Edwin A. Alvarez

Cardiovascular disease is the leading cause of death among endometrial cancer patients

OBJECTIVE To evaluate the causes of death among women with endometrial cancer. METHODS SEER registries from 1973-1988 were queried to perform a retrospective cohort study of women with invasive epithelial endometrial cancer. Causes of death were compared according to grade and stage. RESULTS 33,232 women with incident cases of endometrial cancer had died at the time of last follow up. Overall, women were most likely to die from cardiovascular disease (35.9%, 95% CI 35.3-36.3%), followed by other causes, other malignancies, and endometrial cancer. Women with low grade localized cancer were most likely to die of cardiovascular disease, while women with high grade advanced cancer were least likely to die of cardiovascular disease and most likely to die of endometrial cancer. For the entire population, risk of death from cardiovascular causes surpasses the risk of death from endometrial cancer 5 years after diagnosis. CONCLUSIONS Higher risk of cardiac death among endometrial cancer patients likely reflects the high probability of curative cancer treatment and the prevalence of cardiac disease and risk factors. As the probability of dying of endometrial cancer decreases with time, the probability of dying of cardiovascular disease increases. Interventions and investigations aimed at addressing risk factors for cardiovascular disease may have the greatest potential to improve survival for women diagnosed with endometrial cancer and should feature prominently in treatment and survivorship plans.

Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE This two-stage phase II study was designed to assess the activity of the combination of temsirolimus and bevacizumab in patients with recurrent or persistent endometrial carcinoma (EMC). METHODS Eligible patients had persistent or recurrent EMC after receiving 1-2 prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status ≤ 2. Treatment consisted of bevacizumab 10 mg/kg every other week and temsirolimus 25 mg IV weekly until disease progression or prohibitory toxicity. Primary end points were progression-free survival (PFS) at six months and overall response rate using RECIST criteria. RESULTS Fifty-three patients were enrolled. Forty-nine patients were eligible and evaluable. Median age was 63 years, and prior treatment consisted of one or two regimens in 40 (82%) and 9 (18%), respectively. Twenty (41%) received prior radiation. Adverse events were consistent with those expected with bevacizumab and temsirolimus treatment. Two gastrointestinal-vaginal fistulas, one grade 3 epistaxis, two intestinal perforations and 1 grade 4 thrombosis/embolism were seen. Three patient deaths were possibly treatment related. Twelve patients (24.5%) experienced clinical responses (one complete and 11 partial responses), and 23 patients (46.9%) survived progression free for at least six months. Median progression-free survival (PFS) and overall survival (OS) were 5.6 and 16.9 months, respectively. CONCLUSION Combination of temsirolimus and bevacizumab is deemed active based on both objective tumor response and PFS at six months in recurrent or persistent EMC. However, this treatment regimen was associated with significant toxicity in this pretreated group. Future study will be guided by strategies to decrease toxicity and increase response rates.

Changing demographics of cervical cancer in the United States (1973-2008).

OBJECTIVE To describe changes in the cervical cancer population. METHODS The SEER database 9 registries from 1973 to 2008 were queried to perform a retrospective cohort study of women with invasive cervical cancer. Estimated annual percent change (EAPC) in incidence rates and 95% confidence intervals (CI) over the entire study period were compared according to age, stage, race, and cell type (squamous [SCC] and adenocarcinoma [ACA]). Proportions and odds ratios (OR) were calculated for patients diagnosed during the second half (1990-2008) compared to first half (1973-89) of the study period. RESULTS 40,363 women with cervical cancer were entered into SEER. The EAPC are falling fastest among those with localized disease (-2.5%; 95% CI -2.8 to -2.1), age≥50 (-3.0%; 95% CI=-3.2 to -2.8), and black women (-3.8%; 95% CI=-4.1 to -3.6). The odds of a newly diagnosed cervical cancer patient having advanced disease are 10% higher, being less than age 50 are 37% higher, and being Asian or Pacific Islander are 68% higher in the second time period as compared to the first. CONCLUSIONS In the US, the population with cervical cancer is changing. Patients are presently significantly more likely to be pre-menopausal, Asian or Pacific Islander, and more frequently have non-squamous histology than previously. These progressive and cumulative changes could be due to the disparate impact of current population based screening and prevention strategies. Understanding the implications of these evolving population characteristics may facilitate planning targeted studies and interventions for cervical cancer prevention, screening and treatment in the future.

A tumor-penetrating peptide enhances circulation-independent targeting of peritoneal carcinomatosis

Peritoneal carcinomatosis is a major source of morbidity and mortality in patients with advanced abdominal neoplasms. Intraperitoneal chemotherapy (IPC) is an area of intense interest given its efficacy in ovarian cancer. However, IPC suffers from poor drug penetration into peritoneal tumors. As such, extensive cytoreductive surgery is required prior to IPC. Here, we explore the utility of iRGD, a tumor-penetrating peptide, for improved tumor-specific penetration of intraperitoneal compounds and enhanced IPC in mice. Intraperitoneally administered iRGD significantly enhanced penetration of an attached fluorescein into disseminated peritoneal tumor nodules. The penetration was tumor-specific, circulation-independent, and mediated by the neuropilin-binding RXXK tissue-penetration peptide motif of iRGD. Q-iRGD, which fluoresces upon cleavage, including the one that leads to RXXK activation, specifically labeled peritoneal metastases displaying different growth patterns in mice. Importantly, iRGD enhanced intratumoral entry of intraperitoneally co-injected dextran to approximately 300% and doxorubicin to 250%. Intraperitoneal iRGD/doxorubicin combination therapy inhibited the growth of bulky peritoneal tumors and reduced systemic drug toxicity. iRGD delivered attached fluorescein and co-applied nanoparticles deep into fresh human peritoneal metastasis explants. These results indicate that intraperitoneal iRGD co-administration serves as a simple and effective strategy to facilitate tumor detection and improve the therapeutic index of IPC for peritoneal carcinomatosis.

A phase I study of docetaxel as a radio-sensitizer for locally advanced squamous cell cervical cancer

OBJECTIVES This study was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly docetaxel with concurrent radiotherapy (RT) for the primary treatment of locally advanced squamous cell carcinoma of the cervix. METHODS Eligible patients included those with locally advanced squamous cell cervical cancer without para-aortic lymph node involvement. Docetaxel dose levels were 20 mg/m(2), 30 mg/m(2) and 40 mg/m(2) given intravenously weekly for 6 cycles. Three patients were to be treated at each dose level and 6 to receive the MTD. RESULTS Fifteen patients completed 4-6 cycles of chemotherapy. One of three patients experienced 2 delayed grade 3 severe adverse events (SAE) at the 20 mg/m(2) dose level consisting of colonic and ureteral obstruction. At the 30 mg/m(2) dose level, 1/4 patients had a probable treatment-related celiotomy due to obstipation and a necrotic tumor. Of the 8 patients treated at the 40 mg/m(2) dose level, 1 experienced grade 3 pneumonitis, likely treatment related. Overall, 10/15 (67%) experienced grade 1 or 2 diarrhea, 6 had grade 2 hematologic toxicity, and 2 had grade 2 hypersensitivity. 10 of 16 patients (67%) had no evidence of disease with follow-up ranging from 10-33 months (average 23 months). CONCLUSIONS The recommended phase II dose of docetaxel administered weekly with concurrent radiotherapy for locally advanced squamous cell carcinoma of the cervix is 40 mg/m(2).