Distribution of baseline factors of patients with recurrent/metastatic esophageal carcinoma (n=350)

Median follow-up is 8 months. Response to weekly paclitaxel includes complete remission (CR: 2.5%), partial remission (PR: 29.5%), stable disease (22.8%), and PD (40.6%). In 4.6% patients, the response was not assessable. Patients who had received platinum-based chemotherapy before weekly paclitaxel had a response rate (CR + PR) of 25.8%, whereas patients who were platinum na?ve had a better response rate of 38.9% (P?= 0.03). Median PFS was 4.0 months (95% confidence interval [CI]: 3.6?4.3 months) and median OS was 10 months (95% CI: 8.5?11.4 months) [Figure 1] and [Figure 2]. In univariate analysis, better performance status and pretreatment albumin significantly affected OS [Table 2]. However, multivariate analysis demonstrated good performance status (PS 0?1) as the sole prognostic factor affecting survival outcome [Figure 3] and [Figure 4].

Factors affecting outcomes, progression-free and overall survival (log-rank test)

The most common grade 3/4 toxicities included hyponatremia (14.8%), fatigue (6.3%), diarrhea (6.2%), anemia (27.4%), neutropenia (17.1%), and febrile neutropenia (4%). Two hundred and sixty-eight out of 350 (76.5%) patients underwent salvage therapy beyond weekly paclitaxel progression. Common salvage therapies included capecitabine alone in 153 patients (43.7%) followed by gefitinib/erlotinib in 48 (13.7%), single agent irinotecan in 23 (6.6%), palliative radiotherapy in 21 (6%), irinotecan with capecitabine in 13 (3.7%), and oral methotrexate with celecoxib in 10 patients (2.9%). Remaining patients had rapid deterioriation of performance status and were send for palliative care alone.

Discussion

Esophageal carcinomas are one of the most lethal malignancies with poor long-term outcomes.[6],[7] In patients with locally advanced and metastatic esophageal carcinoma, the goal of treatment remains palliation of symptoms, improving quality of life, and attempt for prolongation of survival.[8] Systemic chemotherapy plays a pivotal role in inducing meaningful and early improvement in local and systemic disease-related symptoms.[4] Use of systemic chemotherapy improves response rates and survival irrespective of primary esophageal histology albeit with some toxicities.[9],[10] Use of combination doublet/triplet chemotherapeutic agents compared to single agent have only produced marginal improvement in response rates with very modest survival benefit but at the cost of much higher toxicities.[2],[11],[12],[13] Single agent weekly paclitaxel in unresectable, recurrent, and metastatic esophageal carcinomas has produced good response rates with median survival of 8?10 months with much better toxicity profile.[1],[14],[15] We report largest patient data of locally advanced and recurrent/metastatic esophageal carcinomas treated with single agent metronomic weekly paclitaxel.

Only a few studies have reported outcomes with the use of weekly palliative paclitaxel regime in advanced, metastatic esophageal carcinoma. In a phase II study, Kato?et al. in a selected cohort of patients with good performance status (PS 0?1) with advanced and recurrent squamous esophageal carcinoma showed a substantial response of 44% with weekly paclitaxel.[15] In predominantly platinum pretreated patients, they demonstrated a PFS of 4.8 months and median survival of 10.8 months. Unlike Kato?et al., Ilson?et al. in a multicentric study, could only demonstrate a modest response rate of 13%, which failed to meet the anticipated response rate of 25%.[14] Having rigid selection criteria of including only patients of performance status 0?2, no comorbidities, and no prior chemotherapy for metastatic disease, they showed a better response rate for adenocarcinoma (15%) compared to squamous carcinoma (8%). The reason of lower response rates in Ilson?et al. compared to Kato?et al. could be due to its multicentric nature of study and lower dose of paclitaxel (80 mg/m 2) used in similar patient cohort. In a more contemporary study, Noronha?et al. demonstrated response rate of 49% in a population which comprised 45% of patients with performance status 2 or more, 41% with comorbidities, 51% had previous platinum exposure, and 76% with distant metastasis.[1]

In our study population of 350 patients, 58% of patients had squamous cell carcinoma histology with 25.4% patients had performance status> 2 before receiving weekly paclitaxel. Nearly 50% of them were platinum pretreated and 39% had history of receiving prior 3 weekly paclitaxel. Hence, our patient population was quite contrary to that reported by Ilson?et al. (N?= 102) where all patients had better PS (<2 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_39_17#JR_14" xss=removed>14] Compared to Kato?et al. study, in which all patients were Eastern Cooperative Oncology Group performance status of <1 class="i" xss=removed>et al.[15] Our reported patient profile is closer to that reported by Noronha?et al. except only 25% patients had PS> 2 in our study compared to 45% reported by them. Our response rates with weekly paclitaxel, 32% (CR + PR) were more modest compared to Kato?et al.[15] and Noronha?et al.[1] However, the median duration of response and PFS was similar across all studies.[1],[14],[15] Our median survival of 10 months is similar to that reported by others except for Noronha?et al. where median OS was 7.5 months.[1],[14],[15] Ilson?et al. and Noronha?et al. both had shown higher responses in platinum na?ve compared to platinum exposed population, 64% versus 35% and 15% versus 5%, respectively; however our result had similar responses irrespective of prior platinum exposure (32% vs. 37%). Our study showed no significant difference in PFS whether squamous or adenocarcinoma histology, unlike reported by Noronha?et al?[Table 3].

Comparison of demographic profiles, outcomes, and toxicity across several reported studies

Progressive dysphagia and weight loss often lead to poor quality of life in patients with esophageal carcinoma, especially after disease progression. The efficacy of any intervention in such cases not only depends on the response rates but also in terms of resolution of dysphagia and independence from feeding tube requirements. Use of weekly paclitaxel in our study produced significant improvement of dysphagia in 51% of patients with median duration of 20 days from first dose. In 31% of patients, the feeding nasogastric tube could be successfully removed. Among several prognostic factors analyzed, only performance status 0?1 before starting chemotherapy and serum albumin> 3.7 g/dL were significant. However, in multivariate analysis, performance status 0?1 was the sole prognostic factor with significant impact on OS. The merit of any systemic therapy is decided by its therapeutic index and toxicity profile. In our cohort of patients treated with weekly paclitaxel, most common grade 3/4 toxicities, beyond 10% incidence, were hyponatremia (14.8%), anemia (27.4%), and neutropenia (17.1%). Grade 3/4 motor-sensory neuropathy and febrile neutropenia were 6% and 4%, respectively, which is similar to that reported in other series.[1],[14],[15]

One of the remarkable findings in our study was that 76.5% of patients had received subsequent salvage chemotherapy after progression on weekly paclitaxel, probably having an impact on longer reported median OS of 10 months. Being retrospective, we do not rule out any selection bias and inadvertent omission of patients which might have inflated the overall outcome, as only patients entered in our prospective database were analyzed which might not have included all patients with locally advanced and metastatic esophageal carcinomas treated or referred in our institute.

Palliative systemic chemotherapy for locally advanced and metastatic esophageal carcinoma has shown very modest to no benefit in OS compared to best supportive care in different studies and systematic reviews.[4],[16],[17],[18],[19],[20] After progression on doublet/triplet, first-line chemotherapy, single-agent chemotherapy with taxanes, or irinotecan provides modest survival benefit with good palliation.[21],[22],[23],[24] Moreover, use of combination chemotherapy compared to single agent after disease progression has shown very modest improvement in responses with no clinically meaning full improvement in OS.[25],[26],[27] We propose single agent metronomic weekly paclitaxel as valid therapeutic option in locally advanced, recurrent, and metastatic esophageal carcinoma. This regimen when used ensures tolerable safety profile and early meaningful improvement in tumor-related symptoms with effective palliation.

Conflict of Interest

There are no conflicts of interest.

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