Cycles Of Carboplatin Research Articles

GCT-06. THE OUTCOMES OF PATIENTS WITH DISSEMINATED GERMINOMA TREATED ON ACNS0232: A REPORT FROM THE CHILDREN’S ONCOLOGY REPORT

Abstract BACKGROUND Central nervous system (CNS) germinomas are curable with craniospinal irradiation (CSI). However, concerns about long-term sequelae led to investigations into neoadjuvant chemotherapy. The ACNS0232 study, a phase III trial, evaluated the efficacy of neoadjuvant chemotherapy followed by response-based radiotherapy (RT) in patients with germinomas. METHODS Patients aged 3-21 years with newly-diagnosed histologically-confirmed germinoma were randomized to standard RT alone (Regimen A: 24 Gy CSI with a boost of 21 Gy) or neoadjuvant chemotherapy followed by response-based RT (Regimen B: 2 cycles of carboplatin/ etoposide, and if not in complete response (CR), two additional cycles of of cisplatin/ cyclophosphamide were administered followed by 21 Gy CSI with boost of 9 Gy). The study objectives included comparing event-free (EFS), overall survival (OS) and evaluating response to pre-RT chemotherapy. RESULTS Twenty-two patients (10 in Regimen A, 12 in Regimen B) were randomized between January 2007 and May 2009, including 13 with disseminated disease (5 in Regimen A, 8 in Regimen B). The study closed early due to low accrual. The median study follow-up time was 5.8 years. The 5-year EFS estimates were 0.89 (95% CI 0.47, 0.98) for Regimen A and 0.92 (95% CI 0.47, 0.99) for Regimen B. Regimen B was well-tolerated and demonstrated a 72.7% CR rate. CONCLUSION Despite the premature closure of the study, ACNS0232 provides valuable insights into the role of neoadjuvant chemotherapy with response-based RT in the treatment of disseminated germinoma. However, it is crucial to acknowledge the limitations of drawing conclusions with such a small sample size. The COG oncology community was not supportive of the proposed phase 3 design, but there is value in expanding the limited experience using Regimen B in a single arm phase 2 study to validate the safety and efficacy of neoadjuvant chemotherapy strategies in patient’s with disseminated CNS germinoma.

Neoadjuvant chemotherapy with bevacizumab for locally advanced vulvar cancer

ObjectivesExternal beam radiation with sensitizing platinum is the recommended therapy for locally advanced vulvar cancers not amenable to curative surgery and is associated with considerable acute and chronic side effects....

Abstract PO1-20-08: Primary breast implant-associated squamous cell carcinoma with subsequent TEMPUS testing and failure of immunotherapy

Abstract Primary squamous cell carcinoma of the breast is a rare entity, and there are a limited number of cases in the literature describing squamous cell carcinoma arising from breast implants. It has been hypothesized that these implant-associated cancers may arise from epithelialization of the implant capsule followed by chronic inflammation. None of the cases in the literature were treated with immunotherapy. We present a case of an aggressive, primary sarcomatoid squamous cell carcinoma of the breast arising from a breast implant that was treated unsuccessfully with simultaneous chemotherapy and immunotherapy following TEMPUS testing. Introduction: Breast augmentation is the most common plastic surgery procedure performed worldwide, with more than 300,000 done in the United States every year. While breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is extensively discussed in recent literature, other breast implant-associated cancers are rarer and less studied. Breast implant-associated squamous cell carcinoma (BIA-SCC) specifically is an extremely rare complication of breast augmentation and no guidelines for treatment exist. The American Society of Plastic Surgeons (ASPS) released a statement on BIA-SCC on 9/2022 following a safety communication from the FDA, and it is recommended health care providers submit case reports of BIA-SCC to a patient registry. Case study: We present the case of a female patient who underwent bilateral breast augmentation in 2006 with Mcghan textured, pre-pectoral, areolar saline implants. In 2022, she presented with swelling and a lump in her breast and underwent bilateral breast implant removal with capsulectomy. Pathology showed triple negative sarcomatoid squamous cell carcinoma of the right breast capsule. TEMPUS testing on the breast biopsy revealed a PIK3CA mutation and PD-L1 negative status. Her case was discussed with a multi-disciplinary team including plastic surgery, multiple oncologists, and radiation oncology and her clinical picture was determined to be most consistent with BIA-SCC. Based on the KEYNOTE-522 study, she was determined to be a candidate for neoadjuvant therapy with pembrolizumab and chemotherapy as she was newly diagnosed, previously untreated, nonmetastatic, and had a triple negative tumor. She received two cycles of carboplatin, paclitaxel, and pembrolizumab but unfortunately rapidly progressed with chest wall extension, multiple new pulmonary nodules, worsening lymphadenopathy, right ventricular tumor thrombus, and new malignant pleural effusion and was transitioned to hospice. Discussion: Seven cases of BIA-SCC, one case of squamous cell carcinoma (SCC) after liquid silicone injection augmentation, one case of squamous metaplasia on the breast implant capsule, and one case of epithelization of the breast implant capsule have been previously described in the literature (Table 1). None of the available cases of BIA-SCC report TEMPUS testing, and none of the patients were treated with immunotherapy. The origin of BIA-SCC is unclear, but several theories have been described including chronic inflammation leading to conversion of epithelial tissue on the capsule to SCC. It is unknown how the breast implant capsule might become epithelialized to begin with – introduction of epithelium intraoperatively during augmentation, rupture of epidermal cysts, existence of epithelium in the area from a childhood injury or from birth, or epithelization from chronic shear forces from the augmentation or leakage of the implant are all possibilities. With the ongoing data gathering through the FDA patient registry, we will continue to learn more about these rare cancers and potentially get further insight into their origins. Table 1 An overview of cases of BIA-SCC in the literature Citation Format: Emily Podany, Katherine Clifton. Primary breast implant-associated squamous cell carcinoma with subsequent TEMPUS testing and failure of immunotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-08.

High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Salvage Therapy of Relapsed/Refractory Germ Cell Tumors: A Single-Center Experience

Introduction: The optimal management of relapsed/refractory germ cell tumors remains unsettled. In this study, we aimed to evaluate the efficacy of high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) as salvage therapy in patients who progressed after at least one line of cisplatin-based chemotherapy. Methods: We retrospectively reported the results of 133 patients who underwent HDCT and ASCT as salvage therapy from 2016 to 2021. Patients received 3 cycles of paclitaxel, ifosfomide and cisplatin (TIP) regimen as induction and 1 cycle of carboplatin 700 mg/m2 on days 1–3 plus etoposide 750 mg/m2 on days 1–3, followed by ASCT. Demographic and clinicopathological features of patients, the International Germ Cell Cancer Collaborative Group (IGCCCG) risk group at diagnosis, serum alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (HCG) levels before HDCT, treatment-related complications and survival outcomes were recorded. Results: The median age of the patients was 31 (range 18–62). The median follow-up was 31.1 months (95% CI, 28.9–33.3 months). During the median follow-up period, 74 of the 133 patients were still alive, and 63 of these were in complete remission. The median progression-free survival (PFS) was 25.8 months (95% CI, 8.1–43.4 months). The 2-year PFS rate was 50.3% and the 2-year overall survival (OS) rate was 60.8%. Variables that remained statistically significant in multivariable analysis and were associated with poor prognosis were mediastinal primary tumor location, presence of brain metastases, and higher AFP and HCG levels at baseline. Conclusion: One course of HDCT and ASCT after induction with TIP is an effective and feasible treatment option for salvage treatment of relapsed/refractory germ cell tumors, with cure rates of up to 60%.

Induction sintilimab and chemotherapy followed by concurrent chemoradiotherapy for locally advanced esophageal cancer: a proof-of-concept, single-arm, multicenter, phase 2 trial

Concurrent chemoradiotherapy is the standard nonoperative treatment for locally advanced esophageal squamous cell carcinoma. However, local recurrence is still the main failure pattern, accounting for more than half of all treatment failures, indicating that the sensitivity of radiotherapy still needs to be improved. This trial aimed at demonstrating whether PD-1 inhibitors followed by chemoradiotherapy could promote esophageal tumor vascular normalization, alleviate hypoxia, and thus enhance radiosensitivity and improve local control. We did a multicenter, single-arm, phase 2 trial in China. Patients with locally advanced esophageal cancer were enrolled in this study. In induction phase, patients received two cycles of sintilimab, paclitaxel and carboplatin once per 21 days. In concurrent phase, patients were treated with five cycles of carboplatin and paclitaxel once per week concurrent with radiotherapy of 50.4Gy delivered in 28 fractions. The primary endpoint was 2-year local control rate. Hypoxia and vessel normalization was assessed before and after induction phase using immunofluorescence and perfusion CT. This trial is registered with ClinicalTrials.gov (NCT03985046). Seventy-five patients with esophageal cancer were enrolled in this study between October 2019 and April 2021. The median follow-up of surviving patients was 33.6 months (IQR 29.3-35.7). The 2-year local control rate was 81.7% (95% confidence interval, 72.7%-90.7%), which was much higher than that in concurrent chemoradiation only (71.3%) in previous studies. Vascular normalization and hypoxia alleviation were observed in both biopsy specimens and perfusion CT. The addition of induction immunotherapy to standard concurrent chemoradiotherapy could improve radiosensitivity for locally advanced esophageal cancer as non-surgical treatment. New treatment combination led to higher local control rate through promoting vascular normalization and alleviating hypoxia. Our findings suggest that induction immunotherapy followed by concurrent chemoradiotherapy could be a potential option in future treatment. National Natural Science Foundation of China and Shanghai Rising-Star Program.

Carboplatin in Metastatic Castrate Resistant Prostate Cancer: A Retrospective Study of Heavily Pretreated Patients (COMPACT)

IntroductionMany clinicians consider carboplatin monotherapy in advanced castrate-resistant prostate cancer (CRPC) patients who have progressed through all available hormonal and standard chemotherapy treatment options, despite the limited evidence to justify its use. Patients and MethodsThis retrospective analysis aimed to evaluate the use of carboplatin monotherapy in patients with refractory prostate cancer in Australia. Efficacy (PSA response, duration, and survival) as well as toxicity was evaluated. Demographic data, PSA response rates, survival data and details of carboplatin treatment protocols, including dose and duration, were collected. Exploratory analyses were conducted on potential prognostic factors. ResultsFifty-one patients received carboplatin: median age 68 (range 55-86 years). Most patients (78.3%) received carboplatin AUC 5 at 3-week intervals. The median number of cycles of carboplatin received was 3 (range 1-17). The median duration of treatment was 63 days (range 1-441). The median overall survival was 6.8 months. Six (11.8%) patients had a PSA response ≥ 50%. The median time to PSA progression on carboplatin, as defined by PCWG,2 was 67 days (range 15-418). Sixteen patients (31%) required dose delays or reductions and 8 patients (15.6%) ceased carboplatin due to treatment toxicity. ConclusionCarboplatin is often used in Australia once all available standard treatment options have been exhausted in patients with CRPC. Toxicity is mild, and a minority of patients have responses, but these responses are rarely durable.

Abstract B001: Identification of monoallelic ATM loss-of-function and homologous recombination deficiency (HRD) in high-grade ovarian tumor with prolonged response to camonsertib and low-dose gemcitabine combination therapy

Abstract Intra-tumor heterogeneity and the prevalent loss-of-function mutations within DNA damage repair (DDR) genes constitute salient hallmarks of high-grade ovarian malignancies. However, the etiological drivers beyond BRCA1/2 mutations, as well as the chronology of tumor evolutionary processes, remain enigmatic. Here, we present the case of a 60-year-old female with high-grade serous ovarian cancer, initially treated with primary debulking surgery followed by 6 cycles of adjuvant intraperitoneal cisplatin and paclitaxel. After a 16-month platinum-free interval, the patient (pt) developed recurrent disease and subsequently received 5 weeks of neoadjuvant olaparib followed by secondary debulking surgery and adjuvant carboplatin as part of a clinical trial (NCT02489006). The pt became platinum refractory after 4 cycles of carboplatin, then received weekly paclitaxel and biweekly bevacizumab with stable disease as best response and eventual progression after 17 cycles. Molecular profiling of the metastatic biopsies at the time of initial recurrence identified a pathogenic ATM (c.4910-1G>A) alteration for which the pt was then enrolled onto the Phase Ib TRESR trial (NCT04497116). The trial enrolled pts ≥18 years, ECOG PS 0-1, with advanced solid tumors with deleterious DDR alterations. The pt received a starting dose of 1000mg/m2 gemcitabine (gem) with 80mg of the ATR inhibitor camonsertib (cam; 3 days [d] on/4d off) on a 21d cycle (2 weeks [w] on/2w off). The pt had a partial RECIST 1.1 response at 4 months (mo) and remains on treatment after 18mo. Due to toxicities (primarily neutropenia) the pt had a series of dose reductions to 200mg/m2 gem with 50mg cam (2d on/5d off) on a 28d cycle (1w on/1w off). Circulating tumor fraction (TF), measured by methylation-based profiling, remained at or below the limit of quantitation of the assay through 11mo (0.01% TF, testing of later timepoints ongoing). At 13mo, the target lesions began increasing in size (-50% to -43%) prompting a dose increase of cam to 80mg (same gem dose), after which the target lesions decreased to nadir (-52%) at 76w with concomitant CA-125 decrease. Retrospective whole-genome sequencing (WGS) of the secondary debulking surgery specimen as well as targeted sequencing (SyNthetic lethal Interactions for Precision Diagnostics [SNiPDx]) and immunohistochemistry of the metastatic biopsy revealed ATM protein loss only in a portion of the tumor and a monoallelic ATM mutation. Genomic signature analysis of WGS indicated presence of single-base substitution signatures 3+8 (HRD-related) and HRD positivity (BRCA1-type; CHORD algorithm). In contrast, while HRD+ was also detected in the primary tumor sample, the ATM alteration was absent and ATM protein expression was uniform, suggesting that ATM loss was a late event in tumor evolution. This case highlights the complexity of intra-tumor heterogeneity and clonal evolution in ovarian tumors and importance of “functional” HRD as no apparent mutational driver was identified. Citation Format: Stephanie Lheureux, Joseph D. Schonhoft, Ian M. Silverman, Julia Yang, Adrienne Johnson, Brooke Grant, Alexander Fortuna, Trevor J. Pugh, Parham Nejad, Bernard Lam, Sahaj Arora, Ashley Adile, Stephenie D. Prokopec, Jeffrey Bruce, Danielle Ulanet, Maria Koehler, Ezra Rosen, Victoria Rimkunas. Identification of monoallelic ATM loss-of-function and homologous recombination deficiency (HRD) in high-grade ovarian tumor with prolonged response to camonsertib and low-dose gemcitabine combination therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B001.

Effectiveness of Carboplatin-Prescreening Intradermal Skin Tests to Reduce Unanticipated Immediate Hypersensitivity Reactions: A Comparative Study

BackgroundCarboplatin administration poses a risk of immediate hypersensitivity reactions (IHRs) that tend to increase with repeated administration and are mostly IgE-mediated. ObjectiveThis study evaluated the usefulness of carboplatin-prescreening intradermal skin tests (IDTs). MethodsCarboplatin-prescreening IDTs were routinely conducted in patients with a history of receiving six or more carboplatin cycles from January 2021. The primary objective was to assess disparities in the incidence of unanticipated IHRs to carboplatin administration. Comparisons were made between patients in the intervention group (period: 2021–2022) and those who did not undergo prescreening IDTs under the same conditions (pre-intervention group; period: 2019–2020). The secondary objectives included evaluating the sensitivity and specificity of the prescreening IDT and the incidence of carboplatin IHR according to the number of infusion cycles. ResultsThe intervention group comprised 67 patients who were administered 347 carboplatin cycles, whereas the pre-intervention group included 96 patients who were administered 464 carboplatin cycles. The risk of unanticipated carboplatin IHRs decreased by 83.2% in the intervention group compared to the pre-intervention group (pre-intervention group: 3.45%, N=16 vs. intervention group: 0.58%, N=2; p=0.005). The prescreening IDT showed a sensitivity and specificity of 77.78% and 99.41%, respectively. The risk of newly developed IHRs based on the number of carboplatin cycles was <1% (cycle 1-5), 2.11% (cycle 6), 3.90% (cycle 7-12), 2.90% (cycle 13-18), and 0.74% (cycle ≥ 19), respectively. ConclusionsInitiating carboplatin-prescreening IDTs from the seventh cycle significantly reduced the risk of unanticipated IHRs.

Case report: prolonged durable clinical benefit and low toxicity from combination endocrine therapy in a patient with recurrent endometrial carcinoma

BackgroundEndometrial carcinoma is the most common gynecologic cancer, with increasing incidence and mortality. Combination endocrine therapy comprised of tamoxifen and progestational agents has demonstrated promising results in treating recurrent disease. This case report describes the prolonged clinical benefit of treatment with tamoxifen and megestrol acetate in a woman with recurrent, metastatic endometrial endometrioid carcinoma positive for estrogen (ER) and progesterone receptors (PR).CaseA 71-year-old gravida 1 para 1 woman presented with postmenopausal bleeding and vaginal discharge. Pelvic ultrasound and magnetic resonance imaging confirmed a 4.7 cm endometrial mass. The patient underwent a total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and cystoscopy; pathology revealed a FIGO stage IA grade 1 ER/PR-positive endometroid endometrial adenocarcinoma. She continued under active surveillance for approximately 42 months until she experienced bone metastases in her pelvis, for which she received radiation therapy. Five months later, pulmonary metastases were detected, and she received six cycles of carboplatin and paclitaxel. She then started megestrol acetate and tamoxifen and has remained clinically stable with minimal side effects and reasonable quality of life for approximately 57 months.ConclusionOur case suggests that combination endocrine therapy has the potential to provide substantial long-term clinical benefit in women with recurrent endometrial cancer and bone metastases, despite multiple prior treatments, allowing patients to experience stable disease and quality of life. In patients with recurrent endometrioid, ER/PR-positive disease, endocrine therapy alone or in combination with other targeted therapies are regimens that may be considered due to their low overall toxicity.

AGO-OVAR 28/ENGOT-ov57. Niraparib alone versus niraparib in combination with bevacizumab in patients with carboplatin-taxane-based chemotherapy in advanced ovarian cancer: a multicenter randomized phase III trial

BackgroundPhase III trial data have shown a significant benefit by the addition of a maintenance treatment with niraparib, irrespective of BRCA or HRD status, in patients with advanced high-grade ovarian...

TROPION-Lung04: Phase 1b, multicenter study of datopotamab deruxtecan (Dato-DXd) in combination with immunotherapy ± carboplatin in advanced/metastatic non-small cell lung cancer (mNSCLC).

TPS3158 Background: Datopotamab deruxtecan (Dato-DXd) is a TROP2-directed antibody drug conjugate that has shown encouraging preliminary activity and safety in patients (pts) with lung or breast cancers. The TROPION-Lung04 study was designed to assess the safety, tolerability, and antitumor activity of Dato-DXd in combination with immunotherapy ± carboplatin in pts with advanced or metastatic NSCLC. Methods: TROPION-Lung04 (NCT04612751) is a Phase 1b, multicenter, open-label, 2-part, dose escalation/confirmation and expansion study in ≈232 pts without actionable genomic alterations. In Part 1 (dose escalation/confirmation), pts will be enrolled to 1 of up to 11 cohorts. Details of cohorts 1–4 (Dato-DXd [4 or 6 mg/kg] + durvalumab [1120 mg Q3W] ± up to 4 cycles of carboplatin [AUC 5] Q3W) were previously described (Borghaei H, et al. JTO 2021;16(10):S1098-S1099). Cohorts 5–11 were recently added to evaluate Dato-DXd in combination with bispecific immunotherapies AZD2936 (anti-PD-1/TIGIT) and MEDI5752 (anti-PD-1/CTLA-4) in treatment-naïve pts. Pts in cohorts 5–8 will receive Dato-DXd (4 or 6 mg/kg) + AZD2936 ± carboplatin; pts in cohorts 9–11 will receive Dato-DXd + MEDI5752 ± carboplatin. Cohorts 5 and 6 will recruit pts with PD-L1 tumor proportion score (TPS) ≥50% in Parts 1 and 2A, and PD-L1 TPS 1–49% in Part 2B. Cohorts 7–11 will recruit pts with PD-L1 TPS &lt; 50% only. Dose confirmation in Cohorts 5–11 will be guided by an mTPI-2 design where a minimum of 6 and a maximum of 9 pts will be assessed for dose-limiting toxicities (DLTs) during Cycle 1; if the DLT incidence meets prespecified toxicity criteria, Part 2 dose expansions may be opened. Pts may continue Dato-DXd or immunotherapy treatment until disease progression (per RECIST v1.1) or unacceptable toxicity. Study endpoints are shown in the table. Enrolment across all combination cohorts is ongoing. Clinical trial information: NCT04612751 . [Table: see text]

Carboplatin beyond 4 cycles during therapy with carboplatin, pemetrexed, and pembrolizumab for advanced non-small cell lung cancer (NSCLC).

e13509 Background: Since the publication of KEYNOTE-189 study , carboplatin/pemetrexed/pembrolizumab (carbo/pem/pembro) has become a common frontline regimen for advanced non-small cell lung cancer (NSCLC). In KEYNOTE-189, carboplatin was administered for a maximum of 4 cycles. To date, the number of carboplatin cycles administered in the real-world setting remains unclear. We analyzed factors predicting the receipt of carboplatin beyond 4 cycles (CB4). Methods: We interrogated a population-based, real-world database by Flatiron for NSCLC patients with no actionable EGFR/ALK who received carbo/pem/pembro from March to July 2019 (pre-pandemic period) and from March to July 2020 (pandemic period). Patients were included if they completed the regimen as shown by transitioning to maintenance pem, pembro, or pem/pembro. Primary endpoint was CB4. Secondary endpoint was overall survival. Multivariable logistic regression analyses were performed to identify independent predictors of receiving CB4. Results: Among 2090 patients treated during the study period, 966 patients (46%) started on carbo/pem/pembro and subsequently proceeded to maintenance therapy. Among them, 134 patients (14%) received CB4. Multivariable analysis revealed the following statistically significant predictors of receiving CB4, along with respective odds ratios (95% CI) and p-values: Non-white race 1.67 (1.09-2.57) (p=0.017), ECOG ≥1 1.66 (1.07-2.59) (p= 0.024), pandemic year 2020 1.68 (1.11- 2.52) (p=0.013), and ever-smoking status 0.51 (0.30-0.87) (p=0.013). Survival analysis is ongoing. Conclusions: A significant number of patients received CB4. Since this practice is not considered a standard practice, the benefits and risks of CB4 is unknown. Predictors of receiving CB4 included year of treatment, race, ECOG, and smoking status. Further investigation is needed to understand patient-physician decision making process with regards to the length of carboplatin administration. [Table: see text]

Cost-effectiveness analysis of tumor molecular testing in stage III endometrial cancer

BackgroundStandard of care for adjuvant treatment of stage III endometrial cancer includes chemotherapy and radiation. In addition to stage, tumor molecular profiles may predict treatment outcomes, and prospective clinical trials are ongoing. However, tumor molecular testing is costly and time-consuming. Our objective was to evaluate the cost-effectiveness of tumor molecular testing in stage III endometrial cancer. MethodsA Markov decision model compared two strategies for stage III endometrial cancer: Tumor Molecular Testing (TMT) versus No TMT. TMT included sequential POLE next generation sequencing, mismatch repair immunohistochemistry (IHC), and p53 IHC. POLE-mutated patients were assigned to adjuvant radiation therapy; all others including controls were assigned to adjuvant chemoradiation. First recurrences were treated with 6 cycles of carboplatin and paclitaxel. Second recurrences were treated with pembrolizumab alone for mismatch repair deficient patients and both pembrolizumab and lenvatinib for other patients. Sensitivity analyses were performed to test model robustness. ResultsCompared to No TMT, TMT was cost saving with equivalent effectiveness. On one-way sensitivity analysis, TMT remained cost saving over all parameter ranges. TMT was also favored on probabilistic sensitivity analysis in 80% of iterations at a willingness-to-pay threshold of $100,000/quality adjusted life-year (QALY) gained. However, when TMT was compared to mismatch repair IHC alone, TMT cost $182,798/QALY gained. ConclusionsIn this model of patients with stage III endometrial cancer, TMT was cost saving compared to No TMT. However, when compared to mismatch repair IHC alone, TMT was economically unfavorable.

E030 Rheumatologists beware! Digital ischaemia as a presenting feature in metastatic ovarian cancer

Abstract Background/Aims Digital ischaemia is an umbrella term to describe the spectrum of acral vascular phenomena irrespective of aetiology, ranging from temporary (as in Raynaud’s phenomenon) to permanent (necrosis). It can be the presenting feature in multiple cancer types, and can be present with or without other features of connective tissue disease. Methods A 54-year-old woman was referred to Rheumatology with a four-day history of acute pain and ischaemic discolouration of all her fingertips bilaterally. There was no history of Raynaud’s phenomenon and no other clinical features of connective tissue disease. She had never smoked. There was a family history of breast cancer in her maternal aunt. She was admitted under vascular surgery for urgent review. All ten fingertips were ischaemic, with a capillary refill time of greater than five seconds. The history was otherwise significant for abdominal bloating, altered bowel habit and fatigue. Examination revealed normal peripheral pulses with no bruits, normal heart sounds and chest sounds. Her abdomen was soft with a mildly enlarged liver. Results FBC, U&amp;E, and LFTs showed no abnormalities. CRP, ESR, ANA, serum protein electrophoresis and complement levels were all normal. Blood tests for ANCA, rheumatoid factor and anti-CCP were also negative. Lupus anticoagulant, anti-cardiolipin and anti-B2-glycoprotein were all negative. The tumour marker CA125 was markedly elevated at 837kU/L (0.0-35.0kU/L). A CT abdomen &amp; pelvis showed a large right-sided adnexal mass with multiple enhancing peritoneal and omental nodules and moderate ascites. Biopsy of a metastatic deposit in the omentum revealed high grade serous ovarian adenocarcinoma. Partial improvement in digital ischaemia was achieved with iloprost and maintenance apixaban and sildenafil. Four cycles of carboplatin and paclitaxel chemotherapy produced near-complete resolution of digital ischaemia symptoms, corresponding to a fall in her CA125 level and reduction in the size of the ovarian mass and intra-abdominal metastases on CT. Ten cases of digital ischaemia associated with ovarian cancer have been described prior to this. The age of onset ranged from 45 to 71, with a median age of 56. Most patients had digital ischaemia without features of connective tissue disease. Four had no blood test abnormalities other than a raised tumour marker CA125. The time from onset of digital ischaemia to diagnosis of ovarian cancer ranged from less than one week to 2 years, with a median time of four months. Conclusion This case study supports previous findings that patients with digital ischaemia associated with ovarian cancer may have normal markers of inflammatory or rheumatological disease. Marked therapeutic responses can be achieved with systemic anti-cancer therapies. Therefore, underlying cancer should be suspected in patients with new-onset or worsening digital ischaemia over the age of 45. A high index of suspicion is required - rheumatologists beware! Disclosure J.H. Miller: None. P. Merry: None.

Outcome of Children and Adolescents With Primary Intracranial Germinoma Treated With Chemotherapy and Reduced Dose-Field Irradiation: A Prospective Brazilian Experience

This prospective Brazilian single-arm trial was conducted to determine response to chemotherapy and survival after response-based radiotherapy in children with intracranial germinomas, in the setting of a multi-institutional study in a middle-income country (MIC) with significant disparity of subspecialty care. Since 2013, 58 patients with histologic and/or serum and CSF tumor marker evaluations of primary intracranial germ cell tumors were diagnosed; 43 were germinoma with HCGβ levels ≤200 mIU/mL and five between 100 and 200 mIU/mL. The treatment plan consisted of four cycles of carboplatin and etoposide followed by 18 Gy whole-ventricular field irradiation (WVFI) and primary site(s) boost up to 30 Gy; 24 Gy craniospinal was prescribed for disseminated disease. Mean age 13.2 years (range, 4.7-25.5 years); 29 were males. Diagnosis was made by tumor markers (n = 6), surgery (n = 25), or both (n = 10). Two bifocal cases with negative tumor markers were treated as germinoma. Primary tumor location was pineal (n = 18), suprasellar (n = 14), bifocal (n = 10), and basal ganglia/thalamus (n = 1). Fourteen had ventricular/spinal spread documented by imaging studies. Second-look surgery occurred in three patients after chemotherapy. Thirty-five patients achieved complete responses after chemotherapy, and eight showed residual teratoma/scar. Toxicity was mostly grade 3/4 neutropenia/thrombocytopenia during chemotherapy. At a median follow-up of 44.5 months, overall and event-free survivals were 100%. The treatment is tolerable, and WVFI dose reduction to 18 Gy preserves efficacy; we have demonstrated the feasibility of successfully conducting a prospective multicenter trial in a large MIC despite resource disparity.

Successful in vitro fertilization following conservative surgery for synchronous endometrioid tumor of ovary and uterus

BackgroundSuccessful pregnancy outcome in women with synchronous ovarian and endometrial cancers is very rare. We report successful pregnancy outcome in a young woman managed conservatively for synchronous endometrial and ovarian cancer.Case presentationThirty years old nulliparous lady presented following exploratory laparotomy, left salpingo-oophorectomy and hysteroscopic polypectomy for left adnexal mass. Histology revealed endometrioid carcinoma of left ovary and moderately differentiated adenocarcinoma in the resected polyp. She underwent staging laparotomy along with hysteroscopy which confirmed above findings without any evidence of further tumor spread. She was treated conservatively with high dose oral progestin (megestrol acetate, 160 mg) and leuprolide acetate 3.75 mg monthly injections for three months along with four cycles of carboplatin and paclitaxel based chemotherapy followed by monthly injection of leuprolide for further three months. After failure of spontaneous conception, she underwent ovulation induction for six cycles along with intrauterine insemination which failed. She underwent in vitro fertilization with donor egg followed by elective cesarean section at 37 weeks of gestation. She delivered a healthy baby of weight 2.7 kg. Intraoperatively 5 × 6 cm right ovarian cyst was found which drained chocolate coloured fluid on puncture and cystectomy was carried out. Histological examination revealed endometrioid cyst of right ovary. Uterus was spared as she wanted to preserve her fertility. She is being followed periodically and is normal nine months following delivery. She is on injection Depot medroxy progesterone acetate once every three months.

Carboplatin in metastatic castrate resistant prostate cancer: A retrospective study of heavily pretreated patients (COMPACT).

158 Background: Despite a lack of up-to-date clinical trial data, many clinicians advocate the use of Carboplatin monotherapy to treat patients with advanced Castrate Resistant Prostate Cancer (CRPC) who have exhausted multiple other treatment options. The aim of this study was to determine the overall survival (OS) and response rate in patients with advanced CRPC treated with Carboplatin monotherapy after progressing on other chemotherapy agents. Methods: Retrospective multicentre study of the use of Carboplatin in advanced CRPC patients in Australia. Demographic data, PSA response rates, survival data and Carboplatin treatment protocols, such as dose and duration, were collected. Exploratory analyses on potential prognostic parameters were performed. Results: 51 patients received Carboplatin: median age 68 (range 55–86 years). Most patients (78.3%) received Carboplatin AUC 5 at 3-weekly intervals. The median number of cycles of Carboplatin was 3 (range 1-17). Median time on treatment was 63 days (range 1-441). Median overall survival was 29.4 weeks (IQR 11.7 weeks). 6 (11.8%) patients had a PSA response ≥50%. The median time to PSA progression on Carboplatin was 67 days (range 15-418). 16 patients (31%) required a dose delay or reduction and 8 patients (15.6%) ceased Carboplatin secondary to side effects/ toxicity. Conclusions: Our findings demonstrate that in heavily pre-treated CRPC, Carboplatin has a modest benefit in a minority of patients with a low rate of toxicity in the advanced prostate cancer population.

5P Physiologically relevant treatment models to investigate epigenetic mechanisms driving platinum resistance in ovarian high grade serous carcinoma

The prognosis for patients with platinum-resistant ovarian High Grade Serous Carcinoma (HGSC) remains poor. BriTROC-1 data indicate that genomic alterations alone cannot explain acquired platinum resistance. We investigate epigenetic changes that may drive platinum resistance in HGSC. Using in an in vitro two-dimensional model, we recreated multiple cycles of chemotherapy. We utilised both established cell lines and primary cultures derived from HGSC ascites. Following cell characterisation (p53, PAX8 IHC), carboplatin sensitivity was assessed (sulforhodamine B assay). Cells were then pulsed with four cycles of carboplatin (50μM for 6 hours) with a week of recovery between each cycle. Methylation (Illumina 850k array), transcriptomic (RNAseq) and chromatin accessibility (ATACseq) assays were performed. Cells were also imaged using Stochastic Optical Reconstruction Microscopy. Firstly, we focused on RNAseq analysis to evaluate genes (and related biological processes) that are consistently enriched following carboplatin cycles and the unique genes that are conversely enriched at cycle level. We attempted to identify uniformly up-/down-regulated pathways across the different cultures. These data were compared with the same results obtained from the OvCar4, an established HGSC cell line and IVR01, an in-vivo resistant OvCar4 derivative. The ATACseq and methylation analyses are still ongoing, aiming to identify possible concordant changes in the chromatin accessibility and the methylation patterns that will allow us to clarify the changes observed in transcriptomic. The preliminary data obtained from the RNAseq analysis show that the highest number of enriched genes seems to occur after the first Carboplatin cycle, with a lower number of progressively enriched genes across all other ones. No constant biological processes were identified for the moment, across the different primary cell cultures. Further comparisons will be certainly needed. Understanding the epigenetic landscape of HGSC using physiologically relevant models will allow us to identify possible therapeutic targets that could eventually prevent platinum resistance.

Persistent Mullerian duct syndrome: An atypical clinical presentation

Abstract Introduction Persistent Müllerian duct syndrome (PMDS) is a rare sexual development disorder characterized by a normal male phenotype. Müllerian structures cannot regress due to the absence of anti-müllerian hormone (AMH) or resistance to AMH receptor. In addition to male internal genitalia, female reproductive organs, including the uterus, uterine tubes, and upper 1/3 of the vagina are also detected. We will present a patient with PMDS who presented with bilateral cryptorchidism. Clinical Case A 31-year-old single man was referred to our clinic because of bilateral undescended testes and a rudimentary uterus detected during the evaluation of the lower abdominal pain. On physical examination, his body mass index (BMI) was 21.2. His arm span was 170 cm, and his upper-lower segment ratio was 0.96. Beard, axilla, and pubic hair development were normal; however, testes were not in the scrotum bilaterally. His karyotype analysis was 46XY. His prenatal, natal, and postnatal histories were not remarkable. His parents were not consanguineous; the younger brother had a history of undescended testis operation at age one. In laboratory examination, blood glucose, renal and liver functions were normal. Androstenedione, DHEAS, total and free testosterone, FSH, LH, total-hCG, AFP were normal. AMH&amp;gt;9µg/L. In the spermiogram, no sperm was observed. A rudimentary uterus and proximal vagina were observed in the abdominal computed tomography (CT). Symmetric solid masses measuring 55×40 mm compatible with bilateral undescended testis were detected in the ovarian lodges. The mass extended to the inguinal canal on the left and the scrotum on the right. In association with these masses, there were also tubular structures with the biggest diameter of 16 mm on the right and 13 mm on the left. Prostate sizes were normal. Seminal vesicles were not observed. PMDS was considered owing to 46 XY karyotypes, normal testosterone level, normal sexual development, external genitalia findings, accompanying Mullerian structures, and a high level of AMH. AMH gene mutation was not detected. However, AMH receptor type 2(AMHR2) gene mutation could not be studied. Bilateral undescended testicles, uterus, uterine tubes, and the tubular structures in the abdomen were excised. Classical type seminoma with lympho-vascular invasion was detected in the right-side tubular structure. Tumor-negative testicular tissue was frozen for possible fertility in the future. The patient received one cycle of Carboplatin. No metastasis was detected in the post-operative PET-CT scan. In post-operative evaluation, FSH, LH levels were high, total and free testosterone levels were low. AMH &amp;lt; 0.01 µg/L. The patient was started on testosterone replacement therapy. Conclusion PMDS is a rare cause of male pseudo-hermaphroditism. Malignant degeneration and infertility are two critical points in terms of treatment. Early diagnosis with increased awareness is essential in preserving fertility and preventing malignant degeneration.

Neoadjuvant chemotherapy with or without nintedanib for advanced epithelial ovarian cancer: Lessons from the GINECO double-blind randomized phase II CHIVA trial

AimThe oral anti-angiogenic therapy nintedanib prolongs progression-free survival (PFS) when combined with chemotherapy after primary surgery for advanced epithelial ovarian cancer. The randomized phase II CHIVA trial evaluated the impact of combining nintedanib with neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer. MethodsPatients with newly diagnosed unresectable FIGO stage IIIC–IV epithelial ovarian cancer received 3–4 cycles of carboplatin plus paclitaxel every 3 weeks as NACT before interval debulking surgery (IDS), followed by 2–3 post-operative cycles. Patients were randomized 2:1 to receive either nintedanib 200 mg twice daily or placebo on days 2–21 every 3 weeks during NACT (omitting peri-operative cycles), and then as maintenance therapy for up to 2 years. The primary endpoint was PFS. ResultsBetween January 2013 and May 2015, 188 patients were randomized (124 to nintedanib, 64 to placebo). PFS was significantly inferior with nintedanib (median 14.4 versus 16.8 months with placebo; hazard ratio 1.50, p = 0.02). Overall survival (OS) was also inferior (median 37.7 versus 44.1 months, respectively; hazard ratio 1.54, p = 0.054). Nintedanib was associated with increased toxicity (grade 3/4 adverse events: 92% versus 69%, predominantly hematologic and gastrointestinal), lower response rate by RECIST (35% versus 56% before IDS), and lower IDS feasibility (58% versus 77%) versus placebo. ConclusionsAdding nintedanib to chemotherapy and in maintenance as part of NACT for advanced epithelial ovarian cancer cannot be recommended as it increases toxicity and compromises chemotherapy efficacy (IDS, PFS, OS).ClinicalTrials.govregistration: NCT01583322.