Adjuvant chemotherapy in stage II–III operated colon cancer patients from a nontrial cohort in a low colon cancer prevalence country with predominant use of modified CAPOX

Anant Ramaswamy; Rushabh Kothari; Ashwin Desouza; Tarachand Gupta; Sandeep Bairwa; Akhil Kapoor; Amit Kumar; Pradeep Ventrapati; Mukta Ramadwar; Sarika Mandavkar; Amit Kumar; Nita Chavan; Avanish Saklani; Vikas Ostwal

doi:10.4103/sajc.sajc_176_18

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ORIGINAL ARTICLE: GI Cancers

08 (

); 160-165

doi:

10.4103/sajc.sajc_176_18

Adjuvant chemotherapy in stage II–III operated colon cancer patients from a nontrial cohort in a low colon cancer prevalence country with predominant use of modified CAPOX

Anant Ramaswamy¹, Rushabh Kothari¹, Ashwin Desouza², Tarachand Gupta¹, Sandeep Bairwa¹, Akhil Kapoor¹, Amit Kumar¹, Pradeep Ventrapati¹, Mukta Ramadwar³, Sarika Mandavkar¹, Amit Kumar¹, Nita Chavan¹, Avanish Saklani², Vikas Ostwal^1,

1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra

2 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra

3 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra

*Corresponding author: Dr. Vikas Ostwal. dr.vikas.ostwal@gmail.com

Published: 2020-12-21

MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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Abstract

Background: Data regarding the practice of adjuvant chemotherapy, specifically with modified CAPOX, and survival outcomes in operated colon cancer patients from a nontrial cohort in a lower-middle income and low prevalence nation like India is scarce. Materials and Methods: Patients who underwent upfront curative resection for colon cancer from January 2013 to December 2016 were analyzed for baseline variables and outcomes. Results: A total of 491 patients underwent curative resection in the predefined time period. The median age of the patients was 53 years (range: 17–87). Patients with Stage I, Stage II, and Stage III disease comprised 7.9%, 44.8%, and 45.4% of the entire cohort, respectively. Patients with Stage I cancer were observed. Adjuvant chemotherapy was planned for 384 patients (78.2%), with the doublet regimens (capecitabine-oxaliplatin, or 5-fluorouracil-oxaliplatin) being used commonly (77.6%). Common toxicities were Hand-foot syndrome (Grade 2/3 - 21.4%) and peripheral neuropathy (Grade 2/3 - 20.1%). About 85% of patients receiving monotherapy (capecitabine or 5 fluorouracil) and 81.2% of patients receiving doublet chemotherapy (mCAPOX or modified FOLFOX-7) completed their planned adjuvant treatment. With a median follow-up of 22 months, estimated 3 years event-free survival was 86%, and overall survival (OS) was 93.6%. Stage, younger age (<50 years), underlying cardiovascular abnormalities, need for dose reductions and noncompletion of planned chemotherapy predicted for inferior estimated 3-year OS on multivariate analysis. Conclusions: Adjuvant chemotherapy especially with modified CAPOX appears well tolerated in the Indian population and early survival outcomes appear to be comparable to published literature.

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References

Mohandas KM. Colorectal cancer in India: Controversies, enigmas and primary prevention. Indian J Gastroenterol 2011;30:3-6.
Gupta S, Bhattacharya D, Acharya AN, Majumdar S, Ranjan P, Das S. Colorectal carcinoma in young adults: A retrospective study on Indian patients: 2000-2008. Colorectal Dis J Assoc Coloproctol G B Irel 2010;12:e182-9.
Kokki I, Papana A, Campbell H, Theodoratou E. Estimating the incidence of colorectal cancer in South East Asia. Croat Med J 2013;54:532-40.
Mallath MK, Taylor DG, Badwe RA, Rath GK, Shanta V, Pramesh CS, et al. The growing burden of cancer in India: Epidemiology and social context. Lancet Oncol 2014;15:e205-12.
NCRP Anual Reports. Available from: http://www.ncrpindia.org/Annual_Reports.aspx. [Last accessed 2017 October 30].
Sinha R, Anderson DE, McDonald SS, Greenwald P. Cancer risk and diet in India. J Postgrad Med 2003;49:222-8.
Påhlman LA, Hohenberger WM, Matzel K, Sugihara K, Quirke P, Glimelius B. Should the benefit of adjuvant chemotherapy in colon cancer be re-evaluated? J Clin Oncol 2016;34:1297-9.
Govaert JA, van Dijk WA, Fiocco M, Scheffer AC, Gietelink L, Wouters MW, et al. Nationwide outcomes measurement in colorectal cancer surgery: Improving quality and reducing costs. J Am Coll Surg 2016;222:19-29.e2.
Hohenberger W, Weber K, Matzel K, Papadopoulos T, Merkel S. Standardized surgery for colonic cancer: Complete mesocolic excision and central ligation – Technical notes and outcome. Colorectal Dis 2009;11:354-64.
Böckelman C, Engelmann BE, Kaprio T, Hansen TF, Glimelius B. Risk of recurrence in patients with colon cancer stage II and III: A systematic review and meta-analysis of recent literature. Acta Oncol 2015;54:5-16.
Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: Results from NSABP C-07. J Clin Oncol 2007;25:2198-204.
André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109-16.
André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: Updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol 2015;33:4176-87.
Dotan E, Cohen SJ. Challenges in the management of stage II colon cancer. Semin Oncol 2011;38:511-20.
Saridaki Z, Souglakos J, Georgoulias V. Prognostic and predictive significance of MSI in stages II/III colon cancer. World J Gastroenterol 2014;20:6809-14.
Mols F, Beijers T, Lemmens V, van den Hurk CJ, Vreugdenhil G, van de Poll-Franse LV, et al. Chemotherapy-induced neuropathy and its association with quality of life among 2- to 11-year colorectal cancer survivors: Results from the population-based PROFILES registry. J Clin Oncol 2013;31:2699-707.
Ishikawa T, Ishiguro M, Nakatani E, Uetake H, Ueno H, Murotani K, et al. Prognostic impact of MSI in stage II colon cancers: An additional translational study of the SACURA trial. J Clin Oncol 2017;35 Suppl 15:e15155.
André T, Iveson T, Labianca R, Meyerhardt JA, Souglakos I, Yoshino T, et al. The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) collaboration: Prospective combined analysis of phase III trials investigating duration of adjuvant therapy with the FOLFOX (FOLFOX4 or modified FOLFOX6) or XELOX (3 versus 6 months) regimen for patients with stage III colon cancer: Trial design and current status. Curr Colorectal Cancer Rep 2013;9:261-9.
ASCO 2017: The IDEA Collaboration: Global Study Sets New Risk-Based Standard to Personalize Chemotherapy for Colon Cancer After Surgery – The ASCO Post. Available from: http://www.ascopost.com/News/55708. [Last accessed on 2017 Oct 04].
Pokharkar AB, Bhandare M, Patil P, Mehta S, Engineer R, Saklani AP, et al. Young vs. old colorectal cancer in Indian subcontinent: A tertiary care center experience. Indian J Surg Oncol 2017;8:491-8.
Tamhankar AS, Ingle P, Saklani A. PWE-284 Signet ring colorectal carcinoma (SRCC): Do we need to improve the treatment algorithm? Gut 2015; 64 Suppl 1:A336-7.
Patil PS, Saklani A, Gambhire P, Mehta S, Engineer R, De'Souza A, et al. Colorectal cancer in India: An audit from a tertiary center in a low prevalence area. Indian J Surg Oncol 2017;8:484-90.
Dimitriou N, Griniatsos J. Complete mesocolic excision: Techniques and outcomes. World J Gastrointest Oncol 2015;7:383-8.
O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997;15:246-50.
Andre T, Colin P, Louvet C, Gamelin E, Bouche O, Achille E, et al. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: Results of a randomized trial. J Clin Oncol 2003;21:2896-903.
Tan Y, Fu J, Li X, Yang J, Jiang M, Ding K, et al. Aminor (<50%) signet-ring cell component associated with poor prognosis in colorectal cancer patients: A 26-year retrospective study in China. PLoS One 2015;10:e0121944.
Hyngstrom JR, Hu CY, Xing Y, You YN, Feig BW, Skibber JM, et al. Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: Analysis from the national cancer data base. Ann Surg Oncol 2012;19:2814-21.
Varghese A. Chemotherapy for stage II colon cancer. Clin Colon Rectal Surg 2015;28:256-61.
Labianca R, Nordlinger B, Beretta GD, Mosconi S, Mandalà M, Cervantes A, et al. Early colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24 Suppl 6:vi64-72.
Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:247-57.
Kim ST, Lee J, Park SH, Park JO, Lim HY, Kang WK, et al. Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy. Cancer Chemother Pharmacol 2010;66:659-67.
Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 2011;29:1465-71.
Park SB, Lin CS, Krishnan AV, Goldstein D, Friedlander ML, Kiernan MC, et al. Long-term neuropathy after oxaliplatin treatment: Challenging the dictum of reversibility. Oncologist 2011;16:708-16.
McCleary NJ, Meyerhardt JA, Green E, Yothers G, de Gramont A, Van Cutsem E, et al. Impact of age on the efficacy of newer adjuvant therapies in patients with stage II/III colon cancer: Findings from the ACCENT database. J Clin Oncol 2013;31:2600-6.
Swaminathan V, Audisio R. Cancer in older patients: An analysis of elderly oncology. Ecancermedicalscience 2012;6:243.
Lund CM, Nielsen D, Dehlendorff C, Christiansen AB, Rønholt F, Johansen JS, et al. Efficacy and toxicity of adjuvant chemotherapy in elderly patients with colorectal cancer: The ACCORE study. ESMO Open 2016;1:e000087.
Kleeff J, Costello E, Jackson R, Halloran C, Greenhalf W, Ghaneh P, et al. The impact of diabetes mellitus on survival following resection and adjuvant chemotherapy for pancreatic cancer. Br J Cancer 2016;115:887-94.
Lin HS, Turner DJ, Srivastava A, Jameson MB. The benefit and tolerability of adjuvant chemotherapy in elderly stage III colon cancer patients: A 3 year retrospective audit. Gerontol Geriatr Res 2016;5:318. doi: 10.4172/2167-7182.1000318. Available from: https://www.omicsonline.org/open-access/the-benefit-and-tolerability-of-adjuvant-chemotherapy-in-elderly-stage-iii-colon-cancer-patients-a-3-year-retrospective-audit-2167-7182-1000318.php?aid=77055. [Last accessed on 2017 Oct 04].
Gajra A, Klepin HD, Feng T, Tew WP, Mohile SG, Owusu C, et al. Predictors of chemotherapy dose reduction at first cycle in patients age 65 years and older with solid tumors. J Geriatr Oncol 2015;6:133-40.
Gupta S, Gudapati R, Gaurav K, Bhise M. Emerging risk factors for cardiovascular diseases: Indian context. Indian J Endocrinol Metab 2013;17:806-14.
Fu J, Yang J, Tan Y, Jiang M, Wen F, Huang Y, et al. Young patients (≤35 years old) with colorectal cancer have worse outcomes due to more advanced disease: A 30-year retrospective review. Medicine (Baltimore) 2014;93:e135.
Yeole BB, Sunny L, Swaminathan R, Sankaranarayanan R, Parkin DM. Population-based survival from colorectal cancer in Mumbai, (Bombay) India. Eur J Cancer 2001;37:1402-8.
Population Pyramids of the World from 1950 to 2100. Available from: https://www.populationpyramid.net/India/2017/. [Last accessed on 2017 Oct 31].

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[1] Mohandas KM. Colorectal cancer in India: Controversies, enigmas and primary prevention. Indian J Gastroenterol 2011;30:3-6.

[2] Gupta S, Bhattacharya D, Acharya AN, Majumdar S, Ranjan P, Das S. Colorectal carcinoma in young adults: A retrospective study on Indian patients: 2000-2008. Colorectal Dis J Assoc Coloproctol G B Irel 2010;12:e182-9.

[3] Kokki I, Papana A, Campbell H, Theodoratou E. Estimating the incidence of colorectal cancer in South East Asia. Croat Med J 2013;54:532-40.

[4] Mallath MK, Taylor DG, Badwe RA, Rath GK, Shanta V, Pramesh CS, et al. The growing burden of cancer in India: Epidemiology and social context. Lancet Oncol 2014;15:e205-12.

[5] NCRP Anual Reports. Available from: http://www.ncrpindia.org/Annual_Reports.aspx. [Last accessed 2017 October 30].

[6] Sinha R, Anderson DE, McDonald SS, Greenwald P. Cancer risk and diet in India. J Postgrad Med 2003;49:222-8.

[7] Påhlman LA, Hohenberger WM, Matzel K, Sugihara K, Quirke P, Glimelius B. Should the benefit of adjuvant chemotherapy in colon cancer be re-evaluated? J Clin Oncol 2016;34:1297-9.

[8] Govaert JA, van Dijk WA, Fiocco M, Scheffer AC, Gietelink L, Wouters MW, et al. Nationwide outcomes measurement in colorectal cancer surgery: Improving quality and reducing costs. J Am Coll Surg 2016;222:19-29.e2.

[9] Hohenberger W, Weber K, Matzel K, Papadopoulos T, Merkel S. Standardized surgery for colonic cancer: Complete mesocolic excision and central ligation – Technical notes and outcome. Colorectal Dis 2009;11:354-64.

[10] Böckelman C, Engelmann BE, Kaprio T, Hansen TF, Glimelius B. Risk of recurrence in patients with colon cancer stage II and III: A systematic review and meta-analysis of recent literature. Acta Oncol 2015;54:5-16.

[11] Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: Results from NSABP C-07. J Clin Oncol 2007;25:2198-204.

[12] André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109-16.

[13] André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: Updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol 2015;33:4176-87.

[14] Dotan E, Cohen SJ. Challenges in the management of stage II colon cancer. Semin Oncol 2011;38:511-20.

[15] Saridaki Z, Souglakos J, Georgoulias V. Prognostic and predictive significance of MSI in stages II/III colon cancer. World J Gastroenterol 2014;20:6809-14.

[16] Mols F, Beijers T, Lemmens V, van den Hurk CJ, Vreugdenhil G, van de Poll-Franse LV, et al. Chemotherapy-induced neuropathy and its association with quality of life among 2- to 11-year colorectal cancer survivors: Results from the population-based PROFILES registry. J Clin Oncol 2013;31:2699-707.

[17] Ishikawa T, Ishiguro M, Nakatani E, Uetake H, Ueno H, Murotani K, et al. Prognostic impact of MSI in stage II colon cancers: An additional translational study of the SACURA trial. J Clin Oncol 2017;35 Suppl 15:e15155.

[18] André T, Iveson T, Labianca R, Meyerhardt JA, Souglakos I, Yoshino T, et al. The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) collaboration: Prospective combined analysis of phase III trials investigating duration of adjuvant therapy with the FOLFOX (FOLFOX4 or modified FOLFOX6) or XELOX (3 versus 6 months) regimen for patients with stage III colon cancer: Trial design and current status. Curr Colorectal Cancer Rep 2013;9:261-9.

[19] ASCO 2017: The IDEA Collaboration: Global Study Sets New Risk-Based Standard to Personalize Chemotherapy for Colon Cancer After Surgery – The ASCO Post. Available from: http://www.ascopost.com/News/55708. [Last accessed on 2017 Oct 04].

[20] Pokharkar AB, Bhandare M, Patil P, Mehta S, Engineer R, Saklani AP, et al. Young vs. old colorectal cancer in Indian subcontinent: A tertiary care center experience. Indian J Surg Oncol 2017;8:491-8.

[21] Tamhankar AS, Ingle P, Saklani A. PWE-284 Signet ring colorectal carcinoma (SRCC): Do we need to improve the treatment algorithm? Gut 2015; 64 Suppl 1:A336-7.

[22] Patil PS, Saklani A, Gambhire P, Mehta S, Engineer R, De'Souza A, et al. Colorectal cancer in India: An audit from a tertiary center in a low prevalence area. Indian J Surg Oncol 2017;8:484-90.

[23] Dimitriou N, Griniatsos J. Complete mesocolic excision: Techniques and outcomes. World J Gastrointest Oncol 2015;7:383-8.

[24] O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997;15:246-50.

[25] Andre T, Colin P, Louvet C, Gamelin E, Bouche O, Achille E, et al. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: Results of a randomized trial. J Clin Oncol 2003;21:2896-903.

[26] Tan Y, Fu J, Li X, Yang J, Jiang M, Ding K, et al. Aminor (<50%) signet-ring cell component associated with poor prognosis in colorectal cancer patients: A 26-year retrospective study in China. PLoS One 2015;10:e0121944.

[27] Hyngstrom JR, Hu CY, Xing Y, You YN, Feig BW, Skibber JM, et al. Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: Analysis from the national cancer data base. Ann Surg Oncol 2012;19:2814-21.

[28] Varghese A. Chemotherapy for stage II colon cancer. Clin Colon Rectal Surg 2015;28:256-61.

[29] Labianca R, Nordlinger B, Beretta GD, Mosconi S, Mandalà M, Cervantes A, et al. Early colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24 Suppl 6:vi64-72.

[30] Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:247-57.

[31] Kim ST, Lee J, Park SH, Park JO, Lim HY, Kang WK, et al. Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy. Cancer Chemother Pharmacol 2010;66:659-67.

[32] Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 2011;29:1465-71.

[33] Park SB, Lin CS, Krishnan AV, Goldstein D, Friedlander ML, Kiernan MC, et al. Long-term neuropathy after oxaliplatin treatment: Challenging the dictum of reversibility. Oncologist 2011;16:708-16.

[34] McCleary NJ, Meyerhardt JA, Green E, Yothers G, de Gramont A, Van Cutsem E, et al. Impact of age on the efficacy of newer adjuvant therapies in patients with stage II/III colon cancer: Findings from the ACCENT database. J Clin Oncol 2013;31:2600-6.

[35] Swaminathan V, Audisio R. Cancer in older patients: An analysis of elderly oncology. Ecancermedicalscience 2012;6:243.

[36] Lund CM, Nielsen D, Dehlendorff C, Christiansen AB, Rønholt F, Johansen JS, et al. Efficacy and toxicity of adjuvant chemotherapy in elderly patients with colorectal cancer: The ACCORE study. ESMO Open 2016;1:e000087.

[37] Kleeff J, Costello E, Jackson R, Halloran C, Greenhalf W, Ghaneh P, et al. The impact of diabetes mellitus on survival following resection and adjuvant chemotherapy for pancreatic cancer. Br J Cancer 2016;115:887-94.

[38] Lin HS, Turner DJ, Srivastava A, Jameson MB. The benefit and tolerability of adjuvant chemotherapy in elderly stage III colon cancer patients: A 3 year retrospective audit. Gerontol Geriatr Res 2016;5:318. doi: 10.4172/2167-7182.1000318. Available from: https://www.omicsonline.org/open-access/the-benefit-and-tolerability-of-adjuvant-chemotherapy-in-elderly-stage-iii-colon-cancer-patients-a-3-year-retrospective-audit-2167-7182-1000318.php?aid=77055. [Last accessed on 2017 Oct 04].

[39] Gajra A, Klepin HD, Feng T, Tew WP, Mohile SG, Owusu C, et al. Predictors of chemotherapy dose reduction at first cycle in patients age 65 years and older with solid tumors. J Geriatr Oncol 2015;6:133-40.

[40] Gupta S, Gudapati R, Gaurav K, Bhise M. Emerging risk factors for cardiovascular diseases: Indian context. Indian J Endocrinol Metab 2013;17:806-14.

[41] Fu J, Yang J, Tan Y, Jiang M, Wen F, Huang Y, et al. Young patients (≤35 years old) with colorectal cancer have worse outcomes due to more advanced disease: A 30-year retrospective review. Medicine (Baltimore) 2014;93:e135.

[42] Yeole BB, Sunny L, Swaminathan R, Sankaranarayanan R, Parkin DM. Population-based survival from colorectal cancer in Mumbai, (Bombay) India. Eur J Cancer 2001;37:1402-8.

[43] Population Pyramids of the World from 1950 to 2100. Available from: https://www.populationpyramid.net/India/2017/. [Last accessed on 2017 Oct 31].

Adjuvant chemotherapy in stage II–III operated colon cancer patients from a nontrial cohort in a low colon cancer prevalence country with predominant use of modified CAPOX

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