State of the science in cervical cancer: where we are today and where we need to go.

Invasive cervical cancer remains an important global cause of death, despite the declining prevalence within the United States. Definitive therapies, including surgical resection of early-stage disease and chemoradiation for locally advanced disease, can be curative. For women who experience local or distant recurrences, the prognosis remains poor and better treatments are required. On July 18, 2013, The Gynecologic Oncology Group sponsored a State of the Science in Cervical Cancer Symposium with experts, researchers, clinicians, and interested stakeholders. This article summarize the progress that has been made, questions that require further investigation, and contemporary genomic findings and innovative treatments that may help inform the next generation of clinical trials for patients with cervical cancer.

Locally advanced adenocarcinoma and adenosquamous carcinomas of the cervix compared to squamous cell carcinomas of the cervix in gynecologic oncology group trials of cisplatin-based chemoradiation.

OBJECTIVE: Conflicting results have been reported for adeno- and adenosquamous carcinomas of the cervix with respect to their response to therapy and prognosis. The current study sought to evaluate impact of adeno- and adenosquamous histology in the randomized trials of primary cisplatin-based chemoradiation for locally advanced cervical cancer. METHODS: Patients with adeno- and adenosquamous cervical carcinomas were retrospectively studied and compared to squamous cell carcinomas in GOG trials of chemoradiation. RESULTS: Among 1671 enrolled in clinical trials of chemoradiation, 182 adeno- and adenosquamous carcinomas were identified (10.9%). A higher percentage of adeno- and adenosquamous carcinomas were stage IB2 (27.5% versus 20.0%) and fewer had stage IIIB (21.4% versus 28.6%). The mean tumor size was larger for squamous than adeno- and adenosquamous. Adeno- and adenosquamous carcinomas were more often poorly differentiated (46.2% versus 26.8%). When treated with radiation therapy alone, the 70 patients with adeno- and adenosquamous carcinoma of the cervix showed a statistically poorer overall survival (p=0.0499) compared to the 647 patients with squamous cell carcinoma of the cervix. However, when treated with radiation therapy with concurrent cisplatin-based chemotherapy, the 112 patients with adeno- and adenosquamous carcinomas had a similar overall survival (p=0.459) compared the 842 patients with squamous cell carcinoma. Adverse effects to treatment were similar across histologies. CONCLUSION: Adeno- and adenosquamous carcinomas of the cervix are associated with worse overall survival when treated with radiation alone but with similar progression-free and overall survival compared to squamous cell carcinomas of the cervix when treated with cisplatin based chemoradiation.

The development of priority cervical cancer trials: a Gynecologic Cancer InterGroup report.

Since the late 1990s, when a spate of US studies reported the benefit of chemoradiation for cervical cancer, there has been a dearth of clinical trials in cervical cancer. This requires to be addressed with urgency because this disease is responsible for a quarter of a million deaths globally each year, mostly in developing countries, but therapeutic advances are required in all health care settings. The Gynecologic Cancer InterGroup (GCIG) is a worldwide collaborative of leading national groups that develops and promotes multinational trials in gynecologic cancer. In recognition of the pressing need for action, the GCIG convened an international meeting with expert representations from most of the GCIG groups and selected large centers in low- and middle-income countries. The focus was to identify consensus on several concepts for clinical trials, which would be developed and promoted by the GCIG and launched with major international participation. The first half of the meeting was devoted to a resume of the current state of the knowledge and identifying the gaps most needing new evidence. The second half of the meeting was concerned with achieving consensus on the way forward. There were 2 principal outcomes. The first was a proposal to establish, under the umbrella of GCIG, a cervical cancer trials network of centers from countries currently outside GCIG (Eastern Europe, India, Thailand, Southern Africa, and South and Central America), which could increase international participation in trials, conducted within the principles of good clinical practice. The second was to identify the priorities for clinical trials. These included additional systemic therapy before or after chemoradiation; less radical surgery for small, early-stage tumors; the use of fewer fractions to improve cost-effectiveness of treatment in centers with limited resources; and chemotherapy to improve resectability of bulky tumors.

Current academic clinical trials in ovarian cancer: Gynecologic Cancer Intergroup and US National Cancer Institute Clinical Trials Planning Meeting, May 2009.

OBJECTIVE: To review the current status of large phase academic clinical trials for women with ovarian cancer, address cross-cutting issues, and identify promising areas for future collaboration. METHODS: In May 2009, the Gynecologic Cancer Intergroup, which represents 19 Cooperative Groups conducting trials for women with gynecologic cancer, and the US National Cancer Institute convened a Clinical Trials Planning Meeting. RESULTS: The topics covered included the impact of new developments in cancer biology upon molecular targets and novel agents, pharmacogenomics, advances in imaging, the potential benefit of diet and exercise to reduce the risk of recurrence, academic partnership with industry, statistical considerations for phases 2 and 3 trials, trial end points, and symptom benefit and health-related quality-of-life issues. The clinical trials discussed spanned the spectrum of ovarian cancer from initial diagnosis, staging, and cytoreductive surgery to consolidation chemotherapy, and treatment of recurrent disease. CONCLUSIONS: Ongoing and effective collaboration with industry, government, and patients aims to ensure that the most important scientific questions can be answered rapidly. We encourage women with ovarian cancer and their oncologists to consider participation in the academic clinical trials conducted by the member groups of the Gynecologic Cancer Intergroup.

Surgical outcomes in women with ovarian cancer.

OBJECTIVE: We sought to assess whether the specialty of the surgeon or the hospital involved in the initial management of women with ovarian cancer determined the likelihood of unnecessary repeated abdominal surgery and long-term patient survival. METHODS: We conducted a population-based study involving women in Ontario, Canada, who had epithelial ovarian cancer treated initially with abdominal surgery between January 1996 and December 1998. We documented incident surgical cases using hospital contact data and the Ontario Cancer Registry. We obtained data on patient characteristics, clinical findings, surgical techniques and perioperative care from electronic administrative data records and patient charts. We performed regression analyses to assess the influence of surgeon and hospital specialization and of case volumes on the likelihood of repeat surgery and survival. We controlled for stage of disease and other factors associated with these outcomes. We also examined the relation between the adequacy of surgery and adjuvant chemotherapy with survival. RESULTS: A total of 1341 women met our inclusion criteria. Our analysis showed that repeat surgery was associated with the surgeon's discipline, younger patient age, well-differentiated tumours and early stage of disease. However, survival was not associated with the surgeon's discipline; rather, it was associated with advanced patient age, increasing comorbidities, advanced stage of disease, poorly differentiated tumours, urgent surgery and adjuvant chemotherapy. We observed a trend between inadequate surgery and a decreased likelihood of survival. CONCLUSION: Further study is needed to understand patterns of repeat surgery for ovarian cancer. Improved quality of operative reporting is required to classify surgical adequacy.

Nomograms Predicting Progression-Free Survival, Overall Survival, and Pelvic Recurrence in Locally Advanced Cervical Cancer Developed From an Analysis of Identifiable Prognostic Factors in Patients From NRG Oncology/Gynecologic Oncology Group Randomized Trials of Chemoradiotherapy.

PURPOSE: To evaluate the prognostic factors in locally advanced cervical cancer limited to the pelvis and develop nomograms for 2-year progression-free survival (PFS), 5-year overall survival (OS), and pelvic recurrence. PATIENTS AND METHODS: We retrospectively reviewed 2,042 patients with locally advanced cervical carcinoma enrolled onto Gynecologic Oncology Group clinical trials of concurrent cisplatin-based chemotherapy and radiotherapy. Nomograms for 2-year PFS, five-year OS, and pelvic recurrence were created as visualizations of Cox proportional hazards regression models. The models were validated by bootstrap-corrected, relatively unbiased estimates of discrimination and calibration. RESULTS: Multivariable analysis identified prognostic factors including histology, race/ethnicity, performance status, tumor size, International Federation of Gynecology and Obstetrics stage, tumor grade, pelvic node status, and treatment with concurrent cisplatin-based chemotherapy. PFS, OS, and pelvic recurrence nomograms had bootstrap-corrected concordance indices of 0.62, 0.64, and 0.73, respectively, and were well calibrated. CONCLUSION: Prognostic factors were used to develop nomograms for 2-year PFS, 5-year OS, and pelvic recurrence for locally advanced cervical cancer clinically limited to the pelvis treated with concurrent cisplatin-based chemotherapy and radiotherapy. These nomograms can be used to better estimate individual and collective outcomes.

Anemia correction in malignancy management: threat or opportunity?

OBJECTIVES: The presence of anemia and/or hypoxia in cancer patients have both been correlated with worse outcomes. While some retrospective data suggest an improvement in outcomes in cervical cancer patients whose anemia has been corrected, the critical level to which hemoglobin should be raised and the issue of whether raising hemoglobin translates into a survival advantage remain controversial. This debate has more recently expanded to concerns over how we raise hemoglobin, with 2 recent randomized trials suggesting impaired survival outcomes in the groups who received poietic proteins to correct hemoglobin levels to normal and above values. METHODS: A comprehensive literature search was performed utilizing combinations of the key search words anemia, hypoxia, radiotherapy, HIF-1alpha, angiogenesis, and erythropoietin. RESULTS: The preponderance of evidence suggest a correlation between both anemia and worse outcome as well as hypoxia and worse outcome; however the relationship between anemia and hypoxia remains complex. A critical review of molecular changes associated with hypoxia that drive the molecular process, anemia correction and the data on the use of poietic proteins, and a review of future directions of research which focus on the opportunity of therapies correcting hypoxia or hypoxia-relevant targets is also presented. CONCLUSIONS: Anemia and hypoxia remain biologically plausible targets for improving therapy. The potential benefit of raising hemoglobin will depend on whether anemia can influence treatment resistance and whether anemia plays a reversible role in driving the molecular milieu contributing to malignant clonogen survival and dissemination.

The use of adjuvant radiation therapy in patients with intermediate-risk Stages IC and II uterine corpus cancer: a patient care evaluation study from the American College of Surgeons National Cancer Data Base.

OBJECTIVE: To determine the outcomes of patients with intermediate-risk Stages IC and II uterine corpus cancer treated with surgery alone or surgery followed by radiation therapy. METHODS: Patients with uterine corpus cancer diagnosed in 1995 were identified from hospitals in the United States with tumor registry databases. Data were collected on histology, surgical treatment, radiation therapy, recurrence, and survival. Survival analysis was performed using life-table computational method. RESULTS: 713 hospitals submitted data on 10,726 patients with uterine corpus cancer. 9977 patients (93.0%) underwent surgery, and 2624 patients (26.3%) received radiation therapy. Patients with clinical Stages IC and IIA disease who underwent surgery followed by radiation therapy compared to surgery alone had a trend toward improved 5-year relative survival (RS) (81.2% vs. 92.5%; 74.3% vs. 96.0%, respectively). The 5-year RS of patients with surgical Stage IC disease was not statistically different between the surgery alone group and the radiation group (93.9% vs. 91.7%). Patients with surgical Stage IIA and IIB disease did not benefit from radiation therapy compared to surgery alone (5-year RS; 83.7% vs. 98.0% and 82.3% vs. 81.8%, respectively). CONCLUSION: There is a trend toward improved survival in patients with clinical Stages IC and IIA uterine corpus cancer when radiation therapy is utilized following surgery. The survival of patients with surgical Stages IC and II uterine corpus cancer is not improved with adjuvant radiation therapy.

Raising hemoglobin: an opportunity for increasing survival?

Although the association between low hemoglobin levels and poorer outcomes in radiation oncology has long been recognized, anemia is often overlooked and untreated. However, a growing body of clinical evidence now indicates that low hemoglobin levels during radiation treatment are associated with decreased response and survival following radiotherapy. For example, a large Canadian retrospective study in patients receiving radical radiotherapy for cervical cancer showed that the 5-year survival rate was 19% higher in those whose hemoglobin during radiation treatment was =12 g/dl compared to those with levels <12 g/dl. The data suggest that clinical trials need to be performed to determine whether increasing hemoglobin levels leads to improved local control and survival. The mechanism by which low hemoglobin levels could cause poorer outcomes is not well understood and needs further elucidation. It is postulated that lower hemoglobin levels resulting in decreased oxygen carrying capacity may lead to increased tumor hypoxia, radiation resistance and increased tumor angiogenesis. The interrelationship of low hemoglobin levels, hypoxia, tumor angiogenesis and survival is explored in this article.

Is there a role for pelvic lymph node debulking in advanced cervical cancer?

OBJECTIVE: The purpose of this study is to determine if a survival advantage exists from surgical debulking of enlarged pelvic lymph nodes in advanced cervical cancer. METHODS: Using information from studies published on the topic of debulking lymph nodes in locally advanced cervical cancer along with baseline control rates of standard treatment and patterns of failure, an estimate of how many patients with bulky pelvic lymph node disease would benefit from this procedure was calculated. The design and feasibility of a randomized trial to test this intervention is also discussed. RESULTS: Based on our calculations 1, 2, and 4% of stage IB, IIB, and IIIB patients, respectively, would benefit from a debulking procedure. Based on our calculations with such small differences in survival along with other inclusion and exclusion criteria, a randomized trial, which would compare chemoradiation to chemoradiation and surgery, would require anywhere from 10,000-30,000 patients per arm. CONCLUSIONS: A very small fraction of patients would benefit from a surgical debulking procedure of pelvic nodes. A randomized controlled trial to test this research question is not feasible. A subset population is identified which may benefit from a debulking approach.