Effect of age and site of primary disease on prognosis in patients with low-grade serous carcinoma of the ovarian or peritoneum: results of a large single-institution rare tumor registry
objective
Low-grade serous ovarian cancer (LGSOC) or peritoneal cancer (LGSPC) is a rare subtype of ovarian or peritoneal cancer characterized by a young age of diagnosis and relative resistance to chemotherapy. This study aims to report our latest experience with women diagnosed with LGSOC or LGSPC to assess the validity of our initial observations.
Patients and methods
The eligibility criteria for patients in our database are: stage I to IV LGSOC or LGSPC, original diagnosis prior to January 2012, and adequate clinical information. All patients were included in progression-free survival, overall survival, and multivariate Cox regression analysis. A subset analysis was performed on patients with stage II to IV low-grade serous carcinoma who received platinum-based chemotherapy after initial surgical treatment.
outcome
We identified 350 eligible patients. Median progression-free survival was 28.1 months; Median overall survival was 101.7 months. In multivariate analysis, women diagnosed at age > 35 years were 43% less likely to die than women aged ≤ 35 years (hazard ratio 0.53; 95% CI, 0.37 to 0.74; P < .001). Women with disease at the time of completion of primary treatment had a 1.78-fold increased risk of death compared with clinically disease-free (P < .001). A similar trend was observed in smaller patient cohorts. In this cohort, women with LGSPC had a 41% lower chance of death compared with women with LGSOC (hazard ratio 0.59; 95% CI, 0.36 to 0.98; P = .04).
conclusion
The prognosis is worst for women younger than 35 years of age with low-grade serous carcinoma and for women whose disease persists after completion of primary therapy. The prognosis appears to be better for patients with LGSPC than for patients with LGSOC.
introduce
Ten years ago, our group first proposed the concept of a binary grading system for ovarian serous carcinoma. Since then, the clinical behavior of low-grade serous carcinoma of the ovary (LGSOC) or low-grade serous carcinoma of the peritoneum (LGSPC) has been well described, and the two-level grading system has been widely accepted. At the same time, our understanding of the molecular biology and genetics of low-grade serous carcinoma has been greatly expanded.
In 2006, we reported clinical experience with female patients newly diagnosed with stage II to IV LGSOC. Distinguishing features of this group of patients include a relatively young age at diagnosis, relative resistance to chemotherapy, and prolonged overall survival (OS). In subsequent publications, we present the experience of patients with LGSOC and LGSPC undergoing neoadjuvant chemotherapy. In 2007, we established a longitudinal database that systematically collected demographic and clinical information on all female patients diagnosed with low-grade serous tumors in our institution. The purpose of this study is to present our experience with a large number of female patients diagnosed with LGSOC or LGSPC in order to reassess the validity of our initial observations.
discuss
The key findings of this study confirm our originally published results showing that patients with low-grade serous carcinoma are on average younger and have longer overall survival compared to patients with high-grade ovarian or peritoneal cancer. In addition, we found that three factors appeared to have a significant impact on patient outcomes: disease status at completion of primary treatment, age, and primary site of disease. The results associated with these variables appeared to be consistent with the two cohorts analyzed.
As in our original study, > 40% of women still had persistent disease at the time of completion of primary treatment, a factor that resulted in significantly shorter median PFS and median OS compared to clinically disease-free women at completion of primary treatment. In a multivariate regression analysis of OS, the HR for disease persistence was 1.77 for all 350 patients and 1.96 for the 287 patient cohort. Because most ovarian cancer trials do not report disease status at completion of primary treatment, we are unable to directly compare our study population with the population in a prospective clinical trial. However, our clinical impression is that the persistent disease rate of > 40% is likely to be higher than the persistent disease rate in patients with metastatic ovarian cancer of all histologic subtypes. Such a high rate of disease persistence may reflect relative resistance to chemotherapy – an observation also supported by reports of neoadjuvant and relapsing chemotherapy. Although platinum-based chemotherapy remains the standard first-line treatment for these patients, there is strong evidence that randomized clinical trials are warranted to test different agents in this setting.
In this larger, long-term follow-up study, two new observations emerged related to the age of diagnosis and the site of the primary disease (ovaries and peritoneum). Patients aged ≤ 35 years make up more than 25% of the study population and have significantly worse outcomes for both PFS and OS compared to women aged > 35 years. Interestingly, breast cancer research reveals a similar trend; Younger breast cancer patients have a worse prognosis compared to older breast cancer patients. In a study of women with invasive breast cancer identified in the British Columbia Cancer Institution Breast Cancer Outcomes Database, luminal breast cancer (estrogen and/or progesterone receptor positive, human epidermal growth factor receptor 2 negative) aged < 40 years with a poor prognosis. Cancello et al. found that patients aged < 35 years with luminal breast cancer had a significantly increased risk of recurrence and death compared with older patients with similar characteristics. Freedholm et al found that women aged 20 to 34 years had the lowest 5-year relative survival rate of all age groups. The fact that there is a high proportion of estrogen or progesterone receptor positivity in metastatic low-grade serous carcinoma suggests that there may be a relationship between hormone receptor positivity and poor prognosis in younger patients. In addition, with or without fertility-sparing surgery, there may be some estrogenic effects in younger patients compared to older patients. These observations clearly merit further study.
In addition, in both cohorts, there was a statistically significant superiority in median PFS and median OS for women with LGSPC compared to patients with LGSOC. This observation was unexpected, and whether it was real or merely accidental remains to be clarified. For ovarian and primary peritoneal cancers of all histological subtypes, studies reported conflicting results on survival comparisons, with some studies showing equal OS time and others suggesting worse OS time in primary peritoneal cancer. Two recent serous histology studies based on large populations have shown that the prognosis of primary peritoneal cancer is significantly worse than that of primary ovarian cancer.
The limitations of such observational studies are obvious, including incomplete data, long study cycles, referral bias, treatment inconsistencies, changes in testing methods, and other confounding factors. Nonetheless, this report details information on a large number of women with rare ovarian cancer and makes hypotheses that may lead to progress that affects women with this disease.
In conclusion, our study not only solidified our group's initial observations, but also provided new insights into the age at diagnosis, the state of the disease at completion of primary treatment, and the impact of the primary site of the disease on patient outcomes. In particular, the youngest group appears to have a significantly worse prognosis, and a similar phenomenon exists in women with intraluminal breast cancer, a finding that raises the question of hormonal effects and hopes to encourage more research in this area.
Impact of Age and Primary Disease Site on Outcome in Women With Low-Grade Serous Carcinoma of the Ovary or Peritoneum: Results of a Large Single-Institution Registry of a Rare Tumor - PubMedTwitterFacebookLinkedInGitHubTwitterSM-FacebookSM-Youtube