RACIAL/ETHNIC DISPARITIES IN OVARIAN CANCER TREATMENT AND SURVIVAL

Abstract

Purpose

Among ovarian cancer patients, African American (AA) women experience poorer survival compared to other race/ethnicity groups. This has been attributed to differences in access to health care.

Experimental Design

We evaluated racial/ethnic differences in chemotherapy dosing and survival in a cohort study among members of Kaiser Permanente Northern California, and thus with equivalent access to health care. Analyses included epithelial invasive ovarian cancer cases (n=793) receiving adjuvant first-line therapy of carboplatin and paclitaxel with curative intent, with median follow-up of 50 months. Relative dose intensity (RDI) was computed for carboplatin and paclitaxel separately as dose administered/week divided by expected dose/week, and average RDI (ARDI) was then calculated for the regimen. Proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) after adjusting for relevant covariates.

Results

Compared to whites, AAs were more likely to have dose reduction (ARDI<85%), treatment delay, and early discontinuation. Hispanics were also more likely to have dose reduction, but less likely to have early discontinuation or treatment delay. After controlling for prognostic factors including ARDI, AA women had the worst survival. Compared to whites, adjusted HRs (95% CI) for overall mortality were 1.56 (1.01-2.39) for AA; 0.89 (0.61-1.31) for Asians; and 1.41 (0.98-2.04) for Hispanics. Findings for ovarian cancer-specific mortality were similar.

Conclusions

Disparities in ovarian cancer treatment and survival in AA persisted among women with equal access to care. These findings warrant further evaluation of biological, personal, and social factors that may be responsible for these differences.

INTRODUCTION

Ovarian cancer is the second most common gynecologic cancer and the leading cause of death from gynecologic malignancies in the US ¹. Among ovarian cancer patients there are well-known racial disparities, with African American (AA) women being less likely to receive adequate treatment and more likely to experience worse survival compared to white women ^{2, 3}. These differences have been attributed to unequal access to care and receipt of treatment ³. AA women are also more likely to be obese and to have related comorbidities ^{4, 5}, which are known to affect chemotherapy dosing, and dose reduction has been shown to reduce ovarian cancer survival ⁶. Previous studies have not taken these factors into account, and possible disparities among other racial/ethnic groups have received little attention. We evaluated race/ethnicity differences in chemotherapy dosing and survival in a cohort study of epithelial invasive ovarian cancer cases, diagnosed and treated as members of Kaiser Permanente Northern California (KPNC), and who thus had equal access to health care.

MATERIALS AND METHODS

The Kaiser Permanente-Research on Ovarian Cancer Survival (KP-ROCS) Cohort Study has been described in detail elsewhere ⁶. In brief, cases of invasive epithelial ovarian cancer 21 years or older and diagnosed from 2000-2013 were identified through the KPNC Cancer Registry. Information on patient demographic and clinical characteristics including dosing was obtained from KPNC electronic medical records, including its Virtual Data Warehouse ^{7, 8}. Information on race/ethnicity was obtained from the VDW's Tumor File, which reflects data from the KPNC Cancer Registry. There were 1,307 whites, 106 AA, 167 Hispanics, 253 Asians, and 13 of “other” race. We excluded these 13 women as the group was too small for meaningful analyses.

Included in the chemotherapy subcohort were patients who received intravenous adjuvant first-line therapy of carboplatin and paclitaxel with curative intent, with complete dosing data, resulting in 793 patients. Demographics and clinical characteristics were similar among women included in the chemotherapy subcohort and the full cohort, with the exception that those receiving chemotherapy were less likely to be over 70 years of age or to have advanced disease, which was expected ⁶.

Relative Dose (RD: actual dose/expected dose for first cycle) and Relative Dose Intensity (RDI: actual dose administered per week/expected dose per week) were computed for paclitaxel and carboplatin separately, and for the combination regimen by computing the average RD (ARD) and average RDI (ARDI), as calculated by others ^9-11 and described in more detail elsewhere ⁶. Expected doses were based on National Comprehensive Cancer Network (NCCN) Guidelines (www.nccn.org). Chemotherapy dose reduction was defined as an RDI for the full regimen of less than 85% ^12-14. Early discontinuation was defined as not completing the full six scheduled treatments ¹⁵, or alternatively, receiving less than 4 cycles. Treatment delay was defined as a delay in receiving scheduled chemotherapy treatment of more than 7 days.

Outcomes included overall mortality and ovarian cancer-specific mortality identified through the KPNC Mortality Linkage System through December 2014, representing a median follow-up of 38 months (50 months for the chemotherapy subcohort). The study was approved by the Institutional Review Boards at KPNC and Rutgers Biomedical and Health Sciences.

Statistical Analyses

Distributions for demographic and clinical characteristics were compared across racial/ethnic groups using chi-square or Fisher's exact test, as appropriate. In stratified analyses by race/ethnicity we compared the proportions of women with dose reduction (RDI<85%), early discontinuation, and treatment delay using chi-square tests, as well as mean values of RD, ARDI, RDI and ARDI, actual dose of paclitaxel and carboplatin, number of cycles, and treatment duration using ANOVA.

Survival for AA, Hispanics, and Asians was compared with that of white women by conducting proportional hazards regression to calculate hazard ratios (HR) and 95% confidence intervals (CI) for overall and ovarian cancer-specific survival, after adjusting for relevant covariates. Potential covariates included age at diagnosis, stage, grade, histologic subtype, body mass index (BMI) at diagnosis, chemotherapy-related toxicities, use of granulocyte-colony stimulating factors (G-CSF) for prophylaxis or treatment of neutropenia, relevant comorbidities, post-treatment CA-125 as a marker of residual disease ^{16, 17}, ARDI, and type of surgery. Chemotherapy-related toxicities considered as potential covariates included severe myelosuppression (severe neutropenia or thrombocytopenia) and neuropathy, grade III/IV, according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCE), version 3.0. Comorbidities included those likely to affect dosing or survival (diabetes, hypertension, cardiovascular disease, and acute kidney disease and chronic renal insufficiency). SAS version 9.2 (SAS Institute) was used for analyses.

RESULTS

Clinical characteristics by race/ethnicity are shown in Table 1. Hispanic and Asian women were younger at diagnosis. AA women were more likely to be diagnosed with advanced disease (26.4%), to have hypertension (75.5%), cardiovascular disease (63.21%), or renal disease (58.5%), not to have surgery (12.3%), and to have elevated post-treatment CA-125 (35.8%), a marker of residual disease, than any other racial/ethnic group. Both AA and Hispanic women had high prevalence of obesity, with Hispanic women having the highest prevalence of diabetes (32%). Compared to white women, Asian women were less likely to have advanced disease or be obese and more likely to have endometrioid and clear cell tumors. Severe neutropenia was more commonly diagnosed among whites and they were more likely to receive G-CSF than any other racial/ethnic group.

Table 1.

Clinical characteristics in KP ROCS (Kaiser Permanente Research on Ovarian Cancer Survival) Cohort Study, 2000 to 2013 (n=1833

Variable	White (n=1307)		African American (n=106)		Hispanic (n=167)		Asian (n=253)
	n	%	n	%	n	%	n	%	P value*
Age at diagnosis (y)									<0.001
21-39	49	3.75	4	3.77	6	3.59	27	10.67
40-49	136	10.41	15	14.15	49	29.34	50	19.76
50-69	698	53.40	62	58.49	85	50.90	130	51.38
≥70	424	32.44	25	23.58	27	16.17	46	18.18
Mean, SD	63.00	12.78	61.43	12.80	56.56	12.14	56.10	13.24	<0.0001
AJCC Stage									0.02
I	265	20.28	19	17.92	40	23.95	78	30.83
II	115	8.80	7	6.60	19	11.38	30	11.86
III	553	42.31	50	47.17	66	39.52	94	37.15
IV	355	27.16	28	26.42	41	24.55	48	18.97
Unknown	19	1.45	2	1.89	1	0.60	3	1.19
Grade (SEER Definition)									0.28
Well differentiated	84	6.43	4	3.77	12	7.19	24	9.49
Moderately different.	165	12.62	13	12.26	27	16.17	30	11.86
Poorly differentiated	479	36.65	34	32.08	64	38.32	84	33.20
Undifferentiated	221	16.91	15	14.15	28	16.77	44	17.39
Unknown	358	27.39	40	37.74	36	21.56	71	28.06
Histology									<0.0001
Serous	715	54.71	52	49.06	88	52.69	103	40.71
Mucinous	67	5.13	2	1.89	4	2.40	21	8.30
Endometrioid	118	9.03	10	9.43	26	15.57	33	13.04
Clear cell	77	5.89	4	3.77	13	7.78	37	14.62
Other	330	25.25	38	35.85	36	21.56	59	23.32
BMI at diagnosis (kg/m2)									<0.0001
Underweight (<18.5)	36	2.75	0	0	1	0.60	11	4.35
Normal (18.5-24.99)	501	38.33	14	13.21	28	16.77	140	55.34
Pre-obese (25-29.99)	384	29.38	30	28.30	70	41.92	81	32.02
Obese I (30-34.99)	205	15.68	27	25.47	39	23.35	15	5.93
Obese II (35-39.99)	101	7.73	22	20.75	20	11.98	4	1.58
Obese III (≥40)	80	6.12	13	12.26	9	5.39	2	0.79
Comorbidities
Diabetes									<0.0001
Yes	221	16.91	33	31.13	54	32.34	54	21.34
No	1086	83.09	73	68.87	113	67.66	199	78.66
Hypertension									0.0007
Yes	779	59.60	80	75.47	92	55.09	134	52.96
No	528	40.40	26	24.53	75	44.91	119	47.04
Cardiovascular disease									0.0002
Yes	735	56.24	67	63.21	73	43.71	116	45.85
No	572	43.76	39	36.79	94	56.29	137	54.15
Renal disease									<0.0001
Yes	412	31.52	62	58.49	49	29.34	64	25.30
No	895	68.48	44	41.51	118	70.66	189	74.70
CA 125 (U/ml)									0.009
<35	847	64.80	58	54.72	119	71.26	186	73.52
35-70	84	6.43	13	12.26	11	6.59	16	6.32
>70	242	18.52	25	23.58	27	16.17	38	15.02
Unknown
Chemotherapy									0.27
Yes	1111	85.00	84	79.25	143	85.63	221	87.35
No	196	15.00	22	20.75	24	14.37	32	12.65
Neutropenia (grade III/IV)a, b									0.88
Yes	172	30.18	12	28.57	21	25.93	29	29.00
No	398	69.82	30	71.43	60	74.07	71	71.00
G-CSF usea									0.02
Yes	146	25.61	7	16.67	13	16.05	14	14.00
No	424	74.39	35	83.33	68	83.95	86	86.00
Surgery type									<0.0001
No surgery	76	5.81	13	12.26	6	3.59	4	1.58
Oophorectomy without hysterectomy	74	5.66	4	3.77	16	9.58	12	4.74
Oophorectomy with hysterectomy	158	12.09	10	9.43	22	13.17	35	13.83
Oophorectomy with omentectomy	47	3.60	3	2.83	4	2.40	14	5.53
Oophorectomy with omentectomy and hysterectomy	247	18.90	20	18.87	35	20.96	67	26.48
Debulking with partial resection of urinary tract	312	23.87	19	17.92	42	25.15	60	23.72
Debulking/exenteration with removal of colon and/or rectum	320	24.48	19	17.92	31	18.56	44	17.39
Other	73	5.59	18	16.98	11	6.59	17	6.72

^*Based on Chi-Square test or Fisher's Exact test, as appropriate.

^aAmong those receiving chemotherapy.

^bSevere neutropenia - grade III/IV according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCE), version 3.0.

G-CSF: granulocyte-colony stimulating factors

Compared to whites, AAs were more likely to have dose reduction (ARDI<85%), treatment delay, and early discontinuation, while Hispanics were also more likely to have dose reduction, but less likely to have early discontinuation or treatment delay (Table 2). However, only early discontinuation was statistically significant.

Table 2.

Chemotherapy dosing, dose delay, and treatment delay, by race/ethnicity, KP ROCS-Chemotherapy Subcohort, 2000-2013.

	White (n=570)		African American (n=42)		Hispanic (n=81)		Asian (n=100)		p value*
(All cycles)	n	%	n	%	n	%	n	%
Paclitaxel
Dose reduction (RDI<85%)†	152	26.67	14	33.33	21	25.93	31	31.00	0.65
Dose delay (>7 days)	170	29.82	14	33.33	19	23.46	29	29.00	0.62
Early discontinuation (<6 cycles)	190	33.33	18	42.86	21	25.93	31	31.00	0.27
Early discontinuation (<4 cycles)	86	15.09	14	33.33	10	12.35	20	20.00	0.01
Carboplatin
Dose reduction (RDI<85%)	339	59.47	21	50.00	53	65.43	44	44.00	0.009
Dose delay (>7 days)	172	30.18	14	33.33	19	23.46	30	30.00	0.60
Early discontinuation (<6 cycles)	188	32.98	18	42.86	20	24.69	34	34.00	0.22
Early discontinuation (<4 cycles)	91	15.96	14	33.33	10	12.35	21	21.00	0.01
Paclitaxel + Carboplatin
Dose reduction (RDI<85%)	237	41.58	20	47.62	41	50.62	36	36.00	0.21
Dose delay (>7 days)	176	30.88	14	33.33	19	23.46	30	30.00	0.56
Early discontinuation (<6 cycles)	194	34.04	18	42.86	21	25.93	34	34.00	0.28
Early discontinuation (<4 cycles)	91	15.96	14	33.33	10	12.35	21	21.00	0.01

	Mean	SD	Mean	SD	Mean	SD	Mean	SD
BSA (calculated)	1.78	0.23	1.89	0.23	1.77	0.19	1.62	0.20	<0.0001
Paclitaxel
RD first cycle (%)†	95.80	13.69	96.17	6.95	93.80	18.90	97.62	5.80	0.30
RDI all cycles (%)	90.51	12.46	87.65	12.63	90.64	11.40	90.63	11.32	0.52
Actual total dose (mg/kg)	22.85	8.16	18.75	8.26	23.48	7.51	23.76	8.09	0.006
Number of cycles	5.28	1.63	4.76	2.03	5.60	1.62	5.17	1.63	0.05
Treatment duration (weeks)	16.96	5.63	15.57	7.53	17.82	5.61	16.72	5.60	0.21
Carboplatin
RD first cycle (%)	86.53	15.36	88.24	14.72	82.07	18.95	91.31	15.03	0.001
RDI all cycles (%)	80.95	17.77	81.75	14.92	78.49	18.87	84.15	16.00	0.18
Actual total dose (mg/kg)	42.50	18.19	35.02	18.17	47.23	18.42	49.72	21.38	<0.0001
Number of cycles	5.26	1.67	4.76	2.03	5.59	1.69	5.05	1.63	0.04
Treatment duration (weeks)	16.95	5.69	15.57	7.53	17.78	5.79	16.55	5.78	0.21
Paclitaxel + Carboplatin
ARD first cycle (%)	91.16	11.22	92.20	9.78	87.94	14.33	94.47	9.40	0.002
ARDI all cycles (%)	85.73	13.04	84.70	12.21	84.57	12.84	87.39	12.31	0.46

^*Based on ANOVA

^†RD: Relative Dose; RDI: Relative Dose Intensity; ARDI: Average RDI.

Mean actual dose (mg/kg of body weight) of paclitaxel and carboplatin was considerably lower for AA women than any other group (p=0.006 and <0.0001, respectively), shown in Table 2. Notably, compared to whites, AA women tended to have higher RD in the first cycle but fewer cycles, while Hispanics had lower RD in the first cycle but longer treatment duration (more cycles), resulting in similar mean total ARDI for AA and Hispanics, with both receiving slightly lower ARDI than white women. In contrast, mean ARDI was highest among Asian women (Table 2).

For the full cohort, although mortality rates were highest for AA women, we did not observe significant differences in survival by race/ethnicity after adjusting for major prognostic factors, including treatment. However, a different picture emerged when analyses were restricted to women receiving the carboplatin and paclitaxel, the most common chemotherapy regimen in the treatment of ovarian cancer¹⁸. Compared to white ovarian cancer patients, AA patients had the worst survival among race/ethnicity groups after taking into account potential clinical and treatment differences (Table 3). After controlling for age at diagnosis, stage, grade, histology, BMI at diagnosis, comorbidities potentially affecting dosing (diabetes, hypertension, cardiovascular diseases, renal disease), surgery type, and post-treatment CA 125, adjusted HRs (95%CI) for overall mortality were 1.56 (1.01-2.40) for AA; 0.95 (0.66-1.39) for Asians; and 1.41 (0.97-2.03) for Hispanics. Further adjusting for ARDI of carboplatin-paclitaxel received, chemotherapy-related toxic effects, and G-CSF use did not impact risk estimates. Findings for ovarian cancer-specific mortality were similar (data not shown).

Table 3.

Risk of all-cause mortality among ovarian cancer patients by race/ethnicity. KP-ROCS Cohort (2000-2014).

	n	Events	HR1 (95% CI)	HR2 (95%CI)	HR3 (95% CI)
Full Cohorta
White	1307	758	1.00	1.00	-
African American	106	69	1.36 (1.06-1.75)	1.14 (0.88-1.48)	-
Asian	253	111	0.93 (0.76-1.13)	0.98 (0.80-1.21)	-
Hispanic	167	88	1.13 (0.90-1.41)	1.04 (0.82-1.30)	-
Chemotherapy Subcohortb
White	570	257	1.00	1.00	1.00
African American	42	25	1.46 (0.96-2.21)	1.56 (1.01-2.40)	1.56 (1.01-2.39)
Asian	100	35	0.93 (0.64-1.34)	0.95 (0.66-1.39)	0.89 (0.61-1.31)
Hispanic	81	41	1.35 (0.96-1.90)	1.41 (0.97-2.03)	1.41 (0.98-2.04)

HR1: Adjusted for age at diagnosis, stage, grade, and histologic type.

HR2: Further adjusted for BMI at diagnosis, diabetes, hypertension, CVD, renal disease, post-treatment CA125, chemotherapy (yes/no) and type of surgery.

HR3. Chemotherapy Subcohort (on carboplatin-paclitaxel regimen). Analyses further adjusted for chemotherapy-related toxicities (severe neutropenia and thrombocytopenia and neuropathy), use of granulocyte-colony stimulating factor, and Average Relative Dose Intensity (ARDI) of carboplatin and paclitaxel (rather than chemotherapy yes/no).

DISCUSSION

Disparities in ovarian cancer survival have been reported using Surveillance, Epidemiology, and End Results (SEER) data, SEER-Medicare data, and a National Cancer Data Base with most reports focusing on differences in AA vs. white women ³. Our study confirms some of the known disparities in ovarian cancer disease presentation, treatment, and survival in AA compared to whites. We found that AA were more likely to be diagnosed with advanced disease, not to have surgery and have post-treatment residual disease, to have the serous histological subtype, and to be obese and have related co-morbidities, and to experience worse survival compared to whites, similar to what has been reported in the literature ². We also found that they were more likely to have treatment delay and early discontinuation, and to receive the lowest mean ARDI for the regimen compared to other racial/ethnic groups, which to our knowledge was not previously evaluated.

Hispanics represent a rapidly growing group in the US, with approximately 16.3% of the total US population in the 2010 Census, representing a 43% increase in the previous decade ¹⁹. However, little is known about ovarian cancer disparities in treatment and survival in this population. Our study agrees with an earlier report using SEER data by Ibeanu et al, which found that Hispanics tended to have an earlier age at diagnosis, compared to white and AA women ²⁰. However, in contrast to our study, the report by Ibeanu et al., which included nonepithelial tumors, found that Hispanic women tended to be diagnosed at an earlier stage and experience better survival than other groups; analyses adjusted for prognostic factors were not presented. Our study is the first to evaluate differences in chemotherapy dosing and to present analyses accounting for detailed clinical information. We observed differences in treatment and poorer survival for this population compared to whites, after adjusting for detailed treatment information including chemotherapy dosing, but risk estimates did not reach statistical significance.

Our results are in general agreement with the few reports evaluating ovarian cancer survival disparities in Asians. As with others ²¹, we found that Asian women tended to be diagnosed at an earlier age and with more localized disease, were more likely to have endometrioid and clear cell tumors, and to experience better survival, compared to whites. They tend to have lower body mass index, which may facilitate earlier detection. Our study is the first to evaluate chemotherapy dosing, and we found that Asians were also less likely to have residual disease and more likely to receive higher RDI than any other racial/ethnic group, which may in part explain their survival advantage.

A limitation of the study is the classification of race/ethnicity in broad groups. For example, Asians include Japanese, Chinese, Korean, Vietnamese, Filipino, and South Asian women of Indian or Pakistani descent, and these subgroups have been shown to have different 5-year ovarian cancer-specific survival experience using SEER data, ranging from 62.1% for Vietnamese to 48.2% for Asian Indian/Pakistani ²¹. It also includes immigrant vs. US-born Asians, who also were found to have somewhat different 5-year disease-specific survival (55% vs. 52%, respectively), but both better than US whites (48%)²¹. The overall observation of better survival for Asians agrees with our findings after controlling for major prognostic factors. Similarly, for Hispanics, we had no information on country of origin and, to our knowledge, no studies have evaluated differences in survival according to sub-ethnicity/indigenous ancestry.

Our study is the first to evaluate disparities using detailed clinical information, including variables that allowed the calculation of RDI for the most common regimen. It is also one of the first to evaluate disparities in an observational study under conditions of potentially equal access to health care. We were also able to take into account differences in severe chemotherapy-related toxicities and G-CSF use, which may have affected chemotherapy dosing. We did not find that severe neutropenia occurred more frequently in AA women, despite their known tendency to have lower white blood cell and absolute neutrophil counts than white women ²². Nevertheless, even after adjusting for these clinical variables, disparities in survival persisted, with AA women experiencing poorer survival. However, there are other factors at the personal level, such as education and cultural beliefs, that may have affected both personal and clinician decisions on treatment. For example, we demonstrated previously that obese women are more likely to have dose reduction, and those with dose reduction have poorer survival ⁶. There may also be biological differences in the disease, by which, for example, AA may be diagnosed with more aggressive disease and have pre-existing conditions that complicate treatment. Similar observations are well-known in breast cancer ^{5, 23}.

In conclusion, survival disparities persisted in a population covered by and who received care from a single large integrated health care provider, after adjusting for detailed treatment and prognostic characteristics. Future studies should explore biological, personal, and social factors to further understand and address these inequities in treatment and survival.

TRANSLATIONAL RELEVANCE.

In this cohort study we explored disparities in treatment and survival among ovarian cancer patients with equivalent access to health care. This is the first study with detailed clinical information so that relative dose intensity could be calculated, and important factors, usually unavailable in epidemiologic studies, such as chemotherapy-related toxicities and comorbidities, could be taken into account. We found that after controlling for these clinical prognostic factors, African American (AA) women had the worst survival. These results suggest that there are other factors aside from access to care that may contribute to the poorer survival in AA women after an ovarian cancer diagnosis. They also suggest the need for research into biological or sociocultural differences that may explain this survival disparity, including molecular features of the tumor microenvironment that may result in more aggressive disease. Future clinical research may also seek to identify more efficient therapies for AA women.