Philippe Tummers

Advanced Ovarian Cancer: Primary or Interval Debulking? Five Categories of Patients in View of the Results of Randomized Trials and Tumor Biology: Primary Debulking Surgery and Interval Debulking Surgery for Advanced Ovarian Cancer

BACKGROUND Standard treatment of stage III and IV advanced ovarian cancer (AOC) consists of primary debulking surgery (PDS) followed by chemotherapy. Since the publication of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial, clinical practice has changed and many AOC patients are now treated with neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). The best option remains unclear. Ovarian cancer is a heterogenic disease. Should we use the diversity in biology of the tumor and patterns of tumor localization to better stratify patients between both approaches? METHODS This analysis was based on results of five phase III randomized controlled trials on PDS and IDS in AOC patients, three Cochrane reviews, and four meta-analyses. RESULTS There is still no evidence that NACT-IDS is superior to PDS. Clinical status, tumor biology, and chemosensitivity should be taken into account to individualize surgical approach. Nonserous (type 1) tumors with favorable prognosis are less chemosensitive, and omitting optimal PDS will lead to less favorable outcome. For patients with advanced serous ovarian cancer (type 2) associated with severe comorbidity or low performance status, NACT-IDS is the preferred option. CONCLUSION We propose stratifying AOC patients into five categories according to patterns of tumor spread (reflecting the biologic behavior), response to chemotherapy, and prognosis to make a more rational decision between PDS and NACT-IDS. IMPLICATIONS FOR PRACTICE Trial results regarding effect and timing of debulking surgery on survival of patients with advanced ovarian cancer have been inconsistent and hence difficult to interpret. This review examines all randomized trials on primary and interval debulking surgery in advanced ovarian cancer, including the results of the newly published CHORUS (chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer) trial. On the basis of findings presented in this review and in view of recent molecular data on the heterogeneity of ovarian tumors, we propose prognostic categorization for patients with advanced ovarian cancer to better distinguish those who would optimally benefit from primary debulking from those who would better benefit from interval debulking following neoadjuvant chemotherapy.

Postoperative Intensity-Modulated Arc Therapy for Cervical and Endometrial Cancer: A Prospective Report on Toxicity

PURPOSE To report on toxicity after postoperative intensity-modulated arc therapy (IMAT) for cervical (CC) and endometrial cancer (EC). METHODS AND MATERIALS Twenty-four CC and 41 EC patients were treated with postoperative IMAT. If indicated, para-aortic lymph node irradiation (preventive or when affected, PALN) and/or concomitant cisplatin (40 mg/m(2), weekly) was administered. The prescribed dose for IMAT was 45 Gy (CC, 25 fractions) and 46 Gy (EC, 23 fractions), followed by a brachytherapeutic boost if possible. Radiation-related toxicity was assessed prospectively. The effect of concomitant cisplatin and PALN irradiation was evaluated. RESULTS Regarding acute toxicity (n = 65), Grade 3 and 2 acute gastrointestinal toxicity was observed in zero and 63% of patients (79% CC, 54% EC), respectively. Grade 3 and 2 acute genitourinary toxicity was observed in 1% and 18% of patients, respectively. Grade 2 (21%) and 3 (12%) hematologic toxicity (n = 41) occurred only in CC patients. Seventeen percent of CC patients and 2% of EC patients experienced Grade 2 fatigue and skin toxicity, respectively. Adding cisplatin led to an increase in Grade >2 nausea (57% vs. 9%; p = 0.01), Grade 2 nocturia (24% vs. 4%; p = 0.03), Grade ≥ 2 hematologic toxicity (38% vs. nil, p = 0.003), Grade ≥ 2 leukopenia (33% vs. nil, p = 0.009), and a strong trend toward more fatigue (14% vs. 2%; p = 0.05). Para-aortic lymph node irradiation led to an increase of Grade 2 nocturia (31% vs. 4%, p = 0.008) and a strong trend toward more Grade >2 nausea (44% vs. 18%; p = 0.052). Regarding late toxicity (n = 45), no Grade 3 or 4 late toxicity occurred. Grade 2 gastrointestinal toxicity, genitourinary toxicity, and fatigue occurred in 4%, 9%, and 1% of patients. Neither concomitant cisplatin nor PALN irradiation increased late toxicity rates. CONCLUSIONS Postoperative IMAT for EC or CC is associated with low acute and late toxicity. Concomitant chemotherapy and PALN irradiation influences acute but not late toxicity.

Interobserver variability of the International Federation of Gynecology and Obstetrics staging in cervical cancer

Objective The objective of this study was to assess the interobserver variability of pelvic examination under anesthesia (EUA) in cervical cancer. Methods Subsequent patients undergoing a staging procedure under anesthesia for primary cervical cancer were enrolled in the study. All clinicians assessed “blinded” tumor size, and the involvement of vagina, parametria, sacrouterine ligaments, pelvic sidewalls, bladder, and/or rectum. Items were scored varying from 1 (“certainly no involvement”), 2 (“not sure about involvement”), to 3 (”involvement”). Each individual decided on the International Federation of Gynecology and Obstetrics (FIGO) stage; also, the urge for imaging and treatment proposal were accounted for. Final FIGO staging was obtained by consensus of the team. Investigators were classified as experienced after more than 50 EUAs. All others were classified less experienced. The free-marginal κ values between experienced and less experienced investigators were calculated for all previously mentioned items. Results Between February 2009 and December 2010, a total of 86 patients were enrolled. Among experienced investigators, a moderate interobserver agreement was found with regard to FIGO stage (free-marginal κ value of 0.49) and an excellent interobserver agreement on their proposed therapy (free-marginal κ value of 0.84). A lower level of agreement was found when comparing experienced with less experienced investigators: only a slight level of agreement on FIGO stage and a substantial agreement on their therapy proposal (free-marginal κ values of 0.03 and 0.66). Conclusions We describe only a moderate interobserver agreement on clinical staging of patients with cervical cancer. The interobserver agreement increases in the group of experienced doctors, indicating that EUA can be learned.

Completion surgery after intensity-modulated arc therapy in the treatment of locally advanced cervical cancer: feasibility, surgical outcome, and oncologic results.

Introduction Since the addition of chemotherapy to radiotherapy, the survival rates of locally advanced cervical cancer (LACC) have improved but are still disappointing. Therefore, the idea of surgery after chemoradiation in case of LACC or bulky disease was adopted. One of the concerns regarding surgery following chemoradiotherapy is surgery-related morbidity. Aim The objectives of this study were to investigate the feasibility of surgery after advanced radiotherapy techniques such as intensity-modulated arc therapy (IMAT) and to describe the morbidity. Methods This was a prospective study of primary inoperable LACC patients primary treated with IMAT, in most cases combined with weekly cisplatin. Then the resectability was reevaluated. If resectable patients were treated with Wertheim type 2 surgery ± pelvic lymphadenectomy (on positron emission tomography–computed tomography indication). If tumor is not resectable, patients were treated with brachytherapy. Results Since 2006, 41 consecutive patients were included. After neoadjuvant IMAT, 34 were considered resectable and underwent surgery, whereas 7 proceeded with brachytherapy. The operative mortality rate was nil. There were no major perioperative complications. No ureter, bladder, or bowel injuries occurred. No postoperative urinary/digestive fistulae or stenoses were noted. Eleven patients had postoperatively urinary retention problems. At the time of discharge, 5 patients still needed self-catheterization. All problems resolved within 3 months. In 4 cases, we saw significant lymphoceles. In all patients intended to treat, overall survival and disease-free survival at 3 years were 63% and 74%. In the Wertheim group, overall survival and disease-free survival at 3 years were 81% and 91%. Conclusions Completing surgery after chemoradiation therapy (with IMAT) for LACC or bulky disease is feasible, and complication rates are comparable with those of primary surgery for cervical cancer.

Value of magnetic resonance and 18FDG PET-CT in predicting tumor response and resectability of primary locally advanced cervical cancer after treatment with intensity-modulated arc therapy : a prospective pathology-matched study

Objective To report on the value of magnetic resonance imaging (MRI) and 2-deoxy-2-[18] fluoro-D-glucose positron emission tomography computed tomography (18FDG PET-CT) in predicting resectability and pathological response of primary locally advanced cervical cancer after neoadjuvant intensity-modulated arc therapy (IMAT) with or without cisplatin (C). Methods and Materials Twenty-seven patients with International Federation of Gynecology and Obstetrics stages IB2 to IVA cervical cancer were treated with IMAT-C followed by extrafascial hysterectomy (EH). All patients received MRI and 18FDG PET-CT after IMAT-C. The end points of this study were to: Assess the ability of MRI to predict negative surgical margins (R0). Assess the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of MRI in predicting the following situation at the EH specimen: “no residual disease or minimal microscopically visible residual tumor.” Assess the sensitivity, specificity, PPV, and NPV value of 18FDG PET-CT in predicting “no residual viable tumor cells” at the EH specimen. Results An R0 resection was obtained in all patients. None of the EH specimens contained macroscopically visible tumor. In 13 patients, no viable tumor cells were found and only 14 had residual microscopic disease. Twenty-four of 27 MRIs were able to correctly predict R0 resection. A negative MRI was 100% predictive for the end point “R0 resection.” The specificity and NPV of MRI (end point 2) were 74% and 100%, respectively. No sensitivity or PPV could be calculated. The sensitivity, specificity, PPV, and NPV of 18FDG PET-CT were 29%, 62%, 44%, and 44%, respectively (end point 3). Conclusions A negative MRI after IMAT-C predicts 100% correctly for R0 resection. The role of 18FDG PET-CT in predicting viable tumor cells at EH specimen is at least debatable.

Primary intestinal type adenocarcinoma of the female genital tract, arisen from a tubulo-villous adenoma: Case report

Highlights ► An extremely rare neoplasm, especially in the absence of DES ► Its important to distinguish it from an adenocarcinoma from another location ► Little is known about the aetiology, several explanations have been postulated.

Mesonephric adenocarcinoma of the cervix: Case report and literature review

A mesonephric adenocarcinoma of the cervix is a very rare tumor deriving from remnants of the mesonephric duct. Differential diagnosis from other cervical carcinomas is difficult and little is known regarding its biological behavior, prognosis, and the optimal management strategy. We present a case of a mesonephric adenocarcinoma of the cervix with a comprehensive review of the existing literature. In this case a 66-year-old woman presented with postmenopausal vaginal bleeding. She was diagnosed with a FIGO stage IIB mesonephric adenocarcinoma of the cervix and treated with neoadjuvant chemoradiotherapy and a Wertheim hysterectomy. The recovery from surgery was uneventful and the patient remains with no evidence of disease with 2 years of follow-up.

Incorporating PARP-inhibitors into clinical routine: A tailored treatment strategy to tackle ovarian cancer

DNA repair mechanisms play a key role in oncogenesis and cancer progression in women with BRCA mutation-positive (BRCAm) ovarian cancer (OC). The BRCA1/2 and poly(ADP-ribose) polymerase (PARP) proteins are considered the foremost mediators among the various components of double-strand and single-strand repair, respectively. A series of new therapeutic drugs that target PARP have been developed for BRCAm OC. This class of agents provokes tumour-specific cytotoxicity with minimal side effects by inducing synthetic lethality, of which they are the first clinical example. The European Medicines Agency granted accelerated licensing approval for the first-in-class-drug that inhibits PARP, olaparib (Lynparza™, AstraZeneca). Olaparib can be used as a monotherapeutic maintenance treatment in patients with platinum-sensitive relapsed (germline and/or somatic) BRCAm high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer responsive to platinum-based chemotherapy. Seen in light of these recent events, this review article will focus on (a) how PARP-inhibitors exploit cancer-specific defects in the homologous recombination repair apparatus and (b) how BRCA testing is implemented in routine clinical care.