|Year : 2022 | Volume
| Issue : 3 | Page : 747-753
Comparative analyses of paclitaxel/carboplatin with cisplatin/5-fluorouracil-based chemoradiation in locally advanced inoperable upper and middle third esophageal cancer: A randomized prospective pilot study
Divyesh Kumar, Treshita Dey, Divya Khosla, Sandeep Gedela, Arun S Oinam, Rakesh Kapoor
Department of Radiotherapy and Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||15-Jan-2021|
|Date of Acceptance||30-May-2021|
|Date of Web Publication||25-Jul-2022|
Department of Radiotherapy and Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
Introduction: Chemoradiation therapy (CRT) remains the treatment of choice for inoperable locally advanced esophageal cancer (LAEC). Several CRT regimens are existent in esophageal cancer, but definitive conclusions are lacking. We performed a pilot study to compare treatment outcome, survival, and toxicities in inoperable upper and middle third esophageal cancer patients undergoing CRT using either paclitaxel/carboplatin or cisplatin/5FU based regimen.
Methods: Patients were randomised in two arms (arm A and arm B). In Arm A, taxane-based (Paclitaxel+carboplatin) and in arm B non-taxane-based (cisplatin+5FU) doublet chemotherapy drugs were given concurrently with external beam radiation therapy (EBRT). EBRT in two phases up to a total dose of 54 Gy/27#@2Gy/# was given. Response was subsequently assessed using Response evaluation criteria in solid tumors (RECIST v1.1) and toxicities utilizing Common Terminology Criteria for Adverse Events (CTCAE v 4.0).
Result: The overall response rate (ORR) in the taxane-based group was higher than the non-taxane-based group, but was not significantly different (p=0.851). Regarding hematological toxicities, anaemia and reduced cell counts were more in the taxane group compared to the non-taxane group while non-hematological toxicities were comparable. Similarly, better survival with late toxicities were seen with taxane-based arm when compared to non-taxane-based arm, though it was not statistically significant.
Conclusion: Our pilot analysis highlights the fact that paclitaxel/carboplatin CRT shows better response, survival, and comparable toxicities when compared to cisplatin/5FU, though statistically nonsignificant. Further randomised prospective trials with large sample size are warranted.
Keywords: Chemoradiation, esophageal cancer, inoperable
|How to cite this article:|
Kumar D, Dey T, Khosla D, Gedela S, Oinam AS, Kapoor R. Comparative analyses of paclitaxel/carboplatin with cisplatin/5-fluorouracil-based chemoradiation in locally advanced inoperable upper and middle third esophageal cancer: A randomized prospective pilot study. J Can Res Ther 2022;18:747-53
|How to cite this URL:|
Kumar D, Dey T, Khosla D, Gedela S, Oinam AS, Kapoor R. Comparative analyses of paclitaxel/carboplatin with cisplatin/5-fluorouracil-based chemoradiation in locally advanced inoperable upper and middle third esophageal cancer: A randomized prospective pilot study. J Can Res Ther [serial online] 2022 [cited 2022 Aug 10];18:747-53. Available from: https://www.cancerjournal.net/text.asp?2022/18/3/747/351803
| > Introduction|| |
Esophageal cancer is a highly fatal disease with significant chances of local recurrence and distant spread. It is the eighth most common cancer worldwide., Overall prognosis remains dismal despite the best management strategies. Treatment options for esophageal cancer include surgery, radiation, and chemotherapy. The majority of patients present in an advanced stage of the disease, with only 20% of patients generally suitable for surgery., Surgery alone results in a 30% local failure rate following esophagectomy for locally advanced esophageal cancer (LAEC). The statement means that if only radiation therapy alone is used without any other modality of treatment the chances of survival are less., Prospective randomized trial comparing chemoradiation (CRT) with RT alone showed a 5-year survival rate of 26% in the CRT arm compared with 0% in the RT-alone arm. CRT is thus considered as the treatment of choice for patients with inoperable LAEC patients with adequate performance status. Although multiple CRT treatment paradigms are existent, unfortunately, the optimum timing, dosing, and choice of systemic agents remain controversial.
Paclitaxel is a broad-spectrum cytotoxic drug that is a promising treatment agent against esophageal cancer, with response rates of approximately 32%. It acts as a mitotic inhibitor that blocks cells in the G2M phase of the cell cycle with a sensitizing enhancement ratio of 1.48. Although various chemotherapy regimens have been tried concurrently with radiation therapy, cisplatin /5FU or Paclitaxel/carboplatin remains the preferred regimen. Our study was one step ahead to confirm it i, e which of the two is better. A comparison of both drugs has rarely been studied prospectively. In this pilot study, we aim to compare treatment outcome, toxicities, and survival in patients of inoperable upper and middle third LAEC, who received either paclitaxel–carboplatin (taxane-based) or cisplatin–5-FU (nontaxane-based) weekly CRT.
| > Patients and Methods|| |
Patient population and eligibility
An analysis of 22 patients from June 2017 to March 2018, who met the following inclusion and exclusion criteria, was performed.
- Pathologically proven squamous cell carcinoma of esophagus (upper and middle one-third)
- Age of 18–65
- Karnofsky performance status (KPS) > =70
- Stage II A–III C (AJCC (American Joint Committee on Cancer) 7th edition)
- Hematological parameters (neutrophil count ≥1.5 × 109/L, leukocyte count ≥3 × 109/L, hemoglobin ≥9.0 g%, and platelet count ≥100 × 109/L), adequate liver function (serum bilirubin = 1.5 mg% and transaminase level ≤2.5 the upper limit of normal), adequate serum creatinine (≤1.2 mg%), and blood urea nitrogen (≤25 mg%)
- Willing to participate in the study.
- Lower one-third esophagus involving gastroesophageal junction
- Previous exposure to radiotherapy or chemotherapy
- Distant metastasis
- Pregnant women
- Histology other than squamous cell carcinoma
- Patients requiring dose adjustments (>2 dose reduction) during CRT, if any.
A prospective pilot study was conducted after obtaining approval from the institutional ethics committee and written informed consent from patients. The primary objective was to assess tumor response and treatment-related toxicities (acute/late), whereas the secondary objective was to analyze progression-free survival (PFS) and overall survival (OS). Patients fulfilling inclusion/exclusion criteria were randomized into two arms, i.e., Arm A and Arm B, using computer-generated randomization software. In Arm A, patients were subjected to taxane-based concurrent CRT, whereas in Arm B, patients were given nontaxane-based CRT. Response assessment was done after 6 weeks of CRT, and toxicity grading was done during weekly visits before chemotherapy administration. On follow-up, long-term toxicities, if any encountered, were noted and managed. Workflow is depicted in [Figure 1].
Baseline workup before the start of treatment was performed which included history, general physical examination, blood investigations (complete blood counts, liver function test, and renal function tests), upper gastrointestinal (GI) endoscopy (UGIE), and radiological investigations (chest X-ray and computed tomography [CT] of the neck, thorax, and abdomen).
In both arms, patients were subjected to external beam RT (EBRT) and concurrent weekly chemotherapy. Chemotherapy (modified departmental chemotherapy regimen) and radiation were given as per protocol. During CRT, patients were assessed weekly for toxicity grading.
Patients in Arm A were treated with taxane-based regimen (injection paclitaxel 50 mg/m2, day 1 + injection carboplatin area under curve (AUC) 2, day 1) intravenous (i/v) weekly, whereas patients in Arm B were treated with the nontaxane-based regimen (injection cisplatin 40 mg/m2, day 1 + 5FU 375 mg/m2, day 1) i/v weekly, total four cycles. All the patients received premedication with antiemetics and steroids before chemotherapy. Complete blood counts were performed before each cycle of chemotherapy. The patient was treated with recombinant human granulocyte colony-stimulating factor (G-CSF) if the white blood cell reduced below 3000/mm3 after the chemotherapy. Dose modifications were done only if, despite the usage of G-CSF support neutropenia developed or if, platelets were reduced to <500,000/μL.
Planning computed tomography scan protocol
For planning purposes, contrast-enhanced CT (CECT) was acquired from the body of the mandible up to L1 vertebrae on an empty stomach (6-h fasting). In the first phase, CT simulation was done in a supine position, with hands by side to fully expose the supraclavicular fossa. In the boost phase, patients were planned in a prone position to displace the esophagus off from the spinal cord. Oral contrast using barium or Gastrografin was not given to avoid artifact which might hamper target delineation. All CT images were acquired using Philips Brilliance Big Bore CT using a slice thickness of 2.5 mm, and all the images were then transferred to the Varian treatment planning system, version 11(Varian Medical Systems, Palo Alto, CA, USA).
In both arms, after planning CT, contouring was done. Gross tumor volume (GTV) was defined as a macroscopic primary tumor and node >1 cm. In Phase I, clinical target volume (CTV) was created using a 3-cm longitudinal and 1.5-cm radial margin respecting the anatomical boundaries (the heart, vertebrae, lungs, and aorta), oriented along the esophagus. CTV node was defined by a 1-cm isotropic margin from the GTV node. Planning target volume (PTV) was given a 1-cm isometric margin from CTV. Along with involved-field radiation, elective nodal irradiation was also done by including the supraclavicular nodes for upper thoracic and periesophageal nodes for both upper and mid-thoracic esophagus. The initial phase was with 40 Gy/20 # at 2 Gy/#, 5 days/week, using the anteroposterior–posteroanterior field [Figure 2]a. For the boost phase, CTV tumor and PTV tumor were generated using margins of 1 cm in the craniocaudal direction and 0.5 cm in the transverse plane each from the GTV tumor. CTV node and PTV node were generated using a 0.5-cm margin each. A boost dose of 14 Gy/7 # @ 2 Gy/#, 5 days/week, by 3-field (1 anterior and 2 obliques) was given, sparing the organ at risk [Figure 2]b. The dose constraints utilized were as follows: lung V20 Gy <30%, V30 <20%, mean lung dose to be limited to 20 Gy, mean heart dose <25 Gy, and spinal cord Dmax 45 Gy. A dose-volume histogram was generated as depicted [Figure 2]c. Thus, EBRT in two phases, to a total dose of 54 Gy in 27 #, was given. Patients were treated with a linear accelerator using energy 6–15 MV. RT was stopped if Grade 3/4 GI reactions or radiation esophagitis were observed, and was discontinued until recovery from toxicity.
|Figure 2: (a) Field arrangement by anteroposterior–posteroanterior. (b) Field arrangement by three-field boost. (c) Dose-volume histogram|
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Patients were assessed for a response using CECT (neck + thorax + abdomen) and UGIE after 6 weeks of completion of CRT. The response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). The response criteria for the target lesions are as follows: RECIST Criteria1.1 is a response criterion as analysed on CECT scan done before and after treatment. Depending upon the response achieved 4 responses can be achieved which is given in terms of complete response, partial response, stable disease or progressive disease. The response criteria for the target lesions are as follows: Complete response (CR), disappearance of all target lesions; partial response (PR), ≥30% decrease; stable disease (SD), neither PR nor PD criteria met; and progressive disease (PD), ≥20% increase or appearance of new lesion(s). Patients with CR + PR were considered as responders, whereas patients with PD + SD were taken as nonresponders. Acute toxicities, if any encountered during CRT, were assessed and documented using Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Periodic follow-up examinations with clinical examination every 3 monthly and CT scan every 6 months starting approximately 6 weeks after the end of CRT were done. Positron emission tomography scan was performed only in patients with suspected PD.
SPSS 23.0 (SPSS Inc., Chicago, IL, USA) software was used for data analyses. A sample size of thirty patients was taken for this pilot study, and patients were randomized equally into two arms. Patients who either defaulted to treatment were excluded from the final analyses. Descriptive analyses were done and compared using Chi-square. PFS was calculated from the date of registration to disease relapse or censored at the last confirmation of survival. For PFS, either a clinical or radiological progression or nonresponders to treatment were considered. OS and PFS were estimated by using the Kaplan–Meier method, and curves were compared using a log-rank test. Kaplan–Meier curves were generated for survival analyses. P =0.05 was considered statistically significant.
| > Results|| |
A total of thirty patients were taken up for the study, 15 patients in each arm. In arm A six patients while in arm B two patients defaulted and were excluded. Hence, a total of 22 patients, Arm A (n = 9) and Arm B (n = 13) were analyzed. The median age involved was 54 years (range, 42–64 years). The two arms were similar for baseline characteristics. The male-to-female ratio was 1:1. The majority of the patients had Stage III B (68.18%) followed by Stage III C (31.82%) at presentation. Patient demographics are depicted in [Table 1].
The overall response rate (ORR) in Arm A, 6/9 (66.66%), was higher than Arm B, 8/13 (61.53%), but was not statistically significant (P = 0.805). In total, 2/9 (22.22%) of the patients in the taxane-based group had PD versus 4/13 (30.76%) in the nontaxane-based group. Furthermore, 1/9 (11.11%) had SD in the taxane-based group compared to the nontaxane-based group 1/13 (7.69%) [Table 2].
Regarding hematological toxicities, anemia (Grade II–IV) was seen in 2/9 (22.22%) patients in Arm A, whereas it was seen in 1/13 patient (7.69%) in Arm B; the results were statistically nonsignificant (P = 0.328). Similarly, reduced cell counts (leukopenia and neutropenia) were observed in 3/9 (33.33%) and 3/9 (33.33%) patients in Arm A, as compared to Arm B where 1/13 (7.69%) and 2/13 (15.38%) patients had leukopenia and neutropenia, respectively. However, results were statistically nonsignificant (P = 0.125 and P = 0.323, respectively). Thrombocytopenia in Arm A was observed in 1/9 patient (11.11%), also in Arm B, 1/13 (7.69%) patient had thrombocytopenia; results were again statistically nonsignificant (P = 0.783) [Table 3].
Similarly, Grade II–IV nonhematological toxicities were observed in both arms. In Arm A, 6/9 (66.66%) patients had Grade II–IV (nausea/vomiting), whereas it was seen in 8/13 (61.53%) patients in Arm B (P = 0.805). Skin reactions and mucositis were observed in 6/9 (66.66%) and 7/9 (77.77%) patients in Arm A, whereas in Arm B, it was observed in 4/13 (30.76%) and 5/13 (38.46%) patients, respectively; results were nonsignificant (P = 0.964 and P = 0.686, respectively) [Table 4].
Long-term toxicities were also observed in both the patient groups. The most common long-term complication encountered in the taxane-based arm was esophageal stricture, seen in 2/9 (22.2%) of the patients. On the other hand, the most frequently observed toxicity in the nontaxane-based arm was esophagitis seen in 4/13 (30.8%) patients. However, there was no statistically significant difference observed in the rates of such complication between the two arms [Table 5].
The median follow-up of the study was 17 months (range, 8–35). The median PFS was 33 months in the taxane-based group compared to 13 months in the nontaxane-based group, though it was not statistically significant (P = 0.284) [Figure 3]. The 1- and 2-year OS rates were 88.9% and 55.6%, respectively, for the taxane-based arm, whereas it was 69.2% and 25.6% in the nontaxane-based arm, respectively (P = 0.165) [Figure 4].
|Figure 3: Kaplan–Meier Plot of Estimated Progression free survival (PFS)|
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| > Discussion|| |
The outcome of patients with advanced esophageal cancer though remains poor, our results demonstrated an ORR of 66.66% in the taxane-based group whereas 61.53% in the nontaxane-based group (P < 0.05). Of the cisplatin-based chemotherapy regimens, cisplatin and 5-FU remains the most commonly used combination. Response rates reported in patients with advanced disease with this combination are 30%–35%, and the median survival is 8–9.5 months. Approximately 50% of patients treated with definitive CRT according to a FU-based regimen developed locoregional recurrence, and the pattern of locoregional recurrence accounted for the largest proportion of recurrence. Shim et al. treated patients with advanced esophageal squamous cell cancer (ESCC) (clinical T2–4, N0–1, M0–M1 lymph node disease) using docetaxel at a dose of 20 mg/m2 and cisplatin at a dose of 25 mg/m2 at weeks 1, 2, 3, 5, 6, and 7 with concurrent radiotherapy (GTV, 54 Gy/27#). They showed an ORR of 85.8%, which was higher than the ORR of 71.6% reported in a retrospective study by Xiao Jiang Sun et al. Li et al. evaluated the feasibility of combination CRT (54–60 Gy) using docetaxel (60 mg/m2) and cisplatin (80 mg/m2) in patients with ESCC and achieved an extremely high response rate of 98.3%, with an ORR of 71.2%. A retrospective comparative analysis done by Li et al. demonstrated that CRT with pemetrexed/cisplatin was similar to cisplatin/5-FU. A response rate of 93.5% was observed compared to the 89.7% response seen in the cisplatin/5-FU arm. Hematological and esophagitis were the major toxicities reported. Cisplatin along with paclitaxel has also been studied as a concurrent chemotherapy regimen. In a study done by Adelstein et al., the median survival was 15 months, with neutropenia (95%) and nausea (95%) as the most frequent Grade III/IV toxicities and neutropenic fever reported in 16 patients (40%). In our analysis, hematological toxicities though were more for the taxane-based group, nonhematological toxicities were comparable. Similar toxicity outcomes have been reported in a retrospective analysis done by Münch et al. Similar to the findings of the ChemoRadiotherapy for Esophageal Cancer followed by Surgery Study trial, higher rates of hematological toxicities (neutropenia and leukopenia) were observed in our study. Leukopenia and neutropenia observed in this trial were 6% and 2%, respectively, whereas it was 3% and 3%, respectively, in our study. In contrast to our findings, which showed favorable outcome and survival (statistically nonsignificant), a multicentric retrospective analysis was done by Honing et al. which showed comparable outcomes, in terms of disease-free survival and OS for carboplatin/paclitaxel compared with cisplatin/5-FU as definitive concurrent CRT treatment in esophageal cancer patients.
It is a randomized prospective pilot study, which is the strength of our study. Besides it, the limitations of our study include its small sample size, and also the quality of life assessment was not done.
| > Conclusion|| |
As per our analysis, the paclitaxel/carboplatin-based CRT regimen showed a favorable response rate and survival, with a comparable toxicity profile when compared to the cisplatin/5-FU regimen, though not statistically significant. However, a definitive conclusion could not be drawn due to the small sample size of the study. Further studies with a large sample size are required for confirmation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]