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ORIGINAL ARTICLE
Year : 2016  |  Volume : 43  |  Issue : 3  |  Page : 140-143

Aflibercept as a second-line therapy in metastatic colorectal cancer: A limited Indian experience


Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Date of Web Publication14-Sep-2016

Correspondence Address:
Umesh Das
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Room No. 5, OPD Block, Bengaluru - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0974-5009.190538

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  Abstract 

Introduction: Aflibercept in combination with FOLFIRI has been shown to improve overall survival in the pivotal VELOUR study. Aflibercept has not yet been marketed in India. Sanofi has made available this drug for Indian patients under a program called Named Patient Access Program (NPP). We present a limited clinical experience with the use of aflibercept at our center. Materials and Methods: We analyzed the data of the patients who received aflibercept under NPP. Aflibercept was given in combination with FOLFIRI as second-line for patients who progressed on oxaliplatin based therapy. Aflibercept was given at 4 mg/kg intravenous (IV) every 15 days. Chemotoxicities were assessed as per CTCAE. Response evaluation was done every four cycles. Results: Five patients were enrolled. The median age was 34 years. The median number of aflibercept cycles administered was 12. Common grade 2/3 toxicities were mucositis, diarrhea, neutropenia thrombocytopenia, and hypertension seen in three (60%), three (60%), two (40%), two (40%), and one patient respectively. After four cycles, the response was assessed as: One complete remission (CR), three partial remissions (PR), and one progressive disease (PD). Three patients completed 12 cycles of chemotherapy and aflibercept. At the end of 12 cycles, one patient still in CR and two patients were in PR. Four patients were alive till date. Conclusion: As we had very less number of patients, it was very difficult to compare it with VELOUR data. It is one of option as second-line in metastatic colorectal cancer (mCRC) who progressed on oxaliplatin chemotherapy. Mucositis, diarrhea, and hematological toxicity were the most common toxicity in our patient.

Keywords: Aflibercept, colorectal cancer, FOLFIRI


How to cite this article:
Babu G, Das U, Lakshmaiah K, Dasappa L, Jacob LA, Babu S. Aflibercept as a second-line therapy in metastatic colorectal cancer: A limited Indian experience. J Sci Soc 2016;43:140-3

How to cite this URL:
Babu G, Das U, Lakshmaiah K, Dasappa L, Jacob LA, Babu S. Aflibercept as a second-line therapy in metastatic colorectal cancer: A limited Indian experience. J Sci Soc [serial online] 2016 [cited 2022 Dec 5];43:140-3. Available from: https://www.jscisociety.com/text.asp?2016/43/3/140/190538


  Introduction Top


Colorectal cancer is the second most common cancer in women and the third most common cancer in men, with an estimated worldwide incidence of more than 1.3 million in 2012, and mortality over 600,000. [1] In India, it is the fifth most common cancer and the fifth most common cancer-related mortality. [1] Fluoropyrimidine-based chemotherapy regimen has represented the backbone of all chemotherapy in colorectal cancer. First-line regimen of chemotherapy in metastatic colorectal cancer (mCRC) is a fluoropyrimidine-based chemotherapy regimen, combining infusional fluorouracil (FU) and leucovorin with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), with a crossover to the alternate regimen for second-line. With the introduction of targeted therapy, the overall survival of mCRC has improved and reached approximately 24 months. [2],[3],[4] Bevacizumab, vascular endothelial growth factor (VEGF) inhibitor blocks VEGF-A, and has been shown to increase survival in the first-line setting when added to irinotecan, bolus FU, and leucovorin or in the second-line setting with the FOLFOX regimen. [5],[6]

Aflibercept known as VEGF trap as well is a recombinant fusion protein containing VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and 2, fused to the Fc portion of human immunoglobulin (Ig) G1. Aflibercept blocks the activity of VEGF-A, VEGF-B, and placental growth factor (PIGF) by acting as a high-affinity ligand trap to prevent these ligands from binding to their endogenous receptors. Aflibercept in combination with FOLFIRI significantly improves overall survival in second-line mCRC patients previously treated with an oxaliplatin-containing regimen. [7] Aflibercept has not yet been marketed in India. Sanofi has made available this drug for Indian patients under a program called Named Patient Access Program (NPP). As per Velour study those patient fulfilled criteria for aflibercept only provided the drug. We present a limited clinical experience with the use of Aflibercept in the prelicensing, post-trial period at a single institution in India.


  Materials and methods Top


We analyzed the data of patients who have received aflibercept under NPP between October 2013 and May 2014. Aflibercept was given in combination with FOLFIRI for patients who failed first-line oxaliplatin-based therapy. Those who fulfilled the eligibility criteria for aflibecept were included and informed about unlicensed access to the drug and consent was taken. Aflibercept was given at 4 mg/kg intravenous (IV) every 15 days. Doses of chemotherapy were irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5FU bolus 400 mg/m 2 , 5FU continuous infusion 2,400 mg/m2 over 46 h. Use of growth factors was allowed. Response evaluation was done after every four cycles as per with contrast-enhanced computed tomography (CECT) of the abdomen and serum carcinoembryonic antigen (CEA) level. Toxicities profile was assessed as pre National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.


  Result Top


Five patients were enrolled in NPP. The median age was 34 years (range 25-53 years) and four females and one male. All patients were Eastern Cooperative Oncology Group (ECOG) performance score 1.Two patients were rectosigmoid, and three were colon cancer. All were stage IV diseases [Table 1]. All were adenocarcinoma patients (One was grade 2 and four were grade 3). All patients progressed on oxaliplatin-based chemotherapy. No patient received any targeted therapy prior aflibercept, and the median number of cycles administered was 12 (4-26). Common grade 2 and 3 toxicities were mucositis three (60%) patients, diarrhea three (60%) patients, neutropenia two (40%) patients, and thrombocytopenia two (40%) patients, hypertension one patient [Table 2]. After four cycles, response was assessed and there were one patient in complete remission (CR), three in partial remission (PR), and one progressive disease (PD). One patient underwent hemicolectomy and liver resection after six cycles and there was no residual tumor in the hemicolectomy specimen, and postoperative period was uneven full. The patient who had progressive disease had withdrawn consent for aflibercept. One patient had myocardial infarction after five cycles of chemotherapy and succumbed to the same. After eight cycles, two patients were maintained in PR and one was maintained in CR. Three patients completed 12 cycles of chemotherapy and aflibercept. At the end of 12 cycles one patient still in CR and two patients in PR. After 12 cycles two patients refused to take both chemotherapy and aflibercept so they were they were kept under follow-up. The third patient is still on aflibercept and he completed 26th cycle till date. All four patients were alive till date [Figure 1] and [Table 3].
Figure 1: Response

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Table 1: Base line characteristics of patients (before starting targeted therapy)

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Table 2: Adverse events

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Table 3: Second line chemo - targeted therapy and response

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  Discussion Top


Aflibercept is a novel fusion protein that acts as a decoy soluble receptor to block VEGF-A, VEGF-B, and PIGF. Aflibercept in combination with FOLFIRI significantly improves overall survival in second-line mCRC patients previously treated with an oxaliplatin containing regime. [7] Thomas et al. reported 22 patients' data of clinical experience with aflibercept in the prelicensing, post-trial period at a single institution in the UK. [8] In this study, the median age of a patient was 58 years (34-79 years) and 77% were male. All patients had received a prior oxaliplatin-based chemotherapy. The median number of aflibercept cycles to date is 4.5 (Range 1-9). Four patients discontinued due to PD after a median of 4.6 cycles; one patient died due to PD. One patient stopped treatment after grade 3 diarrhea; one patient discontinued due to hypertension grade 3. Ten patients were managed with antihypertensive therapy for treatment associated hypertension, an anticipated anti-VEGF related side effect. In this study author had not mentioned about the response rate, median progression-free survival (PFS), median OS, and toxicities. Another post-trial prelicensing multicenter study was published from India by Sirohi et al. [9] In this study, 30 patients were included and final response was assessed in 19 patients-no CR, 4 (21%) PR, 4 (21%) stable disease (SD), and 11 (58%) PD. According to the author of this study, the greater proportion of Indian patients had grade 3 and four mucositis, though the other toxicities were comparable. This may be related to poor nutrition and oral hygiene. Data for diarrhea and hypertension was equivalent. [9] As our study was a minuscule study, it is very difficult to compare with the pivotal study and other published studies.


  Conclusion Top


We present a single institution nontrial patient outcome data with aflibercept in routine clinical practice. As we have few patients, it is rather difficult to compare our data with the VELOUR trial. We can conclude that it is one of the options as a second-line in mCRC who have progressed on oxaliplatin chemotherapy. Mucositis, diarrhea, and hematological toxicity were the most common toxicity in our series.

Acknowledgment

Sanofi.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al.; GLOBOCAN 2012 v1.0. Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11. Available from: accessed on day/month/year. Lyon, France: International Agency for Research on Cancer; 2013.  Back to cited text no. 1
    
2.
Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23-30.  Back to cited text no. 2
    
3.
Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343:905-14.  Back to cited text no. 3
    
4.
Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 2004;22:229-37.  Back to cited text no. 4
    
5.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42.  Back to cited text no. 5
    
6.
Giantonio BJ, Catalano PJ, Meropol NJ, O′Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from The Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539-44.  Back to cited text no. 6
    
7.
Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30:3499-506.  Back to cited text no. 7
    
8.
Thomas BM, Arif S, Brewster A, Yim K, Williams H, Shaw P, et al. Clinical experience with aflibercept in metastatic colorectal cancer (mCRC): A single institution experience. Available from: . [Last accessed on 2013].  Back to cited text no. 8
    
9.
Bhawna S, Ostwal V, Ramanan G, Agarwal S, Joshi A, Bharthuar A, et al. Use of aflibercept (ZALTRAP) as second-line therapy in patients with mCRC in named patient program in India: Preliminary analysis of data from six centers. Ann Oncol 2014;25(Suppl 2):ii14-104.  Back to cited text no. 9
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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