|Year : 2018 | Volume
| Issue : 2 | Page : 144-147
Outcomes with second-line chemotherapy in advanced pancreatic cancers: A retrospective study from a tertiary cancer center in India
Anant Ramaswamy1, Sangeetha Parthiban1, Mridul Malhotra1, Rushabh Kothari1, Alok Goel1, Prabhat Bhargava1, Sujay Srinivas1, Suyash Kulkarni2, Vikas Ostwal1
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radiology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||31-Dec-2018|
Dr. Vikas Ostwal
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Approximately 40% of patients receiving first-line chemotherapy (CT1) for advanced pancreatic adenocarcinomas (PDACs) receive second-line chemotherapy (CT2). The most appropriate regimen to be used has not been identified, and data regarding CT2 in advanced PDAC from India are scarce. MATERIALS AND METHODS: A retrospective analysis of advanced PDAC patients who were evaluated during the period of August 2013 to August 2016 in the Department of GI medical Oncology, at Tata Memorial Hospital was conducted. Patients with histologically proven PDAC and started on CT2 postprogression or recurrence after CT1 were included for analysis. RESULTS: A total of 237 patients received CT1 in the period of study, of which 76 patients (39.66%) received CT2. The median age of patients was 59.5 years (range: 38–82), majority were male (69.7%), and 14 patients (18.4%) had undergone curative pancreatic resection at baseline. The common regimens used as CT2 were modified 5 fluorouracil/leucovorin/irinotecan (mFOLFIRI) (35.5%), gemcitabine-nab paclitaxel (18.4%), and gemcitabine-erlotinib (11.8%). Common grade 3/4 toxicities noted were fatigue (10.3%), anemia (10.3%), neutropenia (7.4%), and vomiting (7.4%). Dose reductions were required in 32.9% of patients. RR, DCR, median event free survival, and median overall survival were 21.1%, 48.7%, and 5.94 months (95% confidence intervals [CI]: 4.68–7.20) and 8.08 months (95% CI: 7.11–9.07) respectively. CONCLUSIONS: CT2 in advanced PDAC appears feasible in the Indian setting if the patients are appropriately selected and they can be treated with acceptable toxicities and reasonable outcomes.
Keywords: Pancreatic adenocarcinoma, second-line chemotherapy, outcomes, India
|How to cite this article:|
Ramaswamy A, Parthiban S, Malhotra M, Kothari R, Goel A, Bhargava P, Srinivas S, Kulkarni S, Ostwal V. Outcomes with second-line chemotherapy in advanced pancreatic cancers: A retrospective study from a tertiary cancer center in India. Indian J Cancer 2018;55:144-7
|How to cite this URL:|
Ramaswamy A, Parthiban S, Malhotra M, Kothari R, Goel A, Bhargava P, Srinivas S, Kulkarni S, Ostwal V. Outcomes with second-line chemotherapy in advanced pancreatic cancers: A retrospective study from a tertiary cancer center in India. Indian J Cancer [serial online] 2018 [cited 2020 Jun 5];55:144-7. Available from: http://www.indianjcancer.com/text.asp?2018/55/2/144/249206
| » Introduction|| |
Survival and outcomes for patients with advanced pancreatic ductal adenocarcinoma (PDAC) have improved slowly over the last two decades.,, The emergence of the FOLFIRINOX (5 fluorouracil-leucovorin-irinotecan-oxaliplatin) regimen as well the gemcitabine-nab-paclitaxel regimens have increased median overall survival (mOS) from approximately 6 months (as seen with single-agent gemcitabine) to anywhere between 8.5 and 11 months.,
A select group of patients with advanced PDAC will be considered fit enough to receive second-line chemotherapy (CT2) postprogression on first-line chemotherapy (CT1). This proportion ranges from 16% to 68% (pooled mean, 43%) based on a systematic review of 95 studies published by Nagrial et al. in 2015. The choice of CT2 has mostly been 5-fluorouracil and leucovorin (5 FU/LV) based, guided by the results of the CONKO and CONKO-003 trials, respectively., The latest addition to the armamentarium is the combination of Nano liposomal irinotecan with 5 FU/LV, which showed a marginal though statistically significant improvement in OS as compared to 5 FU/LV alone (6.1 months vs 4.2 months; P = 0.012). However, patients included in these trials majorly received single gemcitabine as first-line therapy. Single-agent gemcitabine would not be considered upfront in a fit patient with advanced PDAC in the current era, when regimens such as FOLFIRINOX and gemcitabine-nab paclitaxel are available. Secondly, the selection of an appropriate regimen for patients progressing on FOLFIRINOX or gem-nab paclitaxel is also not settled.
Data from India regarding CT1 and CT2 use in advanced PDAC are scarce. In the current scenario of improving first-line regimens and the lack of standardized second-line regimens, we conducted a study of patients with advanced PDAC treated with CT2 in our institution and evaluated their outcomes in terms of median event free survival (EFS) and median overall survival (mOS).
| » Materials and Methods|| |
The study is a retrospective analysis of advanced PDAC patients who were evaluated from August 2013 to August 2016 in the Department of GI Medical Oncology, at Tata Memorial Hospital. Data were obtained from a prospectively maintained metastatic pancreatic cancer database. Patients satisfying all the following criteria were included in the analysis:
- Histologically proven pancreatic adenocarcinoma, either by cytology or biopsy, either during recurrence or before CT1
- Received one line of CT prior, either as neoadjuvant, adjuvant, or palliative CT
- Progression on CT1 or cessation of CT1 due to completion of planned therapy or adverse events/poor tolerance.
Patients were evaluated for fitness for CT by the Department of Medical Oncology and were then offered palliative CT with supportive care. Baseline demographic details, including comorbidities, prior treatment history, and therapeutic options used were recorded.
Toxicity assessment was done at every patient visit and recorded as per NCI–CTCAE version 4.0. Response to treatment was evaluated clinically on every visit and with contrast enhanced computed tomography scan after three to four cycles of CT or earlier as per physician decision. Responses were calculated by RECIST criteria, with responses reported as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), where feasible. If RECIST was not calculable, then the response was quantified based on collusion between treating physician and the GI radiologist as follows: CR, disappearance of all baseline lesions; PR, significant regression of lesions at baseline; SD, no significant regression of baseline lesions and no new lesions; PD, appearance of new lesions or significant increase in baseline lesions. Response rates (RR) and clinical benefit rate were reported as percentages.
EFS was calculated from the date of start of CT2 to date of progression, cessation of CT due to adverse events, loss to follow-up, withdrawal from therapy or death (in case of no documented progression). OS was calculated from the date of diagnosis to date of death. Prognostic factors evaluated were progression-free survival (PFS) of ≥3 months versus <3 months of PFS on CT1, upfront metastatic or not, and whether previous curative pancreatic resection was undertaken or not.
Clinical data collection and statistics
For the purposes of this study, demographic data and baseline, clinical data were collected retrospectively from GI Medical Oncology Information System and Electronic Medical Record System. All data were entered in SPSS (IBM SPSS statistical software version 21) and used for the analysis. Descriptive statistics including median, frequency, and percentage for categorical variables was used to describe age, gender distribution, treatment, and response to treatment. Median EFS and OS were calculated using Kaplan–Meier estimates whereas log-rank test was used for univariate comparisons.
| » Results|| |
A total of 237 patients during the prespecified period of the study received CT1. Of these 237 patients, 94 (39.66%) were offered CT2, 76 patients (32.07%) were finally started on CT2, whereas the remaining 18 patients declined CT2 and were continued on best-supportive care in the Department of Palliative Care at our hospital. Baseline characteristics, chemotherapeutic regimens used in CT1 as well as the reasons for shifting patients from CT1 to CT2 are listed in [Table 1]. Chemotherapeutic regimens administered as CT2 [Supplementary Table 1], adverse events (grades 3 and 4) and dose modifications in CT2 are mentioned in the supplementary tables [Supplementary Table 2].
|Table 1: Demographics, baseline clinical characteristics, and details of first-line treatment of patients treated with second-line therapy|
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Outcome measures [Table 2]
Responses were evaluable in 59 patients (77.6%), whereas they were not evaluable in the remaining patients. Best responses seen were PRs in 16 patients (21.1%), and SD in 21 patients (27.6%), for overall RRs of 21.1% and disease control rates of 48.7%.
With a median follow-up of 7.57 months, the median EFS was 5.94 months (95% confidence intervals [CI]: 4.68–7.20) [Figure 1], and the mOS was 8.08 months (95% CI: 7.11–9.07) [Figure 2].
In patients who had a PFS of >3 months on CT1, median overall survival mOS was 9.62 months (95% CI: 6.33–12.92) whereas patients who had a PFS of ≤3 months on CT1 had a mOS of 7.58 months (95% CI: 6.42–8.75), with no statistically significant difference between the two groups (P = 0.683). In patients who had a PFS of >3 months on CT1, mEFS was 6.34 months (95% CI: 4.64–8.03) whereas patients who had a PFS of ≤3 months on CT1 had a mEFS of 5.94 months (95% CI: 4.01–7.87), with no statistically significant difference between the two groups (P = 0.307).
There was a significant difference in mOS for patients who underwent curative pancreatic resection at baseline as opposed to patients who did not undergo resection (15.08 with CI [10.41–19.74] months versus 7.29 months with CI [6.14–8.44]; P = 0.024). There was also a statistical significant difference in mOS for patients who were upfront nonmetastatic versus who were upfront metastatic 11.86 (9.64–14.07) months versus 6.50 (5.00–8.00) months (P = 0.005).
| » Discussion|| |
Outcomes and survival in PDAC have improved over the last two decades, primarily due to improvement in first-line chemotherapeutic regimens offered to patients. However, as in other difficult to treat gastrointestinal cancers such as gastric cancer and hepatocellular carcinoma, there is a growing role for second-line treatment in advanced PDAC as well.,, The recently published NAPOLI-1 trial clearly shows a statistically significant, but modest OS benefit for the nanoliposomal irinotecan—5 FU/LV combination as opposed to 5FU/LV monotherapy. Whether standard nonliposomal irinotecan with 5 FU/LV (FOLFIRI) would have shown a similar benefit is a moot point, considering FOLFIRI has shown a mOS of 4 months–6.6 months when used as CT2 in various studies.,
The percentage of patients receiving CT2 in this study (39.66%) is consistent with previously published data regarding the use of CT2. Besides the heterogeneity of chemotherapeutic regimens used as CT1, our study had a cohort typical of advanced PDAC. A high incidence of patients with comorbidities such as hypertension (30.3%) and diabetes mellitus (48.7%) was noted.
Six major randomized trials, including NAPOLI-1, evaluating CT2 have all included patients who had progressed on first-line gemcitabine.,,,,, The inclusion criteria of these studies have to be rediscussed in the current scenario given the proven superiority of FOLFIRINOX and gem-nab paclitaxel over single-agent gemcitabine alone as CT1 in advanced PDAC. However, PFS with CT1 does not affect the survival benefit of CT2 as shown in our study even though there is there is an increased usage of multiagent CT as CT1 in our study. A majority of patients in our study had previously received FOLFIRINOX (23.7%), gemcitabine-nab paclitaxel (22.4%), and gemcitabine-erlotinib (11.8%) as opposed to single-agent gemcitabine (15.8%) as CT1.
The most common regimens used as CT2 in our study were modified FOLFIRI (35.5%), and gemcitabine-nab paclitaxel (18.4%). Although the use of mFOLFIRI is based on the common use of 5 FU based regimen as CT2, the use of gemcitabine-nab paclitaxel is indicative of current practices where FOLFIRINOX is commonly used as CT1. A small prospective study of 57 patients has already explored this treatment sequence with impressive survivals (mPFS, 5.1 months and mOS, 8.8 months). A majority of the other regimens used in our study were 5 FU or capecitabine based.
Within the confines of a retrospective analysis in a heterogeneous cohort of second-line chemotherapeutic regimens, we report reasonable outcomes in terms of median EFS (5.94 months) and mOS (8.08 months). This is comparable to the outcomes that have been noted in a majority of the studies involving CT2 in advanced PDAC.,, While we cannot identify a single regimen that may be preferable due to the small numbers, this study is a validation of the need for correct patient selection when administering CT2 in advanced PDAC. The most common regimen used in our study was modified FOLFIRI (used without bolus 5 FU), and it appears to be a regimen that is well tolerated in our setup. Our study suggests that irrespective of PFS on CT1, patients should be offered CT2, especially in those who recurred after previous curative surgery or those who were nonmetastatic to begin with and progressed on CT1.
This study is the first study from India to report on outcomes with CT2 in advanced PDAC. However, we acknowledge multiple caveats in this analysis, considering this is a retrospective study. Patients in this study have received multiple regimens, and we are unable to identify a single suitable regimen for use in our setup due to the small numbers. Data on grade 1/2 adverse events and quality of life are also lacking and this is important considering the modest benefits associated with CT2. The potentially improved outcomes in our study are also biased by the inclusion of operated patients who had initially received CT1 in the adjuvant setting—such patients who received CT on recurrence were also considered to have received CT2.
| » Conclusions|| |
CT2 in advanced PDAC appears feasible in the Indian setting if patients are appropriately selected. The use of CT2 improves survival modestly in this group of patients with acceptable levels of toxicity, with low a threshold for dose reductions keeping second-line treatment in mind. The most commonly used CT in this study was the modified FOLFIRI regimen.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Teague A, Lim KH, Wang-Gillam A. Advanced pancreatic adenocarcinoma: A review of current treatment strategies and developing therapies. Ther Adv Med Oncol 2015;7:68-84.
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al.
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25.
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al.
Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703.
Nagrial AM, Chin VT, Sjoquist KM, Pajic M, Horvath LG, Biankin AV, et al.
Second-line treatment in inoperable pancreatic adenocarcinoma: A systematic review and synthesis of all clinical trials. Crit Rev Oncol Hematol 2015;96:483-97.
Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, et al.
Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: A phase III-study from the German CONKO-study group. Eur J Cancer 2011;47:1676-81.
Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, et al.
Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: Outcomes from the CONKO-003 trial. J Clin Oncol 2014;32:2423-9.
Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, et al.
Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): A global, randomised, open-label, phase 3 trial. Lancet 2016;387:545-57.
Sirohi B, Dawood S, Rastogi S, Pandey A, Bal M, Shetty N, et al.
Treatment of patients with metastatic pancreatic cancer: Experience from a tertiary Indian cancer center. Indian J Cancer 2015;52:449-52.
] [Full text]
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al.
Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. Lancet Oncol 2014;15:1224-35.
Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al.
Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56-66.
Neuzillet C, Hentic O, Rousseau B, Rebours V, Bengrine-Lefèvre L, Bonnetain F, et al.
FOLFIRI regimen in metastatic pancreatic adenocarcinoma resistant to gemcitabine and platinum-salts. World J Gastroenterol 2012;18:4533-41.
Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, et al.
A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer 2009;101:1658-63.
Hurwitz HI, Uppal N, Wagner SA, Bendell JC, Beck JT, Wade SM 3rd
, et al.
Randomized, double-blind, phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J Clin Oncol 2015;33:4039-47.
Ueno M, Okusaka T, Omuro Y, Isayama H, Fukutomi A, Ikeda M, et al.
A randomized phase II study of S-1 plus oral leucovorin versus S-1 monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer. Ann Oncol 2016;27:502-8.
Gill S, Ko YJ, Cripps C, Beaudoin A, Dhesy-Thind S, Zulfiqar M, et al.
PANCREOX: A Randomized phase III study of 5-fluorouracil/Leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy. J Clin Oncol 2016; pii: JCO685776.
Portal A, Pernot S, Tougeron D, Arbaud C, Bidault AT, de la Fouchardière C, et al.
Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after folfirinox failure: An AGEO prospective multicentre cohort. Br J Cancer 2015;113:989-95.
Boeck S, Wilkowski R, Bruns CJ, Issels RD, Schulz C, Moosmann N, et al.
Oral capecitabine in gemcitabine-pretreated patients with advanced pancreatic cancer. Oncology 2007;73:221-7.
Ioka T, Katayama K, Ishida N, Takada R, Yamai T, Fukutake N, et al
. Randomized phase II study of best available fluoropyrimidine compared with continuation of gemcitabine (Gem) monotherapy in patients with Gem-refractory pancreatic cancer. J Clin Oncol 2013;131:287-7.
[Figure 1], [Figure 2]
[Table 1], [Table 2]