Chemotherapy intensity and toxicity among black and white women with advanced and recurrent endometrial cancer

A Gynecologic Oncology Group Study

Abstract

BACKGROUND:

The purpose of this study was to confirm whether black and white women with endometrial cancer are equally tolerant of chemotherapy and identify factors that impact survival.

METHODS:

A retrospective review of 169 black women and 982 white women with the International Federation of Gynecologists and Obstetricians stage III, stage IV, or recurrent endometrial carcinoma was performed. All patients received doxorubicin combined with cisplatin. Chemotherapy parameters that were reviewed included relative dose, relative time, and relative dose intensity. Treatment cycles ≥7 were defined as treatment completion.

RESULTS:

Although black patients were more likely to experience grades 3-4 anemia (20% vs 14%) and genitourinary (5% vs 1%) toxicity, and less likely to experience severe gastrointestinal toxicity (10% vs 17%), the overall incidence of grades 3-4 treatment-related chemotoxicity was the same between the 2 groups (82% vs 82%). There were no differences in the number of cycles received, relative dose (0.57 vs 0.58), relative time (0.77 vs 0.78), or relative dose intensity (0.76 vs 0.76) for black and white patients.

CONCLUSIONS:

Black patients with advanced stage or recurrent endometrial cancer, treated on 4 Gynecologic Oncology Group (GOG) protocols, had similar dose intensity and severe chemotherapy-related toxicity compared with white patients, suggesting that previously described racial disparities in survival among patients in GOG trials may have an novel etiology. Cancer 2010. © 2010 American Cancer Society.

In the United States, approximately 39,000 women will be diagnosed with endometrial cancer and over 7400 deaths will be attributable to this disease.1 Although the incidence of endometrial cancer is 30% lower among black women compared with white women, mortality among Blacks with endometrial cancer is 60% higher.2 The underlying cause of this racial disparity in endometrial cancer outcome among black patients with endometrial cancer is felt to be multifactorial.3-5 Population-based studies have suggested that inequalities in treatment may contribute to poor survival observed among black women with endometrial cancer.6-8 In an effort to further evaluate the racial disparity in endometrial cancer using a clinical setting in which patients received similar care, our group evaluated data from 4 clinical trials performed by the Gynecologic Oncology Group (GOG).9 This analysis showed that black patients had a 26% greater chance of mortality compared with Whites, controlling for performance status, stage, histology, grade, and treatment. The overall response to platinum-based and adriamycin-based chemotherapy for Blacks was 35% compared with 43% for Whites (P < .016). Although the proportion of black and white patients completing the prescribed therapy (46% vs 42%) as well as the proportion of treatment related deaths (1.9% vs 1.6%) was similar, data regarding the dose intensity and duration of chemotherapy or treatment related toxicities was not evaluated.9 The purpose of the current study was to further evaluate these chemotherapy parameters to determine whether black patients are treated less aggressively with adjuvant chemotherapy compared with Whites and whether any differences in dosing parameters affect survival outcome. Racial differences in chemotherapy response and ultimately in survival among endometrial cancer patients would suggest that a biologic etiology may be, in part, associated with the poor outcome observed among black women with advanced stage or recurrent endometrial cancer.

MATERIALS AND METHODS

We reviewed patient data from participants in 4 GOG randomized treatment trials for International Federation of Gynecologic Oncology (FIGO) stage III, stage IV, or recurrent endometrial cancer7: GOG Protocols 107, 139, 163, and 177.10-13 All treatment study arms of the individual protocols were included. All eligible patients had histologically confirmed endometrial cancer with measurable disease and a GOG performance status (PS) of 0 to 2. Prior radiation or hormone therapy, but not prior chemotherapy, was allowed. The treatment regimen for each trial is listed in Table 1. Further details regarding eligibility, treatment, and outcomes have been published previously.10-13 Data on patient demographics, tumor characteristics, and course of treatment were collected. Racial designation as black or white reflected a nonuniform collection of both self-described and investigator-reported methods. Patients from other racial groups were excluded from this analysis secondary to too few numbers for analysis.

Table 1. GOG Treatment Protocols of the Study Group

GOG protocol	Treatment		No. of Patients
	Study Arm A	Study Arm B	White	Black
GOG indicates Gynecologic Oncology Group.
GOG 107	Doxorubicin 60 mg/m^2	Doxorubicin 60 mg/m^2 and cisplatin 50 mg/m^2	237	34
GOG 139	Doxorubicin 60 mg/m^2 over 30 min and cisplatin 60 mg/m^2 over 30 min	Doxorubicin 60 mg/m^2 over 30 min at 6 AM, and cisplatin 60 mg/m^2 over 30 min at 6 PM	271	53
GOG 163	Doxorubicin 60 mg/m^2 and cisplatin 50 mg/m^2	Doxorubicin 60 mg/m^2, 24-h infusion paclitaxel at a dose of 150 mg/m^2, and G-CSF at a dose of 5 mcg/kg on Days 3-12	258	45
GOG 177	Doxorubicin 60 mg/m^2 and cisplatin 50 mg/m^2	Doxorubicin 45 mg/m^2 on Day 1; cisplatin, 50 mg/m^2 on Day 1; 3-h infusion paclitaxel at a dose of 160 mg/m^2 on Day 2; and G-CSF at a dose of 5 mcg/kg on Days 3-12	216	37

Several characteristics of chemotherapy were evaluated in relation to race and outcome. Treatment parameters were defined according to Griggs et al, in their study of breast cancer.16 Relative dose was the ratio of actual: expected dose of chemotherapy in standard chemotherapy regimens. This was calculated for each drug in the chemotherapy. Relative time was defined as the ratio of actual: expected duration of chemotherapy. Relative dose intensity (relative dose intensity) was defined as the ratio of relative dose to relative time. We defined patient completing at least 7 cycles as treatment completion because this was the maximal numbers cycles involving doxorubicin (Adriamycin) received in 3 of the 4 GOG studies included in our analysis and was based solely on precedent at the time of protocol development.13 The relative time was calculated only for up to 7 cycles (prescribed by protocol) and the expected duration of time on chemotherapy was 21 (ie, chemotherapy every 3 weeks) × 7 (ie, total cycles) days. The expected dose was the standard dose required by protocol × 7 (Table 1). Although the protocols required dose adjustment for old age, prior relative time, or body surface area (BSA) > 2, these adjustments were treated as dose reductions. The average relative dose or relative dose intensity calculated based on combination regimens was used as a summarized parameter of the combined regimen, with a ratio <1.0 indicating patient receiving less intensity of chemotherapy than planned.

Statistical Analysis

The mean relative dose, relative time, and relative dose intensity between Blacks and Whites were compared using Student t test. The number of treatment cycles, cause of treatment incompletion, and toxicity were compared by Pearson chi-square or Fisher exact test. The factors associated with treatment incompletion were identified using a logistic regression model. The association of relative dose, relative time, or relative dose intensity with survival was estimated using a Cox regression model, adjusted for established prognostic factors (performance status, stage, tumor grade, histology, prior hysterectomy, type of chemotherapy, and race). The interaction between race and treatment parameters was also assessed. The Kaplan-Meier procedure was used to estimate the cumulative probability of survival. Because patients with disease were more likely to drop the chemotherapy, resulting in dose reduction, and to avoid the possible “outcome to cause bias” or “outcome by outcome analysis”, the survival analysis based on treatment parameters was restricted to patients who completed all 7 cycles of chemotherapy, and the survival was recalculated as the time from the completion of chemotherapy until death, regardless of causes. All statistical analyses were performed using Statistical Analysis System software (SAS version 9.1; SAS Inc., Cary, NC).

RESULTS

A total of 982 white women and 169 black women with FIGO stage III, IV, or recurrent endometrial cancer were assigned to receive doxorubicin and cisplatin chemotherapy (Table 1). Clinical characteristics of this cohort of patients have previously been published.9 Blacks were more likely to have advanced stage disease (P < .001), poorly differentiated tumors (P < .001), papillary serous histology (P ≤ .001), and poor performance status (P = .008) compared with Whites. After adjusting for clinical and treatment factors, black patients were at an increased risk for death (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.06-1.51; P = .010).9

Dose Intensity

There were no differences in treatment parameters between black and white patients (Table 2). The relative dose was similar for the 2 populations (0.56 and 0.58, respectively), as was relative time (0.77 and 0.78, respectively) and relative dose intensity (0.76 and 0.76, respectively). Forty-five percent of Whites completed at least 7 cycles of chemotherapy compared with 40% among Blacks. The majority of patients who did not complete therapy stopped therapy because of disease progression (55% for Whites vs 53% for Blacks). Similar proportions, 29% of black patients and 22.3% of white patients, discontinued therapy because of toxicity. Multivariate analysis revealed that patients with abnormal performance status (P < .001), nonendometrioid cell type (P < .001), or recurrent disease (P < .001) were less likely to complete the treatment cycles required by protocol (Table 3). But, black patients had the same likelihood of completing the treatment as white patients (P > .05).

Table 2. Treatment Parameters by Race

Treatment Parameter	White, n=98	Black, n=169	P
SD indicates standard deviation; pct, percentile. a Ratio of actual to expected dose of chemotherapy. b Ratio of actual to expected duration of chemotherapy. c Relative dose/relative time. d n=542 for white patients and n=101 for black patients.
Relative dosea
Mean (SD)	0.58 (0.28)	0.57 (0.29)	0.55
Median (25^th-75^th pct)	0.63 (0.32-0.81)	0.63 (0.28-0.83)
Relative timeb
Mean (SD)	0.78 (0.36)	0.77 (0.38)	0.62
Median (25^th-75^th pct)	0.93 (0.43-1.05)	0.90 (0.42-1.08)
Relative dose intensityc
Mean (SD)	0.76 (0.14)	0.76 (0.16)	0.91
Median (25^th-75^th pct)	0.76 (0.66-0.88)	0.76 (0.63-0.88)
No. treatment cycles (%)			0.56
0	1.0	2.4
1	8.8	10.1
2	12.9	15.4
3	8.3	9.5
4	8.6	5.9
5	6.7	8.3
6	9.0	8.3
7	44.8	40.2
Cause for < 7 cycles (%)d			0.34
Disease progression	55.2	52.5
Toxicity	22.3	28.7
Other/unknown	22.5	18.8

Table 3. Significant Factors Associated With Treatment Incompletion

Characteristic	Incompletion (%)	Odds Ratio (95% CI)	P
CI indicates confidence interval. Odds ratio estimated by logistic regression model. Race and other patient characteristics (age, tumor grade, prior RT, prior hysterectomy, and type of chemotherapy regimen) not correlated with treatment incompletion (P > .05 for all).
Performance status			<.001
0	47.1	Referent
1	57.0	1.56 (1.21-2.02)
2	79.1	4.44 (2.92-6.90)
Stage			<.001
III/IV	47.9	Referent
Recurrence	59.4	1.87 (1.43-2.45)
Histology			<.001
Endometrioid	50.9	Referent
Clear cell	66.7	2.23 (1.15-4.54)
Serous	61.3	1.70 (1.22-2.39)
Other	60.3	1.59 (1.19-2.13)

Toxicity

For selected common toxicity criteria categories, more grades 3-4 anemia (20.1% vs 14.2%, P = .05) and severe genitourinary toxicity (4.7% vs 1.4%, P = .009) and less severe gastrointestinal toxicity (10.1% vs 16.7%, P = .03) were observed among black patients compared with white patients (Table 4). There is also a suggestion that Blacks experienced less leukopenia (55.6% vs 61.6%; P = .14) than Whites. However, there was no difference for overall severe adverse effects involving Whites and Blacks when considering any grades 3-4 toxicity event that occurred during participation in these clinical trials (82.3% vs 82.1%; P = .96) (Table 4). These results were consistent from multivariate analysis adjusted for age, performance status, body mass index, and prior radiotherapy,

Table 4. Treatment Adverse Effects by Race

Adverse Effect	% White, n=982	% Black, n=169	P
A Pearson chi-square or Fisher exact test was used to compare the group difference.
Selected grade 3 or 4
Leukopenia	61.6	55.6	.14
Thrombocytopenia	10.3	9.5	.75
Neutropenia	67.9	63.9	.30
Anemia	14.2	20.1	.05
Gastrointestinal	16.7	10.1	.03
Genitourinary	1.4	4.7	.009
Neurologic	3.0	3.6	.68
Cardiovascular	5.3	4.1	.53
Any grade 3 or 4	82.1	82.3	.96

The median relative dose, relative time, and relative dose intensity were 0.83, 1.05 and 0.75, respectively, for patients who completed at least 7 cycles of chemotherapy. When analysis was restricted to this population, relative dose in this restricted population appeared to be associated with survival, whereas both relative time and relative dose intensity were not. On the basis of current data, every 10% increase of relative dose is associated with a 9% reduction in the risk of death (HR, 0.91; 95% CI, 0.84-0.99). Figure 1 presents the survival from the completion of chemotherapy stratified by relative dose for the group. For patients with relative dose ≥0.9, the median survival was estimated to be 19.2 months compared with 13.6 months for those with relative dose <0.9 (log-rank test, P = .02). The association of relative dose with survival was not modified by race (P > .05 for test of interaction).

Figure 1. The Kaplan-Meier estimate of survival is depicted according to relative dose.

DISCUSSION

In our assessment of chemotherapy parameters and potential racial disparities in treatment of patients with advanced or recurrent endometrial cancer, we evaluated both the treatment-related toxicity and dose intensity of therapy. Toxicity related to chemotherapy may be an underlying cause for dose adjustments in some patients and, if different among certain minorities, could account for observed differences in cancer outcome. Dose intensity, the amount of drug delivered per unit of time, is an important predictor of outcome in adjuvant chemotherapy for cancer,14 which can be increased by either using higher doses of chemotherapy (relative dose) or shortening the interval between cycles (relative time).15 In a MedLine search of the terms “endometrial cancer” and “chemotherapy”, we did not find any previous reports of these chemotherapy parameters in relation to endometrial cancer, particularly not in the context of racial disparities.

Race was not a predictive factor for early discontinuation of chemotherapy among the patients evaluated. We previously reported that 46.2% of Blacks and 42.2% of Whites completed the required number of cycles (P = .37).9 In our current analysis, we established that the majority of patients had discontinuation of chemotherapy because of disease progression, which was similar between black and white patients (55.2% and 52.5%, respectively). The second most frequent reason for shortening of therapy in Blacks and Whites was treatment related toxicity that prompted protocol-related changes in chemotherapy administration (22.3 vs 28.7%, respectively). The remaining patients in each of the 2 groups had chemotherapy stopped because of poor performance status, a proportion that was similar in the 2 groups.

Blacks experienced a slightly increased incidence of severe (any grade 3 or 4) anemia and severe genitourinary toxicity and a lower frequency of leukopenia and severe gastrointestinal toxicity than white patients receiving chemotherapy. This increased incidence of anemia could be related to a generally higher incidence of baseline anemia found in the black population.5 Nonetheless, we found no evidence that these severe clinical toxicities accounted for any difference in relative dose or relative dose intensity among white and black patients. Overall, 82% of both black and white patients experienced any grade 3 or 4 toxicity while on chemotherapy.

We identified 3 factors associated with discontinuation of chemotherapy in advanced and recurrent endometrial cancer patients when other clinical factors were evaluated using regression analysis. Patients with performance status >0 (P < .001), recurrent disease (P < .001), and nonendometrioid histology (P < .001) were all less likely to complete the number of cycles of intravenous chemotherapy required by each of the protocols. When analysis was restricted to patients who successfully completed 7 cycles of chemotherapy or women who received fewer cycles secondary to toxicity issues, relative dose, relative time, and relative dose intensity were all similar between Blacks and Whites.

Although there are no previous reports in endometrial cancer for comparison, Griggs et al16 found systematic differences in the administration of chemotherapy given to black women with breast cancer. Blacks received lower relative dose (0.80 vs 0.85, P = .03) and relative dose intensity (0.76 vs 0.80, P = .01) than Whites. The authors speculated that these differences in chemotherapy administration could potentially contribute to racial disparities in breast cancer survival.16 Although differences in chemotherapy administration could possibly be a contributor to racial disparities in endometrial cancer outcome on a population basis, our data revealed that racial disparities in survival can persist even when black and white women receive chemotherapy similarly in clinical trial setting.

In our analysis, we found that almost half of the patients enrolled on these protocols were not able to maintain the dosage prescribed (ie, relative dose 0.56 for Blacks and 0.58 for Whites). The main reasons for dose adjustment were progression, toxicity, and poor performance status, which were equivalent among Blacks and Whites. For those patients able to maintain dosage, every 10% increase in relative dose was associated with a 9% reduction in the risk of death.

Previous investigations involving racial disparities in chemotherapy toxicity are limited, particularly in regards to gynecologic cancer. In a study of another disease site, black patients with stage II and stage III colon cancer experienced less overall (defined as toxicity events ≥ grade 1) gastrointestinal treatment-related toxicity (ie, diarrhea, nausea, vomiting, and stomatitis) compared with Whites.17 The only racial difference in severe toxicity observed was specifically for diarrhea, with 23% of Whites experiencing severe diarrhea compared with 8% of Blacks. The clinical relevance of this discrepancy in overall toxicity can be scrutinized, however, as the 2 groups derived similar benefits from the adjuvant chemotherapy administered. Significantly lower rates of gastrointestinal toxicity also have been observed among black cervix cancer patients treated on GOG clinical trials (unpublished correspondence18), suggesting that black patients may have more tolerance to the emetogenic effects of chemotherapy. Ethnic hematologic tolerance associated with chemotherapy may also be different. Lower basal white blood cell and platelet levels have been reported among black women in population-based studies. Ethnic neutropenia has been described in women receiving chemotherapy with reduced white blood cells noted both at baseline and throughout treatment.19 Hershman et al19 found in a study of 472 stage I and stage II breast cancer patients that lower levels of white blood cells were observed in Blacks versus Whites and that this was associated with a prolongation of treatment (19 weeks vs 15 weeks), resulting in less dose intensity treatment. Other studies have shown that although leukopenia is more common in Blacks with colon cancer, severe leukopenia is less frequent when compared with Whites.17 We observed no difference in severe thrombocytopenia or leukopenia between black and white patients.

The data that we have observed in this study and our previous analysis8 suggest that a racial disparity in outcome persists in a setting in which patients receive similar treatment (ie, surgery, radiotherapy, and chemotherapy) for advanced stage or recurrent endometrial cancer. In our current study, Blacks were found to have a lower response rate to platinum- and Adriamycin-based chemotherapy, suggesting that there may be unconventional differences in the endometrial cancers that develop in Blacks compared with Whites. Previous mutational analysis has shown a racial disparity in the 2 most commonly altered tumor suppressor genes found in endometrial cancers. The phosphatase and tensin homologue tumor suppressor gene, which is associated with endometrial cancers that have a more favorable prognosis, is found more often among Whites compared with Blacks.20 Conversely, the mutations in the p53 tumor suppressor gene are more often found in Blacks and associated with a poor prognosis.21, 22 Recent microarray studies have attempted to identify additional racial disparities in global gene expression that could, in part, explain differences in outcome.23, 24 If biologic differences in the endometrial cancers from black and Women exist, future pharmacogenomic or more selective contemporary chemotherapeutic therapy may be used to provide individualized treatment that is targeted to the molecular profile of the patient.25, 26

It should be mentioned that this study was a retrospective analysis. Although the total sample size is large, the number of black patients was still small. We consider the results from these data as exploratory. More data from endometrial cancer or other cancer patients treated with cisplatin-based chemotherapy will be needed to validate if black patients may be less likely to develop some specific type of adverse effects.

CONFLICT OF INTEREST DISCLOSURES

This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27,469) and the Gynecologic Oncology Group Statistical Office (CA 37,517).