Benefit of Targeted Therapies in Metastatic Colon Cancer in the Ivorian Context

In our daily practice, the use of targeted therapies (Bevacizumab and rarely Cetuximab) in metastatic colic cancers is recent. Very few patients benefit from these therapies because of their high cost. In a cohort of 68 patients who received these therapies, a retrospective and prospective study was conducted over three years period (1 January 2013 to 31 December 2015) to evaluate their benefit in terms of quality of life, tolerance and overall survival. These targeted therapies provided a significant clinical and biological gain with acceptable toxicities (most often resolving spontaneously). Moreover, they have allowed a significant improvement in overall survival in first line metastatic treatment. The limiting factor remains their extremely high cost and therefore inaccessibility to the majority of our patients.


Introduction
The increasingly accurate knowledge of colon oncogenesis has enabled the development of targeted therapies [1] [2]. These are generally anti-angiogenic and anti-EGFR antibodies which, in western series, have shown certain activity in first line metastatic colon cancers [3] [4]. These molecules, for the most part, are inaccessible for most patients in sub-Saharan Africa in general and in Côte d'Ivoire in particular. Very few scientific studies have evaluated the benefits of these targeted therapies (TTs) in our current practice. The objective of this study was to contribute to the improvement in management of metastatic colon cancer in the Ivorian context. Specifically, the aim was to identify the contribution of these TTs in terms of response, tolerance and overall survival.

Patients and Methods
This was a preliminary retrospective and prospective study over a three years period (1 January 2013 to 31 December 2015). This study oversaw 68 cases (mean age 49 years) of histologically confirmed metastatic colon cancer in the Oncology Department at the University Hospital of Treichville in Abidjan. The recruitment of patients took place not only at Treichville university hospital, but at the two other University Hospital Centers in Abidjan, namely Cocody and Yopougon. Were included into our study, patients who had at least six courses of chemotherapy including some targeted therapy. Also, patients whose cures were done every 14 days. Criteria for non-inclusion included patients with incomplete records and those with a WHO performance status score of 3 and over.
The data collection was recorded on a question sheet containing the socioeconomic, demographic and other parameters required for our study. For the retrospective aspect, data was collected from patient files seen respectively in hospitalization and in consultation. The operative reports and the histological results recorded in the registries of the pathology departments of Abidjan's University Hospitals were also taken into account. As for the prospective aspect, a thorough interrogation allowed to assess the socio-demographic characteristics, the weight loss percentage calculated from the weight ratio at the time of diagnosis over the initial weight. It also heplped to evaluate functional signs. A rigorous physical examination and endoscopic explorations (total colonoscopy) made it possible to suspect the colonic malignancy. It was during this period that a biopsy with anatomo-pathological examination was systematically performed.
The diagnosis was made on the histology of the surgical specimen. Confidentiality was respected throughout the methodological approach. Following the confirmation of a colon adenocarcinoma, a complete workup including morphological explorations (thoraco-abdomino-pelvic computed tomography) allowed staging by the Union for International Cancer Control (UICC) TNM (Tumor Nodes Metastasis) system [5].
Concerning our Treatment Methodology, a pre-therapeutic assessment was systematically undertaken with the aim to minimizing possible toxicities. These included complete blood count, uremia, serum creatinine and transaminasemia.
As for tumor markers (ACE and CA 19-9), they were done for further monitoring. All patients received a palliative chemotherapy protocol, including some targeted therapy. These protocols were Folfox4-Bevacizumab, Folfox4-Cetuximab, Folfox4 or Folfiri, Fufol-Plattine. The non-mutated K-RAS status was a prerequisite for the administration of Cetuximab.
Response was evaluated according to the RECIST 2000 criteria defining complete response (CR), partial response (PR), tumor stabilization (TS) and tumor progression (TP) [6]. Tolerance was evaluated according to the World Health Organization (WHO) criteria for toxicity of anticancer drugs. Survival was evaluated using the Kaplan Meier method [7].

patients met the criteria for inclusion with an average age of 49 years [29 -
75]. There was a male predominance coming mostly from urban areas. Patients who benefited from these different protocols were most likely to have an average to high socio-economic level and their main source of funding came from private insurance (Table 1). About 86.6% of our patients consulted after 6 months of beginning of symptoms. Pain was the most common clinical symptom encountered in about 80.9% of cases. Left colon was the most frequent primary tumor site (63.2% of cases). Metastatic localization was most often hepatic (70.6% of cases). As for the histological type, it was in 72% of cases a Lieberkhünien adenocarcinoma ( Table 2). All protocols combined showed a significant clinical as well as biological gain in post-treatment (Table 3, Figure 1).  Protocols including targeted therapies provided the most significant therapeutic responses compared to chemotherapy protocols alone (    Figure   2 and Table 6).

Discussion
Bevacizumab followed by Cetuximab are the most widely used targeted therapies   colon cancer. This is Panitumumab (not used in our series) an anti-EGFR which leads to tumor responses along the lines of 13% to 20% in patients with recurrent or refractory colon cancer [12].
The observed toxicities were generally low grade and therefore most often resolved spontaneously. For those patients with febrile leukoneutropenia, man-  [14]. The classic high blood pressure associated with bevacizumab and described in the literature had not been observed in our series. However, it is always necessary to control the blood pressure and test for possible proteinuria during the treatment.
As for cetuximab, the most disabling toxicity was cutaneous, with acneiform eruption sometimes requiring treatment with systemic tetracyclines [15]. This was observed in almost all of our patients under Cetuximab.
The results of our study in terms of overall survival are comparable to the works of Hurwitz et al., who found an overall survival of 16 months [16]. The improvement of survival rate is generally due to the combination of chemotherapy and targeted therapies. Bevacizumab has been shown to be effective in combination with FOLFIRI (irinotecan + 5FU bolus + folinic acid) compared to patients treated with chemotherapy alone.

Conclusion
Therapeutic protocols (targeted therapy and/or chemotherapy) were instituted in 68 patients with metastatic colon cancer. Combined with chemotherapy, targeted therapies have improved the quality of life and comfort of our patients.
According to the RECIST criteria 2000, the most significant objective responses were observed with these different associations. However, these treatments can induce toxicities which generally resolved spontaneously or with treatment.
Moreover, they have allowed first line metastatic colon cancer treatment to improve overall survival. The limiting factor remains their extremely high cost and therefore not readily accessible to patients. This study is a plea to public authorities to facilitate access to these innovative therapies that have revolutionized the prognosis of metastatic colon cancers.