Efficacy and safety of induction weekly paclitaxel and carboplatin in esophageal cancer: A retrospective study : Cancer Research, Statistics, and Treatment

Secondary Logo

Journal Logo

Original Article: Real World Data

Efficacy and safety of induction weekly paclitaxel and carboplatin in esophageal cancer

A retrospective study

Goli, Vasu Babu; Menon, Nandini; Patil, Vijay; Noronha, Vanita; Prabhash, Kumar

Author Information
Cancer Research, Statistics, and Treatment: Apr–Jun 2022 - Volume 5 - Issue 2 - p 247-255
doi: 10.4103/crst.crst_122_22
  • Open

Abstract

INTRODUCTION

Globally, esophageal malignancy is the seventh most frequently diagnosed cancer and the sixth most frequent cause of death related to malignancy.[1] Despite an improvement in survival over the past few years, the outcomes in India are dismal with 5-year survival rates of 31% and 9% in the early and advanced stages, respectively.[2]

The use of combined modality treatment significantly improves outcomes in patients with locoregional disease compared to resection alone. The approaches that have been used prior to resection to improve outcomes include neoadjuvant chemoradiotherapy, perioperative chemotherapy, and neoadjuvant chemotherapy. Preoperative chemoradiotherapy is the standard of care for patients with resectable esophageal cancer with good performance status.[34]

In the meta-analysis by Kaklamanos et al.,[5] neoadjuvant chemotherapy prior to surgery resulted in an absolute 4.4% improvement in the 2-year survival rate compared with surgery alone in patients with resectable esophageal cancer. Cisplatin and infusional 5-fluorouracil (5FU) is the standard induction chemotherapy regimen for resectable esophageal cancer.[6] However, the regimen of cisplatin with infusional 5FU is toxic, causes serious adverse events in 16%–47% of the patients[67] and requires significant logistic support due to the requirement of either an infusion pump or admission to the hospital for the chemotherapy infusion. Alternative chemotherapy regimens like a taxane and platinum are attractive options, due to the relative ease of administration and possibly, less toxicity.

A large proportion of patients with esophageal cancer present with significant weight loss (27%–57%),[89] poor performance status (Eastern Cooperative Oncology Group Scale of Performance Status [ECOG PS] >1 in 28%),[10] and hypoalbuminemia (albumin <4 g/dL in 57.6%).[11] Concurrent paclitaxel and carboplatin administered once-in-3-weeks is an effective treatment in patients with non-metastatic esophageal cancer with an objective response rate of 43%. However, grade 3/4 toxicities occur in 54.5% of the patients.[12] Several patients are not fit to receive the once-in-3-weeks chemotherapy regimen due to various factors including significant weight loss, poor performance status, hypoalbuminemia, advanced age, comorbidities, or organ dysfunction. Paclitaxel has shown clinical activity in advanced esophageal malignancy with low toxicity.[13] The administration of paclitaxel and carboplatin once-a-week is an established regimen in solid cancers,[141516] but has not been well explored in the neoadjuvant setting in esophageal cancer. This regimen might result in an increased dose intensity with less toxicity. The regimen can be given in the outpatient setting and can be administered relatively safely in patients with compromised renal function. At our center, we routinely use the regimen of once-a-week paclitaxel and carboplatin in patients who are unfit for full-dose chemotherapy, cisplatin-ineligible, or are compromised in some other way. We aimed to retrospectively evaluate the efficacy and toxicity of this regimen in the neoadjuvant setting in patients with locally advanced esophageal cancer.

MATERIALS AND METHODS

General study details

This was a retrospective single center observational study of patients with histologically or cytologically proven, locally advanced esophageal cancer who received induction chemotherapy with once-a-week paclitaxel and carboplatin between November 2012 and December 2019 in the Department of Medical Oncology at the Tata Memorial Hospital, a tertiary oncology hospital in Mumbai, India. The study was approved by the Institutional Ethics Committee (Project No. 900617, approved on April 23, 2020; Supplementary Appendix 1) and the requirement for obtaining a written informed consent was waived. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines and those established by the Indian Council of Medical Research. The study was not registered in a public clinical trials registry as it was a retrospective analysis. There was no funding for the study.

Participants

We included patients with newly diagnosed, locally advanced esophageal or gastroesophageal junction (GEJ) cancer who were planned for radical intent therapy (surgery or concurrent chemoradiotherapy) and had received induction chemotherapy with paclitaxel and carboplatin administered once-a-week. We excluded patients with metastatic disease, those who were treated with palliative intent and those who had received paclitaxel and carboplatin therapy earlier.

Aims/objectives

Our primary objective was to determine the overall survival of the patients who received induction chemotherapy with paclitaxel and carboplatin once-a-week in the curative setting. Our secondary endpoints included the progression-free survival, toxicity, radiological response rate, resection rate, pathological complete remission rate, tumor regression grade, patterns of failure, and the identification of possible prognostic factors such as age (<60 vs. ≥60 years), sex, tumor histology (squamous vs. adenocarcinoma), tumor grade (poorly differentiated vs. others), nodal status (node positive vs. negative), and the pre-treatment albumin level (<4 vs. ≥4 g/dL).

Study methodology

We identified the patients for this study from the prospective database maintained in Microsoft Excel in the Department of Medical Oncology. The details in the database were supplemented by the data obtained from the electronic medical records of the Tata Memorial Hospital. We extracted the data for demographics, clinical and treatment-related details, chemotherapy-related toxicity, and survival outcomes. Patients who had not followed up in our clinic were contacted telephonically between September 1, 2020 and September 15, 2020 to update their survival status. The retrospective data collection and analysis were conducted between April 2020 and September 2020.

A multidisciplinary team consisting of a medical oncologist, thoracic surgical oncologist, radiation oncologist, and radiologist discussed the basic workup and plan for all patients. Tumor staging was done according to the American Joint Committee on Cancer: tumor (T), nodes (N), and metastases (M) [AJCC-TNM] staging 7th edition with either a computed tomography (CT) scan or a positron emission tomography and CT (PET/CT). The location of the primary tumor was defined by the epicenter of the tumor and its anatomical location in the esophagus. Esophageal regions were defined based on the endoscopic distance from the incisors as follows: cervical (15–19 cm), upper thoracic (20–24 cm), middle thoracic (25–29 cm), and lower thoracic esophagus (30–39 cm). Tumors in which the epicenter was within the proximal 5 cm of the stomach (cardia) extending into the GEJ or the esophagus were considered GEJ cancers.

The initial management plan was made in the multidisciplinary meeting, considering the histopathological diagnosis, staging, resectability/operability, and the patient's general fitness and socioeconomic status. The induction chemotherapy regimen consisted of paclitaxel 80 mg/m2 and carboplatin AUC 2 (area under the free carboplatin plasma concentration vs. time curve-calculated by Calvert method) once-a-week for 6–8 weeks. Response to induction chemotherapy was assessed as per the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. A measurable lesion in the esophagus primary tumor was defined as a lesion with a maximum transverse diameter of ≥10 mm. Toxicity was graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5. The Mandard system was used to report the tumor regression grade (TRG), which classifies the primary tumor regression into five categories ranging from TRG 1 (complete regression) to TRG 5 (absence of regression).[17]

Definitions

Overall survival was calculated from the date of histologically confirmed diagnosis until the patient's death or last follow-up. Progression-free survival was calculated from the date of histologically confirmed diagnosis till the first evidence of disease recurrence or progression (either radiologic or endoscopic or clinical) or death from any cause, whichever occurred first. Objective response rate (ORR) was defined as the proportion of patients who had a partial or complete response to therapy. The resection rate was calculated as the proportion of patients who underwent surgery after induction therapy divided by the total number of patients who were planned initially for surgery after induction therapy. R0 resection was defined as the absence of microscopic residual tumor at the surgical margins, including the circumferential resection margin. Pathological complete remission (pCR) was defined as the absence of any viable tumor cells at the primary tumor site as well as in the regional lymph nodes. pCR rate was calculated as the percentage of patients who attained a pCR with the denominator being the total number of patients who underwent surgery. Tracheobronchial infiltration was defined as the presence of tracheobronchial fistula, or the appearance of restricted mobility of the tracheobronchial mucosa on fiberoptic bronchoscopy.

Statistics

No formal sample size calculation was done, as it was a retrospective analysis. We included all eligible patients in the study period. Data were entered in the Statistical Package for the Social Sciences (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.) and RStudio Version 1.2.5019. We used descriptive statistics for describing the patient demographics, clinical, and toxicity data. Survival was estimated using the Kaplan–Meier method.[18] Prognostic factors for survival (progression-free and overall survival) were identified by univariate analysis using the log rank test. The factors that were noted to be significant in the univariate analysis were then tested using the Cox regression for the multivariate analysis.[1920] P value < 0.05 was considered statistically significant.

RESULTS

Baseline patient characteristics

Between November 2012 and December 2019, there were 240 patients whose details had been entered in the induction chemotherapy for esophageal carcinoma database. Of these, 141 patients were included in the study. The details of patient enrollment are provided in Figure 1. The median age of the cohort was 60 years (IQR, 20–81). The tumor histology was squamous cell carcinoma in 123 patients (87%). Pre-treatment baseline characteristics are shown in Table 1.

F1-10
Figure 1:
The flow chart of patients evaluated and enrolled in the study
T1-10
Table 1:
Demographics and clinicopathological information

Endoscopic ultrasonography was done in only 5 patients (3.5%). Radiologic staging consisted of a PET-CT in 40 patients (28.3%) and CT in 101 patients (71.6%). The indications for prescribing the once-a-week induction chemotherapy regimen included age ≥70 years (n = 32, 22.7%), advanced age with deranged renal function (estimated glomerular filtration rate [eGFR] calculated by Cockcroft–Gault method <50 mL/min (n = 29, 20.3%), advanced age with comorbidities (n = 17, 12.1%), ECOG PS ≥2 (n = 16, 11.3%), deranged renal function (n = 11, 7.8%), advanced age with ECOG PS ≥2 (n = 11, 7.8%), and others (n = 25, 17.7%).

The initial resectability status was documented in 135 patients (95.7%). In 44 patients (32.5%), the tumors were deemed resectable at baseline and in 65 (48.1%) the tumors were considered borderline resectable. The most common reason for borderline resectability was a loss of the fat planes between the tumor/lymph node and the adjacent structures (n = 16, 24.6% of the borderline resectable tumors) on radiologic imaging. Other reasons included a loss of fat planes between the aorta and the bronchus (n = 14, 21.5%), both bulky disease and loss of fat planes with adjacent structures (n = 11, 16.9%), bulky disease (n = 6, 9.2%), bulky gastrohepatic (n = 5, 7.69%), and tracheo-esophageal node (n = 2, 3%), bulky disease and tracheo-esophageal node (n = 3, 4.6%), the presence of a gastro-hepatic node and loss of fat planes with adjacent structures (n = 3, 4.6%), and long segment disease (n = 4, 6.1%). The disease was deemed unresectable in 26 patients (19.2%). In 14% of the patients with unresectable disease, the final treatment to be delivered after the completion of induction therapy was to be decided based on the response to induction chemotherapy.

Chemotherapy details

The median number of chemotherapy cycles administered was 6 (IQR, 5–9). All patients received chemotherapy in the outpatient setting. Dose delays occurred in 15 patients (11%) due to toxicity (attributable to carboplatin in 3 patients [2%] and paclitaxel in 12 patients [9%]). Treatment interruptions occurred in 8 patients (6%).

Efficacy

The details of efficacy are provided in Table 2. Following the completion of neoadjuvant chemotherapy, disease restaging was done with CT scans in all patients. An ORR after 6 cycles of paclitaxel and carboplatin administered once-a-week was noted in 87 patients (61%). There were 35 patients (24%) who defaulted after the definitive treatment plan was made post-neoadjuvant therapy. Eighty-one (57%) patients could be treated with radical intent therapy. Surgery was performed in 36 of the initial 109 patients planned for surgery; thus, the surgical resection rate was 35%. Of the patients who underwent surgery, 35 patients (95%) had an R0 resection. pCR were noted in 4 patients (10.8%). Of the 26 patients with unresectable disease at baseline, 16 (62%) received radical intent therapy (chemoradiotherapy in 13 and radical radiotherapy in 3). The details of the initial treatment planned, and the final treatment received are shown in Figure 2. At a median follow-up of 56 months (95% CI, 48–63), the median progression-free survival was 15 months (95% CI, 11–26) [Figure 3a] and the median overall survival was 20 months (95% CI, 12–29 months) [Figure 3b].

F2-10
Figure 2:
Details of the initial treatment planned and the final treatment received
F3-10
Figure 3:
Panel A: The median progression free survival was 15 months (95% CI, 11–26). Panel B: The median overall survival was 20 months (95% CI, 12–29)
T2-10
Table 2:
Efficacy of paclitaxel and carboplatin given once-a-week as induction chemotherapy for locally advanced esophageal cancer

The patterns of failures were available for 74 patients (52%). The most common site of failure was locoregional (n = 37, 50%). Both locoregional and distant failures occurred in 17 (22%) patients. Distant failure occurred in 20 patients (27%); the commonest site was lung (n = 15, 20%), followed by bone (n = 5, 7%).

Factors affecting the progression-free and overall survival

On univariate analysis, female sex was associated with a better progression-free survival (P = 0.023) while female sex (P = 0.028) and borderline resectability (P = 0.012) were associated with a better overall survival. On the multivariate analysis, only borderline resectability status retained significance; P = 0.013. [Supplementary Table 2]

Toxicity

Grade 3/4 toxicities occurred in 30 patients (21%). Toxicities were predominantly hematological (n = 30, 21%), especially grade 3 and higher neutropenia in 18 patients (13%) and grade 3 and higher anemia in 15 (10%). Febrile neutropenia occurred in 8 patients (6%). Gastrointestinal toxicity was mainly grade 1/2 with anorexia being the most common, followed by nausea and vomiting. Neuropathy was predominantly sensory, and grade 1/2 (n = 29, 20%). Adverse events rarely resulted in treatment delays with delays occurring in only 15 patients (11%). Hospitalization was required in 8 patients (6%); in all these patients, the adverse event that required inpatient management was febrile neutropenia. Detailed toxicities are provided in Table 3.

T3-10
Table 3:
Toxicity of paclitaxel and carboplatin given once-a-week as induction chemotherapy for locally advanced esophageal cancer

DISCUSSION

The standard of care for resectable and locally advanced esophageal/GEJ cancer is neoadjuvant chemoradiotherapy followed by surgery or neoadjuvant or perioperative chemotherapy.[321] However, the trials that established these treatments enrolled a highly selective group of patients with good ECOG PS, no significant weight loss, and good renal function. Performance status, hypoalbuminemia, and weight loss have been associated with inferior outcomes in patients with esophageal cancer.[891011] These compromised patients were not included in the landmark trials and there is a lack of evidence to help guide the management of these patients. Our study included a cohort of patients who were not considered fit for standard induction chemotherapy or chemoradiotherapy, because of various reasons, including advanced age, borderline PS, renal dysfunction, and multiple comorbidities. Paclitaxel and carboplatin given once-a-week resulted in an ORR of 61%, with only mild toxicities. This excellent response rate translated into improved outcomes as evidenced by the fact that 57% of the patients could undergo radical treatment after completing the neoadjuvant therapy. The regimen was given on an outpatient basis. The incidence of grade 3/4 toxicities was low at 21% and consisted predominantly of hematological toxicities. Only 13% of the patients experienced severe neutropenia, which was reflected both in the low occurrence of febrile neutropenia (6%) and the low requirement for hospitalization (6%).

The median age of the patients in our study was 60 years, which was similar to that reported by de Man and colleagues, who also studied the once-a-week regimen of paclitaxel and carboplatin, and that reported from a once-in-3-weeks regimen [Table 4]. In de Man and colleagues' study, carboplatin (AUC 4) and paclitaxel (100 mg/m2) given once-a-week was found to be an effective regimen, both in the neoadjuvant and the palliative settings for individuals with advanced esophageal cancer.[22] In this study, 122 patients received induction chemotherapy. The median number of cycles of induction chemotherapy was 7. The results of this study were similar to those of our study; the objective response rate to induction chemotherapy was 48%. Following induction chemotherapy, 42% of the patients underwent esophagectomy or definitive chemoradiotherapy. The median progression-free survival (PFS) and overall survival (OS) for patients who received induction chemotherapy were 12 and 15 months, respectively; which were also relatively similar to what we noted in our patients.[22] The incidence of neuropathy and febrile neutropenia were also similar to our study.

T4-10
Table 4:
Outcomes of patients with esophageal cancer who received induction chemotherapy with paclitaxel and carboplatin once-a-week

D'Addario and colleagues treated 131 individuals with solid organ malignancies (both pretreated and chemotherapy naive) with paclitaxel (75 mg/m2) and carboplatin (AUC 2 to 3) on days 1, 8, and 15; cycles repeated every 4 weeks. In this study, 19 patients with esophageal malignancies received 2 cycles of induction chemotherapy followed by surgery; the response rate was 84.2% and the pCR rate was 26.3%.[23] The rates of grade 3 and 4 leukopenia and thrombocytopenia were 15.2% and 3.2%, respectively. Thus, paclitaxel and carboplatin administered once-a-week appears to be an efficacious induction chemotherapy regimen.

The traditional therapy for a significant proportion of patients who are unable to receive standard induction regimens, either full-dose neoadjuvant chemotherapy or chemoradiotherapy would be palliative intent therapy. Treating these patients with effective and less toxic regimens may permit the eventual delivery of radical therapy and improve outcomes without affecting the quality of life. The major difference between our study and the other studies was that 31% of the patients in our study had PS >1, compared with 6% in the study by de Man et al.[22] and none in the Dutch Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study (CROSS) trial.[3] Squamous cell carcinoma predominated in our study (87%) compared with 48% in the study by de Man et al.[22] and 23% in the CROSS trial.[3] The doses of paclitaxel (80 mg/m2) and carboplatin (AUC 2) were lower in our study compared with those used in the other studies (except for CROSS). However, the ORR was similar in our study at 61%, compared with 48% in the study by de Man et al.[22] and 61% in the study by Keresztes et al. with the regimen of paclitaxel (200 mg/m2) and carboplatin AUC 6 given once-in-3-weeks.[24]

Our hospital is a tertiary care cancer center, and only 20% of the patients treated are from the local state of Maharashtra. The remaining 80% come from other parts of India. Hence, our patient cohort represented a real-world scenario, which may be considered similar to a multicentric study, in which patients from various different locations are enrolled. The important limitation of our study was that it was a retrospective observational study rather than a randomized trial. Other limitations include the fact that endoscopic ultrasonography was not done for the majority of patients, and hence accurate staging of the tumors may not have been done, especially for the primary tumor and the nodes. Thirty-five patients (25%) defaulted and were lost to follow-up after the initial induction therapy, which could have impacted the outcomes.

CONCLUSION

Induction chemotherapy with paclitaxel and carboplatin given once-a-week is safe, efficacious, and can be given in the outpatient setting. Excellent tolerability with acceptable rates of hematological and non-hematological adverse effects permits this regimen to be administered in older patients and in those who are frail and compromised for various other reasons. A phase III study in these subsets of patients with paclitaxel and carboplatin once-a-week may help to establish the true value of this regimen in clinical practice.

Data sharing statement

Individual deidentified participant data will be made available on reasonable request, starting from the date of publication, until 10 years after publication. Requests beyond this timeframe will be considered on a case-by-case basis. In addition, the study protocol, including the statistical plan is already available as a supplementary appendix attached to this manuscript. Requests for data should be directed to Dr. Kumar Prabhash at [email protected]

Author contributions

Substantial contributions to the conception or design of the work: VBG, VN, KP, VP and NM; acquisition, analysis, or interpretation of the data for the work: VBG and VN; drafting the work or revising it critically for important intellectual content: VBG, VN and KP, with important contributions from NM, VP; final approval of the version to be published: all authors; accountable for all aspects of the work: all authors

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Title: Efficacy and Toxicity of Weekly Paclitaxel/Carboplatin in the Neoadjuvant Setting in Esophageal Cancer: A Retrospective Observational Study

Principal Investigator: Dr. Kumar Prabhash

Co- Principal Investigator: Dr. Vasu Babu Goli

Co-Investigators: Dr. Vanita Noronha, Dr. Amit Joshi, Dr. Vijay Patil, Dr. Nandini Menon

Document: Protocol

Type: Investigator Initiated

Version: 1.0

Date: 12/11/2019

  • Background information-

STUDY PROTOCOL INTRODUCTION:

Esophageal cancer is the sixth most common cancer in India with approximately 52,000 cases per year. It is also the sixth most common cause of cancer-related deaths in India with approximately 46,000 deaths per year (1).

It has been shown that neoadjuvant chemotherapy (NACT) before surgery improves survival compared with surgery alone. In Medical Research Council's OEO2 trial in 802 patients planned for radical surgery, who were randomized to two cycles of preoperative chemotherapy (cisplatin and infusional 5-fluorouracil [5FU]) followed by surgery versus surgery alone, the 5-year overall survival rate was 23% in the NACT group compared with 17% in the surgery-alone group at a median follow-up of 6 years; hazard ratio (HR), 0.84; 95% confidence interval (CI), 0.72 to 0.98; P = 0.03 (2). A Japanese trial (JCOG9907) compared neoadjuvant with adjuvant chemotherapy in 330 patients with clinical stage II or III squamous cell carcinoma (SCC) of the thoracic esophagus. Patients were randomly assigned to surgery with either induction or adjuvant chemotherapy consisting of two cycles of cisplatin (80 mg/m2 on day 1) with infusional FU (800 mg/m2 daily for 5 days) given every 3 weeks. Five-year overall survival was significantly higher in the group receiving preoperative chemotherapy (55% vs. 43%, P = 0.04) (3). Kaklamanos et al. in their meta-analysis of 11 randomized trials including a total of 2311 patients showed an absolute improvement in the 2-year survival rate of 4.4% (95% CI, 0.3–8.5) in the NACT group compared with surgery alone. When the analysis was restricted to the four trials that had been most recently conducted, the absolute 2-year survival benefit from NACT was found to be 6.3% (95% CI, 1.8% to 10.7%). The treatment-related mortality was also increased by 1.7% (95% CI, −0.9% to 4.3%) in the patients who received NACT (4).

The Fédération Francophone de Cancérologie Digestive (FFCD) trial evaluated the role of perioperative cisplatin and infusional 5FU (2 or 3 cycles of NACT, followed by surgery followed by 3 or 4 adjuvant chemotherapy cycles) versus surgery alone in 224 patients with resectable adenocarcinoma of the lower esophagus, gastroesophageal junction (GEJ), or stomach. The five-year overall survival (OS) rate was 38% in the NACT group versus 24% in the surgery-alone group (P = 0.02); the disease-free survival was also better (5-year DFS rate: 34% in NACT vs. 19% in surgery alone group with HR, 0.65, P = 0.003). In the multivariate analysis, the favorable prognostic factors for survival were perioperative chemotherapy (P = 0.01) and tumor localization in the stomach (P = 0.01). Perioperative chemotherapy significantly improved the curative resection rate (84% vs. 73%; P = 0.04). Grade 3 to 4 toxicity occurred in 38% of the perioperative chemotherapy + surgery patients (mainly neutropenia) but postoperative morbidity was similar in the two groups (5). All these trials used cisplatin (CDDP) and 5-fluorouracil (5FU) as the NACT regimen. Thus, the standard NACT regimen in resectable esophageal cancer is cisplatin with infusional 5FU.

The cisplatin and infusional 5FU regimen is toxic and requires significant logistic support due to the requirement of either an infusional pump or admission to the hospital for the infusional chemotherapy. Alternative chemotherapy regimens like taxane and platinum would be attractive option, due to the relative ease of administration and possibly, less toxicity. Paclitaxel and carboplatin chemotherapy administered once in 3 weeks has been tried as NACT in esophageal cancer. In a retrospective analysis of esophageal cancer patients with involvement/infiltration of the tracheobronchial tree who received induction chemotherapy, 79.6% of patients received taxane and platinum (once-in-3-weeks) as induction therapy. The objective response rate was 67% among the patients who underwent restaging scans following induction chemotherapy; 79.5% of the patients could receive radical intent therapy, either concurrent chemoradiotherapy, or radiation alone, or surgery in one patient. At a median follow-up of 28 months in surviving patients, the estimated median PFS was 8 months (95% CI, 5.5–10.5) and the estimated median OS was 17 months (95% CI, 5.6–28.4) (6). Taxanes and platinum, especially used as once-in-3-weeks regimen have efficacy in esophageal cancer in palliative setting (7). Paclitaxel and carboplatin administered once-in-a-week have been used as concurrent chemoradiotherapy in the CROSS concurrently with radiotherapy and the multimodality approach showed a significant 5-year overall survival benefit (8).

D'Addario and colleagues treated 131 solid tumor patients (both pretreated and nonpretreated) with paclitaxel 75 mg/m2 and carboplatin dosed at area under the curve (AUC) 2 to 3 on days 1, 8, and 15 every 4 weeks. The study included 19 esophageal cancer patients who received two cycles of chemotherapy with NACT intent. In this trial, the overall response rate (ORR) was 84.2% and the pathological complete response (CR) rate was 26.3% in esophageal cancer patients (9). Femke M. de man and his colleagues from Netherland demonstrated that weekly carboplatin (AUC4) and paclitaxel (100 mg/m2) is a well-tolerated and effective induction or palliative treatment regimen for patients with locally advanced or metastatic disease. In these study, 122 patients received induction chemotherapy. The median number of cycles received in induction chemotherapy arm was 7. Over all response rates in this study with induction chemotherapy was 48%. A total of 42% of patients who received induction chemotherapy underwent esophagectomy or definitive chemoradiotherapy. The median PFS and OS for patients who received induction chemotherapy was 22.1 months and 26.8 months, respectively. (10)

Rationale behind study: Weekly administration of paclitaxel and carboplatin has not been well explored in the NACT setting in esophageal cancer. This regimen allows increased dose intensity with reduced toxicity. It can be administered in the outpatient setting and in patients with compromised renal function. At Tata Memorial Hospital, we use NACT in patients with locally advanced esophageal cancer prior to surgery in our routine practice. Several patients are not fit to receive full dose 3-weekly chemotherapy, either because of borderline performance status, advanced age, comorbidities, or organ dysfunction. The regimen of weekly paclitaxel and carboplatin has been used routinely in our hospital in the neoadjuvant setting and we intend to evaluate the efficacy and toxicity of this regimen.

AIMS AND OBJECTIVES

Aims –

To evaluate the efficacy of weekly paclitaxel and carboplatin chemotherapy in the neo-adjuvant setting in patients with locally advanced esophageal or gastroesophageal junction cancer.

Primary Objective-

  1. Overall Survival

Secondary Objectives-

  1. Toxicity
  2. Radiologic response rate
  3. Resection rate
  4. R0 resection rate
  5. Tumor Regression Grade
  6. Pathologic complete remission rate
  7. Progression-free survival (PFS)
  8. Patterns of failure
  9. Factors that affect survival

DESIGN OF STUDY

Retrospective Cohort study

Inclusion Criteria-

  1. Patients with histologic or cytologic diagnosis of esophageal cancer or gastroesophageal junction cancer, planned for NACT followed by reassessment for radical therapy, who have received paclitaxel and carboplatin weekly with NACT intent.
  2. We will include all patients whose details have been entered into the prospective database maintained in the department of medical oncology between November 2012 and October 2019.

Exclusion Criteria-

  1. Patients with metastatic disease.
  2. Patients with esophageal or gastroesophageal junction cancer who received weekly paclitaxel and carboplatin chemotherapy, but concurrently with radiotherapy, either in the neoadjuvant or the definitive setting.

Study methodology

Retrospective analysis of a prospectively collected database, which was collected in Microsoft excel format. These data will be analyzed using Statistical Package for Social Sciences (SPSS) v. 20.

Sample size:

No formal sample size calculation will be done, as this is a retrospective analysis of patients who have already received therapy. Patients data from November 2012 and December 2019 will be included.

Variables:

  1. Demographics, risk factors, baseline disease characteristics and clinicopathological details, toxicity, response rate, resectability, pathologic complete remission (pCR) rate, and tumor regression grade (TRG) will be evaluated using descriptive statistics, absolute numbers with simple percentages, and cross tabulation and Chi-square test, as relevant.
  2. Radiological response rate: Assessment of response to neoadjuvant chemotherapy will be as per RECIST criteria version 1.1. Measurable lesions defined as maximum transverse diameter of more than or equal to 10 mm.
    • Complete Response: defined as disappearance of both target and nontarget lesions.
    • Partial response: defined as ≥30% decrease in the sum of the longest diameters of target lesions compared with baseline.
    • Progressive disease: ≥20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more new lesions.
    • Stable disease: Neither partial response nor progressive disease.
  3. Overall survival: The time from date of diagnosis to death from any cause: Kaplan–Meier plot, log rank test
  4. Progression free survival: The time from date of diagnosis until first evidence of disease recurrence or progression is documented (either radiologic or endoscopic or clinical) or until death from any cause, whichever comes first. Kaplan–Meier plot, log rank test
  5. pCR rate: The percentage of patients with no residual carcinoma (primary or nodes) in the surgical specimen.
  6. TRG: Tumor regression grade: A histomorphological assessment of the amount of residual tumor cells compared with the regressive changes. Mandard system has been used to report TRG, which classifies primary tumor regression into five TRGs ranging from TRG 1 (complete regression) to TRG 5 (absence of regression).
  7. R0 Resection rate: The percentage of patients without evidence of residual tumor at margins-circumferential/proximal/distal.
  8. Toxicity will be reported using CTCAE, version 5.
  9. Pattern of failures: Classified as locoregional or distant. Locoregional relapses are defined as disease recurrence at the site of the primary tumor or the locoregional lymph nodes. Lymph node recurrence in the celiac trunk region or the supraclavicular region will also be classified as locoregional relapses. Distant recurrences are defined as nonregional lymph node recurrences, malignant pleural or pericardial effusion, peritoneal metastases, or systemic metastases.
  10. Following factors will be evaluated to assess the impact on survival: Age (<60 years vs 60 years and over), sex (male vs female), T stage (T0, T1, T2 vs. T3, T4), N stage (N0, 1, 2 vs. N3), site of origin of tumor (cervical/upper thoracic vs. mid thoracic vs. lower thoracic/GEJ), ECOG PS (PS 0/1 vs. PS 2), histology (squamous cell carcinoma vs. adenocarcinoma/others), histologic grade (well differentiated vs. poorly differentiated), type of final therapy (surgery vs chemoradiotherapy vs. other), surgical margin (R0 vs R+), and pretreatment albumin (>/=4 g/dL vs. <4 g/dL).

Ethical Considerations

Since this is a retrospective analysis of patients who have received routine therapy, there are no ethical considerations. We request the IEC to grant a waiver of the requirement to take informed consent from the patients. At the time of analysis and publication, the patient data will be anonymized, and no form of patient identity will be revealed.

REFERENCES:

  1. http://cancerindia.org.in/globocan-2018-india-factsheet/12/08/2019
  2. Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer, J Clin Oncol 2009;27;5062-7.
  3. Ando, N., Kato, H., Igaki, H., Shinoda, M., Ozawa, S., Shimizu, H., Fukuda, H. (2011). A Randomized Trial Comparing Postoperative Adjuvant Chemotherapy with Cisplatin and 5-Fluorouracil Versus Preoperative Chemotherapy for Localized Advanced Squamous Cell Carcinoma of the Thoracic Esophagus (JCOG9907). Ann Surg Oncol 2012;19;68–74.
  4. Kaklamanos IG, Walker GR, Ferry K, Franceschi D, Livingstone AS. Neoadjuvant treatment for resectable cancer of the esophagus and the gastroesophageal junction: A meta-analysis of randomized clinical trials. Ann Surg Oncol 2003;10:754-61.
  5. Y. M. et al., Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: An FNCLCC and FFCD multicenter phase III trial. Journal of Clinical Oncology. 29(2011), pp. 1715–1721.
  6. Noronha, V., Joshi, A., Patil, V. M., Purandare, N., Jiwnani, S., Ghosh-Laskar, Prabhash, K. (2016). Efficacy and Safety of Induction Chemotherapy in Esophageal Cancer with Airway Involvement. Journal of Gastrointestinal Cancer, 47(3), 294–304.
  7. Prithviraj, G. K., Baksh, K., Fulp, W., Meredith, K., Hoffe, S., Shridhar, R., & Almhanna, K. (2014). Carboplatin and paclitaxel as first-line treatment of unresectable or metastatic esophageal or gastric cancer. Diseases of the Esophagus, 28(8), 782–787.
  8. Shapiro, J., van Lanschot, J. J. B., Hulshof, M. C. C. M., van Hagen, P., van Berge Henegouwen, M. I., Wijnhoven, van der Gaast, A. (2015). Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. The Lancet Oncology, 16(9), 1090–1098.
  9. D'Addario, G., Morant, R., Boehme, C., & Cerny, T. (2002). Feasibility and Toxicity of Weekly Paclitaxel-Carboplatin in 131 Patients with Pretreated and Non-Pretreated Solid Tumors. Oncology Research and Treatment, 25(2), 152–157.doi: 10.1159/000055225.
  10. Femke M. de Man, Ruben A.G. van Eerden, Esther Oomen-de Hoop, Joris N. Veraart, Nadia van Doorn, Leni van Doorn et al., Efficacy and Toxicity of Weekly Carboplatin and Paclitaxel as Induction or Palliative Treatment in Advanced Esophageal Cancer Patients. Cancers, 11(6), nn 826.

VISUAL ABSTRACT

.

SUPPLEMENTARY APPENDIX 2 (SUPPLEMENTARY TABLE 1)

.

REFERENCES

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin. 2018;68:394–424
2. Simha V, Patil V, Joshi A, Prabhash K, Noronha V. Role of palliative chemotherapy and targeted therapy in advanced esophageal and gastroesophageal junction cancers Cancer Res Stat Treat. 2019;2:172–81
3. Shapiro J, van Lanschot JJ, Hulshof MC, van Hagen P, van Berge Henegouwen MI, Wijnhoven BP, et al Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): Long-term results of a randomised controlled trial Lancet Oncol. 2015;16:1090–8
4. Dora TK, Aeron T, Chatterjee A, Deshmukh J, Goel A, Bose S, et al Neoadjuvant chemoradiotherapy followed by surgery for operable carcinoma esophagus: Ground reality in a tertiary care center of rural India-A retrospective audit Cancer Res Stat Treat. 2021;4:647–55
5. Kaklamanos IG, Walker GR, Ferry K, Franceschi D, Livingstone AS. Neoadjuvant treatment for resectable cancer of the esophagus and the gastroesophageal junction: A meta-analysis of randomized clinical trials Ann Surg Oncol. 2003;10:754–61
6. Medical Research Council Oesophageal Cancer Working Group. . Surgical resection with or without preoperative chemotherapy in oesophageal cancer: A randomised controlled trial Lancet. 2002;359:1727–33
7. Klevebro F, Alexandersson von Döbeln G, Wang N, Johnsen G, Jacobsen AB, Friesland S, et al A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction Ann Oncol. 2016;27:660–7
8. Shen S, Araujo JL, Altorki NK, Sonett JR, Rodriguez A, Sungur-Stasik K, et al Variation by stage in the effects of prediagnosis weight loss on mortality in a prospective cohort of esophageal cancer patients Dis Esophagus. 2017;30:1–7
9. Daly JM, Fry WA, Little AG, Winchester DP, McKee RF, Stewart AK, et al Esophageal cancer: Results of an American College of Surgeons patient care evaluation study J Am Coll Surg. 2000;190:562–72
10. Song T, Wan Q, Yu W, Li J, Lu S, Xie C, et al Pretreatment nutritional risk scores and performance status are prognostic factors in esophageal cancer patients treated with definitive chemoradiotherapy Oncotarget. 2017;8:98974–84
11. Wu N, Chen G, Hu H, Pang L, Chen Z. Low pretherapeutic serum albumin as a risk factor for poor outcome in esophageal squamous cell carcinomas Nutr Cancer. 2015;67:481–5
12. El-Rayes BF, Shields A, Zalupski M, Heilbrun LK, Jain V, Terry D, et al A phase II study of carboplatin and paclitaxel in esophageal cancer Ann Oncol. 2004;15:960–5
13. Noronha V, Patil V, Bhosale B, Joshi A, Purandare N, Prabhash K. Metronomic weekly paclitaxel in advanced unresectable esophageal cancer Indian J Cancer. 2013;50:128–34
14. Pêtre A, Dalban C, Karabajakian A, Neidhardt EM, Roux PE, Poupart M, et al Carboplatin in combination with weekly Paclitaxel as first-line therapy in patients with recurrent/metastatic head and neck squamous cell carcinoma unfit to EXTREME schedule Oncotarget. 2018;9:22038–46
15. Patil V, Noronha V, Joshi A, Muddu V, Dhumal S, Arya S, et al Weekly chemotherapy as Induction chemotherapy in locally advanced head and neck cancer for patients ineligible for 3 weekly maximum tolerable dose chemotherapy Indian J Cancer. 2014;51:20–4
16. Chen XS, Nie XQ, Chen CM, Wu JY, Wu J, Lu JS, et al Weekly paclitaxel plus carboplatin is an effective nonanthracycline-containing regimen as neoadjuvant chemotherapy for breast cancer Ann Oncol. 2010;21:961–7
17. Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, et al Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations Cancer. 1994;73:2680–6
18. Chakraborty S. A step-wise guide to performing survival analysis Cancer Res Stat Treat. 2018;1:41–5
19. Dessai S, Simha V, Patil V. Stepwise cox regression analysis in SPSS Cancer Res Stat Treat. 2018;1:167–70
20. Dessai S, Patil V. Testing and interpreting assumptions of COX regression analysis Cancer Res Stat Treat. 2019;2:108–11
21. Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, et al Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): A randomised, phase 2/3 trial Lancet. 2019;393:1948–57
22. de Man FM, van Eerden RA, Oomen-de Hoop E, Veraart JN, van Doorn N, van Doorn L, et al Efficacy and toxicity of weekly carboplatin and paclitaxel as induction or palliative treatment in advanced esophageal cancer patients Cancers (Basel). 2019;11:826
23. D'Addario G, Morant R, Boehme C, Cerny T. Feasibility and toxicity of weekly Paclitaxel-Carboplatin in 131 patients with pretreated and non-pretreated solid tumors Onkologie. 2002;25:152–7
24. Keresztes RS, Port JL, Pasmantier MW, Korst RJ, Altorki NK. Preoperative chemotherapy for esophageal cancer with paclitaxel and carboplatin: results of a phase II trial J Thorac Cardiovasc Surg. 2003;126:1603–8
Keywords:

Compromised; esophageal cancer; gastroesophageal junction; neoadjuvant; preoperative

© 2022 Cancer Research, Statistics, and Treatment | Published by Wolters Kluwer – Medknow