Correspondence
Huaxi Student Society of Oncology Research, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China (LD, FN, JW); and Department of Thoracic Cancer, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 37# Guoxuexiang, Chengdu, 610041, Sichuan, China (YL) 1
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Goss PE, Strasser-Weippl K, Lee-Bychkovsky BL, et al. Challenges to effective cancer control in China, India, and Russia. Lancet Oncol 2014; 15: 489–538. Wang J, Kushner K, Frey JJ 3rd, Ping Du X, Qian N. Primary care reform in the Peoples’ Republic of China: implications for training family physicians for the world’s largest country. Fam Med 2007; 39: 639–43. Deng L, Na FF, Wang JW, et al. Insufficient screening knowledge in Chinese interns: a survey in ten leading medical schools. Asian Pac J Cancer Prev 2011; 12: 2801–06.
Cancer care in Sikkim, India Rengaswamy Sankaranarayanan1 briefly describes the deficiencies in cancer care in India. He mentioned the cervical cancer screening programme in the Himalayan state Sikkim, located in the fairly remote and underserved northeastern region of India. Although the programme has been implemented in the state, it has recently faced legal issues over safety aspects of the vaccination programme.2 Also, in the absence of reliable and comprehensive cancer care facilities and specialists in Sikkim, most of the patients with cancer have to travel to distant places—eg, Kolkata, Delhi, and Mumbai—for definitive oncology treatment and follow-up. Although the cost of treatment is reimbursed by the state government, such a facility is available only to patients with valid domicile documents and to state government employees.3 With a growing population coming into the state for work, a large proportion of the population of the state has to incur huge costs not only for treatment, but also for travel and accommodation, in addition to the loss of income for more than one family member. A major hurdle in providing specialised and comprehensive e301
cancer care is the small number of cases in the state. For most cancer sites, the yearly incidence of new cases is seldom in double figures.4 This low incidence is due to the small population in the state (600 000 as per the 2011 census).5 Creating extensive infrastructure within the state for a small population might not be cost effective. At the same time, the health needs of the population cannot be ignored. The state has a long way to go before the entire population has convenient access to the entire range of oncology services within the state with financial assistance or insurance cover without disparities for residents and nonresidents. A possible solution lies in converting Himalayan states like Sikkim into health-care hubs. The hilly Indian states have a temperate climate, by contrast with the tropical climate in the rest of the country, and hence could provide a more comfortable environment for convalescence. Such a measure would make expensive cancer care infrastructure cost effective. I declare no competing interests.
Abhijeet Bhatia
[email protected] Sikkim Manipal Institute of Medical Sciences, Gangtok 737102, India 1
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Sankaranarayanan R. Cancer prevention and care in India: an unfinished agenda. Lancet Oncol 2014; 15: 554–55. Sarkar D. Sikkim to go slow on multimillion cervical cancer vaccine project. Himalayan Mirror (Gangtok Ed) May 11, 2013: 1. Verma Y, Pradhan P. Population based cancer registry, Sikkim state. Three year report of population based cancer registries 2009–2011. Bangalore: National Centre for Disease Informatics and Research, National Cancer Registry Program, 2013, 492–509. Verma Y, Pradhan PK, Gurung N, et al. Population-based cancer incidence in Sikkim, India: report on ethnic variation. Br J Cancer 2012; 106: 962–65. Provisional population totals paper 1 of 2011: Sikkim. New Delhi: The Registrar General and Census Commissioner, Government of India. 2010–11 http://www.censusindia.gov.in/2011prov-results/prov_data_products_sikkim.html (accessed June 12, 2014).
ASPECCT: panitumumab versus cetuximab for colorectal cancer We read with interest the Article by Timothy Price and colleagues,1 in which they reported that panitumumab and cetuximab provide similar overall survival and toxicity profiles as would be expected in heavily pretreated patients with colorectal cancer. Their results also showed that the incidence of grade 3 or 4 hypomagnesaemia was greater in patients receiving panitumumab than in those receiving cetuximab, although the incidence of severe skin toxicities was similar in the two groups. A meta-analysis of randomised studies that included panitumumab and cetuximab in the treatment of several cancer types showed that risk of the hypomagnesaemia to be even higher for panitumumab than for cetuximab.2 Magnesium is absorbed in the gut and reabsorbed in the ascending limb of the loop of Henle by TRMP6, the activation of which is mediated by EGFR signalling. Magnesium wasting is thought to be caused by anti-EGFR agents inhibiting the regeneration of tubular epithelial cells and the activation of TRMP6.3,4 Hence, it is biologically plausible that higher affinity binding of panitumumab to EGFR might contribute to a difference in the incidence of severe hypomagnesaemia between the panitumumab and cetuximab groups, as suggested by Price and colleagues. However, hypomagnesaemia was the only toxicity more frequently noted in patients receiving panitumumab than in those receiving cetuximab in the study. Additionally, the results showed that these anti-EGFR antibodies provide no difference in overall survival benefit in heavily pretreated patients with colorectal cancer. Whether the higher affinity binding of panitumumab to EGFR than that of cetuximab causes a difference www.thelancet.com/oncology Vol 15 July 2014
Correspondence
in only the incidence of severe hypomagnesaemia is questionable. Van Cutsem and colleagues5 showed in the EVEREST study of cetuximab dose escalation that the proportions of patients with hypomagnesaemia and severe skin toxicities were both higher in the dose-escalated cohort than in the fixed-dose cohort. The first prospective study to measure magnesium concentrations was reported by Tejpar and colleagues.4 According to their findings, serum magnesium concentration slopes and time to development of hypomagnesaemia were inversely correlated to the serum magnesium concentrations at baseline. Anti-EGFR antibody-induced hypomagnesaemia was shown to be associated with survival.6,7 In the ASPECCT study, overall toxicity and incidence of most toxicities, except hypomagnesaemia, were similar in the panitumumabtreated and cetuximab-treated patients. Moreover, the results of the study indicated that in terms of overall survival, panitumumab is noninferior to cetuximab in patients with colorectal cancer. We think that more detailed information about the serum magnesium concentrations at baseline and the antitoxicity interventions, including use of skin moisturisers, sunscreen, topical steroids, and doxycycline for skin toxicities, might help us better understand the results from the ASPECCT study. We suggest that the authors investigate whether there were differences between patients receiving panitumumub and cetuximab in the serum magnesium concentrations at baseline and in the use of supportive care for skin toxicities. YSu declares no conflicting interests. WI has received honoraria from Merck Serono, BristolMyers Squibb, and Takeda Pharmaceutical. YSa has received honoraria from Merck Serono and consulting fees from Takeda Bio.
Yu Sunakawa, *Wataru Ichikawa, Yasutsuna Sasaki
[email protected]
www.thelancet.com/oncology Vol 15 July 2014
Division of Medical Oncology, Department of Internal Medicine, Showa University Northern Yokohama Hospital, Kanagawa, Japan (YSu); and Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8, Hatanodai, Shinagawa, Tokyo, 142-8555, Japan (WI, YSa) 1
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Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 2014; 15: 569–79. Petrelli F, Borgonovo K, Cabiddu M, et al. Risk of anti-EGFR monoclonal antibody-related hypomagnesemia: systematic review and pooled analysis of randomized studies. Expert Opin Drug Saf 2012; 11 (suppl 1): S9–19. Groenestege WM, Thebault S, van der Wijst J, et al. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest 2007; 117: 2260–67. Tejpar S, Piessevaux H, Claes K, et al. Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol 2007; 8: 387–94. Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol 2012; 30: 2861–68. Vincenzi B, Galluzzo S, Santini D, et al. Early magnesium modifications as a surrogate marker of efficacy of cetuximab-based anticancer treatment in KRAS wild-type advanced colorectal cancer patients. Ann Oncol 2011; 22: 1141–46. Vickers MM, Karapetis CS, Tu D, et al. Association of hypomagnesemia with inferior survival in a phase III, randomized study of cetuximab plus best supportive care versus best supportive care alone: NCIC CTG/AGITG CO.17. Ann Oncol 2013; 24: 953–60.
We read with interest Timothy Price and colleagues’ report of the results of ASPECCT,1 a randomised phase 3 trial that compared cetuximab and panitumumab in patients with chemotherapy-refractory KRAS exon 2 wild-type colorectal cancer. The results confirm that these drugs can be used interchangeably; however, despite selection of patients based on the almost decade-old knowledge that KRAS exon 2 mutations predict a lack of benefit from anti-EGFR antibodies, the proportion of patients who responded to treatment remained only 20%. This raises the question: how far beyond KRAS have we really come? The results of other analyses of mutations in KRAS exons 3 and 4, and
NRAS exons 2 and 3 have confirmed that patients with RAS wild-type tumours derive a greater benefit from EGFR monoclonal antibodies.2,3 In many colorectal cancer trials, assessment of the true predictive nature of biomarkers has been challenging because of the use of chemotherapy in combination with anti-EGFR therapy. Therefore, similar analyses in the chemorefractory ASPECCT population should provide confirmatory data of the predictive value of the additional RAS mutations. Price and colleagues are of the opinion that without a placebo group, additional conclusions will not be meaningful. We, however, argue that a response rate approaching 0% in patients with mutated RAS would be sufficient to lend support to what is fast becoming routine practice—restricting anti-EGFR therapy to patients with all-RAS wild type. Furthermore, these analyses could help clarify the predictive nature of BRAF, PIK3CA, and other biomarkers. The frequency of these additional mutations is low, though, so how far beyond KRAS will these analyses take our patients? The identification and targeting of biomarkers for other tumour types is surpassing that in colorectal cancer, resulting in clinically significant improved outcomes. In colorectal cancer, other druggable targets have been identified—eg, BRAF, HER2, cMET, and IGFR1.4 These targets are infrequent and have largely been dismissed or targeted in isolation, perhaps explaining the failure to improve outcomes. Biomarker data for colorectal cancer are almost invariably derived from analyses of surgical resection or diagnostic biopsy specimens. Although KRAS mutation is an early event, with proven concordance between primary and metastatic sites, many other mutations are not. As anti-EGFR therapies are integrated earlier in the course of treatment for metastatic colorectal cancer, the identification of acquired mutations will gain increasing importance. e302
