Strategies for the delay of surgery in the management of resectable hepatobiliary malignancies during the COVID-19 pandemic.

Objective: We aimed to review data about delaying strategies for the management of hepatobiliary cancers requiring surgery during the covid-19 pandemic. Background: Given the covid-19 pandemic, many jurisdictions, to spare resources, have limited access to operating rooms for elective surgical activity, including cancer, thus forcing deferral or cancellation of cancer surgeries. Surgery for hepatobiliary cancer is high-risk and particularly resource-intensive. Surgeons must critically appraise which patients will benefit most from surgery and which ones have other therapeutic options to delay surgery. Little guidance is currently available about potential delaying strategies for hepatobiliary cancers when surgery is not possible. Methods: An international multidisciplinary panel reviewed the available literature to summarize data relating to standard-of-care surgical management and possible mitigating strategies to be used as a bridge to surgery for colorectal liver metastases, hepatocellular carcinoma, gallbladder cancer, intrahepatic cholangiocarcinoma, and hilar cholangiocarcinoma. Results: Outcomes of surgery during the covid-19 pandemic are reviewed. Resource requirements are summarized, including logistics and adverse effects profiles for hepatectomy and delaying strategies using systemic, percutaneous and radiation ablative, and liver embolic therapies. For each cancer type, the long-term oncologic outcomes of hepatectomy and the clinical tools that can be used to prognosticate for individual patients are detailed. Conclusions: There are a variety of delaying strategies to consider if availability of operating rooms decreases. This review summarizes available data to provide guidance about possible delaying strategies depending on patient, resource, institution, and systems factors. Multidisciplinary team discussions should be leveraged to consider patient- and tumour-specific information for each individual case.

Supportive oncofertility care, psychological health and reproductive concerns: a qualitative study.

PURPOSE: Impaired fertility in cancer patients and survivors of reproductive age (15-45 years) may lead to psychological distress and poor mental health outcomes, and may negatively impact quality of life. Limited research has focused on the fertility experiences of those who have had access to supportive oncofertility care. This study aims to explore the fertility-care experiences and reproductive concerns of reproductive age cancer patients at the time of their cancer diagnosis who have had access to oncofertility care. METHODS: The qualitative data from a larger mixed method study is presented, comprising 30 semi-structured telephone interviews with newly diagnosed cancer patients across Australia and New Zealand, undertaken between April 2016 and April 2018. RESULTS: Interviews were undertaken with 9 male patients and 21 female patients aged between 15 and 44 years. All patients recalled a discussion about fertility and majority underwent some form of fertility preservation. Thematic analysis identified five main themes: (i) satisfaction with oncofertility care, (ii) a need for individualised treatment and support, (iii) desire for parenthood, (iv) fertility treatment can be challenging, and (v) fertility preservation provides a safety net for the future. CONCLUSIONS: Participants who access supportive oncofertility care report low emotional impact of threatened future infertility at the time of cancer diagnosis. These results suggest that such services may assist in lowering the emotional burden of potential infertility in survivors. Long-term research is needed to assess the longitudinal benefits for different models of care.

The impact and indications for Oncotype DX on adjuvant treatment recommendations when third-party funding is unavailable.

OBJECTIVES: Industry-supported decision impact studies demonstrate that Oncotype Dx (ODX) changes treatment recommendations (TR) in 24-40% of hormone receptor+/HER2- patients. ODX is not reimbursed by third-party payers in Australia, potentially resulting in more selective use. We sought to evaluate the impact of self-funded ODX on TRs. METHODS: Data collected included demographics, tumor characteristics, indication for ODX and pre- and post-recurrence score (RS) TR. Primary endpoint was frequency of TR change and associations with TR change were sought. RESULTS: Eighteen physicians contributed 382 patients (median age 54). A total of 232 (61%) of tumors were T1 and were grade 1, 2 and 3 in 49 (13%), 252 (66%) and 79 (21%). A total of 257 (67%) were node negative. Assay indications were: confirm need for chemotherapy (CT) (36%), confirm omission of CT (40%) and genuine equipoise (24%). RS was low (≤17) in 55%, intermediate (18-31) in 36% and high (≥32) in 9%. Thirty-eight percent of patients had TR change post-ODX. Sixty-five percent of patients recommended CT pre-ODX changed to hormone therapy alone (HT)-more likely if lower grade and if ER and/or PR > 10%. Fourteen percent of patients with pre-ODX TR for HT added CT-more likely if ER and/or PR ≤10% and if Ki67 > 15% Overall, TR for CT decreased from 47% to 24%. CONCLUSION: Patient-funded ODX changed TRs in 38% of patients, de-escalating 65% from CT to HT and adding CT to 14% of those recommended HT. These changes were greater than an industry-funded study suggesting that physicians can identify situations where the assay may influence decisions.

JRK is a positive regulator of ß-catenin transcriptional activity commonly overexpressed in colon, breast and ovarian cancer.

The loss of ß-catenin inhibitory components is a well-established mechanism of carcinogenesis but ß-catenin hyperactivity can also be enhanced through its coactivators. Here we first interrogated a highly validated genomic screen and the largest repository of cancer genomics data and identified JRK as a potential new oncogene and therapeutic target of the ß-catenin pathway. We proceeded to validate the oncogenic role of JRK in colon cancer cells and primary tumors. Consistent with a ß-catenin activator function, depletion of JRK in several cancer cell lines repressed ß-catenin transcriptional activity and reduced cell proliferation. Importantly, JRK expression was aberrantly elevated in 21% of colorectal cancers, 15% of breast and ovarian cancers and was associated with increased expression of ß-catenin target genes and increased cell proliferation. This study shows that JRK is required for ß-catenin hyperactivity regardless of the adenomatous polyposis coli/ß-catenin mutation status and targeting JRK presents new opportunities for therapeutic intervention in cancer.

The role of biological therapy in metastatic colorectal cancer after first-line treatment: a meta-analysis of randomised trials.

PURPOSE: Biologic agents have achieved variable results in relapsed metastatic colorectal cancer (mCRC). Systematic meta-analysis was undertaken to determine the efficacy of biological therapy. METHODS: Major databases were searched for randomised studies of mCRC after first-line treatment comparing (1) standard treatment plus biologic agent with standard treatment or (2) standard treatment with biologic agent with the same treatment with different biologic agent(s). Data were extracted on study design, participants, interventions and outcomes. Study quality was assessed using the MERGE criteria. Comparable data were pooled for meta-analysis. RESULTS: Twenty eligible studies with 8225 patients were identified. The use of any biologic therapy improved overall survival with hazard ratio (HR) 0.87 (95% confidence interval (CI) 0.82-0.91, P<0.00001), progression-free survival (PFS) with HR 0.71 (95% CI 0.67-0.74, P<0.0001) and overall response rate (ORR) with odds ratio (OR) 2.38 (95% CI 2.03-2.78, P<0.00001). Grade 3/4 toxicity was increased with OR 2.34. Considering by subgroups, EGFR inhibitors (EGFR-I) in the second-line setting and anti-angiogenic therapies (both in second-line and third-line and beyond settings) all improved overall survival, PFS and ORR. EGFR-I in third-line settings improved PFS and ORR but not OS. CONCLUSIONS: The use of biologic agents in mCRC after first-line treatment is associated with improved outcomes but increased toxicity.

Mechanisms determining sensitivity to cisplatin in three mutant Chinese hamster ovary cell lines.

To gain insight into factors determining the response of tumours to cisplatin, we studied pathways involved in resistance to cisplatin: drug uptake, cytoplasmic detoxification and DNA repair, in three cisplatin-sensitive Chinese hamster ovary (CHO)2 mutant cell lines. The mutant lines, CHO-MMC6, CHO-MMC1, CHO-MMS2, displayed inherent sensitivity to cisplatin (2.2, 4.1 and 10.6-fold, respectively) compared to the CHO-K1 line from which they were derived. CHO-MMS2 was the only mutant to show sensitivity to UV and this was slight (< 2-fold). None of the mutants displayed increased sensitivity to X-irradiation. The CHO-MMS2 cell line appeared to have multiple mechanisms involved in its sensitivity to cisplatin, including increased drug accumulation, decreased levels of glutathione and a decreased capacity for DNA repair. The CHO-MMC1 mutant demonstrated reduced ability for DNA repair in a host cell reactivation assay, but no difference in drug accumulation or glutathione levels compared to the parent. The CHO-MMC6 cell line was not defective in any of the mechanisms studied. These three mutant cell lines demonstrate that similar mechanisms may account for inherent sensitivity or resistance to cisplatin, and suggest that multiple mechanisms may determine the sensitivity of human tumours to cisplatin.

Long term response to chemotherapy in patients with visceral metastatic melanoma.

PATIENTS AND METHODS: Eight patients who remain in long term remission 4 to 15 years after chemotherapy for visceral metastatic melanoma are described. These patients were observed among some 1100 patients with visceral melanoma seen at the Sydney Melanoma Unit between 1977 and 1989. Only about one-third of such patients received chemotherapy, almost always with single agent dacarbazine or a nitrosourea. RESULTS: The apparently cured patients did not differ from the overall group of patients with visceral metastases in baseline characteristics, but 6 of the 8 had nodular lung metastases. CONCLUSIONS: While the mechanism remains uncertain, one possibility could be that chemotherapeutic agents cause mutations which allow expression of antigenicity in tumour cells. In any case, the fact of occasional exceptionally good responses, perhaps amounting to cure, constitutes an argument for a trial of chemotherapy in patients with visceral metastatic melanoma.

Cisplatin-based chemotherapy for ovarian germ cell malignancies: the Australian experience.

PURPOSE: This study was performed to evaluate the Australian experience with cisplatin-based treatment of ovarian germ cell tumors (OGCT) with respect to survival and toxicity of treatment. PATIENTS AND METHODS: A retrospective review was undertaken based on a standardized questionnaire, which was sent to all major gynecologic oncology centers in Australia. RESULTS: Data on 58 patients were obtained. Overall survival at 5 years for all patients was 87%. There was one death from disease among 14 patients with dysgerminoma, and four deaths from disease among 44 patients with nondysgerminomas. Cisplatin-based chemotherapy was associated with a low incidence of serious complications, with only one treatment-related death (from bleomycin-induced respiratory failure). CONCLUSION: Our large series demonstrates that cisplatin-based chemotherapy is highly effective for patients with OGCT. Although direct comparisons cannot be made, the survival of our patients with advanced tumors was comparable to that seen in male germ cell tumors, rather than inferior as is commonly believed. Future studies should aim to refine treatment to minimize toxicity, while further increasing curability.

A phase II study of carboplatin and cisplatin in advanced ovarian cancer.

In view of the single agent activity of both cisplatin and carboplatin in epithelial ovarian cancer, and their different toxicity profiles, we carried out a phase II study of low dose cisplatin (50 mg/m2) in combination with moderate dose carboplatin (300 mg/m2) in patients with advanced ovarian cancer. Fourteen patients, all of whom had bulky disease and over half of whom had Stage IV disease, were eligible for assessment of response and toxicity. An overall response rate of 71% was demonstrated (57% complete response, 14% partial response), which is at least equivalent to other regimens used in first line treatment of ovarian cancer. Toxicities encountered were nausea/vomiting and myelosuppression, however no serious renal neuro or ototoxicity was observed and the regimen does not cause significant alopecia. This combination may be a practical alternative to regimens which use high dose cisplatin to achieve similar efficacy.

The impact of histological review on clinical management of testicular cancer.

Accurate histological diagnosis and staging are critically important in determining the optimal management of patients with testicular cancer. We have assessed the importance of histological review of "outside" pathology reports from 87 patients referred to the Urological Cancer Research Unit. In 28 patients (32%), the reviewed pathology report differed from the outside report. In 10 of these patients (11%), the pathology review resulted in a change of treatment or prognosis from that which would have obtained in the absence of such histological review. Pathology review at a major cancer centre with a subspecialist interest in tumour pathology and a large experience in the management of germ cell malignancy is an essential first step in the treatment of testicular cancer.

Risk factors, epidemiology, screening, and prognostic factors in female genital cancer.

This review, which due to limitations of space cannot be exhaustive, summarizes the recent literature on risk factors and epidemiology, screening and prognostic factors in a cervical, ovarian, and endometrial cancer. There have been a large number of pertinent publications during this period and this paper summarizes and highlights recent advances in the identification of women at particularly high risk of developing gynecologic cancer, analyzes studies on early detection and screening, and reviews prognostic studies with particular reference to selection of therapy according to risk of relapse and likelihood of benefit.

Redressing the balance--the ethics of not entering an eligible patient on a randomised clinical trial.

A double standard exists whereby a treatment given outside a clinical trial is less stringently reviewed than a protocol treatment. We propose a remedy which would require the decision not to participate in an approved, available clinical trial to be subject to the same ethical requirements as trial entry.