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  Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 4  |  Page : 631-633
 

Safety and antitumor activity of arsenic trioxide plus infusional 5-fluorouracil, leucovorin, and irinotecan as second-line chemotherapy for refractory metastatic colorectal cancer: A pilot study from South India


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

Date of Web Publication30-Jul-2018

Correspondence Address:
Dr. Tamojit Chaudhuri
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_374_17

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 » Abstract 


BACKGROUND: After failing oxaliplatin-based first-line chemotherapy (CT), approximately 4%–21% of patients with metastatic colorectal cancer (mCRC) respond to irinotecan-based second-line treatment. Earlier studies have demonstrated that arsenic trioxide (ATO) can significantly resensitize resistant colon cancer to 5-fluorouracil (5-FU) by downregulating thymidylate synthase (TS). We hypothesized that a combination of ATO with infusional 5-FU, leucovorin, and irinotecan (FOLFIRI) regimen in mCRC patients refractory to first-line FOLFOX/CAPOX could further improve the outcome of second-line CT. MATERIALS AND METHODS: Patients were administered ATO 0.15 mg/kg/day on days 1–2 along with FOLFIRI regimen at standard doses every 2 weeks, until disease progression, unacceptable toxicity, or patients' refusal. Responses to CT were reported according to RECIST 1.1. Adverse events were classified based on CTCAE version 4.0. RESULTS: Between September 2016 and July 2017, 17 patients with refractory mCRC were treated with this investigational combination. The median age was 49 years; 13 males and 4 females; ECOG PS 0–1/2, 14/3. The most common site of metastases was liver (n = 11) followed by peritoneum (n = 7) and number of involved metastatic sites 1–2/≥3, 9/8. After 6 cycles of CT, overall response rate and disease control rate were 17.6% and 82.4%, respectively (complete remission = 0, partial remission = 3 patients, stable disease = 11 patients). Median progression-free survival was 5.3 months (95% confidence interval [CI]: 4.3–7.0) and median overall survival was 9 months (95% CI: 7.4–10.5) from the initiation of ATO plus FOLFIRI. The toxicities were as follows: Grade 1/2 toxicity: fatigue (7 patients), constipation (2), and nausea and vomiting (2); Grade 3 toxicity: fatigue (3), neutropenia (2), febrile neutropenia (1), diarrhea (2), and QTc prolongation (1). No patient experienced Grade 4 toxicities. CONCLUSIONS: The addition of ATO to FOLFIRI regimen as second-line CT in patients with refractory mCRC offered an encouraging antitumor effect at the cost of manageable toxicity.


Keywords: Arsenic trioxide, infusional 5-fluorouracil leucovorin and irinotecan regimen, refractory metastatic colorectal cancer, thymidylate synthase


How to cite this article:
Lakshmaiah K C, Chaudhuri T, Babu GK, Lokanatha D, Jacob LA, Suresh Babu M C, Rudresha A H, Lokesh K N, Rajeev L K. Safety and antitumor activity of arsenic trioxide plus infusional 5-fluorouracil, leucovorin, and irinotecan as second-line chemotherapy for refractory metastatic colorectal cancer: A pilot study from South India. Indian J Cancer 2017;54:631-3

How to cite this URL:
Lakshmaiah K C, Chaudhuri T, Babu GK, Lokanatha D, Jacob LA, Suresh Babu M C, Rudresha A H, Lokesh K N, Rajeev L K. Safety and antitumor activity of arsenic trioxide plus infusional 5-fluorouracil, leucovorin, and irinotecan as second-line chemotherapy for refractory metastatic colorectal cancer: A pilot study from South India. Indian J Cancer [serial online] 2017 [cited 2019 Aug 22];54:631-3. Available from: http://www.indianjcancer.com/text.asp?2017/54/4/631/237893





 » Introduction Top


For the last 4 decades, 5-fluorouracil (5-FU) has been the backbone of chemotherapy (CT) in metastatic colorectal cancer (mCRC). The reported response rate of single-agent 5-FU in mCRC ranges from 10% to 30% although the median survival remained less than 12 months.[1] In the past decade, two new conventional CT agents, oxaliplatin and irinotecan, have been introduced into clinical practice. Oxaliplatin as a single agent has shown a 20% response rate in patients with mCRC.[2] However, the combination of oxaliplatin, 5-FU, and leucovorin (FOLFOX-4 regimen) increased the response rate to 51% and the median survival to 16.2 months in a landmark phase III study.[3] Unfortunately, the reported median progression-free survival (PFS) of first-line oxaliplatin-based multiagent CT in mCRC ranges from 9 to 11 months;[3],[4] and after failing oxaliplatin-based first-line treatment, approximately 4–21% of patients respond to irinotecan-based second-line CT.[4],[5],[6],[7]

Clearly, it seems likely that the development of 5-FU resistance in CRC will have a substantial negative impact on the outcome of 5-FU-based multiagent CT. A major mechanism of 5-FU resistance in CRC is overexpression of the dTMP-synthesizing enzyme thymidylate synthase (TS), which occurs after prolonged exposure of colon cancer cells to 5-FU. Quite conspicuously, strategies to avoid cellular resistance to 5-FU have the potential to create new treatment options for mCRC patients. Recently, an in-vitro study has demonstrated that arsenic trioxide (ATO) can significantly resensitize resistant colon cancer cells to 5-FU by downregulating TS.[8] In a subsequent phase I study by the same group, it has shown the feasibility of combining ATO with 5-FU/leucovorin with a manageable toxicity profile in patients with refractory mCRC.[9] ATO can also act as a vascular-disrupting agent and has a synergistic effect with irinotecan on tumor growth delay.[10]

We hypothesized that a combination of ATO with infusional 5-FU, leucovorin, and irinotecan (FOLFIRI) regimen in mCRC patients refractory to first-line FOLFOX/CAPOX could further improve the outcome of second-line CT.


 » Materials and Methods Top


Patient selection

Patients older than 18 years of age were eligible for inclusion in this prospective single-center pilot study if they had pathologically proven mCRC; ECOG PS ≤2; refractory to oxaliplatin-based first-line CT (FOLFOX/CAPOX); not affording for biologic agents due to economic constraint; adequate renal, hepatic, and hematologic functions; and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Major exclusion criteria were: ≥2 lines of previous CT for metastatic disease, congestive cardiac failure, concurrent second malignancy, and evidence of brain metastases.

Treatment assignment

Patients who fulfilled all the eligibility criteria were administered ATO 0.15 mg/kg/day (2-h intravenous infusion in 100 ml NS) on days 1–2 along with FOLFIRI regimen at standard doses[11] every 2 weeks. CT dose adjustments and treatment delays were allowed and were at the discretion of the treating physician. All patients were monitored for signs of cardiac toxicity (hypertension, arrhythmias, weight gain, and QTc prolongation), neuropathy (lethargy and peripheral neuropathy), hepatotoxicity, nephrotoxicity, electrolyte disturbances, and skin toxicity. A 20% dose reduction in subsequent cycles was done in patients developing any Grade 4 or life-threatening toxicity. Treatment was continued until disease progression, unacceptable toxicity, or patients' refusal. After failure of this second-line CT, patients were kept on best supportive care.

Evaluation and outcomes

Before treatment assignment, a complete evaluation was carried out, including full medical history, physical examination, complete blood count, serum biochemical analysis, electrocardiography, and 2-dimensional echocardiography. Baseline disease status assessment was done with colonoscopy and contrast-enhanced computed tomography (CECT) of the thorax, abdomen, and pelvis. CECT scans were repeated every 3 months during CT as a departmental strategy. In case of clinical suspicion of disease progression, urgent CECT scans were requested whenever needed and were at the discretion of the treating physician. Responses to therapy were reported according to the RECIST 1.1. Adverse events were classified based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary endpoints were toxicity and overall response rate (ORR). The secondary endpoints were PFS and overall survival (OS).

Statistical analysis

Continuous variables were presented as medians and range and categorical variables as counts and percentages. Kaplan–Meier method was used to estimate the survival distributions. All statistical analyses have been performed using SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA).


 » Results Top


Patient characteristics

Between September 2016 and July 2017, 17 patients with refractory mCRC were treated with this investigational combination at the department of medical oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India. The median age was 49 years (range, 32–65), and majority of the patients (76.5%, n = 13) were males. ECOG PS was determined as ≤ 1 in most (82.4%, n = 14) of the patients. Ten patients (58.8%) had rectal primary, and others had primary tumor in the colon. Median baseline serum CEA was 56 ng/ml (range, 8.3–836). The most common site of metastases was liver (n = 11) followed by peritoneum (n = 7), lungs (n = 5), and nonregional lymph-nodes (n = 4). Approximately 47% (n = 8) of the patients had ≥3 metastatic disease sites involvement at the baseline.

Chemotherapy characteristics

The median number of CT cycles received was 9 (range 4–13). Dose reduction was required in none of the patients. One patient was given secondary G-CSF prophylaxis after developing grade 3 febrile neutropenia.

Efficacy and survival

After 6 cycles of CT, ORR and disease control rate (DCR) were 17.6% and 82.4%, respectively (complete response in 0, partial response in 3 patients, and disease stabilization in 11 patients). Eleven patients (64.7%) experienced a ≥50% decline in serum CEA level. At a median follow-up of 7.5 months (range, 4–11), 14 patients had disease progression and 9 of them died, while on best supportive care, 3 patients were still on study drugs. Median PFS was 5.3 months (95% confidence interval [CI]: 4.3–7.0) and median OS was 9 months (95% CI: 7.4–10.5) [Figure 1], from the initiation of ATO plus FOLFIRI.
Figure 1: Kaplan Meier curves of progression-free survival and overall survival (in months) of the whole cohort (n = 17)

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Toxicity profile

The toxicities were as follows: Grade 1/2 toxicity: fatigue (7 pts.), constipation (2), nausea and vomiting (2), and peripheral edema (1); Grade 3 toxicity: fatigue (3), neutropenia (2), febrile neutropenia (1), diarrhea (2), and QTc prolongation (1). No patient experienced Grade 4 toxicities.


 » Discussion Top


In the modern era of CT, ATO has been rediscovered as a highly active agent for the treatment of acute promyelocytic leukemia.[12] Moreover, it has also been investigated as a potential treatment option in several solid tumor cell lines targeting various mechanisms.[13],[14] Studies have shown that 5-FU resistance in mCRC patients is highly associated with overexpression of intratumoral TS mRNA.[15],[16] In a phase I study, Ardalan et al. have shown ATO to inhibit TS at the mRNA level, effectively maximizing tumor response to 5-FU in refractory mCRC patients.[9] Other studies have also found ATO to exhibit antitumor effect against CRC cell lines by activating apoptosis through the Caspase-3 pathway and its substrate PARP.[17],[18] In addition, ATO may induce apoptosis by increased expression of p21 protein, activating cell cycle arrest, as well as increased expression of GADD proteins.[17] Clearly, further research into the mechanisms of reversal of 5-FU resistance by ATO in mCRC patients is warranted.

In the current study, we have used a combination of ATO with standard FOLFIRI regimen as a second-line treatment in refractory mCRC patients. To our knowledge, this is the first report of this novel combination in mCRC. Although only 3 patients (17.6%) achieved a partial response after 6 cycles of treatment, another 11 patients achieved prolonged disease stabilization in our study; therefore, the DCR was 82.4% (n = 14). As per the reported data, approximately 4%–21% of patients respond to irinotecan-based second-line CT after failing oxaliplatin-based first-line therapy.[4],[5],[6],[7] Hence, the results of the current study are not very much encouraging.

However, at the same time, it has to be kept in mind that the present study has recruited a very poor subgroup of mCRC patients, which has refractory disease to first-line FOLFOX, 59% of patients with rectal primary and 47% of patients with ≥3 metastatic disease sites involvement at baseline. Clearly, a DCR of 82.4% (n = 14), median PFS of 5.3 months, and median OS of 9 months in the second-line setting with this novel combination of ATO + FOLFIRI regimen seem to be quite exciting. The high rate of disease control (82.4%, n = 14) with a manageable toxicity profile from this clinical experience may indicate an effective alternative treatment option for refractory mCRC patients particularly in resource-constrained settings and warrants further clinical research.


 » Conclusions Top


In the current study, the addition of ATO 0.15 mg/kg/day on days 1–2 to standard FOLFIRI regimen as second-line CT in patients with refractory mCRC offered an encouraging antitumor effect at the cost of manageable toxicity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Braun AH, Achterrath W, Wilke H, Vanhoefer U, Harstrick A, Preusser P, et al. New systemic frontline treatment for metastatic colorectal carcinoma. Cancer 2004;100:1558-77.  Back to cited text no. 1
    
2.
Díaz-Rubio E, Sastre J, Zaniboni A, Labianca R, Cortés-Funes H, de Braud F, et al. Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: A phase II multicentric study. Ann Oncol 1998;9:105-8.  Back to cited text no. 2
    
3.
de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938-47.  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.
Seymour MT for the UK NCRI Colorectal Clinical Studies Group. MRC Clinical Trial Unit: Fluorouracil, oxaliplatin and CPT-11 (irinotecan) use and sequencing (MRC FOCUS). A 2135-patients randomized trial in advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol 2005;23:16S. [Abstr 3518].  Back to cited text no. 5
    
6.
Pluzanska A, Mainwaring P, Cassidy J, Utracka-Hutka B, Zalucki J, Glynne-Jones R, et al. Final results of a randomized phase III study evaluating the addition for oxaliplatin first-line to 5-FU followed by irinotecan at progression in advanced colorectal cancer (Life study). Proc Am Soc Clin Oncol 2005;23:16S. [Abstr 3517].  Back to cited text no. 6
    
7.
Grothey A, Jordan K, Kellner O, Constantin C, Dietrich G, Kroening H, et al. Capecitabine/irinotecan (Capiri) and capecitabine/oxaliplatin (CapOx) are active second-line protocols in patients with advanced colorectal cancer (ACRC) after failure of first-line combination therapy: Results of a randomized phase II study. Proc Am Soc Clin Oncol 2004;23:254. [Abstr 3534].  Back to cited text no. 7
    
8.
Subbarayan PR, Lee K, Ardalan B. Arsenic trioxide suppresses thymidylate synthase in 5-FU-resistant colorectal cancer cell line HT29 in vitro re-sensitizing cells to 5-FU. Anticancer Res 2010;30:1157-62.  Back to cited text no. 8
    
9.
Ardalan B, Subbarayan PR, Ramos Y, Gonzalez M, Fernandez A, Mezentsev D, et al. A phase I study of 5-fluorouracil/leucovorin and arsenic trioxide for patients with refractory/relapsed colorectal carcinoma. Clin Cancer Res 2010;16:3019-27.  Back to cited text no. 9
    
10.
Lee JC, Lee HY, Moon CH, Lee SJ, Lee WH, Cha HJ, et al. Arsenic trioxide as a vascular disrupting agent: Synergistic effect with irinotecan on tumor growth delay in a ct26 allograft model. Transl Oncol 2013;6:83-91.  Back to cited text no. 10
    
11.
André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer 1999;35:1343-7.  Back to cited text no. 11
    
12.
Niu C, Yan H, Yu T, Sun HP, Liu JX, Li XS, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: Remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999;94:3315-24.  Back to cited text no. 12
    
13.
Pettersson HM, Pietras A, Munksgaard Persson M, Karlsson J, Johansson L, Shoshan MC, et al. Arsenic trioxide is highly cytotoxic to small cell lung carcinoma cells. Mol Cancer Ther 2009;8:160-70.  Back to cited text no. 13
    
14.
Fröhlich E, Czarnocka B, Brossart P, Wahl R. Antitumor effects of arsenic trioxide in transformed human thyroid cells. Thyroid 2008;18:1183-93.  Back to cited text no. 14
    
15.
Bathe OF, Franceschi D, Livingstone AS, Moffat FL, Tian E, Ardalan B, et al. Increased thymidylate synthase gene expression in liver metastases from colorectal carcinoma: Implications for chemotherapeutic options and survival. Cancer J Sci Am 1999;5:34-40.  Back to cited text no. 15
    
16.
Paré L, Marcuello E, Altés A, del Rio E, Sedano L, Barnadas A, et al. Transcription factor-binding sites in the thymidylate synthase gene: predictors of outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin? Pharmacogenomics J 2008;8:315-20.  Back to cited text no. 16
    
17.
Li X, Ding X, Adrian TE. Arsenic trioxide causes redistribution of cell cycle, caspase activation, and GADD expression in human colonic, breast, and pancreatic cancer cells. Cancer Invest 2004;22:389-400.  Back to cited text no. 17
    
18.
Nakagawa Y, Akao Y, Morikawa H, Hirata I, Katsu K, Naoe T, et al. Arsenic trioxide-induced apoptosis through oxidative stress in cells of colon cancer cell lines. Life Sci 2002;70:2253-69.  Back to cited text no. 18
    


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