Characteristics and outcomes for patients with advanced vaginal or vulvar cancer referred to a phase I clinical trials program: the MD Anderson cancer center experience

Background Early-stage vaginal and vulvar cancer can be cured. But outcomes of patients with metastatic disease are poor. Thus, new therapeutic strategies are urgently required. Methods In this retrospective study, we analyzed the clinical outcomes of consecutive patients with metastatic vaginal or vulvar cancer who were referred to a phase I trial clinic between January 2006 and December 2013. Demographic and clinical data were obtained from patients’ electronic medical records. Results Patients with metastatic vaginal (n = 16) and vulvar (n = 20) cancer who were referred for phase I trial therapy had median overall survival durations of 6.2 and 4.6 months, respectively. Among those who underwent therapy (n = 27), one experienced a partial response and three experienced stable disease for at least 6 months. Patients with a body mass index ≥30 had a significantly longer median overall survival duration than did those with a body mass index <30 (13.2 months versus 4.4 months, p = 0.04). Preliminary data revealed differences in molecular profiling between patients with advanced vaginal cancer and those with advanced vaginal cancer. Conclusions Metastatic vaginal and vulvar cancers remain to be difficult-to-treat diseases with poor clinical outcomes. The currently available phase I trial agents provided little meaningful clinical benefits. Understanding these tumors’ molecular mechanisms may allow us to develop more effective therapeutic strategies than are currently available regimens.


Background
Vaginal and vulvar cancers comprise approximately 8 % of all malignant neoplasms of the female genital tract: approximately 3,000 vaginal cancers and 4,500 vulvar cancers are diagnosed annually in the United States [1]. Most of these tumors are squamous cell carcinomas, but melanoma, sarcoma, adenocarcinoma, and other histological types also occur [2][3][4][5][6]. All vaginal and vulvar cancers are associated with similar risk factors: cigarette smoking, human papillomavirus infection, and a history of other gynecological malignancies [7,8]. Early-stage vaginal and vulvar cancer can be cured, but if the disease is not amenable to radical local excision or curative chemoradiation therapy [9][10][11], patients with recurrent or metastatic vaginal or vulvar cancers have a poor prognosis [12,13]. Palliative systemic therapy results in limited clinical benefit [14].
The overall poor prognosis of these patients warrants the development of novel therapeutic regimens [15]. Therefore, we conducted a retrospective chart review to identify the demographic characteristics and major clinical outcomes, such as mutational status, clinical response, and survival duration, of patients with metastatic vaginal or vulvar cancer who were referred to a designated phase I trial clinic. These data may lead to the development of new drugs for the treatment of patients with these diseases.

Patient selection
We included all consecutive patients with metastatic or recurrent vaginal or vulvar carcinoma who were referred to the Department of Investigational Cancer Therapeutics (a phase I clinical trials program) at The University of Texas MD Anderson Cancer Center between January 1, 2006, and December 31, 2013 in this retrospective chart review. Follow-up was defined as the time of the initial phase I clinic visit until death or the last date of the study, censored on August 8, 2014. This study was conducted in accordance with MD Anderson's institutional review board guidelines.

Data collection
During the data collection phase, two members of the research team worked independently: one reviewed patients' electronic medical records, and the other audited and checked the accuracy of the collected data. Any data discrepancy was resolved by a consensus after group discussion. The collected clinical information included race, treatment history (e.g., surgery, radiation therapy, and chemotherapy), date of birth, Eastern Cooperative Oncology Group performance status at the initial phase I clinic visit, mutation profile of the tumor specimen, phase I clinical trial therapies, and clinical outcomes (progression-free survival [ Clinical objective responses were evaluated using Response Evaluation Criteria in Solid Tumors software version 1.0 or 1.1, per individual study protocols [16,17]. The PFS duration was defined as the interval from the date of initial treatment to the first objective documentation of disease progression, the time of death, or the last date of contact (August 8, 2014), at which time the patients' data were censored. OS duration was estimated from the date of the initial phase I clinical trial therapy to death or the last date of contact. The enrollment of eligible patients into specific phase I trials was dependent on trial availability at the time of presentation and the preference of the treating physician, according to good clinical practice. If a phase I agent was unsuccessful, another was used as long as the patient was eligible and willing to participate.

Statistical analyses
Categorical data were described using contingency tables. Continuously scaled measures were summarized with descriptive statistical measures (i.e., the median and the range), whereas PFS and OS rates were estimated using the Kaplan-Meier method. Patients who were still alive at the time of data analysis were censored at that time. Fisher's exact test was used to assess the association between categorical variables. Statistical inferences were based on two-sided tests at a significance level of p <0.05. Statistical analyses were carried out using SPSS Statistics software version 22 (IBM, Inc., Armonk, NY).

Exploratory molecular analysis
Molecular marker studies were performed of available tumor specimens in a Clinical Laboratory Improvement Amendments-certified molecular diagnostic laboratory. Table 3 lists the limited molecular aberrations per tumor type. In patients with metastatic vaginal cancer, the PI3K/AKT/mTOR pathway was activated, which was supported by the finding of frequent PIK3CA mutations and PTEN loss or mutation. A loss of STK11 and FBXW7 mutations was also observed in these patients. Furthermore, treatment with everolimus and pazopanib led to a partial response for 18.2 months in one patient with metastatic squamous cell carcinoma that harbored PIK3CA (E545K), PTPRD (S1845fs*2), and STK11 losses.  Treatment with erlotinib and pralatrexate resulted in stable disease for approximately 15 months in a patient with metastatic squamous cell carcinoma that harbored ERBB2 (S310F), ERBB4 (D609N), FBXW7 (R479Q), RB1 (E539*), and ARID2 (Q1194*) and amplification of EPHBI, PIK3CA, and SOX2. In patients with metastatic vulvar cancer, we found no common intracellular transduction pathway mutations; rather, mutations were found in TP53, c-KIT, BRAF, and KRAS. One patient with metastatic KRAS wild-type squamous cell carcinoma experienced stable disease for about 11 months after being treated with epithelial growth factor inhibition-based phase I trial regimens, while another patient had stable disease for 6 months after being treated with erlotinib and valproic acid.

Discussion
Patients with metastatic or recurrent vaginal or vulvar cancer have limited therapeutic treatment options [18][19][20]. In this study, we found that these patients did not experience a meaningful clinical benefit from novel phase I therapeutics: there were low rates of objective responses and a median OS duration of only 5.6 months. Further evaluation is warranted to determine the effects of novel cancer therapeutics, molecular profiling, and targeted therapy on patient outcomes in the phase I setting.
There were several notable observations in our study. In general, patients with metastatic vaginal squamous cell carcinoma had a median OS duration of 7.1 months compared with 4.4 months in those with metastatic vulvar squamous cell carcinoma. Both cohorts of patients had poor clinical outcomes and low antitumor activity in response to currently available phase I agents. These patients had significantly shorter OS durations than did other patients with other metastatic or recurrent solid tumors [21][22][23]. Second, patients with metastatic vaginal cancer had a higher prevalence of PI3K/AKT/mTOR pathway activation, while patients with metastatic vulvar cancer had no common transduction pathway mutations. Therefore, early molecular profiling is urgently required to further explore therapeutic options for these patients. Third, since the association between obesity and survival in patients with metastatic gynecological malignancies remains equivocal, we determined the relationship between BMI and major clinical outcomes. Patients with BMIs of ≥30 had a significantly longer median OS duration (13.2 months) than did those with BMIs <30 (4.4 months), suggesting that further studies are warranted of the effects of excess body weight on tumor biology. Elucidating the molecular mechanisms of vaginal and vulvar cancer may result in the development of more effective therapeutic strategies [24,25].
A limited sample size was available for subgroup analyses, which confounded our ability to validate statistical significance in the category assessment. Nevertheless, the findings of this retrospective study should be considered preliminary evidence for generating hypotheses that will require further validation in larger prospective studies.

Conclusion
In conclusion, metastatic vaginal and vulvar cancers are difficult-to-treat diseases with poor clinical outcomes. The currently available phase I trial agents provided little meaningful clinical benefits. Preliminary data revealed differences in molecular profiling between patients with advanced vaginal cancer and those with advanced vaginal cancer. Therefore, we advocate the earlier use of molecular profiling to obtain a better understanding of their tumorigenesis and development. Biomarker-driven therapies based on complex molecular profiles may be an initial step to develop effective therapeutic regimens treating these malignancies.