Abstract
Background/Aim: Ethnicity of cancer patients is increasingly being recognized as an important factor that may influence intergroup variation in toxicity and efficacy of chemotherapy. Data from our institution suggested that differences in chemotherapy-associated toxicity are not limited to distanced ethnic subgroups, such as Caucasians, Afro-Americans, or Asians, but may exist even between two closely related Caucasian ethnic subgroups, such as Ashkenazi and Sephardic Jews. This study aimed to explore differences in severity and frequency of various side effects, including neurotoxicity between patients from the two Jewish subgroups receiving oxaliplatin-containing adjuvant chemotherapy for colon cancer (CC). Patients and Methods: We recruited 75 patients, with performance status 0-1 and no background of neuropathy between 2012 and 2016. All patients completed a neurotoxicity questionnaire (NQ) and a QoL questionnaire (QoLQ) at baseline and the NQ also at each treatment cycle; during follow up, patients filled out the NQ and the QoLQ every four months for a total of one year. Results: Of the 75 participants, 66 were evaluable for the study including 34 (52%) Sephardic and 32 (48%) Ashkenazi Jews. Grade ≥2 vomiting and diarrhea occurred more often in Sephardic than in Ashkenazi patients (p=0.008 and 0.012, respectively). Of the 66 evaluable patients, 11 (17%) developed grade 3 neurotoxicity; of these, 9 were Sephardic and 2 were Ashkenazi (p=0.028). There were no significant differences in the dynamics of QoL between both subgroups. Conclusion: Sephardic patients receiving oxaliplatin-containing regimens are at an increased risk for neurotoxicity and other side effects as compared to their Ashkenazi counterparts.
Ethnic diversity in efficacy and toxicity is now recognized as an important factor accounting for inter-individual variation in anticancer drug treatment (1, 2). Nonetheless, most treatment guidelines for patients with cancer refer to the general population without taking into account ethnical differences.
Current knowledge on ethnic differences in toxicities of antineoplastic agents are almost exclusively limited to comparisons between Caucasians, Afro-Americans, and Asians (3, 4), relatively distant sub-populations, socially and biologically. Data on subtle yet potentially important differences between closely related subpopulations are nevertheless nearly missing. The Jewish population in Israel can serve as an adequate model to address this issue, as its population is comprised of two main subgroups that are closely related, namely, Ashkenazi and Sephardic Jews. Having lived for centuries in different regions of the world, these two subpopulations represent two Caucasian ethnic groups with distinct genetic and lifestyle differences yet with similar access to health services in Israel and can therefore help to test the influence of subtle ethnic differences on the tolerability, toxicity and even efficacy of diverse oncologic treatment strategies.
There is evidence regarding differences between Ashkenazi and Sephardic Jews in disease incidence (5), genetic variation (6) and tissue metabolism (7). However, there are currently scant data on possible differences between these ethnic subgroups with regard to anticancer treatments (8). Older studies, performed decades ago, on the incidence and clinical features of malignant diseases in Israel did not address issues on tolerability and toxicity of chemotherapy by ethnic groups (9, 10). The first study on this issue, from our institution, defined differences in tolerability of adjuvant chemoradiation following resection of gastric cancer between Israeli Ashkenazi and Sephardic Jews, and found mostly significantly higher rates of fatigue, anorexia, and grade 3-4 dysphagia in the former (8). Additionally, preliminary observations in our institution suggested that there may be differences also in oxaliplatin-induced toxicity and quality of life (QoL) between Ashkenazi and Sephardic patients. To the best of our knowledge, such observations have not been addressed until now. We therefore conducted this prospective study using adjuvant chemotherapy with an oxaliplatin-containing regimen for colon cancer (CC), a uniform treatment plan, as a platform to evaluate differences in toxicity and tolerability between Ashkenazi and Sephardic Jews; an in-depth understanding of possible ethnic variations could contribute to modify toxicity management strategies accordingly.
CC is the third most common cancer worldwide (11). Approximately 1.2 million patients are diagnosed with CC annually and close to 600,000 will succumb to the disease (12). Standard treatment of node positive (stage III) CC and commonly also for deeply invading (stage II) tumors with high-risk features, consists of the administration of oxaliplatin-based adjuvant chemotherapy, combining intravenous (IV) oxaliplatin with a fluoropyrimidine, either IV 5-Fluorouracil (5-FU), usually in the mFOLFOX6 regimen, or oral capecitabine (Xeloda), in the XELOX regimen (13). These commonly used treatments, shown to significantly improve long-term outcomes in stage II-III CC, are associated, however, with substantial toxicities, including nausea and vomiting, diarrhea, stomatitis, myelosuppression, hand and foot syndrome, and peripheral neuropathy (14). Clearly, adjuvant oxaliplatin-based chemotherapy for stage II-III CC, a common treatment for a frequent medical problem, can serve as an optimal clinical setting to examine subtle differences in tolerability and toxicity between different Caucasian sub-populations.
Patients and Methods
Patients. Between October 2012 and November 2016, 75 patients with surgically removed stage II-III CC or stage IV without evidence of disease after metastasectomy were recruited into the study. All patients were considered candidates for adjuvant chemotherapy with either the FOLFOX or XELOX protocols. They all had a good performance status (ECOG 0) and had no background of peripheral neuropathy. Prior to participation, the patients gave written informed consent; the study was approved by the institutional ethics committee. Baseline characteristics were documented for all patients including ethnic origin, socioeconomic variables, past medical history, and characteristics and treatment of the CC.
Toxicity and quality of life assessment. At baseline, the patients filled out a neurotoxicity questionnaire (NQ), adapted from FACT/GOG-NTX-13 v4 (15) and a QoL questionnaire (QoLQ) QLQ-C30 v3 (16). In addition, the study physician evaluated the patients for baseline signs and symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 (17). At each treatment cycle patients filled out the NQ; every other cycle they were evaluated by the study physician with particular emphasis on neurotoxicity and other adverse events (AEs). After the completion of chemotherapy, patients filled out both NQ and QoLQ every 4 months for up to 12 months. Patients were followed for disease recurrence and overall survival (OS).
Statistical analysis. Statistical analysis was performed using Microsoft Excel and SPSS version 25 (IBM Corp., Armonk, NY, USA). Descriptive statistics methods were used to depict patient, disease, and treatment characteristics. Comparisons of proportions between subgroups were made using the Chi test. For each patient, the time from the onset of treatment until the development of grade 2-3 neurotoxicity was documented. Disease-free survival and OS were calculated using the standard Kaplan–Meier method. Differences between groups in changes of QoL scores were assessed using a one-way ANOVA test.
Results
Patient and tumor characteristics. Table I summarizes patient and tumor characteristics. Of the 75 patients, 34 (45%) were of Ashkenazi and 36 (48%) of Sephardic ethnic origin. Within the Sephardic subgroup, Table I shows a breakdown according to their ancestral region of origin; five patients were excluded from the study: two (3%) patients were of mixed Jewish descent and three (4%) were non-Jewish patients. There were no significant differences in patient and tumor characteristics between the Ashkenazi and Sephardic subgroups.
Patient and tumor characteristics.
Treatment and outcome. Four patients (two Ashkenazi and two Sephardic) withdrew consent to participate before the onset of treatment. Thus, of the 66 evaluable patients, 34 (52%) were Sephardic and 32 (48%) were Ashkenazi. Table II summarizes the details of treatment delivery; 96% and 93% of the planned cycles were delivered to patients who received FOLFOX and XELOX, respectively. Treatment delays occurred in 4% of all cycles; the main reasons were hematologic and gastro-intestinal (GI) toxicities. There were no differences in treatment delivery between Ashkenazi and Sephardic patients.
Treatment delivery.
With a median follow up of 47.6 months, disease recurred in 12 (17%) patients, with one death. Median OS had not been reached and no differences in OS or in recurrence rates have been observed between Ashkenazi and Sephardic patients.
Toxicity. Grade 2 and 3 treatment-related AEs are summarized in Table III; there were no grade 4 toxicities. The main toxicities were hematologic and GI. Significantly higher rates of vomiting and diarrhea, grade 2 and higher, occurred in Sephardic patients than in their Ashkenazi counterparts: 32% vs. 6% (p=0.008) and 44% vs. 16% (p=0.012), respectively.
Treatment toxicity (Grade 2,3).
Neurotoxicity. During treatment, 47/66 (71%) patients developed grade ≥2 neurotoxicity and 11 (17%) experienced grade 3 neurotoxicity. The median number of cycles to the development of grade 2 or 3 neurotoxicity was 7. Of the 11 patients who suffered from grade 3 neurotoxicity, 9 were Sephardic and 2 were Ashkenazi; therefore, severe neurotoxicity appears to occur more frequently in the Sephardic group (p=0.028). The mean time to the development of grade 3 neurotoxicity was significantly shorter among Sephardic Jews, 22.3 weeks compared to 24.5 weeks among Ashkenazi Jews (p=0.027), whereas no difference was found in time to develop grade 2 neurotoxicity. Sephardic patients developed neurotoxicity symptoms faster than Ashkenazi patients and recovered faster.
Table IV summarizes the delivered cumulative doses of oxaliplatin; Sephardic Jews who developed grade 3 neurotoxicity received a non-statistically significant, numerically higher cumulative dose of the drug. In accordance with the lower rates of toxicity among the Ashkenazi Jews, the median cumulative dose of oxaliplatin was higher among these patients, 816 mg/m2 (range=493-1,030), than among the Sephardic patients, 749 mg/m2 (range=377-1,020) (p=0.019).
Cumulative dose and number of cycles with oxaliplatin.
Quality of life. QoL was assessed at baseline and 4, 8, and 12 months after the onset of treatment. We estimated the changes in QoL from baseline over time; as can be expected, QoL scores decreased toward the end of adjuvant treatment and recovered afterwards. There were no significant differences in the dynamics of QoL between Ashkenazi and Sephardic patients (Figure 1).
Mean quality of life questionnaire score.
Discussion
There is a growing body of evidence regarding ethnicity of cancer patients as an important factor that may influence both efficacy and toxicity of chemotherapy (1, 2). Ethnic subgroups may differ in their genome resulting in differences in the pharmacokinetics and tissue susceptibility of cytotoxic agents (6). For example, Loh et al. summarized the frequency of 51 pharmacogenetic variants in East Asians and Caucasians and found significant population differences in genotype distribution (18).
In the current study, we identified some substantial ethnical differences in the pattern of toxicity of adjuvant oxaliplatin-containing chemotherapy in patients with resected CC. Sephardic Jews experienced higher rates of grade 3 neurotoxicity and of grade 2 or higher diarrhea and vomiting than their Ashkenazi counterparts; the overwhelming majority (97%) of Sephardic patients developed grade 2-3 neuropathy; in fact, 9 of 11 patients suffering from grade 3 neuropathy belonged to this ethnic group; nonetheless, the need for dose adjustments of chemotherapy and the patients’ prognoses did not differ between the groups. In this study, we did not observe any toxicity that was more prevalent among Ashkenazi Jews.
While our study deals with subpopulations within the Caucasian group, i.e., Ashkenazi and Sephardic Jews, most studies to date on the impact of ethnicity on the toxicity and efficacy of chemotherapy, have dealt with comparisons of the main ethnic groups (Caucasians, Africans, Asians). To our knowledge, no systematic review has been performed on the differences in tolerability of anticancer chemotherapy between African-Americans and Caucasians; available data on this issue come from single publications, which have consistently shown differences in side effects between these groups; most commonly, African-Americans suffer from higher rates of hematological toxicity, whereas Caucasians report more GI adverse events. For instance, in a large cohort of 3,380 CC patients on treatment with 5-FU-based regimens, McCollum et al. found that anemia and leukopenia were more common in African-Americans than in Caucasians, while suffering less nausea, vomiting, and diarrhea (19). Vincristine-associated neurotoxicity was reported to occur at a higher rate in African-American children suffering from acute lymphoblastic leukemia than in their white counterparts (20). Differences in tolerability to chemotherapy have been demonstrated also between East Asians and Caucasians; in Japan, for instance, the administration of reduced doses of docetaxel, cisplatin and 5-FU is a common practice due to intolerance to standard Western doses (21). Hasegawa and collaborators identified 14 phase II and III chemotherapy trials involving patients suffering from non-small cell lung cancer in which ethnicity was reported; severe (grade 3/4) toxicity, mostly anemia and neutropenia, was significantly higher in Asian than in non-Asian patients (22). Han et al. reported on racial differences in acute toxicity among four ethnic groups receiving neo/adjuvant chemotherapy for early breast cancer and found that patients from Asia had a higher rate of grade 3 hematological toxicity than the other three subgroups, Caucasians, African Americans, and Hispanics (23).
As can be expected, most previous studies on differences between Ashkenazi and Sephardic cancer patients have been performed in Israel; they were all retrospective, and aside of several studies from our institution, they were done several decades ago, on old drugs that are rarely used nowadays (10, 24). In a series of recent retrospective studies in gastric, esophageal, and colorectal cancers, including hundreds of patients, we have identified several differences in clinical features and in the tolerability of chemotherapy between the two main Jewish subgroups (25-27). For example, in a study on 144 patients with locally advanced gastric cancer treated with standard postoperative chemoradiation, Ashkenazi Jews had a higher rate of fatigue, anorexia, and diarrhea (8). The main difference between the current study and the earlier ones is that the former is the only one carried out prospectively, in which ethnicity, patient, and tumor characteristics as well as treatment and its outcomes were documented in detail.
Differences in the tolerability of anticancer treatments between Ashkenazi and Sephardic Jews can be primarily due to biological and genetic factors, some of which have been recognized (6); alongside ethnic differences in the prevalence of various non-malignant illnesses, such as Tay-Sachs (28), Gaucher (29), and Familial Mediterranean Fever (FMF) (30), Ashkenazi Jews suffer more from colon, breast, and ovarian cancers (31) and less from nasopharyngeal tumors and Kaposi’s sarcoma (32, 33). However, differences in tolerability of chemotherapy may be attributed also to sociological and cultural factors as well, including, for instance, dissimilar dietary habits and coping mechanisms. In any event, the underlying causes for the differences in the toxicities observed in our study, largely supported by our earlier investigations, remain to be elucidated.
Our study has several strengths and weaknesses. Its most prominent strength relies on its prospective design, providing defined eligibility criteria and study procedures as well as detailed and accurate patients’ data, including their ethnicity, the treatment administered and its toxicity and efficacy. Other strengths include the fact that it was conducted in a single institution, increasing the uniformity of treatment and study procedures, and the relatively homogeneous patient population and treatment regimens, allowing an effective evaluation of the study’s main clinical question. A major weakness of the study is however, its relatively small size. While the main observed differences were all statistically significant, minor differences in the characteristics of the two groups, including, for example, age and sex, uncontrolled due to the small sample size, could have influenced its main findings. Another weakness is the actual heterogeneity of our two cohorts; assuming that Sephardic Jews represent a relatively uniform subpopulation, one may be missing subtle differences between Sephardic Jews with ancestral roots in different regions of the globe. For example, Sephardic Jews living or originating from North Africa present different medical conditions than those living or originating in Asia. This limitation is also relevant to studies comparing Caucasians to Afro-Americans or Asians, ignoring subgroups within these populations.
In summary, we have shown, in a cohort of Israeli patients with CC receiving oxaliplatin-based adjuvant chemotherapy, that Sephardic Jews are more prone to develop high grade peripheral neuropathy as well as GI toxicity compared to their Ashkenazi counterparts. Our results highlight the differences in the tolerability of chemotherapy even among two relatively close subgroups of Caucasians and not only between distanced populations like Caucasians and Asians. These findings illustrate well the fact that clinicians should be aware of the ethnic composition of the populations being evaluated in pivotal studies, which lay the basis for their treatment algorithms; more importantly, they should be aware of the ethnicity of their patients for possible differences in the tolerability of the planned treatment. Specifically, and in accordance with our findings, special caution is recommended with the use of oxaliplatin-based regimens in patients of Sephardic descent. Further research, with a larger number of patients, is needed to confirm our results, to better understand their underlying mechanisms and to possibly recommend appropriate interventions.
Acknowledgements
We thank Zoya Cohen, PhD, for technical assistance.
Footnotes
Authors’ Contributions
Conception and design: B. Brenner, Y. Stern. Administrative Support: B. Brenner. Provision of Study Material and Patients: Y. Stern, T. Fuks. Collection and Assembly of Data: Y. Stern, T. Fuks. Data Analysis and Interpretation: B. Brenner, A. Sulkes, N. Gordon. Manuscript Writing: A. Sulkes, B. Brenner. Final Approval: All Authors.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
- Received November 2, 2022.
- Revision received November 29, 2022.
- Accepted November 30, 2022.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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