|Ahead of print
Efficacy and safety of capecitabine and oxaliplatin (CAPOX) treatment in colorectal cancer: An observational study from a tertiary cancer center in South India
Ashok V Kalidindi1, Biswajit Dubashi2, M Jayanthi1, DG Shewade1
1 Department of Pharmacology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India
2 Department of Medical Oncology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India
|Date of Submission||12-Jul-2019|
|Date of Decision||27-Jul-2019|
|Date of Acceptance||27-Mar-2020|
|Date of Web Publication||10-Dec-2020|
Department of Medical Oncology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry
Source of Support: None, Conflict of Interest: None
Background: 5-fluorouracil (5-FU) was the standard treatment care for colorectal cancer (CRC), however, its efficacy was limited due to safety concerns. Capecitabine and oxaliplatin (CAPOX) treatment was found equivalent to 5-FU in efficacy and preferred now due to easy management and convenience in administration. Hence, the present study aims to determine the efficacy and safety associated with CAPOX treatment in a real world non clinical setting.
Methods: 145 treatment-naive and newly diagnosed CRC patients were recruited in the study. Each patient received oxaliplatin 130 mg/m2 infusion over 2 hours on day 1 and oral capecitabine 1000 mg/m2 in divided doses twice daily for the next 14 days of a 21-day cycle.
Results: In the adjuvant setting, the observed disease-free survival rate was 62% (n=34) in the colon and 67% (n=15) in the rectum cancer patients at 2 years. The observed overall survival rate in the colon and rectal cancer was 80% (n=44) and 83% (n=18) respectively at 2 years. In the palliative setting the observed progression-free survival rate was 28% (n=13) in the colon and 33% (n=7) in rectal cancer patients at 2 years. The observed OSR at 2 years was 64% (n=30) in the colon and 67% (n=14) in the rectal cancer patients. Thrombocytopenia (17, 11.7%) and diarrhea (8, 5.5%) were the most commonly observed grade 3/4 hematological and gastrointestinal toxicities. Hand-foot syndrome and peripheral neuropathy were the major contributors for dose reduction (14, 9.6%), treatment delay (8, 5.4%), and drug discontinuation (9, 6.1%) in the study cohort.
Conclusion: CAPOX treatment was found to be effective but associated with several dose-limiting toxicities.
Keywords: CAPOX, Colorectal cancer, response, survival, toxicities, tertiary care center, south Indian patients
Key Message CAPOX regimen was found to be effective in the management of colorectal cancer in a real world nonclinical trial setting. The toxicities associated with the treatment were manageable.
|How to cite this URL:|
Kalidindi AV, Dubashi B, Jayanthi M, Shewade D G. Efficacy and safety of capecitabine and oxaliplatin (CAPOX) treatment in colorectal cancer: An observational study from a tertiary cancer center in South India. Indian J Cancer [Epub ahead of print] [cited 2021 Jan 24]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=302941
| » Introduction|| |
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the western world and now a major concern in developing countries, too. Globally, it accounts for over 9% of all cancer incidences. Incidence rates of CRC are similar in both the sexes, with a slight male predominance. According to GLOBOCAN 2018 report, colon cancer is the fourth most common cancer in the world, while cancer of the rectum is the eighth most incident. Together, CRC is the third most commonly diagnosed cancer globally, comprising 11% of all cancer diagnoses. The CRC is more common among men than women and 3–4 times more common in developed than in developing nations. In India, as per the Indian Council of Medical Research (ICMR), consensus document on management of CRC 2014, the annual incidence rates (AARs) of colon and rectal cancer in men are 4.4 and 4.1 per 100000 respectively. The AAR for colon cancer in women is 3.9 per 100000.
From the clinical perspective CRC is classified into four stages (I, II, III, and IV). The survival rate of the patient depends on the disease stage. It was reported that the 5-year survival rate in patients with stage IV metastatic disease is only about 10–15%. In metastatic disease, it is difficult to decide the therapeutic options like radiation or surgery, and chemotherapy remains the major component of standard and supportive care in these patients. For the last three decades, 5-fluorouracil (5-FU)-based regimens like FOLFOX (5-FU + leucovorin + oxaliplatin) and FOLFRI (5-FU + leucovorin + Irinotecan) were the standard treatment care for CRC. The 5-FU-based treatment has improved the overall survival rate in CRC patients. However, the efficacy is often limited due to toxicities. Capecitabine is an oral prodrug of 5-FU, whereas oxaliplatin is 3rd generation platinum derivative. Capecitabine and oxaliplatin (CAPOX) treatment is found to be non-inferior to FOLFOX and FOLFRI in efficacy and being routinely used as a standard treatment for CRC in the last few years due to its easy management and convenience in administration.,, The aim of our study is to give an insight into the efficacy, survival and toxicities associated with CAPOX in CRC patients.
| » Patients and Methods|| |
Patients who are ≥18 years of age of either gender, newly diagnosed and treatment-naive patients were included in the study. Previously treated, pregnant, lactating women, and patients with abnormal liver function (serum transaminases ≥2 times the upper normal limit) or renal function (serum creatinine greater than 1.5 g/dL) are excluded from the study. The baseline computed tomography (CT) details, demographic and other characteristics like age, sex, cancer diagnosis, disease stage, treatment setting, comorbidities, smoking, and drinking habits were collected. Apart from the above data, baseline hematological values ((Hemoglobin (HB), Red Blood Cell (RBC), White Blood Cell (WBC)), and platelets), renal (creatinine) and liver (Alanine Transaminase (ALT), Alkaline Phosphatase (ALP), and Aspartate Transaminase (AST)) function parameters and a starting dose of CAPOX were recorded.
From May 2016 to November 2018 (28 months), we recruited a total of 145 CRC patients from the regional cancer center, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER) who received CAPOX as their standard treatment care. Each patient received a standard treatment schedule of oxaliplatin 130 mg/m2 infusion over 2 hours on day 1 and oral capecitabine 1000 mg/m2 in divided doses twice daily for the next 14 days of a 21-day cycle. Each patient received a capecitabine total dose of 14 g/m2 per one cycle of chemotherapy. The cumulative dose of capecitabine received for each patient will be equal to 14 g/m2 × number of cycles received. The median number of CAPOX cycles administered was 12 in the adjuvant setting and eight in the palliative setting. Patients who were on the adjuvant setting, the response was assessed in terms of median disease-free survival (mDFS), disease-free survival rate (DFSR), median overall survival (mOS), and overall survival rate (OSR) at 2 years. Patients who are on palliative care the response was assessed in terms of objective response rate (ORR), median progression-free survival (mPFS), progression-free survival rate (PFSR) at 2 years, mOS, and OSR at 2 years. The ORR is assessed by following response evaluation criteria for solid tumors (RECIST) by comparing the baseline CT scan with the the CT done at the end of the chemotherapy.
Efficacy endpoints taken for survival analysis were defined as follows
- Median DFS: Time from the date of treatment till recurrence or the last date at which the patient was known to be disease-free.
- DFSR: Percentage of patients who are disease-free at 2 years
- OS: Time from the date of treatment until the date of last follow-up or death from any cause.
- OSR: Percentage of patients surviving at 2 years
- Median PFS: Time from the initial diagnosis to disease progression at any time or death from any cause.
- PFSR: Percentage of patients with progression-free survival at 2 years
- ORR: Any partial response (PR), complete response (CR) to chemotherapy is considered as objective response rate. (ORR = PR + CR)
During each cycle, the treatment-related toxicities were assessed and graded for severity by using common terminology criteria for adverse events (CTCAE). Apart from this, the starting dose of CAPOX for each patient, any dose reduction or treatment delay or drug discontinuation and treatment-related deaths were recorded during each follow-up.
Ethics and approvals
The study was approved by the institute scientific advisory committee (JSAC Reg.No.JSAC 34/6/2016) and institute ethics committee (JEC Reg.No: 25-5-2016). The study was carried out in accordance with the standards of the institutional ethics committee and within the principles of the Declaration of Helsinki. Informed consent was obtained from all the study patients.
Demographic parameters were expressed as mean ± standard deviation. We used Kaplan-Meier survival curves for analyzing survival data. Adverse effects are graded for severity according to common terminology criteria for adverse effects (CTCAE) guidelines. All toxicities were represented in percentages and analyzed descriptively.
| » Results|| |
The mean age of the patients was 50 ± 12.8 with 90 men and 55 women. The age range was 34-72 years in men and 32-68 years in women. The diagnosis included colon cancer (n = 102) and rectum cancer (n = 43). The number of patients in each treatment setting included adjuvant (n = 77) and palliative care (n = 68). The median follow-up was 18 months. The median number of CAPOX cycles administered in adjuvant and palliative settings were 12 and 8, respectively. Other baseline characteristics are described in [Table 1]. Response assessment was available for 145 patients. In the adjuvant setting, the median OS was not reached (NA) in both colon and rectal cancer patients. This indicates more than half of the CRC patients are event-free, that is, death at the time point of survival analysis. [Figure 1] Similarly the median DFS was not reached in both colon and rectal cancer patients at 2 years [Figure 2]. The DFSR was 62% in the colon and 67% in rectal cancer at 2 years. The observed OSR at 2 years was 80% in colon cancer and 83% in rectal cancer [Table 2].
|Figure 1: Overall survival analysis –adjuvant treatment setting (colon versus rectal cancer) mOS = Median overall survival; NR= Not reached|
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|Figure 2: Disease free survival - Adjuvant treatment setting (colon versus rectal cancer). mDFS= Median disease free survival, NR= not reached|
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|Table 2: Response assessment in adjuvant and palliative care treatment setting|
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In palliative care patients, the observed ORR (CR + PR) was 40% in colon cancer and 36% in rectal cancer. The combined (colon + rectum) ORR was 38%. PFSR in the colon and rectal cancer at 2 years was 28% and 32%, respectively. The OSR at 2 years was 64% in the colon and 68% in rectal cancer [Table 2] The median OS was 16 months in the colon and not reached in rectal cancer patients. The median PFS was 10 months in both the cancers [Figure 3] and [Figure 4].
|Figure 3: Overall survival analysis – Palliative care setting (colon versus rectal cancer). mOS = median overall survival, NR = not reached, M= Months|
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|Figure 4: Progression free survival– Palliative care setting (colon versus rectal cancer). mPFS = Median progression free survival, M= Months|
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We analyzed median OS and OSR at 2 years between left versus right-sided colon cancer. We observed a median overall survival of 20 months in the left colon and 18 months in right colon cancer patients [Figure 5]. The OSR at 2 years in the left-sided colon was 74% and 69% in right-sided colon cancer [Table 3].
|Figure 5: Over survival analysis – right side colon cancer versus left side colon cancer. mOS = median overall survival, M= Months|
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The overall hematological toxicities observed of any grade were anemia (59, 40.6%), thrombocytopenia (50, 34%), and neutropenia (31, 21%). However, the most commonly observed grade 3/4 (G3/G4) hematological toxicity was thrombocytopenia (17, 11.7%). The commonly observed gastrointestinal toxicities were vomiting (58, 40%) and diarrhea (33, 23%). The G3/G4 diarrhea was more frequent compared with vomiting (8, 5.5%) versus (4, 2.8%). Hand-foot syndrome (HFS) is a specific dose-limiting toxicity of capecitabine and was observed in 63 (42%) patients of which 18 (12%) patients have developed G3 toxicity. Peripheral neuropathy (PN) is specific dose-limiting toxicity associated with oxaliplatin and was observed in 46 (31.7%) patients of which 14 (9.6%) patients have developed G3 toxicity [Table 4]. We also assessed liver and renal toxicity with CAPOX treatment. Liver toxicity was observed in 30 (20.6%) patients of which 3 (2%) patients developed G3 toxicity. The liver toxicity could be due to underlying liver metastasis and may not be directly related to treatment. Renal toxicity was observed in 5.8% of the patients in the total cohort. In the study a total of 24% of patients needed dose reduction, 14% of patients needed treatment delay and 10.3% needed drug discontinuation due to CAPOX related toxicities. However, no toxicity-related deaths were observed [Table 5].
|Table 4: Toxicity profile of patients based on common terminology criteria for adverse events guidelines (CTCAE)|
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|Table 5: Number of patients with dose reduction or treatment delay or drug discontinuation due to toxicities|
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| » Discussion|| |
In adjuvant treatment setting with colon cancer patients, the DFSR results of our study were found to be slightly lower (62% versus 70%) when compared with another study by Haller et al., however, the OSR results were similar (80% versus 78%) when compared between both the studies. The DFSR observed in our study is in line (62% versus 63%) when compared with a study by Osawa et al.; however, the observed OSR in our study was higher (80% versus 71%). In rectal cancer patients, the DFSR and OSR results of our study were found to be lower (67% versus 71%) and (83% versus 92%) when compared to phase 2 study by Nishimura et al. The differences in the study results might be due to dissimilar follow-up periods across the studies.
Few recent studies have reported clinical, pathological, and survival differences between the right versus left-sided colon cancer. The patients with left-sided colon cancer were found to have better survival rates when compared to right side, In our study we also observed a difference in median OS (18 months versus 20 months) and OSR (69% versus 74%) when compared between right versus left colon cancer. However, the observed differences are not statistically significant (P-value = 0.2) on Kaplan-Meier survival analysis.
In our study, the combined (colon + rectum) ORR (38% versus 48%) and the observed median PFS (10 versus 7 months) were found to be slightly different when compared with a phase III study by Porschen et al. However the combined (colon + rectum) ORR observed in our study was found to be similar (38% versus 38%) when compared to a phase 2 study by Rosati et al. The differences in the results may be due to different sample sizes and follow-up periods across the studies which cannot be ruled out.
In our study, G3 toxicities like thrombocytopenia, HFS and PN are the major contributors for the dose reduction or treatment delay or drug discontinuation with CAPOX. The overall incidence (OI) of thrombocytopenia observed in our study was found to be slightly similar (34% versus 29%) when compared to a study by Iveson et al. HFS was found to be the major contributor for capecitabine dose reduction or discontinuation in the present study. The symptoms of HFS range from mild blackish skin discoloration to severe skin changes like peeling, blisters, bleeding, and pain mainly on the palm of the hands and sole of the feet. In the present study, grade 1 or 2 HFS was more common during the early cycles (1–4) of chemotherapy and whereas the grade-3 HFS was found to be a late toxicity and developed after 6 or 7 cycles of chemotherapy. The OI and G3 HFS incidence observed in our study were found higher (OI-42% versus 27%, G3-10% versus 6.5%), (OI-42% versus 36%, G3-10% versus 3%) when compared with two other studies available in the literature., PN is dose-limiting toxicity associated with oxaliplatin and occurs due to drug accumulation either in the sensory or motor neurons. The involvement of sensory neurons often results in disturbing sensations like numbness, burning, and shooting pain in the affected areas. Motor involvement often causes muscle weakness and paralysis. In the present study, sensory disturbances are early toxicities and found to develop during oxaliplatin infusion or during 1–6 cycles of chemotherapy. The muscular involvement of PN was late toxicity and observed after seven cycles of chemotherapy. The OI of PN observed in our study was 31% and G3 toxicity was 9%. The OI and G3 toxicity were lower (OI-30% versus 57%, G3-9.6% versus 17%) when compared with a study on CAPOX treatment in CRC patients. Liver toxicity was the other major toxicity observed in our study (29%); however, it cannot be directly related to CAPOX treatment as it could be due to underlying liver metastasis also.
| » Conclusion|| |
We describe the real-life experience of CRC patients treated with CAPOX. The treatment with CAPOX was effective but associated with several dose-limiting toxicities. A total of 48% of the patients in our study cohort needed either dose reduction or treatment delay or drug discontinuation due to CAPOX treatment-related toxicities.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]