International models of investigator-initiated trials: implications for Japan.

BACKGROUND: Academic/institutional investigator-initiated clinical trials benefit individuals and society by supplementing gaps in industry-sponsored clinical trials. MATERIALS: In May 2010, experts from Japan, the Republic of Korea, the UK, and the United States, met at a symposium in Tokyo, Japan, to discuss how policies related to the conduct of clinical trials, which have been shown to be effective, may be applied to other regions of the world. RESULTS: In order to increase the availability of anticancer drugs world-wide, nations including Japan should examine the benefits of increasing the number of investigator-initiated clinical trials. These trials represent one of the most effective ways to translate basic scientific knowledge into clinical practice. These trials should be conducted under GCP guidelines and include Investigational New Drug application submissions with the ultimate goal of future drug approval. CONCLUSIONS: To maximize the effectiveness of these trials, a policy to educate health care professionals, cancer patients and their families, and the public in general on the benefits of clinical trials should be strengthened. Finally, policies that expedite the clinical development of novel cancer drugs which have already been shown to be effective in other countries are needed in many nations including Japan to accelerate drug approval.

Demographic, clinical, and treatment trends among women diagnosed with vulvar cancer in the United States.

OBJECTIVE: Describe the treatment and survival patterns among a population-based sample of vulvar cancer patients diagnosed in the United States in 1999. METHODS: Cases were identified for the National Cancer Institute's Patterns of Care Study (POC) using the Surveillance, Epidemiology, and End Results Program (SEER). A stratified random sample of non-Hispanic white, non-Hispanic black, and Hispanic women age 20 years and older was selected from cases reported by 11 SEER registries. Analyses of the association between vulvar cancer and key demographic, clinical, and hospital characteristics by stage were performed. Cox proportional hazards was used to estimate the odds of death due to cancer. All estimates were weighted, and analyses were conducted with SUDAAN. RESULTS: Ninety percent of cases were diagnosed with in situ or early-stage invasive disease. Older patients were more likely to present at advanced stages. Twenty-five percent of women with Stage III-IV vulvar cancer received chemotherapy plus radiation. We noted widespread use of radical local excision among women with Stage I/II cancer, but 46-54% with invasive disease underwent a radical or total vulvectomy. Factors associated with cancer death were limited to age and stage. Women 75 years and older were at higher risk compared to women aged 20-49 years and the risk of death increased with advancing stage. CONCLUSIONS: Vulvar cancer is diagnosed at early stages. Late-stage disease is associated with a significant increase in mortality. Radical surgery was still commonly performed in 1999. Radiation was more common in women diagnosed at late stage, while the use of chemoradiation remained limited.

National Cancer Institute-United States strategy regarding intraperitoneal chemotherapy for ovarian cancer.

On the basis of three large randomized phase III trials, the National Cancer Institute (NCI) issued a Clinical Announcement in January 2006 recommending that women with optimally debulked stage III ovarian cancer and their physicians consider a combination of intravenous (IV) and intraperitoneal (IP) chemotherapy. The combination of IV and IP chemotherapy is associated with a clinically significant benefit in survival, although it does also confer an increased risk of toxicity compared to IV chemotherapy alone. The NCI Clinical Announcement was issued as part of a broader educational campaign, designed in conjunction with professional societies, cancer centers, Clinical Trials Cooperative Groups, and cancer advocacy organizations. The further development of IP chemotherapy in ovarian cancer requires additional clinical and translational research.

Representation of African-Americans, Hispanics, and whites in National Cancer Institute cancer treatment trials.

BACKGROUND: The National Cancer Institute (NCI)-sponsored clinical trials cooperative groups place more than 25 000 American patients in treatment trials every year. Equal access and proportional representation of all races/ethnicities is desired. PURPOSE: Our objectives were to evaluate the inclusion of African-Americans, Hispanics, and non-Hispanic whites in NCI-sponsored treatment trials and to determine if there is proportional racial/ethnic representation. METHODS: During the period of January 1, 1991, through June 30, 1994, 99 495 cancer patients were enrolled in clinical trials and declared themselves as non-Hispanic black, non-Hispanic white, or Hispanic (of any race). In the analysis, participants in NCI treatment trials were subdivided into three age groups: birth to 19 years, 20-49 years, and 50 or more years. The racial/ethnic composition of each of these age groups was compared with the racial/ethnic makeup of the American population with cancer. Estimates of the number of incident cancer cases per year were made for each racial/ethnic group within each age group using data from the Surveillance, Epidemiology, and End Results (SEER) Program and the 1990 Census. The percentage of all cancer patients who were in each racial/ethnic group were compared with the population that entered clinical trials. Comparisons are also made separately for patients with leukemia and breast, colorectal, lung, and prostate cancers. RESULTS: Among patients 0-19 years old, 20-49 years old, and 50 years old or older there is relatively proportional representation of non-Hispanic blacks, Hispanics, and non-Hispanic whites in trials. It is noted that more than 70% of cancer patients aged 0-19 years are estimated to enter cooperative group clinical trials compared with 4.0% of cancer patients aged 20-49 years and 1.5% of patients aged 50 years or older. CONCLUSIONS: Accrual of American cancer patients to NCI-sponsored treatment trials generally parallels the incident burden of disease among non-Hispanic African-Americans, Hispanics, and non-Hispanic whites. IMPLICATIONS: This study shows that the NCI clinical trials are, as a whole, racially/ethnically representative of the American population and suggests that there is equal access to NCI clinical trials.

Patterns of care for women with ovarian cancer in the United States.

PURPOSE: To characterize treatments for ovarian cancer, to determine if recommended staging and treatment were provided, and to determine factors that influence receipt of recommended staging and treatment. METHODS: A total of 785 women diagnosed with ovarian cancer in 1991 were selected from the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) program. Type and receipt of recommended staging and treatment were examined using data on surgery and physician-verified chemotherapy. RESULTS: Most women with presumptive stage I and II ovarian cancer were treated with surgery alone (58%), while women with stage III or IV disease were treated with surgery plus platinum-based chemotherapy (75% stage III, 56% stage IV). Approximately 10% of women with presumptive stage I and II, 71% with stage III, and 53% with stage IV disease received recommended staging and treatment. The absence of lymphadenectomy and assignment of histologic grade were the primary reasons women with presumptive stage I and II cancer did not receive recommended staging and treatment, whereas for stages III and IV, it was due to older women not receiving surgery plus platinum-based adjuvant chemotherapy. Age, stage, comorbidity, "other" race/ethnicity, and treatment at a facility with an approved residency training program were associated with whether recommended staging and therapy were received. CONCLUSION: Older women with late-stage disease did not receive recommended treatment. The majority of women with early-stage disease did not receive recommended staging and treatment.

Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103.

PURPOSE: To provide an investigational drug, paclitaxel, now commercially available, to women with refractory ovarian cancer and to evaluate response and toxicity in these patients. PATIENTS AND METHODS: Patients with platinum-refractory ovarian cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3, at least three prior chemotherapy regimens, adequate hepatic and renal function, and no significant cardiac history were eligible. Patients were treated with paclitaxel 135 mg/m2 administered by 24-hour continuous intravenous infusion every 3 weeks. RESULTS: Leukopenia was the most frequent toxicity, with 78% of patients experiencing grade 3 or 4 toxicity. Other grade 3 and 4 toxicities were less common: fever (33%), infection (12%), thrombocytopenia (8%), vomiting (7%), cardiac (2%), neurologic (2%), and mucositis (1%). Fifteen treatment-related deaths (1.5%) were reported. The objective response rate was 22% (4% complete response [CR], 18% partial response; 95% confidence interval [CI] for overall response, 19% to 25%). The median time to progression from treatment initiation was 7.1 months in responding patients and 4.5 months for all patients. The median survival duration was 8.8 months. CONCLUSION: Paclitaxel has shown activity in women with platinum-refractory ovarian cancer, and it can be administered with an acceptable safety profile. Further research is needed to determine the optimal role of paclitaxel in the primary and salvage treatment of ovarian cancer.

Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 E7.

Human papillomavirus (HPV) infection has been causally associated with cervical cancer. We tested the effectiveness of an HLA-A*0201-restricted, HPV-16 E7 lipopeptide vaccine in eliciting cellular immune responses in vivo in women with refractory cervical cancer. In a nonrandomized Phase I clinical trial, 12 women expressing the HLA-A2 allele with refractory cervical or vaginal cancer were vaccinated with four E786-93 lipopeptide inoculations at 3-week intervals. HLA-A2 subtyping was also performed, and HPV typing was assessed on tumor specimens. Induction of epitope-specific CD8+ T-lymphocyte (CTL) responses was analyzed using peripheral blood leukapheresis specimens obtained before and after vaccination. CTL specificity was measured by IFN-gamma release assay using HLA-A*0201 matched target cells. Clinical responses were assessed by physical examination and radiographic images. All HLA-A*0201 patients were able to mount a cellular immune response to a control peptide. E786-93-specific CTLs were elicited in 4 of 10 evaluable HLA-A*0201 subjects before vaccination, 5 of 7 evaluable HLA-A*0201 patients after two vaccinations, and 2 of 3 evaluable HLA-A*0201 cultures after all four inoculations. Two of three evaluable patients' CTLs converted from unreactive to reactive after administration of all four inoculations. There were no clinical responses or treatment toxicities. The ability to generate specific cellular immune responses is retained in patients with advanced cervical cancer. Vaccination with a lipidated HPV peptide epitope appears capable of safely augmenting CTL reactivity. Although enhancements of cellular immune responses are needed to achieve therapeutic utility in advanced cervical cancer, this approach might prove useful in treating preinvasive disease.

Innovative therapies for advanced ovarian cancer.

The emergence of drug-resistant tumors during therapy for ovarian cancer remains an obstacle to improving long-term outcomes. Active areas of ovarian cancer research include clinical evaluation of non-cross-resistant antineoplastic agents that demonstrated single-agent activity in ovarian cancer during the 1990s: oxaliplatin, the new anthracyclines (epirubicin, liposomal doxorubicin), topotecan, oral etoposide, gemcitabine, and vinorelbine. Most of these new agents are currently being evaluated as a component of doublet and triplet combination regimens for advanced ovarian cancer, with use of sequential alternating doublet regimens gaining interest. The potential role of intraperitoneal therapy continues to be investigated. In addition, there are a variety of innovative treatment strategies on the horizon that are targeted at underlying disease processes, including anticancer vaccines, gene therapy, and antiangiogenic therapy. Based on this multitude of investigational questions and the low cure rates currently achieved, all women with advanced ovarian cancer should be offered participation in clinical trials.

Management of stage II endometrial adenocarcinoma.

Charts of 36 patients with clinical stage II endometrial adenocarcinoma over ten years were reviewed. All were staged before any treatment, in accordance with International Federation of Gynecology and Obstetrics (FIGO) guidelines. Although details of treatment varied, two main protocols were used. Fourteen patients were treated with the "standard" protocol involving external whole-pelvis radiation, followed by intracavitary cesium and then hysterectomy. In 1981, a "modified" protocol was introduced, which called for a hysterectomy immediately following intrauterine and vaginal cesium. External radiation therapy was given only to those patients found to have deep myometrial invasion or cervical involvement. Of 14 patients treated by this protocol, seven had no surgical indication for postoperative external radiation. There was no increase in recurrence in these patients, and the five-year survival rate was 76% for patients treated with the modified protocol compared with 65% for those who had standard therapy. Morbidity related to external radiation therapy occurred in two patients with the standard protocol and one patient who received pelvic radiation on the modified protocol.

Diagnosing the correct ovarian cancer syndrome.

We report four sisters whose maternal pedigree suggested a site-specific ovarian cancer syndrome, whereas their paternal pedigree closely fit the Cancer Family Syndrome (Lynch II). Eliciting a complete family history, both maternal and paternal, is important for defining the correct ovarian cancer syndrome. Once the definition is made, the patient and other family members at risk must be counseled and encouraged to begin the appropriate schedule of screening and intervention. These recommendations may be summarized as follows: 1) site-specific ovarian carcinoma: screening with physical examination, CA 125, and ultrasound, and bilateral oophorectomy after childbearing has been completed; 2) breast/ovary syndrome: screening for ovarian cancer as above, mammography and bilateral oophorectomy as above, and possible prophylactic mastectomy; and 3) Lynch Cancer Family Syndrome: screening for ovarian cancer as above, colonoscopy and endometrial biopsy, and prophylactic hysterectomy and bilateral oophorectomy once childbearing is complete.

Peritoneal sarcoidosis and elevated CA 125.

Although CA 125 is generally considered a serum marker of malignant tumors, it may be elevated in conditions characterized by peritoneal inflammation. We report a patient with known pulmonary sarcoidosis who presented with an adnexal mass and an elevated CA 125. At laparotomy, she was found to have miliary peritoneal disease simulating the appearance of metastatic cancer. Microscopic examination revealed a benign ovarian cyst and diffuse granulomatous disease similar to that present in the lung.

A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small-volume residual ovarian cancer.

PURPOSE: Because intraperitoneal (i.p.) therapy may provide a therapeutic advantage and because hyperthermia enhances carboplatin (CBDCA) cytotoxicity, we evaluated the feasibility, toxicity, and pharmacokinetics of CBDCA given via continuous hyperthermic peritoneal perfusion (CHPP) in patients with small-volume residual ovarian cancer. PATIENTS AND METHODS: Six patients underwent optimal cytoreductive procedures (residual disease < or =5 mm) as initial treatment of stages II and III epithelial ovarian adenocarcinoma. All patients received a 90-min CHPP at a CBDCA dose of 800-1200 mg/m2, with the perfusate being recirculated rapidly from a reservoir through a heat exchanger, resulting in i.p. temperatures of 41-43 degrees C. Plasma, perfusate, and urine samples were collected and platinum was quantified by flameless atomic absorption spectrophotometry. RESULTS: At no time did any patient's core temperature exceed 40 degrees C. Peak perfusate platinum concentrations were 8- to 15-fold higher than peak ultrafilterable plasma concentrations. The permeability-area product was extremely high and variable (14-90 ml/min), resulting in a regional advantage of 1.9-5.3. The percentage of the dose absorbed ranged widely from 27% to 77%. Dose-limiting hematologic toxicity was observed at a dose of 1200 mg/m2 and this was associated with a CBDCA AUC in plasma of 11 mg min ml(-1). CONCLUSION: CHPP with CBDCA was safely given to three patients at a dose of 800 mg/m2, and dose-limiting hematologic toxicities observed at 1200 mg/m2, correlated with the plasma CBDCA exposure established when lower doses of CBDCA are given systemically. The pharmacokinetic data are consistent with the expected effect of vigorous mixing on the exposed peritoneal surface area. Variable drug absorption and clearance make the prediction of systemic exposure highly uncertain. These findings may have important implications for novel therapies given i.p.

Melanomas of the vulva and vagina.

Melanomas of the vulva and vagina comprise < 2% of melanomas in women. Although their biologic behavior appears to be similar to that of cutaneous melanoma, vulvar and vaginal melanomas appear to have a different etiology. Women presenting with pigmented vulvar lesions should undergo expedited examination and full-thickness biopsy. Vulvar and vaginal melanomas should be staged surgically using the AJCC system, which incorporates Breslow and Clark microstaging. Adverse prognostic factors include advanced age at diagnosis, central location of tumor, capillary lymphatic space involvement, ulceration, high mitotic rate, and aneuploidy. Primary surgery should include radical local excision with 1-cm skin margins for melanomas < 1 mm thick and 2-cm margins for melanomas 1 to 4 mm thick. Deep margins should be at least 1 to 2 cm. Femoral inguinal lymphadenectomy should be performed in patients at increased risk of lymph node metastases on the basis of primary tumor characteristics. Adjuvant interferon-alfa appears to confer survival benefits in patients with regional nodal disease. Effective salvage therapy has not yet been identified.

Treatment of platinum-resistant ovarian cancer.

In the United States, almost 70% of the 23,000 women diagnosed annually with epithelial ovarian cancer present with advanced disease (FIGO stages III-IV). Primary therapy for these patients includes surgical cytoreduction and 6-8 courses of platinum- and taxane-based chemotherapy. Although 90% of patients will respond to this multi-modality combination regimen, most patients will experience recurrences. The 5 year survival for women with stage III disease is 15-30% and 0-20% for those with stage IV disease. Medical and gynecological oncologists, therefore, must be prepared to treat many women with recurrent ovarian cancer.

Saving the lymph nodes.

We need improved imaging and staging techniques to identify metastatic disease in the lymph nodes. Once we are able to do this accurately, then we can save the lymph nodes. Until that time, however, gynecologic oncologists should give careful thought as to which nodes they choose to remove and how lymph node removal may affect short-term and long-term morbidity.