|Year : 2018 | Volume
| Issue : 2 | Page : 138-143
Treatment practices for metastatic pancreatic cancer: Can we deliver an appropriately efficacious and safe regimen in Indian patients?
Anant Ramaswamy1, Vikas Ostwal1, Alok Goel1, Prabhat Bhargava1, Sujay Srinivas1, Sanyo Dsouza1, Shailesh V Shrikhande2
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Surgical Oncology, 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: The median overall survival (mOS) in metastatic pancreatic cancers (PCs) hovers between 6 months to 11 months. MATERIALS AND METHODS: The study is a retrospective analysis of metastatic PC patients who were evaluated from August 2013 to August 2016 in the Department of Gastrointestinal (GI) Medical Oncology, Tata Memorial Hospital (TMH). RESULTS: Out of 218 patients, 24 patients (11%) were not planned for chemotherapy and referred to the Department of Palliative Care for further supportive care. One hundred and fifty-three patients received palliative chemotherapy in TMH with median age of 56 years (range: 23–79), male (60.1%), and nonresident in Maharashtra (60.1%). Regimens used most commonly were gemcitabine–nab-paclitaxel in 60 patients (39.2%), gemcitabine–erlotinib in 25 patients (16.3%), and modified FOLFIRINOX in 21 patients (13.7%). A total of 58 patients (43%; n = 135) had Grade 3/4 toxicities. As of cutoff date for the analysis of outcomes, 139 patients (90.8%) patients had ceased first-line chemotherapy, due to radiologically proven progressive disease (PD) in 89 patients (64%), repeated Grades 3 and 4 adverse events in 26 patients (18.7%), and clinically PD in 18 patients (12.9%). With a median follow-up of 278 days, the mOS was 217 days (95% confidence interval [CI]: 175–258), and the median event-free survival was 125 days (95% CI: 107–122). CONCLUSION: Dose modifications for chemotherapy are required commonly when treating metastatic PC, with common reasons for dose reduction being toxicities, Eastern Cooperative Oncology Group performance status >=2, and low albumin levels. Studies evaluating logistic and financial aspects of treating metastatic PC with chemotherapy in India are warranted.
Keywords: Chemotherapy, dose modification, Indian patients, metastatic pancreas
|How to cite this article:|
Ramaswamy A, Ostwal V, Goel A, Bhargava P, Srinivas S, Dsouza S, Shrikhande SV. Treatment practices for metastatic pancreatic cancer: Can we deliver an appropriately efficacious and safe regimen in Indian patients?. Indian J Cancer 2018;55:138-43
|How to cite this URL:|
Ramaswamy A, Ostwal V, Goel A, Bhargava P, Srinivas S, Dsouza S, Shrikhande SV. Treatment practices for metastatic pancreatic cancer: Can we deliver an appropriately efficacious and safe regimen in Indian patients?. Indian J Cancer [serial online] 2018 [cited 2019 Jun 18];55:138-43. Available from: http://www.indianjcancer.com/text.asp?2018/55/2/138/249205
| » Introduction|| |
The rates of improvement in survival in pancreatic cancer (PC) have been slow compared with the advances seen in other malignancies. Despite advances in understanding the biology of PCs, clinically relevant improvement in survival has been difficult to attain in PC. This is particularly true in metastatic PCs, where median overall survival (mOS) hovers around approximately 6–11 months only.,
Palliative chemotherapy with gemcitabine has remained the cornerstone of the treatment for metastatic PC, but improvements in mOS have been seen with combination regimens such as gemcitabine–erlotinib, gemcitabine–capecitabine, gemcitabine–nab-paclitaxel, and FOLFIRINOX.,,, While the improvements in overall survival (OS) with combinations are statistically and potentially clinically significant, the adoption of these regimens into practice has been tempered due to concerns of toxicity and cost-effectiveness.,
The administration of combination regimens in PC has multiple nuances to be evaluated, before actually being used in clinical practice. The incidence of baseline comorbidities (e.g., diabetes, hypertension etc.), the need and maintenance of a chemo-port or peripherally inserted central line for infusions, and treating patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) >=2 are issues that are seldom dealt with in trials. Direct translation of trial data to clinical practice in PC is fraught with these concerns, especially when the incremental improvements in survival are in the range of a few weeks as compared with single-agent gemcitabine. The increased incidence of toxicities with combination chemotherapy also may be magnified in clinical practice, where patients are an unselected heterogeneous cohort as opposed to a homogenous trial population.
The relevance of cost-effectiveness data from the West with regard to these combinations also carries important caveats when being considered in the Indian context. A study from Ontario suggested that the FOLFIRINOX regimen had a >85% probability of being cost-effective when a threshold of $100,000 (approximately INR 6,500,000) is considered. The figure of $100,000 was selected based on Canadian empirical evidence showing that cost-effectiveness ratios above $100,000 negatively affected oncology drug funding recommendations. India has a vastly different health care and health care delivery system, besides patients having an obviously lower spending power as compared with their counterparts in the West.,
With this background, we conducted a study of patients with metastatic PC treated at our institution with a four-fold aim—assess practice patterns in terms of patients registered and those who underwent chemotherapy versus those planned for supportive care alone, chemotherapeutic regimens administered for metastatic PC, evaluate outcomes in terms of median event-free survival (EFS) and mOS, as well as recording adverse events and tolerance seen with these regimens.
| » Materials and Methods|| |
The study is a retrospective analysis of metastatic PC patients who were evaluated from August 2013 to August 2016 in the Department of Gastrointestinal (GI) Medical Oncology, Tata Memorial Hospital (TMH). As per the ethical guidelines of the Declaration of Helsinki, data were obtained from a prospectively maintained metastatic PC database. Decisions regarding metastatic nature of disease and palliative intent of therapy were made by a GI multidisciplinary joint clinic (MDJC), comprising a dedicated surgical oncologist, medical oncologist, radiation oncologist, gastroenterologist, and radiologist.
Patients satisfying all the following criteria were included in analysis:
- Histologically proven pancreatic adenocarcinoma, either by cytology or biopsy
- Definitive evidence of metastatic disease, as per scans.
Post-MDJC, patients were evaluated for fitness for chemotherapy by the Department of Medical Oncology and were then offered palliative chemotherapy with supportive care or best-supportive care alone. Patients receiving palliative chemotherapy were then followed up at our clinic, while patients offered best supportive care were referred to the Department of Palliative Care for further treatment.
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 chemotherapy 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 diagnosis to date of progression, cessation of chemotherapy 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.
A comparison of RR, adverse events, dose modifications, and survival between two artificially created groups—the “newer regimens” group (gemcitabine–erlotinib, gemcitabine–capecitabine, gemcitabine–nab-paclitaxel, and modified FOLFIRINOX [mFOLFIRINOX]) and the “older regimens” group (single agent gemcitabine, gemcitabine-platinum, and FOLFIRI) was also evaluated. All chemotherapeutic regimens were used as per standard protocols, excepting the FOLFIRINOX regimen, where the bolus 5-fluorouracil was not administered, and hence is considered as mFOLFIRINOX.
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 software version 21 and used for the analysis. Descriptive statistics including median, frequency, and percentage for categorical variables were used to describe age, gender distribution, treatment, and response to treatment. Median EFS and OS were calculated using Kaplan–Meier estimates, while the log-rank test was used for univariate comparisons.
| » Results|| |
A total of 218 patients were diagnosed with metastatic PC in the period of the study. Twenty-four patients (11%) were not planned for chemotherapy and referred to the Department of Palliative Care for further supportive care. Reasons for this subset of patients not being offered palliative chemotherapy are enumerated in [Figure 1]. Further 41 patients (18.8%) wished to take chemotherapy elsewhere and hence did not follow-up further in our institution. One hundred and fifty-three patients received palliative chemotherapy in TMH—their demographic data and baseline characteristics are outlined in [Table 1]. Briefly, median age was 56 years (range: 23–79), with a majority being male (60.1%) and nonresident in Maharashtra (60.1%). Seventy-two patients (47.1%) had diabetes mellitus, while 44 patients (28.8%) had hypertension prior to chemotherapy. One hundred twenty-three patients were metastatic upfront (80.4%), while the remaining 30 patients (19.6%) had received prior curative intent treatment (resection, neoadjuvant intent chemoradiation, etc.).
|Table 1: Demographics and baseline clinical characteristics of treated patients|
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Chemotherapeutic regimens, adverse events, and efficacy
Regimens used as first line are shown in [Figure 1]. The regimens used most commonly were gemcitabine–nab-paclitaxel in 60 patients (39.2%), gemcitabine–erlotinib in 25 patients (16.3%), and mFOLFIRINOX in 21 patients (13.7%).
Adverse events and response rates
Grades 3 and 4 adverse events were reported for all the regimens combined. Adequate data for toxicity analysis were available for 135 patients (88.2%). Fifty-eight patients (43%; n = 135) had Grade 3 or 4 toxicities [Table 2]. Common toxicities included fatigue in 25 patients (18.5%), neutropenia in 18 patients (13.3%), nonneutropenic infections in 17 patients (12.6%), and peripheral neuropathy (Grade 2 or 3) in 15 patients (11.1%). Seventeen patients (11.1%) on chemotherapy were admitted for the management of chemotherapy-related complications [Table 3].
Best responses seen were PRs in 48 patients (31.4%), and SD in 28 patients (18.3%), for overall RR of 31.4% and disease control rates of 49.7%. A total of 38 patients (24.8%) have radiologically PD, while 16 patients (10.5%) had clinical disease progression before first planned radiological response evaluation. Responses were not evaluable in 23 patients (15%) due to premature cessation of chemotherapy before radiological assessment.
Delivery of chemotherapy
Chemotherapy was delayed for ≥1 week in 43 patients (28.1%). The reason for delaying chemotherapy was adverse events in 33 patients (21.6%), delayed availability of daycare appointments in 7 patients (4.6%), and noncompliance in 3 patients (2.0%).
A total of 67 patients (43.8%) received dose-modified schedules of chemotherapy. Thirty-eight patients (56.7%; n = 67) underwent upfront dose reduction, with reasons quoted being low albumin levels (22.4%), ECOG PS 2 (16.4%), and poorly controlled comorbidities (11.9%). Dose modifications in later sessions of chemotherapy were done in 29 patients (43.3%; n = 67), with common reasons being stated as Grade 3 or 4 toxicities (31.3%; n = 67) and multiple Grade 2 or 3 toxicities (4.5%; n = 67). Seventeen patients (11.1%) were hospitalized for the management of potentially, chemotherapy-related complications.
As of cutoff date for the analysis of outcomes, 139 patients (90.8%) patients had ceased first-line chemotherapy due to radiologically proven PD in 89 patients (64%), repeated Grades 3 and 4 adverse events in 26 patients (18.7%), and clinically, PD in 18 patients (12.9%). Sixty-six patients (43.1%, n = 153) received second-line therapy and a further 23 patients (15%; n = 153) received third-line therapy. Details of second- and third-line therapies are summarized in [Table 3].
Outcomes and comparison of regimens
With a median follow-up of 278 days, the mOS was 217 days (95% confidence interval [CI]: 175–258) [Figure 2] and the median EFS was 125 days (95% CI: 107–142) [Figure 3].
On comparing outcomes between the “older” and “newer” sets of regimens administered, there was no difference in median EFS and mOS. While a greater percentage of patients receiving “newer” regimens required dose modifications as compared with the “older regimens” (47.32 vs. 34.15%), there was no statistically significant difference between the two groups (P = 0.179). There were no statistically significant differences in the other variables examined between the two groups [Supplementary Table 1].
| » Discussion|| |
The selection of an appropriate chemotherapeutic regimen for advanced PC in clinical practice is a decision that should balance the purported benefits with newer regimens (based on trial data with a homogenous well-selected patient cohort) with the issues of administration of these regimens, and a potentially increased incidence of adverse events in the real world and issues of logistics. These issues are magnified in a country like India and furthermore in our institutional practice. While situated in the western part of India, a majority of our patients come from different states (non-Maharashtra: 60.1%) as seen in this study. This gives us an early insight as to some of the issues that might be faced by patients traveling to our center for treatment along with referral delay and increased disease burden.
Of the 218 patients registered and evaluated for metastatic PC in our institution, 11% were planned for best supportive at the outset. This is in keeping with previously published data by Sirohi et al. from our institution, with regard to the proportion of patients considered for best supportive care. Again, a further 18.8% of patients took treatment at centers elsewhere after an initial evaluation and plan in TMH. This is a further reflection of logistic issues faced by patients, when traveling from their native regions to geographically distant cities for cancer directed therapy.
Demographic characteristics of treated patients in our study are consistent with a typical population of metastatic PC. We noted a high incidence of baseline diabetes mellitus (47%), which is partially explainable by the high incidence of cardiovascular diseases in India as well as the longstanding conundrum of “diabetes causing PC or vice versa.”,,
A majority of patients were treated with “newer” regimens, predominantly gemcitabine–nab-paclitaxel (39.2%), gemcitabine–erlotinib (16.3%), and mFOLFIRINOX (13.7%), as opposed to “older” regimens such as gemcitabine-platinum (13.1%) or single-agent gemcitabine (7.8%). The proportion of patients receiving mFOLFIRINOX (6.9–13.7%) and gemcitabine–nab-paclitaxel (5.9–39.2%) has increased, whereas the proportion receiving gemcitabine–erlotinib has decreased (29.7–16.3%) as compared with the earlier published data from our institution. This is consistent with the worldwide patterns of increased usage FOLFIRINOX and gemcitabine–nab-paclitaxel, as well as dwindling usage of gemcitabine–erlotinib based on survival benefits (or lack of) and cost-effectiveness ratios.,,,, In the context of this practice pattern, it is important to note the findings of a study from British Columbia, which found that only 25% and 45% of advanced PC patients from routine clinical practice would be eligible for FOLFIRINOX and gemcitabine–nab-paclitaxel, respectively, if strict trial criteria for the selection of patients were used. The selection of chemotherapeutic regimen in our study is reflective of such a clinical bias.
Our study attempted to examine the delivery of chemotherapy for metastatic PC in the Indian setting and we were able to identify certain practice points. Dose modifications, essentially dose reductions, appear to be a common practice and are used even during the initial phase of therapy. While dose reductions due to Grades 3 and 4 toxicities are expected, low albumin levels and an ECOG PS >=2 necessitating dose reductions appear to be common reasons for dose reduction. While prospective evidence backing such strategies is lacking, large-scale retrospective data, largely from first-line trials in colorectal cancer, have shown that patients with ECOG PS 2 derive an equal benefit from superior therapies as patients with ECOG PS 0–1, but with an increased risk of toxicities and early mortality.,, The evidence for low albumin levels predicting for increased chemotherapy-induced toxicity also exists though predominantly in lung cancers. In a setup where a balancing act between benefit and risk is essential, using clinical indicators such as ECOG PS and low albumin levels to potentially reduce side effects maybe more practical than evidence based.
The adverse events recorded in our study are Grades 3 and 4 and hence offer no information of important Grades 1 and 2 toxicities that have an important bearing of quality of life. A majority of the toxicities appear similar to published data, with the exception of nonneutropenic infections (12.6%) and thrombocytopenia (8.9%), which are slightly higher; 11.1% of patients were hospitalized due to chemotherapy-related complications—this percentage is only indicative of the patients who got admitted, as opposed to the percentage of patients requiring admission.
The survival outcomes for patients with metastatic PC in our study are lower than published trial data, especially when compared with the PRODIGE and IMPACT studies, though consistent with survival that would be obtained if treatment with single-agent gemcitabine, gemcitabine–capecitabine, or gemcitabine–erlotinib was used., When we divided patients into artificial groups as described, we did not find any differences in survival between the patients treated with the “newer” and “older” regimens, though the cohorts are extremely heterogeneous and small in number to draw any definite conclusions. What we can suggest is that the “older” regimens show expected outcomes, while the application of the “newer” regimens in a nontrial real-world setup such as ours requires further enunciation and evaluation to improve applicability and survival. A similar percentage of patients received second-line chemotherapy in both groups (39.02 and 44.64%), and this percentage is consistent with the actual number of patients who receive second-line chemotherapy for metastatic PC world over.
Any discussion on the appropriateness of a chemotherapeutic regimen for routine practice in India is incomplete without a commentary on the cost of these regimens. Unfortunately, cost-effectiveness studies with regard to chemotherapy in India are few and there are none evaluating metastatic PC. A majority of Indian patients do not have access to insurance, besides having to bear treatment and logistic expenses on their own., It is beyond the scope of this study to examine these constraints, but these are questions that require answering due to the potentially limited benefits of multiagent chemotherapeutic regimens in a real-world setting.
Our study has multiple caveats. The real-world study population examined in this study meant that these patients were a heterogeneous cohort treated with multiple regimens, thereby limiting the generalizability of these outcomes. The artificial division into “older” and “newer” regimens is not based on the actual temporal advent of these regimens in treating PC. The reasons described for upfront dose reduction of chemotherapy are based on individual clinician preference rather than firm recommendations regarding the same. The RR available is not strictly by RECIST, with 15% of patients not having an evaluable response.
| » Conclusion|| |
Our study examines the applicability of various regimens used in routine clinical practice while treating metastatic PC. Dose modifications for chemotherapy are required commonly when treating metastatic PC, with common reasons for dose reduction being toxicities, ECOG PS >=2 and low albumin levels. There is a trend toward using more effective regimens such as mFOLFIRINOX and gemcitabine–nab-paclitaxel, but within the confines of a small cohort, these regimens seem similar in efficacy and adverse event profile to older regimens such as single-agent gemcitabine or gemcitabine-platinum. Studies evaluating logistic and financial aspects of treating metastatic PC with chemotherapy in India are warranted.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]