.2. Initial workup
Pretreatment evaluation in both groups included patient history, physical examination, complete blood count, serum chemistry, bronchoscopy, chest rentgenography, ultrasound or computed tomography (CT) of the abdomen, bone scan and brain CT. Mediastinoscopy was not routinely used at the time this material was collected and neither bone biopsy was done. Chest CT was done in all patients from surgical group and in a majority of patients from non-surgical group. The histological diagnosis in non-surgical group was established based on examination of specimen obtained in bronchoscopy, otherways thranstoracal biopsy was done. Clinical staging was performed in all patients according to UICC classification from 1986 [6]. Patients treated with surgery were additionally staged based on pathological examination of resected specimen. Patients from surgery group assigned to cN2 category had minimal mediastinal involvement and thus were considered eligible for surgery.
2.3. Treatment
All patients in the surgical group underwent radical pulmonary resection including pneumonectomy (30 cases) and lobectomy (37 cases). In all patients surgery was followed by chemotherapy. Four different regimes were used: CAV (cyclophosphamide, doxorubicin and vincristin) 4–8 cycles, CDE (cyclophosphamide, doxorubicin, etoposide) 4–6 cycles, VP (cisplatine, etposide) 4–6 cycles and MCCC/CAV/VI (metotrexate, cyclophosphamide, CCNU, ifosfamide, etoposide) 4–6 cycles. Twenty three patients in the surgery group received additionally elective cranial irradiation.
In patients treated with conservative approach two chemotherapy regimes were used: CCMV (cyclophosphamide, CCNU, metotrexate, vincristin) and ACOM (doxorubicin, CCNU, methorexate, vincristin). Irradiation to the primary tumor and mediastinal lymph nodes was administered in 39 patients. Doses of 30 Gy in 10 fractions, 40 Gy in 20 fractions or 50 Gy in 25 fractions were used. No elective cranial irradiation was used in this group of patients.
2.4. Statistical methods
Survival times were calculated from the time of diagnosis until the date of death or last follow up. Time to local relapse was defined as time to local tumor recurrence (in patients managed with surgery and in complete responders to chemo(radio)therapy), or as time to progression (in non-surgical patients who had not achieved complete response to chemo(radio)therapy). Actuarial survival curves were computed using the Kaplan-Meyer method and comparisons of survival were done with the log-rank test. In analysis of prognostic factors, the proportional-hazard backward stepwise regression model was used. Categorical data were compared with 
2 test and Fisher's exact test. Wilcoxon test was used to asses differences between continues variables. In this study, a P value of 0.05 or less was considered significant.
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3. Results
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Statistical analysis included all 134 patients of whom 67 underwent surgery followed by chemotherapy and 67 were treated with non-surgical approaches. Median follow-up for all patients was 72 months. Median survival for the entire group was 16.1 months and by the time of the final analysis 116 patients (87%) have deceased. Median survival for patients treated with and without surgery was 22.3 months and 11.2 months, respectively (Fig. 1)
. One- and two-year survival probabilities in patients managed with surgery were 70 and 43%, and in patients treated with conservative approach 45 and 17%, respectively, (P<0.001). Relative hazard ratio of death in patients treated with surgery was 0.42 (95% confidence interval 0.28–0.61). Five-year survival probability in patients treated with and without surgery was 27 and 4%, respectively.
Survival advantage related to surgery was observed in patients with cT1 and cT2 disease, and in patients with cN0 and cN1 disease (Table 2)
, whereas in patients with cN2 disease the difference did not reach the level of significance (Figs. 2 and 3)
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By the time of this analysis a total 90 patients developed relapse or disease progression; 34 (53%) in surgical group and 56 (86%) in non-surgical group (P<0.001). Median time to relapse or disease progression in patients treated with or without surgery was 20.9 and 7.0 months, respectively, (P<0.001). Likewise, local relapse probabilities in these groups were 15 and 55%, respectively, (P<0.001). The probabilities of distant metastases did not differ significantly in both groups (36 and 40%, respectively, P=0.54).
Multivariate analysis of prognostic factors included the following variables: surgical treatment, sex, cT category, cN category, weight loss, performance status, age and tumor size. Three independent, significant factors reducing the risk of death were identified: surgical treatment, female sex and no involvement of regional lymph nodes (Table 3)
.
In patients managed with thoracic surgery there was a 39% discrepancy between the N stage established clinically (cN) and pathologically (pN) and 26% discrepancy between cT and pT. In this group, clinical staging did not influence prognosis, whereas in patients managed with surgery pathological nodal involvement (pN1-2) carried worse prognosis than pathological N0 disease (P=0.02). No impact on prognosis was found in relation to T stage established either clinically or pathologically.
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4. Discussion
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For more then three decades now standard management of SCLC has included chemotherapy or chemotherapy combined with irradiation. Nevertheless, the role of surgery in the multimodality treatment remains to be debated. In the 1980s several studies using surgery as a part of the multimodality treatment were published and their results were controversial. In the largest prospective study, 148 SCLC patients who underwent radical resection were randomised to one of four adjuvant chemotherapy regimes [7]. Five-year survival was 23% for the entire group, 59% for T1N0M0, 31% for T1N1M0 and only 3.6% for patients with mediastinal lymph node involvement. Similar outcomes were obtained in other retrospective studies employing resection as a primary treatment or after standard chemotherapy. Five-year survival rates reported in these studies were in the range of 30–80% [8–10], considerably higher then with non-surgical approaches. It is debatable though of whether this favourable survival was related to surgery added to systemic treatment or to the patient selection. SCLC patients eligible for resection represent a special subset characterised by early clinical stage and good performance status. In consequence their prognosis is better irrespective of whether surgery is attempted or not. This favourable preselection may considerably influence the results of the published studies. In the present study we used matched case-control methodology to optimise comparative analysis and to minimise selection bias. Thus, the two groups of patients subjected to this analysis were well balanced for the most important prognostic factors—disease stage, sex and performance status. However, due to retrospective character of our study, there were several limitations making its interpretation difficult. The patients were treated over a period of 12 years; within this time treatment standards have been a subject of various modifications. For example, chemotherapy regimes used in both groups were different, and some combinations are no longer in routine clinical use. Many patients in the non-surgical group did not receive thoracic irradiation or received doses that may now be considered suboptimal, and prophylactic cranial irradiation was not used in those patients. Despite that, treatment results in this group were similar to those reported by other authors using currently available chemotherapy regimes [11] and even somewhat better than expected, possibly due to aforementioned selection criteria. Our results suggest that surgery added to chemotherapy may be associated with therapeutic benefit in limited SCLC. Two-year and five-year survival probabilities of 43 and 27%, respectively, were similar to the results in other series of limited-stage SCLC patients managed by surgery [7,9,12]. Five year survival of 27% in patients who underwent resection is strikingly higher then a mere 5% in the group treated with conservative approach. Similar outcomes were achieved by Hara et al. [13]; in their study five-year survival probabilities in patients treated with and without surgery were 33 and 4%, respectively.
The only randomised trial evaluating the role of surgery in limited-stage SCLC was that conducted by the Lung Cancer Study Group [14]. This study included 144 SCLC patients, all administered chemotherapy followed by chest irradiation. The patients were then randomised to surgery or no further treatment. No impact of surgery on survival was found, with two-year survival probability of 20% in both study arms. However, this study included only patients with regional nodal involvement (T3N1M0–T3N2M0), and patients with early disease who were most likely to benefit from surgical treatment were excluded. Thus, it is difficult to extend the results of this trial on the entire population of SCLC patients potentially eligible for surgery. Other retrospective comparative studies showed contradictory results. Southwest Oncology Group Protocol 7628 demonstrated two-year survival of 45 and 14% in patients treated with and without surgery, respectively, [15], whereas in the retrospective study of Valdiviesco et al. [16] the use of surgery was not associated with any survival gain.
In the majority of published studies survival benefit related to surgery was limited to stage I and II disease [7,17]. This finding is concordant with our observations demonstrating no significant survival benefit in patients with mediastinal lymph node involvement. Hence, patients without mediastinal lymph node involvement at preoperative staging seem to be optimal candidates in future studies evaluating the role of surgery in limited-stage SCLC.
Our data showed 39% inaccuracy in the clinical assessment of mediastinal nodal involvement in patients treated with surgery, and a high percentage of pN2 disease, most likely reflecting a high metastatic potential of SCLC. These findings were mainly due to avoiding preoperative mediastinoscopy in the analysed period. Currently mediastinoscopy is considered a standard procedure in preoperative work-up of lung cancer patients. In the study of Inoue et al. [18] mediastinoscopy findings correlated with final examination of surgical specimen in more then 80% of operated SCLC patients.
Multivariate analysis of overall survival in our series demonstrated three independent prognostic factors: involvement of regional lymph nodes, surgical treatment and sex. Performance status, considered an important prognostic factor in SCLC [19], did not correlate with treatment outcome in this study. This can probably be explained by small patient sample and exclusion of patients with performance status of 2 or more.
Although SCLC, due to its very high metastatic potential, is considered a systemic disease, local relapse occurs in up to 80% of limited-stage patients managed with chemotherapy alone [20]. Autopsy data shows that up to 16% of limited-stage SCLC patients die with a relapse confined to the thorax [21]. Clearly, there is a subset of patients that may potentially benefit from more aggressive local treatment. In our study in the surgical group the chest tumour was removed prior to chemotherapy. Nevertheless, we intentionally decided not to select patients in the control group based on complete remission after chemotherapy, as this might have produced a substantial bias (chemosensitivity, an important prognostic factor in SCLC, could not be assessed in the surgery group). In our study local relapse probability was significantly lower in patients treated with surgery (15%) than in those approached with non-surgical methods (55%), whereas distant relapse rates were similar in both groups: 36 and 40%, respectively. Similar results were published by other authors [22,23]. Metaanalysis published in 1992 demonstrated that radiation therapy given to mediastainum and primary tumor area is associated with prolonged survival in limited-stage SCLC patients [5]. Further improvement has also been achieved with the use of more intensive, hyperfractionated irradiation, as compared to conventional radiotherapy [24]. These data suggest that improved local control may possibly be translated into prolonged survival in selected limited-stage SCLC patients.
We are aware of numerous limitations of our study, making its interpretation difficult, nevertheless improved local control and prolonged survival in selected SCLC patients managed with surgery is an intriguing finding and warrants further exploration. Therefore, a randomised study assessing the role of surgery in combined modality treatment of selected SCLC patients with limited disease seems to be justified. Such a study should include patients who are most likely to benefit from surgical treatment; operable limited disease patients without mediastinal lymph nodes involvement. Status of mediastinal lymph-nodes should be assessed by mediastinoscopy in all patients. Study arms could include surgery followed by chemotherapy and chemotherapy combined with thoracic irradiation with prophylactic cranial irradiation in both arms. Estimated number of patients required to detect a difference of 20% in two year survival between those groups is in a range of 90 in each arm of the study. In a similar study designed in Germany, patients are randomised to induction chemotherapy, surgery and thoracic irradiation or chemotherapy and adjuvant radiotherapy [25].
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5. Conclusions
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- Our results suggest that surgery added to chemotherapy may improve local control and be associated with therapeutic benefit in limited SCLC.
- Survival benefit related to surgery is probably limited to clinical stage I and II disease.
- A randomised study assessing the role of surgery in combined modality treatment of selected SCLC patients with limited disease seems to be justified.
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Abstract
1. Introduction
