Overall Survival in Metastatic Renal Cancer in the Central Region of Morocco: A Real Life Experience Over One Decade

Background: Available treatments for metastatic RCC (mRCC) are usually non-curative. In the last decade, novel targeted therapies have signicantly improved mRCC outcome. The objective in this study was to describe outcomes in patients with mRCC in Morocco. Methods: 100 patients with mRCC were recruited between January 2008 and December 2018 in the Hassan II University Hospital of Fez. Data were retrospectively collected. Kaplan-Meier survival analysis was used to determine overall survival (OS) and progression free survival (PFS). Results: Mean age of the patients was 58.6 years(±12). Sixty seven percent of patients were male. Clear cell carcinoma was the most common histological subtype (78%). According to the IMDC scoring, 72% of patients were in the intermediate and 18% in the poor risk groups. Seventy patients received targeted therapy. Overall response rate (according to RECIST criteria version 1.0) was 38.6%. The median PFS was 7.0 months (95% CI, 4.6 to 9.4). The median OS was 11.6 months (95% CI, 7.9 to 15.3). In the multivariate analysis, cancer specic mortality was impacted by treatment with VEGFR inhibitors (HR: 0.2; 95% CI, 0.1 to 0.4; p =0.001) and IMDC score (intermediate risk group HR: 3.5 (95% CI, 1.4 to 9.1; p =0.009); and poor risk group HR: 5.5 (95% CI, 1.9 to 16.1; p =0.002)). Conclusion: This is the rst report from clinical practice in an African country of OS data in mRCC. The study showed high mortality rates. However, outcomes of VEGFR inhibitors are consistent with studies investigating these treatments.


Background
Renal-cell carcinoma is the most common cancer of the kidney and accounts for 2.2% of all adult cancers worldwide [1]. In Morocco, basing on Grand Casablanca Cancer Registry, the incidence of kidney cancer from 2008 to 2012 was about 0.9% [2]. Clear cell is the most common subtype accounting for 70-85% of renal cell carcinoma [3]. In case of metastatic RCC (mRCC) the available treatments are usually non-curative. Over the last decade, targeted therapies including inhibitors of vascular endothelial growth factor receptors (VEGFR inhibitors), inhibitors of the mammalian Target of Rapamycin (mTOR inhibitors) and recently immune-check point inhibitors have signi cantly improved therapeutic results [4].However, few data about real life outcomes, beyond clinical trials, are available especially in developing countries. Our objective in this study was to describe patterns and therapeutic results including survival and adverse events in patients with mRCC in Morocco.

Patients:
100patients with mRCC were recruited between January 2008 and December 2018 in the Medical Oncology Department of Hassan II University Hospital of Fez, the main health structure that offers tertiary care in the Central Region of Morocco Data collection including information on baseline patient, tumor characteristics, treatments, response and toxicity were retrospectively collected from the hospitals' electronic databases and from patients' medical records. This research was conducted in accordance with the institutional research ethics committee.
Staging, response and outcome evaluation: Tumor stage at initial diagnosis was categorized according to the American Joint Committee on Cancer (AJCC) TNM classi cation of malignant tumors, 7th edition, 2009 [5].Patients received Sunitinib, Pazopanib, Sorafenib or were observed (untreated) according to availability of targeted therapies. Overall response rate (ORR) was de ned according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.0 [6]. Progression-free survival (PFS) was de ned as the time from start of therapy to disease progression or death, whichever occurred rst. Overall survival (OS) was de ned as time from diagnosis of metastatic disease to death by any cause.
International Metastatic RCC Database Consortium (IMDC) score was used to determine the risk groups based on the presence of the following factors: karnofsky performance status (PS) less than 80%, haemoglobin inferior to the lower limit of normal, time from diagnosis to treatment less than 1 year, corrected calcium above the upper limit of normal, platelets greater than the upper limit of normal, neutrophils greater than the upper limit of normal. The patient was classi ed in the IMDC favorable risk group in case of absence of any prognostic factor, in the intermediate risk group in case of presence of 1 or 2 prognostic factors and in the poor risk group in case of 3 or more prognostic factors [7].

Statistical analysis
Descriptive statistics were used to describe baseline characteristics and treatment patterns using means and Standard deviations for continuous variables and frequencies for categorial variables. To determine risk factors affecting overall and progression free survivals, we used CHI-SQUARE test. Kaplan-Meier survival analysis was used to determine OS and PFS. Comparisons of outcome parameters were calculated using the Cox proportional hazard modeling analysis to estimate the hazard ratio (HR) of cancer speci c mortality (CSM). We used a signi cance level of p < 0.05 for all tests. SPSS statistical software version 22 (IBM Corporation, New York, USA) was used for all analyses.

Patients:
Mean age of the patients was 58.6 years (± 12). Sixty seven percentof patients were male. Seventy three percent of themhad ECOG (Eastern Cooperative Oncology Group) performance status of 0-1.The Majority (76%) had metastatic disease at presentation while 24% of the cases had localized disease at presentation and had undergone radical nephrectomy.
Clear cell carcinoma was the most common histological subtype (78%). At the time of diagnosis of metastatic RCC, lung was the most common site of metastases (58%), followed bone (35%) and liver (33%). According to the IMDC scoring, 10 % of patients were in the favorable risk group, 72%in the intermediate group, while18% were in the poor risk group. We summarized patient's baseline characteristics in table n°1.  Tolerance: The most commonly reported non-hematological grade 2 adverse events included fatigue (40.6%), mucositis (27.7%), hand-foot syndrome (22.8%) and diarrhea (20.8%). Hypertension was observed only in 10% of cases. The most hematological disturbances were anemia (39.6%), and leucopenia (13.9%). Hypothyroidismwas reported in 20% of cases. Grade 3-4 adverse events were reported in 5% of cases.
In the multivariate analysis, cancer speci c mortality was impacted by treatment with VEGFR inhibitors (

Discussion
This retrospective study included patients with the diagnosis of mRCC treated at our department between 2008 and 2018. This analysis of "real world" offers information on treatment of patterns and outcomes of mRCC patients from the University Hospital of FEZ. In the present study, the median age and sex distribution were typical to kidney cancer [3].However, as this was a real-life study, we included patients with histology of non clear-cell mRCC (22%), ECOG performance status more than 1 (27%) and even untreated patients (30%), because of poor performance status or treatment unavailability, which was not the case in pivotal studies [8][9][10][11][12][13][14][15].
Some patterns of tumor aggressiveness were observed in our population comparatively to other real world studies [16][17][18] including the high rate of intermediate and poor risk groups (90%), of synchronous metastases (76%) andperformance status alteration (30%). The lattermay be explained by the delays between rst symptoms and cancer diagnosis in our population [19]. All these reasons cited above explain the low overall survival in the population of the study (11.6 months, 95% CI, 7.9 to 15.3).Through univariate and multivariate analyses we could con rm the impact of VEGFR inhibitors on survival and prognostic value of IMDC score by showing signi cantly different survival rates.
Among the treated population, 74.3% of the cases received sunitinib as rst line treatment reason for which we compared our therapeutic results with those of trials investigating (or comparing with) sunitinib (Table 2). In term of e cacy of the rst line, our ORR (38.6%) was in the large range of response rates observed in thesunitinib phase III trials (varying from 47% in the pivotal study to 9% in the CABOSUN trial including exclusively intermediate and poor risk groups) [8][9][10][11][12][13][14][15].
The incidence of grade 3 and 4 adverse events (AE) in our study was lower than the one in phase III trials, this may be due to underreporting in real life contrasting with rigorous collection of AE data in clinical trials [8][9][10][11][12][13][14][15].
Although our results are consistent with studies investigating these treatments, they should be interpreted with caution. Our limitations are that the data were obtained retrospectively from patients' records, the follow-up duration between patientswas variable and the sample size for each treatment agent was limited.
This is the rst report, to our knowledge, of mRCC OS data from real-world clinical practice in an African country. Challenges consist on availability of targeted therapies in our populations and regionalization of cancer care to improve diagnostic delays and overall outcomes

Conclusion
This study showed a high mortality rates in our population; mostly because of late diagnosis at a stage of performance status deterioration leading to therapeutic abstention. We also con rmed, through this study, that VEGFR inhibitorsare effective and safe in our population.

Patient summary
In this report, we examined the results of survival in kidney cancer patients in the Moroccan population. We found high mortality rates due to late diagnosis and performance status deterioration and TKIs were well effective with acceptable tolerability. Ethics approval and consent to participate: The informed consent of the patient was not requested by the ethics committee as it is a retrospective study with the impossibility of obtaining the consent of all patients Full name of the ethics committee: Fez University Hospital Ethics Committee.
Reference number: 10/19. You will nd below the opinion as well as the reference of the ethics committee.