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In patients with resected lung cancer, sarcomatoid carcinomas are reputed to carry a worse prognosis. Although generally felt to be chemo-refractory, little data is available about chemotherapy in these patients. We sought to determine the effect of perioperative chemotherapy in patients with completely resected sarcomatoid carcinomas of the lung.
We reviewed the pathology reports of 4,675 consecutively resected patients at Memorial Sloan-Kettering between 2000–2010. Charts and images were reviewed for patients with a histological diagnosis of sarcomatoid carcinoma. Response to neoadjuvant chemotherapy was assessed radiographically. Kaplan-Meier disease free probability (DFP) curves were compared for patients who did and did not received perioperative chemotherapy, stratified by pathological stage.
Of the 4675 patients who underwent an R0 lung cancer resection, 56 were diagnosed with sarcomatoid carcinomas (1%). Twenty received neoadjuvant and/or adjuvant chemotherapy. Overall radiographic response rate (minor + major) to neoadjuvant chemotherapy was 73% (95% CI 48–90%) in the 15 evaluable patients. The median DFP of patients who received chemotherapy was 34 months versus 12 months in those who did not (p=0.37). Subset analysis did not reveal a benefit to perioperative chemotherapy in patients with stage Ib-IIa, whereas a benefit was seen in patients with IIb-IIIa disease (p=0.02).
While sarcomatoid carcinomas are felt to be chemo-refractory, our results demonstrate radiographic responses to neoadjuvant chemotherapy and an improvement in DFP in patients with stage IIb-IIIa disease. The use of pathological stage in this analysis may underestimate this benefit. Perioperative chemotherapy should be considered in these patients.
In completely resected non-small cell lung cancers (NSCLCs), post-operative cisplatin-based chemotherapy has been shown to improve overall survival in multiple large, randomized clinical trials.1, 2 Early trials of neoadjuvant chemotherapy in Stage IIIa disease also showed improvement in disease free and overall survival.3 Studies of neoadjuvant chemotherapy in earlier stage disease were either underpowered to show a survival benefit or closed early when the previously mentioned data on adjuvant therapy was appreciated.4, 5 A meta-analysis has demonstrated a survival benefit with neoadjuvant chemotherapy similar to that observed in studies of adjuvant chemotherapy for Stages Ib-IIIa NSCLCs.6
Historically, clinical trials in both advanced and resectable lung cancers have been designed to treat non-small cell lung cancers, regardless of pathologic sub-classifications. In the past decade, it has become evident that pathologic and molecular subgroups are critical in selecting therapy. These relevant therapeutic advances include the identification of somatic oncogenic driver-mutations in >50% of patients with adenocarcinomas7, the superiority of pemetrexed over gemcitabine in the non-squamous subset of NSCLCs8 and the safety of bevacizumab in patients with squamous cell carcinomas.9 This increasing attention to histology both in clinical practice and in trial design has brought to light the less common lung cancers such as large cell carcinomas, large cell neuroendocrine carcinomas, NSCLCs not otherwise specified, and sarcomatoid carcinomas.
The lung cancers collectively referred to as sarcomatoid carcinomas includes a spectrum of pulmonary malignancies which total ~1% of NSCLCs.10 Despite this small percentage, it accounts for over 2,000 diagnoses per year in the United States alone. Histologically, the category of sarcomatoid carcinoma is a group of poorly differentiated NSCLCs that is either pleomorphic or contains a sarcomatoid or spindle cell components. This includes pleomorphic carcinomas, spindle cell carcinomas, giant cell carcinomas, carcinosarcomas and pulmonary blastomas.11
Clinically, sarcomatoid carcinomas are generally felt to portend a poor prognosis.12, 13 At presentation, tumors are often large and either centrally invasive of the proximal airways and vessels or peripherally invasive of the chest wall.14, 15 Treatment revolves around surgical management, although outcomes are worse than other lung cancers.16–18 Data in advanced disease suggest that sarcomatoid carcinomas rarely respond to systemic chemotherapy.19 All clinical trials of perioperative chemotherapy in resected NSCLCs have not distinguished this rare subgroup. To our knowledge, no systematic reports of perioperative chemotherapy in this rare subset of NSCLCs have been published. We therefore sought to determine the effect of perioperative chemotherapy on disease free survival in patients with resectable sarcomatoid carcinomas of the lung with the secondary objective of evaluating radiographic responses.
Of the 4675 patients who underwent a complete (R0) resection for primary lung cancer between 2000 and 2010 at Memorial Sloan-Kettering Cancer center, we identified 56 patients (1%) with sarcomatoid lung cancers. Histology was based upon the World Health Organization classification of sarcomatoid carcinoma defined at the time of surgical resection.11, 20
Clinical information was compiled from the medical record. The final pathological staging was assigned based upon the American joint commission on cancer (AJCC) 7th edition tumor-nodemetastasis (TNM) staging system.21 Available CT images were reviewed by a dedicated thoracic radiologist among review of other protocol images and without further information on treatment or goals of image review. Response to neoadjuvant chemotherapy was determined by bi-dimensional primary tumor measurements per WHO, which categorizes response as minor or major, 25% or 50% decrease in products of the diameters, respectively.22, 23 RECIST responses are listed for comparison.
All reviews were carried out under Institutional Review Board/Privacy Board – approved waivers.
The clinical characteristics of patients who received and did not receive neoadjuvant therapy were compared using Wilcoxon sign-rank test (for continuous variables) and Fisher’s Exact Test (for categorical variables). Disease-free probability (DFP) was calculated from date of surgery. Patients were followed until recurrence, or censored at the date of death or last contact. DFP was calculated by the Kaplan-Meier method and compared across groups using the log-rank test. All statistical analyses were carried out using SAS statistical software (SAS Institute, Cary, NC).
Of the 4,675 patients who underwent a R0 resection for primary lung cancer, 56 (1%) were classified as sarcomatoid carcinomas. The baseline patient characteristics, including pathological stage and surgical procedure, are listed in Table 1. Of 38 patients with preoperative biopsies, in only 3 patients (8%) were spindle and/or giant cell features identified. In the remaining cases the preoperative diagnoses were non-small cell carcinoma (n=11), adenocarcinoma (n=13), squamous cell carcinoma (n=9), large cell carcinoma (n=1) and large cell neuroendocrine carcinoma (n=1). Of note, 16 (29%) patients had multifocal disease with a synchronous primary of alternative histology. All synchronous primaries were Stage Ia and were invasive adenocarcinomas or adenocarcinoma with a lepidic component These synchronous primaries occurred with 7 Stage 1a, 3 Stage Ib, 2 Stage IIa, 3 Stage IIb and 1 Stage IIIa sarcomatoid carcinomas and all were completely resected.
Twenty patients (36%) received perioperative chemotherapy including 17 neoadjuvant and 5 adjuvant (2 patients received both). Patients who received neoadjuvant chemotherapy tended to be younger than those who did not (p<0.001). In the 17 patients who received neoadjuvant chemotherapy, the diagnosis of sarcomatoid carcinoma was suspected based on pretreatment cytology or small biopsy in 3 (18%) of cases. In the remaining patients the diagnoses were 5 unclassified NSCLCs, 4 adenocarcinomas, 4 squamous cell carcinomas and 1 large cell neuroendocrine carcinoma. All but 1 patient received a cisplatin or carboplatin-based doublet regimen either preoperatively or postoperatively. One patient with a documented EGFR exon 19 deletion received neoadjuvant erlotinib in combination with pemetrexed. Four of the 17 patients who received neoadjuvant chemotherapy did so with concurrent radiation therapy – one for a pancoast tumor and three treated at outside institutions with neoadjuvant chemoradiation.
Objective responses to neoadjuvant chemotherapy and chemoradiation were evaluable in 15 of the 17 patients who received preoperative therapy. Four patients had a minor response and 7 patients had a major response to induction therapy, 6 with chemotherapy and 1 with concurrent chemoradiotherapy. The evaluable chemotherapy regimens and best responses are listed in Table 2. A representative example of pre- and post-treatment CT images from a patient who received neoadjuvant cisplatin and docetaxel is presented in Figure 1.
With a median follow-up of 12 months, 28 (50%) patients have recurred with a median disease free probability (DFP) of 13 months. Seven of the patients who have recurred had a synchronous Stage Ia adenocarcinoma. Recurrence was confirmed to be the sarcomatoid histology in 5 of the 7; the other 2 recurred within 3 months of the resection of their sarcomatoid carcinoma and did not undergo repeat biopsy. The median DFP was 12 months in the patients who did not receive perioperative chemotherapy and 34 months in the patients who did receive perioperative chemotherapy (Figure 2). This difference did not reach statistical significance (p=0.37). In a subgroup analysis, the difference in DFP was statistically significant in favor of perioperative chemotherapy in pathologic Stage IIb-IIIa patients (p=0.02) but not in pathologic Stage Ib-IIa patients (p=0.82) (Stage IA p=0.6, Stage IB p=0.33, Stage IIA p=0.43). Kaplan- Meier DFP curves for the Stage IIb-IIIa cohort are depicted in Figure 3. Despite the heterogeneous patient population, sex, smoking status and pneumonectomy versus a lesser surgical resection did not have a statistically significant impact on recurrence free probability, unadjusted or when adjusted for stage (Table 3).
Of the 28 patients with recurrence, 15 recurred with local disease only, 5 with both local and distant disease and 8 with distant disease only. The pattern of recurrence was not different in those who did and did not receive perioperative chemotherapy. Sites of distant disease included brain (4), adrenal (4), bone (2), liver (1) and skin/subcutaneous tissue (3). Of the 28 patients who recurred, 11 were treated with chemotherapy, 5 of these had been treated previously with perioperative chemotherapy. There was 1 objective response out of 6 patients treated with a cisplatin or carboplatin-based doublet. The patient who responded at the time of disease recurrence had not received perioperative chemotherapy. There were no responses to single-agent therapy. The only patient who received bevacizumab developed hemoptysis. Of the 28 patients who have recurred, 22 have died of their recurrent sarcomatoid carcinoma. The median time from recurrence to death was 3 months (range 1 – 21 months).
Our series confirms that sarcomatoid carcinoma accounts for ~1% of all surgically resected NSCLCs. Interestingly, of the 56 patients with sarcomatoid carcinomas, 16 (29%) had synchronous stage Ia NSCLCs with glandular differentiation. Those with 2 primary lung cancers had a higher cumulative tobacco use than those without (median 50 versus 32 pack years) but no statistical difference in the number of smokers versus never smokers. Forty-five of 56 patients in this series had pathological Stage Ib-IIIa and therefore meet criteria for perioperative chemotherapy, either neoadjuvant or adjuvant.24 Perhaps due to the time of surgery relative to the literature supporting perioperative chemotherapy, other co-morbid conditions, or the reputation for chemoresistance in this patient population, only 20 of the 45 eligible patients in this series received perioperative chemotherapy. While one may hypothesize that neoadjuvant chemotherapy may select for sarcomatoid histology in the residual tumor, the fact that the majority of the patients in this series did not receive neoadjuvant chemotherapy makes this difficult to test theory unlikely.
We set out to evaluate the impact of perioperative chemotherapy on disease free survival and responses to neoadjuvant chemotherapy in the evaluable subset. We chose pathological stage as the categorical variable for analysis as clinical stage was not systemically evaluable in all patients. Given the heterogeneous patient population with multiple medical co-morbidities that were not uniformly documented, disease free and not overall survival was felt to be the endpoint more representative of treatment effect. It is worth noting that using pathological stage may minimize the benefit of neoadjuvant chemotherapy because patients who receive neoadjuvant therapy tend to have a higher clinical stage, and if they are down-staged they are included in the lower risk group and compared directly to patients with earlier stage disease. We found that 11 of the 15 patients who received neoadjuvant chemotherapy and had CT images available for review had objective responses. Furthermore, patients with pathological stage IIb-IIIa who received perioperative chemotherapy had a significant improvement in disease free survival.
There are obvious limitations and potential biases in this analysis. We cannot clearly determine what led physicians to choose to administer perioperative chemotherapy to some patients and not others. The group who received chemotherapy was significantly younger with fewer comorbid conditions, perhaps influencing this decision, whereas nearly half of the group that did not receive chemotherapy had Stage I disease. The rate of sub-lobar resections was not statistically different than that of lobectomy in the two groups and 5 of 7 sub-lobar resections in the patients who did not receive chemotherapy were performed for Stage I disease, a stage where no benefit was seen with chemotherapy. Among the higher stages, the group that did not receive chemotherapy may have been predisposed to disease recurrence due to fewer pneumonectomies, though all resection specimens had pathologically negative margins and 4 of the 5 patients who underwent pneumonectomy and received perioperative chemotherapy have recurred, negating the potential impact of more extensive resection in the chemotherapy group on the study findings.
The literature is devoid of clinical trial data on sarcomatoid carcinomas of the lung and treatment recommendations are based entirely on small case series reports. One of the challenges is the difficulty in preoperative diagnosis as we found the diagnosis of sarcomatoid carcinoma was suspected in only 8% of all cases that were biopsied and in 18% of those that received neoadjuvant therapy. The only prior report of resectable sarcomatoid carcinomas in which adjuvant (but not neoadjuvant) chemotherapy was reported is a 20 patient series in which 14 patients with lymph node positive disease received adjuvant cisplatin and gemcitabine. None of the 6 lymph node negative patients received chemotherapy. While the 2 groups were not compared, the median disease free survival of the entire cohort was only 5 months and overall survival 8 months. The authors concluded that this disease is not chemotherapy sensitive.17 Additional surgical case series reports have been published describing poor outcomes, though few patients received either adjuvant or neoadjuvant chemotherapy.16, 18 The data on chemotherapy in advanced disease is equally discouraging, with no objective responses seen in 13 sequentially treated patients with metastatic sarcomatoid carcinomas.19
Our findings differ from the literature, with both objective responses to neoadjuvant chemotherapy and improvement in disease free survival observed in patients with resectable Stage IIb-IIIa sarcomatoid carcinoma of the lung who were treated with perioperative chemotherapy. While we did not see a benefit to perioperative chemotherapy in earlier stage disease (Ib-IIa), randomized studies designed to show this magnitude of benefit in all NSCLCs required 10 times the number of patients. Despite the obvious limitations of a retrospective study of a less common lung cancer, we can conclude that not all sarcomatoid carcinomas of the lung are chemotherapy refractory. As the prognosis following relapse of sarcomatoid carcinoma is poor, all attempts should be made to prevent or at least delay the time to relapse. Limitations of available data, combined with our data, are such that therapeutic nihilism is not warranted. In patients with resectable sarcomatoid carcinoma of the lung, neoadjuvant or adjuvant chemotherapy should be considered.