Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial.

BACKGROUND: Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial. METHODS: ICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC-IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified according to GCIG group, disease stage, and timing and outcome of cytoreductive surgery. Patients and clinicians were not masked to group allocation. The scheduling of surgery and use of neoadjuvant chemotherapy were determined by local multidisciplinary case review. In this post-hoc exploratory analysis of ICON8, progression-free survival was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This definition is different from the intention-to-treat primary progression-free survival analysis of ICON8, which defined progression-free survival as the time from randomisation to the date of first clinical or radiological progression or death, whichever occurred first. We also compared the extent of surgical cytoreduction with RECIST and GCIG CA125 responses. This post-hoc exploratory analysis includes only women recruited to ICON8 who were planned for neoadjuvant chemotherapy followed by DPS and had RECIST and/or GCIG CA125-evaluable disease. ICON8 is closed for enrolment and follow-up, and registered with ClinicalTrials.gov, NCT01654146. FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 women were enrolled in ICON8, of whom 779 (50%) were planned for neoadjuvant chemotherapy followed by DPS. Median follow-up was 29·5 months (IQR 15·6-54·3) for the neoadjuvant chemotherapy followed by DPS population. Of 564 women who had RECIST-evaluable disease at trial entry, 348 (62%) had a complete or partial response. Of 727 women who were evaluable by GCIG CA125 criteria at the time of diagnosis, 610 (84%) had a CA125 response. Median progression-free survival was 14·4 months (95% CI 9·2-28·0; 297 events) for patients with a RECIST complete or partial response and 13·3 months (8·1-20·1; 171 events) for those with RECIST stable disease. Median progression-free survival for women with a GCIG CA125 response was 13·8 months (95% CI 8·8-23·4; 544 events) and 9·7 months (5·8-14·5; 111 events) for those without a GCIG CA125 response. Complete cytoreduction (R0) was achieved in 187 (56%) of 335 women with a RECIST complete or partial response and 73 (42%) of 172 women with RECIST stable disease. Complete cytoreduction was achieved in 290 (50%) of 576 women with a GCIG CA125 response and 30 (30%) of 101 women without a GCIG CA125 response. INTERPRETATION: The RECIST-defined radiological response rate was lower than that frequently quoted to patients in the clinic. RECIST and GCIG CA125 responses to neoadjuvant chemotherapy for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients who are likely to benefit from DPS, but instead used in conjunction with the patient's clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST or GCIG CA125 response. FUNDING: Cancer Research UK, UK Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.

Tumour-infiltrating lymphocyte scores effectively stratify outcomes over and above p16 post chemo-radiotherapy in anal cancer.

BACKGROUND: The majority (90%) of anal cancers are human papillomavirus (HPV)-driven, identified using immunochemistry for p16. Compared with HPV- patients, those with HPV+ disease generally show improved survival, although relapse rates around 25% indicate a need for further stratification of this group. METHODS: Using two cohorts of anal cancer, previously characterised for p16, we assessed the prognostic value of tumour-infiltrating lymphocytes (TILs). RESULTS: Tumour-infiltrating lymphocyte scores were used to stratify p16+ cases, where tumours with absent/low levels of TIL had a relapse-free rate of 63%, as opposed to 92% with high levels of TIL (log rank P=0.006). CONCLUSIONS: Assessment of TIL adds to p16 status in the prognosis of anal cancer following chemo-radiotherapy and provides evidence of the clinical importance of the immune response.

High-sensitivity human papilloma virus genotyping reveals near universal positivity in anal squamous cell carcinoma: different implications for vaccine prevention and prognosis.

BACKGROUND: Characterisation of human papilloma virus (HPV) infection in anal squamous cell carcinoma (ASCC) may have dual importance: first, aetiological; second, prognostic, informing outcome after chemo-radiotherapy (CRT). We undertook HPV genotyping, and allelic characterisations, to evaluate the aetiological role of HPV while simultaneously evaluating the impact of HPV genotyping on relapse-free (RFS) and overall survival (OS). METHOD: Dual-primer HPV genotyping (subtypes 6, 11, 16, 18, 31, 33, 45, 52, 58) and DNA sequencing of HPV 16 positive tumours were analysed in 151 consecutively referred ASCCs, previously characterised by immunohistochemistry for p16 expression. In 110 patients treated with CRT, factors influencing RFS and OS were evaluated using univariate and multivariate models. RESULTS: HPV positivity was observed in 95%. HPV 16 accounted for 89%; of these, 64% harboured the T350G E6 variant. HPV 16 positivity was significantly correlated with improved 5-year RFS (62% versus 40%; p = 0.027) and OS (59% versus 38%; p = 0.019). p16 expression was also significantly correlated with improved 5-year RFS (positive versus negative: 65% versus 16%; p < 0.0001) and OS (63% versus 13%; p < 0.0001). In multivariable models that included HPV 16 status, p16 status, sex, and age, p16 expression remained an independent prognostic factor for RFS (p < 0.0001) and OS (p = 0.002). CONCLUSION: In ASCC, near-universal HPV detection rates were demonstrated, higher than generally reported in the literature, and supporting the development of multivalent HPV vaccinations for prevention. By contrast, p16 negatively, but not HPV 16 genotype, is an independent adverse prognosticator after chemo-radiotherapy in patients with ASCC.

p16INK4A, p53, EGFR expression and KRAS mutation status in squamous cell cancers of the anus: correlation with outcomes following chemo-radiotherapy.

BACKGROUND AND PURPOSE: Squamous cell carcinomas of the anal canal are associated with infection with Human Papilloma Viruses (HPVs). Chemo-radiotherapy (CRT) gives 70% 3-year relapse-free survival. Improved predictive markers and therapeutic options are required. METHODS: Tumours from 153 patients treated with radical chemo-radiotherapy (50.4 Gy in 28# with concurrent Mitomycin and 5-Fluorouracil between 2004 and 2009) were retrieved and immunohistochemistry performed for p16(INK4A), p53 and EGFR and correlated with outcome. Primary and relapsed samples were analysed for mutations in KRAS. RESULTS: 137/153 (89.5%) stained moderately or strongly for p16(INK4A). p16(INK4A) correlated strongly with outcome. 37/137 patients demonstrating moderate/strong p16(INK4A) expression relapsed (27.0%), as opposed to 10/16 (62.5%) with absent/weak staining (log rank test p<0.001). p16 and p53 expression were inversely correlated. p16(INK4A) negative tumours were more frequent in men. p16(INK4A) negative patients had significantly worse overall survival (p<0.001). No mutations in KRAS were identified in primary tumours or relapses following treatment. CONCLUSIONS: p16(INK4A) is strongly associated with relapse in SCC of the anus and identifies patients with very poor rates of relapse-free and overall survival. Primary and recurrent anal cancer expresses wild type KRAS, unaffected by treatment, supporting trials targeting EGFR in poor risk/recurrent anal cancer.

A rare case of anal tumor: Anal carcinosarcoma.

Sarcomatoid carcinoma is a rare tumor with a poor prognosis, otherwise known as carcinosarcoma. Gastrointestinal origin is very rare and only a limited number of anal carcinosarcomas have been reported in the literature. The management of this rare cancer type is controversial. The aim of this case report was to confirm that by combining treatment modalities we can achieve long disease free intervals. Concomitant chemoradiotherapy led to a good partial response and this was followed by a consolidation surgical endo-anal excision.

FDA drug approval summary: bevacizumab plus interferon for advanced renal cell carcinoma.

On July 31, 2009, the U.S. Food and Drug Administration granted approval for the use of bevacizumab (Avastin(R); Genentech, Inc., South San Francisco, CA) in combination with interferon (IFN)-alpha2a for the treatment of patients with metastatic renal cell carcinoma. The approval was primarily based on results from a randomized, double-blind, placebo-controlled clinical trial. The primary efficacy endpoint, progression-free survival (PFS), was assessed by investigators and by an independent review committee (IRC) blinded to treatment assignment. In total, 649 patients (bevacizumab plus IFN, 327; placebo plus IFN, 322) were enrolled. The median PFS times, by investigator determination, were 10.2 months for the bevacizumab plus IFN arm and 5.4 months for the placebo plus IFN arm (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.49-0.72; p < .0001). The IRC analysis of 569 patients with available radiographs yielded similar results (median PFS time, 10.4 months versus 5.5 months; HR, 0.57; 95% CI, 0.45-0.72; p < .0001). There was no survival advantage (HR, 0.86; 95% CI, 0.72-1.04; p = .13). Support for the above results was provided by summarized results of a North American cooperative group study of bevacizumab plus IFN-alpha2b versus IFN-alpha2b alone. The median PFS times were 8.4 months versus 4.9 months in favor of the bevacizumab combination. There was no survival advantage. In the reviewed trial, serious adverse events and National Cancer Institute Common Terminology Criteria for Adverse Events grade >/=3 adverse events were reported more frequently in bevacizumab-treated patients (31% versus 19% and 63% versus 47%, respectively). The most common bevacizumab-related toxicities were bleeding/hemorrhage, hypertension, proteinuria, and venous or arterial thromboembolic events.

Changes to somatosensory detection and pain thresholds following high frequency repetitive TMS of the motor cortex in individuals suffering from chronic pain.

Research has shown that transcranial magnetic stimulation (TMS) results in a transient reduction in the experience of chronic pain. The present research aimed to investigate whether a single session of high frequency TMS is able to change the sensory thresholds of individuals suffering from chronic pain. Detection and pain thresholds for cold and heat sensations were measured before and after 20Hz repetitive TMS (rTMS) administered over the motor cortex. A significant decrease in temperature for cold detection and pain thresholds and a significant increase in temperature for heat pain thresholds were evident following a single session of rTMS. In contrast, no change in detection and pain thresholds was obtained following sham rTMS. The finding that rTMS can have a direct effect on sensory thresholds in individuals suffering from chronic pain has implications for the therapeutic use of rTMS in the relief of chronic pain.