Low-grade serous carcinoma (LGSC) of the ovary is a rare tumor that is distinct from its high-grade counterpart. The objective of this study was to determine whether patient demographic factors and clinical treatment histories affected survival in a population of women with LGSC.
A review of patients who had pathologically confirmed LGSC of the ovary diagnosed between 1977 and 2009 was performed. Abstracted data included medical and social histories, anthropometric measurements, and details about diagnosis, treatment, and follow-up. Statistical analyses included Fisher exact tests, Cox proportional hazards models, and the Kaplan-Meier method.
The study sample included 194 patients who had a median follow-up of 60.9 months (range, 1-383 months). In multivariate analyses, smoking had a negative association with both overall survival (OS) (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.03-2.92; P = .04) and progression-free survival (PFS) (HR, 1.72; 95% CI, 1.00-2.96; P = .05). The median OS was shorter in current smokers than in former/never smokers (48.0 months vs 79.9 months; P = .002). PFS also was predicted by year of diagnosis >1994 (HR, 1.74; P = .01). Although the difference was not statistically significant, hormone consolidation appeared to be associated with better OS (HR, 0.15; P = .06) and better PFS (HR, 0.44; P = .07). A smaller proportion of the patients who received hormone consolidation experienced disease recurrence compared with the patients who did not receive hormone consolidation (66.7% vs 87.6%; P = .07).
In 2004, Malpica et al1 described a new 2-tier system for grading ovarian serous carcinoma as either high-grade or low-grade based primarily on the degree of nuclear atypia. Since then, both clinical and molecular evidence has accumulated in support of this distinction. Molecularly, low-grade tumors lack the activated pathways for cellular proliferation and cell-cycle progression observed in high-grade lesions.2 Whereas mutations in the p53 tumor suppressor gene are common in high-grade serous carcinoma, mutations in the proto-oncogenes v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and K-ras are encountered more frequently in its low-grade counterpart.3, 4 In addition, low-grade serous tumors more highly express both estrogen receptor (ER) and progesterone receptor (PR),5 suggesting that hormone-antagonistic agents may be of use in the treatment of this disease.
Clinically, patients with low-grade disease are diagnosed at a much younger age and have substantially longer overall survival than patients with high-grade serous carcinoma.6 Low-grade carcinoma also is relatively chemoresistant, not only to up-front agents but also in the setting of recurrent disease.7, 8 In 2006, Gershenson et al6 reported on a cohort of 112 patients with stage II, III, and IV low-grade serous carcinoma from The University of Texas MD Anderson Cancer Center and identified clinical factors that affected outcome. Persistent disease after primary chemotherapy was associated with a >3-fold increase in the risk of death and a 2-fold increase in the risk of progression, independent of disease stage and the presence of residual disease after primary surgery.6 Those authors also noted that age >45 years at diagnosis was associated with longer progression-free survival (PFS).6
To date, little research has been done to investigate the patient-specific factors that may contribute to survival outcomes among women with low-grade disease. To our knowledge, possible associations between survival and medical comorbidities, social habits, and body mass index (BMI), for example, have not been studied. Because the life expectancies in these patients are predictably long, identifying factors that affect survival may permit the initiation of lifestyle modifications aimed at optimizing outcomes. Considering these factors in relation to treatment practices is important, because the physician is expected to address all of these factors in developing a plan of care. To this end, the objective of the current study was to estimate whether patient demographic and clinical factors affected both PFS and overall survival (OS) in a historic cohort of women with low-grade serous carcinoma of the ovary.
MATERIALS AND METHODS
After we received approval from The University of Texas MD Anderson Cancer Center Institutional Review Board, 281 gynecologic oncology patients who were diagnosed with low-grade serous carcinoma of the ovary between 1977 and 2009 and were treated at MD Anderson Cancer Center were identified, and their medical records were reviewed. Patients who were diagnosed with International Federation of Gynecology and Obstetrics (FIGO) grade 1 or 2 disease before the description of low-grade serous carcinoma in 2004 had their pathology reports reviewed by a group of gynecologic pathologists at our institution to determine whether their tumors met low-grade criteria. Patients with serous tumors of low malignant potential, nonserous histology, or nonovarian primary tumors (including primary peritoneal tumors) were excluded along with patients who had never undergone debulking surgery.
Abstracted historic data included age at diagnosis, race/ethnicity, anthropometric measurements, past medical history, and social history. Age was recorded categorically in 5-year intervals for analysis, resulting in 12 distinct age groups. Patient race was classified as either white or nonwhite. To account for the potential confounding effect of ascites, BMI was calculated using height and weight measurements that were obtained within 8 weeks after primary surgical intervention. Specific medical comorbidities ascertained included diabetes mellitus, hypertension, history of myocardial infarction, history of cerebrovascular accident, and presence of other pre-existing cardiovascular disease (congestive heart failure, coronary artery disease, carotid artery disease, and peripheral vascular disease). Medical comorbidities were classified categorically as either present or absent. Smoking and alcohol use also were classified as categorical variables, and patients were designated as current users, former users, or never users.
Treatment information was collected and included date of diagnosis, surgical procedures performed, disease stage, and presence of residual disease after debulking (≥2 cm vs <2 cm). Although, by modern convention, residual disease >1 cm is associated with poorer overall outcomes, cytoreductive surgeries were considered “optimal” if there was <2 cm of residual tumor for more than a decade during the study interval. To maintain consistency, we used this 2-cm cutoff to determine the presence of residual disease. Hormone receptor status (positive or negative), adjuvant chemotherapy and radiation treatments, the use of consolidation regimens, recurrences, and dates of last follow-up also were recorded. Patients were classified as either alive or dead at last contact, and mortality was not disease-specific. The year of diagnosis was included to account for potential temporal bias associated with changing practice patterns, and patients were classified into 1 of 2 groups segregated by the median year of the study interval (1994). This year was selected because it coincided with an increased use of taxanes at our institution. Consolidation therapy was defined as receipt of hormone treatment at the completion of adjuvant therapy for patients who were without evidence of disease (negative physical examination and negative radiographic imaging; or, if such data were not available, then a negative second-look surgery) at the conclusion of primary therapy. Maintenance therapy was defined as receipt of hormone therapy at the completion of primary chemotherapy for patients who had stable, persistent disease on physical examination and/or imaging studies but did not demonstrate evidence of disease progression. OS was measured from the time of diagnosis until the date of death or last contact. PFS was measured from the time of diagnosis until clinical recurrence of disease, or disease progression through a first-line chemotherapeutic agent, or as the time from diagnosis to last follow-up if the patient did not develop recurrent disease. The date of clinical recurrence/progression was defined as the day on which new findings on physical examination were evident, the date radiographic imaging demonstrated a new or larger lesion, or the date a new therapy was initiated.
Statistical analyses were performed using the STATA (version 10.0; Stata Corp. College Station, Tex) and SPSS (version 17.0; SPSS Inc., Chicago, Ill) software packages. Summary statistics were generated to describe the patient cohort. The student t test was used to compare groups on continuous variables. Chi-square tests (or the Fisher exact test when appropriate) were used to analyze associations between categorical variables. Linear regression analyses were performed to estimate associations between continuous variables. The Mann-Whitney test was used for nonparametric comparisons. Univariate and multivariate Cox proportional hazards regression, the log-rank test, and the Kaplan-Meier method were used to assess survival outcomes. To avoid inadvertently eliminating potential confounding factors that affected survival, stepwise backwards multivariate regression analyses included covariates with P values ≤ .25 from the univariate models. All tests were 2-sided, and P values < .05 were considered statistically significant.
Two-hundred eighty-one patients with low-grade serous carcinoma of the ovary were identified during the study interval. Of these, 194 patients met inclusion criteria. Patient demographics are presented in Table 1. The mean age of patients at diagnosis was 44.9 years, and the median follow-up for the entire study group was 60.9 months (range, 1-383 months). For patients who were alive at last contact (n = 76), the median follow-up also was 64.5 months (mean, 78.4 months; range, 2-230 months). The majority of patients were Caucasian, which was consistent with the racial demographics at our institution. Anthropometric data were available for 137 patients. Of these, 25 patients (18.2%) had a BMI ≥30 kg/m2. Twenty percent of patients had at least 1 major medical comorbidity, and more than half had reported no history of smoking or alcohol consumption. Surgical management varied by patient; 164 patients (84.5%) underwent oophorectomy, and 148 patients (76.3%) underwent hysterectomy. Thirty women (15.5%) had >2 cm of residual disease at the conclusion of primary surgery, and 175 women (91.8%) had stage III or IV disease. When immunostaining was performed, tumors were ER-positive in 44 of 49 women (89.8%) and PR-positive in 25 of 45 women (55.6%). The majority of patients (191 of 194; 98.5%) received platinum treatment, and 121 patients (62.4%) received adjuvant taxane therapy. Thirty-two patients (16.5%) received additional consolidation treatment after adjuvant chemotherapy, and 50 patients (25.7%) received maintenance therapy. Eighty-six percent of patients eventually experienced recurrent or progressive disease after all primary therapies were completed.
Table 1. Demographic and Clinical Characteristics (N=194)
Table 2 summarizes the univariate analysis of factors that affected OS. Because the effects from former smoking on outcome were similar to those from not smoking, we combined these 2 groups and designated smoking status as “current smoker yes” versus “current smoker no” for the final analyses. The same approach was used for data on alcohol consumption. Current smoking (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.29-3.34; P = .002), comorbidities (HR, 1.56; 95% CI, 1.04-2.33; P = .03), and a BMI ≥35 kg/m2 (HR, 2.53; 95% CI, 1.19-5.38; P = .02) were associated significantly with a greater likelihood of dying. Hormone treatment received after primary chemotherapy also was associated significantly with OS (P = .017); specifically, hormone consolidation was associated with a decreased likelihood of dying (HR, 0.13; 95% CI, 0.018-0.94; P = .04).
Table 2. Cox Univariate Analysis of Factors That Affected Overall Survival
No. of Patients
HR, hazard ratio; CI, confidence interval; ER, estrogen receptor; PR, progesterone receptor; CV, cardiovascular; DM, diabetes mellitus, BMI, body mass index.
These covariates were included in the multivariate regression model. BMI was included as a continuous variable because of its smaller P value (P = .05) in the univariate analysis.
In the multivariate model for OS, current smoking (HR, 1.73; 95% CI, 1.03-2.92; P = .04) retained a significant association with shorter survival. The median OS was 79.9 months for never/former smokers versus 48.0 months for current smokers (P = .002). A Kaplan-Meier curve for OS by smoking status is depicted in Figure 1. Current smokers were diagnosed with disease at a significantly younger age than never/former smokers (mean age, 37.0 years vs 45.1 years; P = .01), whereas a greater proportion of never/former smokers had medical comorbidities (24% vs 4.5%; P = .05). More current smokers were diagnosed with disease before 1994 (50% vs 28.7%; P = .04), whereas more former/never smokers had received treatment with a taxane (68.3% vs 45%; P = .04). The proportions of suboptimal debulking (22% of nonsmokers vs 31% of smokers; P = .60) and recurrence (85% of nonsmokers vs 91% of smokers; P = .52) did not differ by smoking status. Hormone treatment after primary chemotherapy also was associated significantly with survival (log-rank P = .028). Although the difference was not statistically significant in a multivariate setting, compared with women who did not receive any hormone treatment after primary chemotherapy, data suggested a protective effect for hormone consolidation (HR, 0.146; 95% CI, 0.02-1.05; P = .056).
PFS was analyzed using the same group of variables. Several variables demonstrated statistically significant associations with PFS in the univariate analysis, including disease stage, use of a taxane agent, year of diagnosis, and BMI as a continuous variable. Although the difference was not statistically significant, current smoking appeared to suggest shorter PFS (Table 3). In the multivariate model, current smoking (HR, 1.72; 95% CI, 1.00-2.96; P = .049) and year of diagnosis after 1994 (HR, 1.74; 95% CI, 1.12-2.69; P = .011) were associated with shorter PFS. Hormone consolidation was associated with longer PFS, but the difference was not statistically significant (HR, 0.44; 95% CI, 0.18-1.08; P = .07). The median PFS was 76.4 months for women who received hormone consolidation, 22.93 months for women who received hormone maintenance, and 18.7 months for women who received no hormone treatment after adjuvant chemotherapy (pairwise P = .033 for hormone maintenance vs consolidation, Fig. 2) In addition, the proportion of women who experienced disease recurrence or progression was lower in the hormone consolidation cohort compared with women who did not receive hormone consolidation (66.7% vs 87.6%; P = .07).
Table 3. Cox Univariate Analysis of Factors That Affected Progression-Free Survival
No. of Patients
HR, hazard ratio; CI, confidence interval; ER, estrogen receptor; PR, progesterone receptor; CV, cardiovascular; DM, diabetes mellitus, BMI, body mass index.
These covariates were included in multivariate regression model. BMI was included as a continuous variable because of its smaller P value (P=.05) in the univariate analysis.
Because of the improvement in PFS observed among women who received hormone consolidation, this subset of patients was evaluated further. Only 9 women had data readily available on length of hormone consolidation treatment, and the characteristics of these women are described in Table 4. The median length of hormone consolidation treatment was 16.8 months (range, 4.9-70.8 months). ER/PR staining was positive in the tumors from Patients 1 and 8, and no other patients had hormone receptor assessment performed. The majority of women who discontinued hormone consolidation therapy either developed recurrent disease or decided to discontinue treatment for unspecified reasons. Compared with women who had no evidence of disease and did not receive hormone consolidation, PFS was longer in the women who received hormone consolidation (30.1 months vs 76.4 months; P = .29). Because the median OS was not reached in the hormone consolidation group, comparing the median OS between these women and those who had no evidence of disease but did not receive hormone consolidation was not possible. However, survival curves suggested that hormone consolidation afforded an OS advantage (log-rank P = .07).
Table 4. Characteristics of the Women Who Received Hormone Consolidation
Low-grade serous carcinoma of the ovary is a unique tumor that is distinguished from high-grade serous carcinoma by differences in both its associated molecular changes and its natural clinical course. Since the introduction of the 2-tier system,1 low-grade serous carcinoma has been characterized distinctly by younger median age at diagnosis and prolonged OS.6 In the current study, we investigated the adverse effects of smoking and the protective effects of hormone antagonism on survival in a population of patients with this disease.
The association between smoking and survival in patients with ovarian cancer has been debated, and there is little consensus regarding its true effects. In a large, prospective, population-based study, it was noted that neither smoking status at diagnosis nor daily cigarette consumption was associated with survival outcomes in women with epithelial ovarian cancer.9 However, in that report, there was no distinction made between tumors of differing grades or histologies. Other studies have suggested that current cigarette use at the time of ovarian cancer diagnosis increases the risk of death by as much as 65%.10, 11 Although those investigations adjusted for such variables as tumor histology, stage, chemotherapy, and grade, the grading systems did not follow the 2-tier system or FIGO grading criteria, which makes their conclusions difficult to interpret.
Interpreting the results from the current investigation emphasizes the question of whether or not the effect of smoking is tumor-related; and, given the associations between smoking and both PFS and OS, either one may be true. From a general medical standpoint, smoking has numerous detrimental effects, including impairment of fasting glucose and an increased risk for non-ST elevation myocardial infarction.12, 13 In women, smoking has been associated with a reduction in overall life expectancy up to 7.7 years, and greater proportions of smokers experience lung cancer and chronic obstructive pulmonary disease.14 Therefore, it is reasonable to expect that continued exposure to cigarettes may be a detriment to systems other than those affected by the primary malignancy.
However, it has been demonstrated that smoking exposure significantly affects the biology of cancer cells. Dasgupta et al15 reported that, after exposure to nicotine, breast and lung cancer cell lines demonstrated a down-regulation of E-cadherin and β-catenin with a concomitant up-regulation of vimentin, suggesting that nicotine promotes phenotypic changes consistent with the epithelial-to-mesenchymal transition. Nicotine specifically has been associated strongly with increased angiogenesis as well, namely, by stimulating increased expression of vascular endothelial growth factor (VEGF).16, 17 It also has been demonstrated that the human VEGF gene has an estrogen-responsive element18 and that, in malignancies of the human reproductive tract, VEGF messenger RNA expression is regulated by estrogen.19 In tumors like low-grade serous carcinoma, the majority of which demonstrate hormone sensitivity, it is possible that the stimulatory effects of estrogen and nicotine may be additive with respect to tumor growth and angiogenesis. If this hypothesis holds true, then both antiangiogenic therapy and hormone antagonists may prove to be effective therapies in this setting.
Treatment with hormone consolidation afforded an extension in PFS for our cohort of patients. The increased disease-free interval observed among women who received hormone consolidation is important, especially because patients with low-grade serous carcinoma are relatively young. Consolidation with agents that have comparatively fewer side effects than cytotoxic therapy may afford patients an interval of time with a high quality of life during which they can continue to work and maintain their functional and social well being.
Because of the rarity of low-grade serous carcinoma, few studies have investigated the success of hormones in the overall treatment algorithm. In 1989, Kavanagh et al20 reported a prospective trial of 18 patients with refractory or persistent epithelial ovarian cancer who received subcutaneous leuprolide therapy. Six of those patients had FIGO grade 1 disease. Although the study was performed before implementation of the current 2-tier system, low-grade and FIGO grade 1 histologies probably are comparable. Of the 6 patients, 3 had partial responses, and 2 had stabilization of disease.20 In contrast, only 1 response was observed among patients who had high-grade lesions. The treatment was well tolerated, and only mild side effects (pedal edema, hot flashes, mild nausea) were noted in <33% of patients.
It is important to consider why the patients who received consolidation were selected for such therapy, because this may be an inherent selection bias that affected the outcomes between groups. To date, there are no official recommendations for the use of consolidation treatments in patients with epithelial ovarian carcinoma. In fact, randomized phase 3 studies have failed to document any significant change in OS when cytotoxic consolidation is administered,21 and in only 1 study did prolonged treatment with paclitaxel produce an improvement in PFS.22 In none of these studies was a subset analysis performed to evaluate survival by tumor grade. With no grade-specific criteria to triage patients for consolidation or no further treatment after adjuvant chemotherapy, it is up to the individual physician to determine whether the patient should proceed with consolidation. However, if the assumption is made that patients deemed to have the best overall prognosis are those who do not receive consolidation, then our finding that patients who received hormone consolidation had longer PFS than those who did not receive consolidation suggests that, regardless of the treating physician's bias about anticipated patient outcome, consolidation with a hormone antagonist may be beneficial.
There are expected limitations to our conclusions because this was a retrospective study. The long study interval, incomplete patient information, various treatments for both primary and recurrent disease, the inability to definitively assess cause of death, and misclassification bias all are factors that may confound interpretation of these data. In addition, the assumption that smoking at the time of diagnosis correlates with continued smoking throughout the disease course and the inability to quantify smoking exposure makes definitive associations difficult. However, because of the rarity of low-grade serous ovarian carcinoma, hypothesis-generating data like these are important to delineate areas for future study. The potential for collaborative prospective trials based on retrospective data continues to grow as more oncologists recognize the unique nature of this disease.
Low-grade serous carcinoma of the ovary is a unique tumor that should be considered independent for the purposes of patient counseling and management. Here, we demonstrated 2 significant findings: Smoking has a negative impact on both OS and PFS, and consolidation therapy with hormone antagonists may prolong the disease-free interval after adjuvant chemotherapy. These data present the gynecologic oncologist with opportunities both to consider the molecular aberrations induced by smoking and to design patient interventions aimed at reducing the risk of negative health effects associated with tobacco use. In addition, the data highlight the potential benefit of modifying current practice algorithms for low-grade serous carcinoma to more regularly use noncytotoxic, antihormone medications. Ultimately, a multifaceted approach in women with low-grade serous ovarian carcinoma that addresses both modifiable factors and alternatives to cytotoxic therapies should continue to be studied to maximally optimize patient outcomes.
CONFLICT OF INTEREST DISCLOSURES
This research was sponsored in part by a National Institutes of Health T32 Training Grant (T32CA101642).