Small Cell Carcinoma Esophagus: Experience of an Indian Tertiary Cancer Center

Background: Small cell carcinoma of the esophagus (SCCE) is a rare and aggressive tumor with no established standard treatment. Methods: This is a retrospective study of adult patients with histologically proven SCCE registered between February 2011 and March 2020 at Tata Memorial Hospital in Mumbai. Results: There were 56 patients with 29 (51.8%) having limited-stage disease (LD) and 27 (48.2%) having extensive-stage disease (ED). The median age was 58 (IQR 51-65) years, 57.1% were men, 40% were smokers. Amongst LD-SCCE patients, 23 underwent local therapy i.e. radiation (19, 65.5%), surgery (4, 13.8%) and 27 received chemotherapy in and settings. was delivered to and Signi ﬁ cant grade ≥ 3 chemo-toxicities in LD-SCCE and included febrile neutropenia in 33.3% and 23.5%, anemia in 9.5% and 17.6%, and dyselectrolytemia in 14.3% and 11.8%, respectively. The median overall survival (OS) in LD-SCCE and ED-SCCE were 22.9 (95% CI 1.8-44.1) months and 11.8 (95% CI 7.3-16.4) months, respectively. Age <60years (p=0.004) and tumor epicenter in lower third esophagus (p=0.002) were good prognostic factors for OS in LD-SCCE and ED-SCCE patients respectively. The incidence of brain metastasis was low, both at presentation (1/27, 3.7%) and at relapse (5/56, 8.9%).

Background Esophageal cancer is the sixth most common cancer with an incidence of 5.04% in India as per WHO, GLOBOCAN 2018 [1]. Squamous carcinoma and adenocarcinoma are the common histological types, while small cell carcinoma is rare, having an incidence of 0.1-2.4% of all esophageal cancers [2 HYPERLINK "https://paperpile.com/c/MEMnMb/boGbQ+u8iT7",3 HYPERLINK "https://paperpile.com/c/MEMnMb/boGbQ+u8iT7"]. SCCE is a highly aggressive malignancy, with approximately half of the patients presenting with metastatic disease [3,4] and has a poor prognosis [5,6].SCCE is thought to behave clinically similarly to small cell lung cancer (SCLC) and the management of SCCE is often extrapolated from small cell lung cancer. Chemotherapy, surgery and radiotherapy have been used with inconsistent outcomes. Randomized studies are not available owing to the rarity of this malignancy. Several retrospective studies have reported differences in survival depending on the treatment modality [3,4].However data regarding toxicity is scarce .Hence, we retrospectively analysed the available clinical data of SCCE patients registered at our institute for treatment strategy, outcome, toxicity and reviewed the literature.gy. EFS was calculated as the time from registration to the rst event, where events included progression, recurrence, second malignancy or death. Censoring was done for patients who did not experience an event or were lost to follow up for > 6 months by the end of the follow-up period. OS was calculated from date of registration until death from any cause or last documented follow-up with appropriate censoring.

Results
Patients and tumor characteristics (Table 1) Of 8342 patients with esophageal malignancies, 59(0.7%) had SCCE. No clinical details could be retrieved for 3 SCCE patients and they were therefore excluded. We included 56 patients in the study. Dysphagia (54 cases, 96.4%) was the commonest presenting symptom with a median duration of 2 months before presentation. Two patients (3.6%) had a family history of malignancy.
The tumors commonly arose in the middle and lower third of the esophagus. FDG PET-CT was done in 40(71.4%) patients, contrast-enhanced CT instead of PET-CT was done in 14(25%) as there was obvious metastasis in CT scan and 2 (3.6%) patients defaulted before completion of staging work up .However , these 2 defaulters had CT thorax showing metastatic disease. Brain imaging at baseline was available as MRI brain in 14 (25%) cases, FDG PET-CT in 30(53.6%) cases, while in the remaining 12 patients (21.4%) no cross-sectional brain imaging was available. Of the total of 56 patients analyzed, 29 (51.8%) had LD-SCCE, and 27 (48.2%) had ED-SCCE.
Pathology ndings: The tumors showed uniform histology in all the cases, characterized by crushed hyperchromatic cells with scant to absent cytoplasm, prominent nuclear molding and absent to inconspicuous nucleoli. The immunohistochemistry panel utilized for diagnosis included synaptophysin, chromogranin and CD56. All performance status (PS).Of 28 patients considered for tumor-directed therapy, local therapy was delivered in 23 (radiotherapy in 19, surgery in 4). The remaining 5 patients who were planned, but did not undergo any local therapy included 3 patients who defaulted post neoadjuvant chemotherapy (NACT) and 2 patients who died from chemotherapy-related toxicities on NACT. NACT and adjuvant chemotherapy were administered in 23(79.3%) and 4(13.8%) cases, respectively. Concurrent chemoradiation (CRT) was planned for all patients undergoing radiation as local therapy, except one patient, who was deemed un t for chemotherapy. Eleven (37.9%) patients received PCI. Surgery:

ED-SCCE
Five LD-SCCE patients were planned for surgery. Of these, four underwent esophagectomy with three-field lymph node dissection (cervical, mediastinal, and perigastric lymph nodes), while one patient defaulted post NACT. All 4 patients had R0 resection and had received NACT with EP -3cycles in two cases, 4 cycles in one case and 6 cycles in one case. Histopathology revealed scanty residual tumor in one case, one focus of in situ carcinoma in one case, while there was evidence of residual invasive carcinoma in the remaining two cases. None of these patients received adjuvant chemotherapy. Radiotherapy: The median dose of radiotherapy delivered as external beam radiotherapy (EBRT) in LD-SCCE was 63Gy/35# to loco-regional site. All received conventional fraction EBRT with 45Gy/25# in one, 50.4Gy/28# in two, 55.8Gy/31# in one, 59.4Gy/33# in one, 60Gy/30# in three and 63Gy/35# in the remaining eleven patients. Two patients with ED-SCCE received palliative RT to the local site. The PCI dose regimens included 24.75Gy/11# in six patients, 25Gy/10# and 24Gy/8# in two each with a median dose of 24.75Gy/11# in both LD and ED-SCCE.

Relapse in brain:
Of all the patients with LD-SCCE, 18 (62.1%) patients completed the planned therapy without disease progression and were advised PCI. However, some of these patients underwent PCI and some didn't. Similarly, PCI was considered for 10 (37%) patients with ED-SCCE who did not have brain metastasis and attained CR or PR at the completion of the rst line of chemotherapy. Of these 28 patients, 18 (18/28, 64.3%) received PCI (LD-SCCE:11, ED-SCCE:7). A total of 5 patients relapsed in the brain(LD-SCCE:2, ED-SCCE:3) (Supplementary Figure 2) Prognostic factors (Table 2) Entire cohort: In univariate analysis, female sex, history of substance abuse, palliative intent treatment and raised LDH predicted for poorer EFS. History of substance abuse was the only independent prognostic factor for EFS while no factor independently prognosticated OS.

Discussion
In our SCCE cohort of 56 patients, the median OS was 22.9 (95% CI 1.8-44.1) months for LD-SCCE and 11.8 (95% CI 7.3-16.4) months for ED-SCCE. As per Ding et al. LD-SCCE patients, who underwent surgery and postoperative chemotherapy achieved a median OS of 26 months [11]. Moreover, the use of chemotherapy in combined modality treatment doubled the median OS from 11 months to 22 months (HR = 2.30,p = 0.001). As per the published literature, the median OS of patients with LD-SCCE treated with a multimodality approach ranges from 14 months to as high as 39.7 months[6, [11][12][13]. In our study, only one patient with LD-SCCE was offered single modality radical therapy (radiotherapy) as he was un t for systemic therapy. Hence, we were unable to estimate the incremental bene t of systemic therapy in our patients with LD-SCCE. In a systematic analysis of 19 SCCE case series, the median OS in 88 patients with ED-SCCE was 9 months [14]. The OS of ED-SCCE was similar in other studies as well [5,6,14]. Thus, the outcomes of our patients with LD-SCCE and ED-SCCE were similar to those in the published literature.
In our study, approximately half the patients (30 of 66) had a history of either smoking or alcohol consumption. While there are no well-de ned risk factors for SCCE, they appear to be similar to those for squamous cell esophageal cancer (history of alcohol consumption and smoking) [15]. Smoking has been identi ed as a signi cant risk factor in patients with SCLC, with a history of smoking being elicited in more than 90% of cases [16]. In our cohort of patients with SCCE, smoking appeared to be less important as an etiologic factor. As per the Global Adult Tobacco Survey, smoking is less common in India, with 19% of men and 2% of women being smokers [17].In our earlier studies, we had noted that 10-15% of our patients with SCLC and 55% of patients overall with lung cancer were non-smokers [18][19][20].
The optimal loco-regional treatment for LD-SCCE is controversial. There are several reports and metaanalyses that recommend surgery as the local therapy of choice [2,21,22]. Regarding radiotherapy, several studies have reported that CRT can also achieve long-term survival in LD-SCCE patients [13,23,24]. A retrospective study that directly compared surgery and radiotherapy as local treatments found no difference in survival or loco-regional recurrence between patients treated with the two modalities[6].In our study, radiotherapy was the local treatment in a majority (65.5%)of the LD-SCCE patients and surgery was the local treatment modality in only 4(13.8%)patients. Given the non-randomized nature and small sample size of this study, comparing the outcomes of patients treated with radiotherapy to surgery is inappropriate. However, the ndings of our study indicate that CRT may be regarded as an alternative radical treatment strategy in LD-SCCE, with the bene t of preventing surgical complications and delaying the start of postoperative chemotherapy.
The most common chemotherapy-related toxicity was febrile neutropenia seen in 30% of patients in our study and the overall rate of grade ≥ 3 toxicity was 50%. In a study by Chen et al., the overall rate of grade 3-4 toxicities was 37.5% [13]. There is a paucity of chemotherapy toxicity data as most studies are retrospective in nature and focused on outcomes rather than adverse events [12][13][14]. We observed that older age was associated with inferior OS in our LD-SCCE patients. Analysis of the SEER database had also revealed that older age was associated with a worse OS [3,25]. Other researchers have also made similar observations, albeit the association was not statistically signi cant [13,26].Patients with a history of substance abuse had worse EFS in our cohort. However, a history of smoking had no impact on survival in other studies [13,27]. Amongst our patients with ED-SCCE, those with a primary in the lower third esophagus had better outcomes than others. An earlier study described origin in the middle third esophagus as a predictor for better OS in univariate analysis [27], while others did not nd any signi cant correlation of primary tumor location and outcome [28,29]. Small sample sizes of the various studies and different tumor biology may be the reasons for the apparent differences in prognostic factors.
PCI is practiced in SCCE as an extrapolation of the data from SCLC, where the incidence of brain metastasis is as high as 50-80% at 2 years [30]. According to previous studies, the rate of brain metastasis in SCCE is 5-6%, which is much lower than the rate in SCLC [23]. In our study, only 1 patient (1/27, 3.7%) with ED-SCCE had brain metastasis at presentation. We also observed the brain relapse rate was much lower than what has been historically reported in patients with SCLC. We observed the proportion of patients developing brain metastasis in both LD-SCCE and ED-SCCE were similar irrespective of PCI. Hence, PCI may be cautiously avoided in patients with SCCE with close clinicoradiological follow up. This hypothesis is supported by other studies as well [5,12].
The main limitations of our study are the small sample size, retrospective nature and single-institution study. Since none of our patients received immunotherapy, we are unable to determine the e cacy of immune checkpoint inhibitors in SCCE. Some of the records, such as those relating to past history, environmental exposures and quality of life, were limited. The availability of detailed systemic therapy toxicity data in the majority of patients is the strength of our study. The rarity of this malignancy makes the conduct of a randomized trial di cult. In such cases, retrospective studies and clinicians' experiences become important means to guide management.

Conclusion
Although the survival of LD-SCCE is better than ED-SCCE, it is still under 2 years with ample room for improvement .Brain metastasis is not common and PCI can be avoided in patients who are reliable for close clinico-radiological follow up. National and international collaboration is needed to conduct prospective studies to bridge the gap in the knowledge of treatment and prognostic factors in this rare tumor. Treatment details of small cell carcinoma esophagus