Cycles Of Carboplatin Research Articles

Survival After Secondary Cytoreductive Surgery and Chemotherapy Compared With Chemotherapy Alone for First Recurrence in Patients With Platinum-Sensitive Epithelial Ovarian Cancer and No Residuals After Primary Treatment. A Registry-Based Study

(Abstracted from Acta Obstet Gynecol Scand 2018; doi: 10.1111/aogs.13361) Standard treatment for women with epithelial ovarian cancer (EOC) generally is primary surgery (with the aim of complete cytoreduction) followed by 6 cycles of carboplatin and taxanes every 3 weeks.

Does adjuvant chemotherapy dose modification have an impact on the outcome of patients diagnosed with advanced stage ovarian cancer? An NRG Oncology/Gynecologic Oncology Group study

PurposeTo determine the relationship between chemotherapy dose modification (dose adjustment or treatment delay), overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma (PPC) who receive carboplatin and paclitaxel. MethodsWomen with stages III and IV EOC and PPC treated on the Gynecologic Oncology Group phase III trial, protocol 182, who completed eight cycles of carboplatin with paclitaxel were evaluated in this study. The patients were grouped per dose modification and use of granulocyte colony stimulating factor (G-CSF). The primary end point was OS; Hazard ratios (HR) for PFS and OS were calculated for patients who completed eight cycles of chemotherapy. Patients without dose modification were the referent group. All statistical analyses were performed using the R programming language and environment. ResultsA total of 738 patients were included in this study; 229 (31%) required dose modification, 509 did not. The two groups were well-balanced for demographic and prognostic factors. The adjusted hazard ratios (HR) for disease progression and death among dose-modified patients were: 1.43 (95% CI, 1.19–1.72, P < 0.001) and 1.26 (95% CI, 1.04–1.54, P = 0.021), respectively. Use of G-CSF was more frequent in dose-modified patients with an odds ratio (OR) of 3.63 (95% CI: 2.51–5.26, P < 0.001) compared to dose-unmodified patients. ConclusionDose-modified patients were at a higher risk of disease progression and death. The need for chemotherapy dose modification may identify patients at greater risk for adverse outcomes in advanced stage EOC and PPC.

Abstract 4715: Mifepristone extends both length and quality of life in a patient with advanced non-small cell lung cancer that progressed despite chemotherapy and check-point inhibitors

Abstract The US FDA approved an investigator initiated phase II 40 patient study to treat patients with stage IIIB or IV non-small cell lung cancer who have progressed despite a minimum of 2 rounds of chemo or immunotherapy with the progesterone receptor modulator mifepristone taken orally at 300mg/day (www.clinicaltrials.gov). The first patient in the study reported at the 2017 AACR meeting with stage IV lung cancer with brain metastasis has had non-progressive disease with excellent quality of life (ECOG-zero) after 24 months on mifepristone therapy. His lung cancer was PD-L1 negative, and thus he did not receive check-point inhibitors. We report, herein, the clinical outcome of the second patient with stage IV disease who not only progressed despite 3 chemotherapy regimens but also nivolumab (she was positive for the PD-L1 marker). The second patient in the study began 300mg/day oral mifepristone at age 68. Her stage IV lung cancer had progressed despite 4 cycles of carboplatin, permetrexed, and bevacizumab, 6 cycles of carboplatin and docetaxel, and 6 cycles of erlotinib. Finally she progressed and treatment was stopped after 11 cycles of nivolumab (PD-L1 marker present). After 1 year of oral mifepristone there have been no new metastatic lesions. She is ECOG 1 (related to chronic obstructive lung disease). Her cancer is stable with slight reduction in some metastatic lesions. More importantly she states she feels better than at any time since her initial diagnosis. The mechanism of action of mifepristone is hypothesized to be related to suppressing a key immunosuppressive protein that seems to be required for rapidly growing cells (e.g., possibly cancer stem cells), to proliferate known as the progesterone induced blocking factor (PIBF). This protein stablizes perforin granules in natural killer cells, thus obviating their mechanism for cytotoxicity. Mifepristone has been shown to suppress the intracytoplasmic immunosuppressive isoform in cancer cell line studies. Mifepristone can also diminish T-cell cytotoxicity. Progesterone receptor modulators may provide a new treatment option for advanced non-small cell lung cancer, even those positive for the PD-L1 marker that progresses despite treatment with chemotherapy and check-point inhibitors. Because intracytoplasmic PIBF is present in only mesenchymal, embryonic, trophoblast, or cancer cells suppressing this protein does not engender any health risks - oral mifepristone is well tolerated. Citation Format: Jerome H. Check, Diane Check, Trina Poretta. Mifepristone extends both length and quality of life in a patient with advanced non-small cell lung cancer that progressed despite chemotherapy and check-point inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4715.

Abstract 5547: Durable remission with nivolumab, anti-PD-1 monoclonal antibody, in a patient with advanced thymic carcinoma

Abstract Thymic carcinoma is a rare neoplasm with poor prognosis that forms on the outside surface of the thymus. Due to the rarity of the disease, there are no randomized clinical trials that guide therapy. Currently, there are clinical trials under way to assess the efficacy of anti-programmed death 1 (PD-1) monoclonal antibodies for the treatment of advanced thymic carcinomas. However, the role of PD-1 inhibitors in treating thymic carcinoma remains mostly unknown. Here we present a case of a patient with thymic carcinoma who showed durable remission when treated with nivolumab. 61-year-old male was diagnosed with thymic carcinoma during an episode of COPD exacerbation in April 2015. The patient was treated with neoadjuvant chemotherapy regimen consisting of four cycles of carboplatin and paclitaxel every three weeks from June to September 2015. The mass was resected in October 2015. Margins were found to be grossly positive. The patient was deemed a poor candidate for adjuvant chemotherapy, and in February 2016 the decision was made to begin 3 mg/kg nivolumab therapy considering the poor prognosis of disease and high risk of recurrence. Close to two years after initiating therapy, he currently has no measurable disease and tolerates the medication without side effects. This is the first report demonstrating durable remission of thymic carcinoma with nivolumab treatment. Our case suggests that prospective trials evaluating the use of nivolumab in patients with thymic carcinoma are warranted. Citation Format: Young Kwang Chae, Anderson Cho, Kyunghoon Rhee, Andrew Davis, Wade Iams, Manali Bhave, Marcelo Cruz, Lee Chun Park. Durable remission with nivolumab, anti-PD-1 monoclonal antibody, in a patient with advanced thymic carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5547.

Intrathoracic Axial Osteosarcoma

Background: Bone tumors have a challenging diagnosis and treatment. Osteosarcoma is the name given to a heterogeneous group of malignant, agressive and invasive tumors that often determine bone lysis. Almost all of the animals develop lung metastases, progressing to death. Usually affect the appendicular skeleton, but can also occurs in others areas, although these presentations are rare. Prognosis is always poor. The aim of this paper is to report a case of a dog with osteoblastic osteosarcoma of the sternum, which was diagnosed by computed tomography and histopathologic analysis after excisional biopsy.Case: A male Cocker Spaniel dog, weighing 25 kg, elderly, was examined at the Veterinary Hospital. As main complaint was reported soft swelling on the ventral cervical region causing dyspnea. The patient had previously been medicated with dexamethasone with a significant decrease in the swelling, however recurrence was observed with the cessation of the treatment. Due to the presence of heart murmur, patient underwent to chest radiography and eletrocardiography. Images showed a tumor in the sternal lymph node region, displacing the heart caudally, trachea and esophagus dorsally, causing cranial edema due to a compression of the venous return by the cranial vena cava and subsequent dyspnea. Furosemide (Lasix®) was administered during ambulatorial treatment and prescribed to home, with satisfactory results, with decreased edema and consequent improvement of respiratory symptoms. It was decided to perform computed tomography to better design of the chest structure. The structure located in cranial thoracic region measured about 10.5 cm long x 5.8 cm high x 8.4 cm wide. The patient was undergone to sternotomy to remove the mass that was closely adhered to the sternum and pericardium. The pericardectomy and sternum removal were not performed due to animal being old and present metabolic and cardiopulmonary conditions. Some samples were collected for histological examination resulting in osteoblastic osteosarcoma. After surgical treatment, the patient showed improvement of dyspnea, more active and no signs of pain at the surgical site. Due to the unfavorable result of the histopathological analysis, it was decided to star chemotherapy. The protocol chosen was carboplatin (Carboplatino®) as a single drug, every 21 days totalizing four applications as recommended by literature. Two cycles of carboplatin were done as adjuvant chemotherapy. The patient supported the treatment very well without any clinical or laboratory abnormality. Any radiographic signs of pulmonary metastasis or local recurrence was seen, however, after 18 months of survival, the patient died of non-related cause.Discussion: Osteosarcoma is the most commonly diagnosed bone tumor in dogs. Intense dyspnea and the swelling in the submandibular region was due to the compression of thoracic structures by the size of the tumor and the internal location within the chest. The cranial swelling is due to the syndrome caval that is rare in veterinary medicine and is describe in some specific conditions. Computed tomography was performed to better tumor delineation, as it is an important tool to assess the extent of the tumor and other characteristics, allowing optimal surgical planning for each case. Histophatological diagnosis of osteoblastic osteosarcoma is characterized by new bone formation that appears radiographically with increased radiopacity, as observed in all images. Gold standard treatment of neoplasms is the association of surgical excision followed by chemotherapy, which was effective in this case reported, since it provided quality of life during 18 months, three times higher than the majority of cases reported in the literature, being death due to causes unrelated to the tumor.

Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study

After neoadjuvant chemoradiotherapy for oesophageal cancer, roughly half of the patients with squamous cell carcinoma and a quarter of those with adenocarcinoma have a pathological complete response of the primary tumour before surgery. Thus, the necessity of standard oesophagectomy after neoadjuvant chemoradiotherapy should be reconsidered for patients who respond sufficiently to neoadjuvant treatment. In this study, we aimed to establish the accuracy of detection of residual disease after neoadjuvant chemoradiotherapy with different diagnostic approaches, and the optimal combination of diagnostic techniques for clinical response evaluations. The preSANO trial was a prospective, multicentre, diagnostic cohort study at six centres in the Netherlands. Eligible patients were aged 18 years or older, had histologically proven, resectable, squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction, and were eligible for potential curative therapy with neoadjuvant chemoradiotherapy (five weekly cycles of carboplatin [area under the curve 2 mg/mL per min] plus paclitaxel [50 mg/m2 of body-surface area] combined with 41·4 Gy radiotherapy in 23 fractions) followed by oesophagectomy. 4-6 weeks after completion of neoadjuvant chemoradiotherapy, patients had oesophagogastroduodenoscopy with biopsies and endoscopic ultrasonography with measurement of maximum tumour thickness. Patients with histologically proven locoregional residual disease or no-pass during endoscopy and without distant metastases underwent immediate surgical resection. In the remaining patients a second clinical response evaluation was done (PET-CT, oesophagogastroduodenoscopy with biopsies, endoscopic ultrasonography with measurement of maximum tumour thickness, and fine-needle aspiration of suspicious lymph nodes), followed by surgery 12-14 weeks after completion of neoadjuvant chemoradiotherapy. The primary endpoint was the correlation between clinical response during clinical response evaluations and the final pathological response in resection specimens, as shown by the proportion of tumour regression grade (TRG) 3 or 4 (>10% residual carcinoma in the resection specimen) residual tumours that was missed during clinical response evaluations. This study was registered with the Netherlands Trial Register (NTR4834), and has been completed. Between July 22, 2013, and Dec 28, 2016, 219 patients were included, 207 of whom were included in the analyses. Eight of 26 TRG3 or TRG4 tumours (31% [95% CI 17-50]) were missed by endoscopy with regular biopsies and fine-needle aspiration. Four of 41 TRG3 or TRG4 tumours (10% [95% CI 4-23]) were missed with bite-on-bite biopsies and fine-needle aspiration. Endoscopic ultrasonography with maximum tumour thickness measurement missed TRG3 or TRG4 residual tumours in 11 of 39 patients (28% [95% CI 17-44]). PET-CT missed six of 41 TRG3 or TRG4 tumours (15% [95% CI 7-28]). PET-CT detected interval distant histologically proven metastases in 18 (9%) of 190 patients (one squamous cell carcinoma, 17 adenocarcinomas). After neoadjuvant chemoradiotherapy for oesophageal cancer, clinical response evaluation with endoscopic ultrasonography, bite-on-bite biopsies, and fine-needle aspiration of suspicious lymph nodes was adequate for detection of locoregional residual disease, with PET-CT for detection of interval metastases. Active surveillance with this combination of diagnostic modalities is now being assessed in a phase 3 randomised controlled trial (SANO trial; Netherlands Trial Register NTR6803). Dutch Cancer Society.

Concurrent Radiotherapy and Triweekly Carboplatin for the Definitive Treatment of Locally Advanced Laryngeal Carcinoma.

In 2003, our institution adopted triweekly carboplatin (tCb) area under the curve (AUC) 5 as an alternative to high-dose cisplatin (100 mg/m) for select patients receiving definitive concurrent chemoradiation for locally advanced laryngeal carcinoma (LALC). Here, we present our experience and outcomes with this definitive concurrent chemoradiation regimen. From January 2003 through December 2013, 53 patients with stage III (60%) or IVA (40%) LALC were treated with tCb AUC 5 and concurrent radiotherapy to 70 Gy without neoadjuvant chemotherapy. Reasons for using carboplatin instead of cisplatin in these patients were: age 70 and older (21%), poor renal function (6%), presence of 1 or more major comorbid condition(s) (36%), and per discretion of the treating medical oncologist (38%). Primary disease site was glottis in 22 (42%) patients and supraglottis in 31 (58%) patients. Median follow-up time was 63 months for surviving patients. Out of the 53 patients, 43 (81%) received all 3 cycles of carboplatin and all patients received their intended dose of radiotherapy. Although 17 (32%) patients required a feeding tube during treatment, only 2 (4%) required it long term. There were no acute treatment-related grade 4 or 5 hematologic toxicities. On last follow-up, 14 (26%) patients had died of intercurrent disease. For the subgroup of "RTOG 9111 eligible" patients in our cohort (n=46), 5-year estimates of overall survival, disease-free survival, laryngectomy-free survival, larynx preservation, and locoregional control were: 49%, 42%, 39%, 80%, and 63%, respectively. In patients with LALC who are suboptimal candidates for high-dose cisplatin, our experience suggests that tCb AUC 5 with concurrent radiotherapy provides acceptable outcomes with tolerable toxicity.

Adjuvant radiation “sandwiched” between 6 cycles of carboplatin and paclitaxel for FIGO stage III endometrioid adenocarcinoma.

e17567Background: Locally advanced endometrioid adenocarcinoma (EAC) is an aggressive disease with the potential of metastatic spread and local recurrence after initial surgical resection. Adjuvant...

Dendritic cell vaccine (DCVAC) with chemotherapy (ct) in patients (pts) with recurrent epithelial ovarian carcinoma (EOC) after complete response (CR) to 1st-line platinum (Pt)-based ct: Primary analysis of a phase 2, open-label, randomized, multicenter trial.

e17515 Background: When pts with EOC relapse, their response to subsequent therapy is reduced. We hypothesized that autologous DCVAC could potentiate the antitumor response to ct and delay progression. Methods: Key eligibility criteria were FIGO stage III - IV EOC (serous, endometrioid, or mucinous), PS 0 - 2, CR after 1st-line Pt-based ct that lasted > 6 months, and at least 1 measurable lesion per RECISTv1.1. We randomized pts up to 6 weeks after relapse was confirmed by CT/MRI, 1:1, into arm A (A; DCVAC concomitantly with ct) and arm B (B; ct alone). Pts were stratified by previous bevacizumab use (yes/no) and duration of remission (6 - 12/ > 12 months). Ct consisted of 6 - 10 cycles of carboplatin (AUC 4 - 5; D1) and gemcitabine (1000mg/m2; D1, D8). Pts in A were to receive 10 doses of DCVAC (1 x 107 DCs/dose). The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results: Between November 2013 and May 2015, 71 pts were randomized in 3 countries (A/B, 39/32). Median age was 58.5 years in A and 60.5 years in B. After excluding pts who failed leukapheresis or manufacturing, the intention-to-treat population included 32 pts in each arm. A mean of 9.8 doses of DCVAC were administered in A. Median follow-up time was 28.2 months (range, 23.8 - 41.6 months). Median PFS was 10.9 months in A and 9.4 months in B; HR (95% CI) = 0.74 (0.42 - 1.30), p = 0.29. The corresponding ORR (95% CI) was 87.5% (71.0% - 96.5%) in A and 62.5% (43.7% - 78.9%) in B. In November 2017, median OS was not reached in A, while it was 30 months in B (44% events); HR (95% CI) = 0.62 (0.29 - 1.34). The majority of adverse events (AEs) were related to ct (thrombocytopenia [A: 64.9%, B: 80.6%], anemia [A: 64.9%, B: 67.7%], neutropenia [A: 59.5%, B: 67.7%], and leukopenia [A: 45.9%, B: 32.3%]). There were no grade ≥ 3 AEs related solely to DCVAC. Most common leukapheresis-related AEs were mild pyrexia and moderate hypocalcemia. Conclusions: Primary analysis showed better ORR and a trend towards improved OS in the DCVAC arm. Clinical trial information: NCT02107950.

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer

The majority of patients with ovarian cancer (OC) receive an initial diagnosis of advanced disease that has spread from the ovaries to the peritoneal surface. The most effective treatment for patients with advanced disease is cytoreductive surgery followed by systemic chemotherapy. As an alternative, interval cytoreductive surgery is performed after 3 cycles of chemotherapy. Following these treatments, the primary site of disease recurrence is the peritoneal surface. Delivery of chemotherapy by the intraperitoneal (IP) route enhances drug delivery at the peritoneal surface and eliminates residual microscopic peritoneal disease more efficiently than intravenous administration. Previous trials have shown that after primary cytoreductive surgery combined use of intravenous and IP chemotherapy results in longer overall survival among patients with stage III OC compared with intravenous administration alone. Combined intravenous/IP chemotherapy has several drawbacks that have hampered its adoption in many countries. These include catheter-related problems, increased demands on the patient, and gastrointestinal and renal adverse effects. Most of these drawbacks can be circumvented by delivery of the IP chemotherapy at the end of surgery. Delivery of IP chemotherapy during surgery under hyperthermic conditions—termed hyperthermic IP chemotherapy (HIPEC)—increases the penetration of chemotherapy at the peritoneal surface. Although addition of HIPEC to interval cytoreductive surgery is feasible in women with OC, efficacy data from randomized trials are lacking. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of interval cytoreductive surgery with HIPEC as compared with interval cytoreductive surgery without HIPEC in patients with stage III epithelial OC. Subjects were patients receiving neoadjuvant chemotherapy who had at least stable disease after 3 cycles of carboplatin (area under the curve of 5–6 mg/mL per minute) and paclitaxel (175 mg/m2 of body surface area). Of these patients, 245 were randomized: 122 to the surgery-plus-HIPEC group and 123 to the surgery-without-HIPEC group. Randomization was performed at the time of surgery in cases in which surgery that would result in complete cytoreduction (no visible disease) or optimal cytoreduction (≥1 residual tumors measuring ≤10 mm in diameter) was deemed to be feasible. Patients received an additional 3 cycles of carboplatin and paclitaxel postoperatively. Recurrence-free survival was the primary study end point. Key secondary end points were overall survival and the side effect profile. Data for recurrence-free and overall survival were analyzed according to intention to treat. Among patients who underwent cytoreductive surgery, disease recurrence or death occurred in 89% (110/123) of patients in the surgery-without-HIPEC group and 81% (99/122) of patients in the surgery-plus-HIPEC group; the hazard ratio for disease recurrence or death was 0.66, with a 95% confidence interval of 0.50 to 0.87, P = 0.003. The median recurrence-free survival was 3.5 months longer in the surgery-plus-HIPEC group than in the surgery-without-HIPEC group (14.2 vs 10.7 months). At a median follow-up of 4.7 years, 62% (76/123) of patients in the surgery-without-HIPEC group and 50% (61/122) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% confidence interval, 0.48–0.94; P = 0.02). There were no significant differences in the incidence of adverse events of any grade between the 2 groups (25% in the surgery-withoutHIPEC group and 27% in the surgery-plus-HIPEC group, P = 0.76). These data indicate that among patients with stage III epithelial OC addition of HIPEC to interval cytoreductive surgery provides longer recurrence-free survival and overall survival compared with surgery alone and no higher rates of adverse effects.

Pulmonary metastasis from endometrial carcinoma

A woman aged 69 years was referred to our department for the evaluation of a solitary pulmonary nodule. She had undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy on diagnosis of...

Use of AUC7 adjuvant carboplatin in patients with stage I seminoma: systematic review of the literature.

Among the adjuvant options to be proposed to patients with stage I seminoma after orchiectomy, the administration of a single cycle of carboplatin, at the dosage reaching an area under the curve of 7 mg/mL/min (AUC7), is a relatively recent introduction in clinical practice. On April 1, 2016, we performed a systematic review of the literature to identify studies on the use of AUC7 carboplatin in the adjuvant setting for stage I seminoma patients. The studies were identified by searching the PubMed electronic database from July 2005 up to April 2016. The aim of this review is to clarify the state of art of this adjuvant option. Adjuvant AUC7 carboplatin is an effective adjuvant treatment, able to reduce relapse rate in stage I seminoma patients. The heterogeneity of the methods for estimation and measurement of glomerular filtration rate represents an important issue in the administration of the optimal dose of carboplatin. Even with the lack of validated prognostic factors for relapses, a risk-adapted choice is commonly used to identify the optimal patient to be proposed this treatment. One cycle of AUC7 carboplatin is an effective, feasible, and safe adjuvant option to be discussed with stage I seminoma patients.

Abstract OT2-07-08: Substantially improving the cure rate of high-risk BRCA1-like breast cancer patients with personalized therapy (SUBITO) - an international randomized phase III trial

Abstract Background: An intact homologous repair (HR) pathway is essential for error-free repair of DNA double strand breaks (DSB). Preclinical and clinical data have shown that breast cancer (BC) cells with a defect in the HR pathway are a target for DNA DSB inducing agents and PARP inhibition. HR deficiency (HRD) causes genomic instability with a typical profile of DNA copy number aberrations (CNA) as seen in tumors of patients with a BRCA1 germline mutation. In the Netherlands Cancer Institute (NKI) the BRCA1-like test, a biomarker for HRD, was developed. The test calculates the probability that the genomic profile of DNA CNA of a breast tumor is similar to that of BRCA1 mutated BCs. When this probability is above a certain cutoff, depending on the platform, the test is positive in a small percentage of estrogen receptor positive and over 50% of triple negative BCs. In retrospective analyses, the test appeared to be a predictive biomarker for sensitivity to adjuvant intensified alkylating chemotherapy with autologous stem cell rescue (IA-CT). For example in stage III HER2-negative BRCA1-like BC, the 7-year recurrence free survival improved from 30% with 5 cycles of 5-fluorouracil-epirubicin-cyclophosphamide (FEC) to 78% when treated with 4 cycles of FEC followed by IA-CT (adjusted hazard rate 0.12; p=0.001). There was no benefit in non-BRCA1-like patients. Prospective validation in a randomized phase III trial is eagerly awaited and will possibly result in a practice changing outcome. We hypothesize that, although treatment with IA-CT is controversial, by selecting the right patients, we may substantially improve survival in high risk BRCA1-like BC. Eligibility criteria: Patients, 18 to 66 years old, with HER2-negative BRCA1-like or germline BRCA1 or BRCA 2 related stage III BC, who are fit to undergo IA-CT. Trial Design: In this phase III trial, patients will be randomized to (neo)adjuvant treatment with 4 cycles of dose dense doxorubicin-cyclophosphamide (ddAC) followed by two cycles of IA-CT or followed by 4 cycles of carboplatin(q3)-paclitaxel(q1) and one year of olaparib (300mg twice daily). Adjuvant endocrine treatment is added according to guidelines. Primary outcome is overall survival (OS), analyzed with the intention to treat principle. To detect an improvement of 35% OS (40% vs 75%) with a 2-sided alpha of 0.05 and a power of 0.8 at 10 years, 174 patients should be enrolled. Secondary outcomes are toxicity, quality of life, cost-effectiveness and cognitive function. Additionally we plan to analyze potential biomarkers, like 53BP1 and cancer-immune interaction. The SUBITO trial is part of a Coverage with Evidence Development program, which is a policy which allows conditional funding of a promising health intervention while more conclusive evidence is gathered to prove its (cost-)effectiveness. Since January 2017 we recruited 8 patients in 2 hospitals. Ten other hospitals, including two in France and one in Germany, are expected to start enrollment soon. The Medical Ethical Committee approved the trial. The trial is registered at clinicaltrials.gov (NCT02810743). Contact information for people with a specific interest in the trial: e-mail: subito@nki.nl Citation Format: Vliek S, Jager A, Jonge-Lavrencic M, Lotz J-P, Gonçalves A, Graeser M, Nitz U, Mandjes IAM, Holtkamp MJ, Schot M, Retel VP, Kuip EJ, Wymenga MN, Konings IR, Tjan-Heijnen VCG, Kroep JR, Schroeder CP, Van der Wall E, Linn SC. Substantially improving the cure rate of high-risk BRCA1-like breast cancer patients with personalized therapy (SUBITO) - an international randomized phase III trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-08.

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer

BackgroundTreatment of newly diagnosed advanced-stage ovarian cancer typically involves cytoreductive surgery and systemic chemotherapy. We conducted a trial to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer.MethodsIn a multicenter, open-label, phase 3 trial, we randomly assigned 245 patients who had at least stable disease after three cycles of carboplatin (area under the curve of 5 to 6 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area) to undergo interval cytoreductive surgery either with or without administration of HIPEC with cisplatin (100 mg per square meter). Randomization was performed at the time of surgery in cases in which surgery that would result in no visible disease (complete cytoreduction) or surgery after which one or more residual tumors measuring 10 mm or less in diameter remain (optimal cytoreduction) was deemed to be feasible. Three additional cycles of carboplatin and paclitaxel were administered postoperatively. The primary end point was recurrence-free survival. Overall survival and the side-effect profile were key secondary end points.ResultsIn the intention-to-treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; P=0.003). The median recurrence-free survival was 10.7 months in the surgery group and 14.2 months in the surgery-plus-HIPEC group. At a median follow-up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% CI, 0.48 to 0.94; P=0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery-plus-HIPEC group, P=0.76).ConclusionsAmong patients with stage III epithelial ovarian cancer, the addition of HIPEC to interval cytoreductive surgery resulted in longer recurrence-free survival and overall survival than surgery alone and did not result in higher rates of side effects. (Funded by the Dutch Cancer Society; ClinicalTrials.gov number, NCT00426257; EudraCT number, 2006-003466-34.)

Une tumeur mullérienne mixte maligne rétropéritonéale de localisation et pronostic exceptionnels

Primary retroperitoneal carcinosarcoma or mixed malignant mullerian tumor (MMMT) is an extremely rare clinical entity. These aggressive tumors arise most commonly from genital tract. The retroperitoneal location is exceptional. Here we report the case of a 63-years old female diagnosed with heterologous, extra-genital, retroperitoneal carcinosarcoma, with malignant cells in the ascitic fluid and extra-ovarian metastatic implants. She was treated with complete radical surgical treatment consisting of resection of the retroperitoneal tumor, with omentectomy, hysterectomy, bilateral salpingooophorectomy and lumbo-aortic and pelvic lymphadenectomy. She received adjuvant chemotherapy with 6 cycles of Carboplatin and Paclitaxel. She is in complete clinical and radiological remission since the end of chemotherapy, for a total of 113 months. To our knowledge, this is the longest reported disease free survival of the extra-genital retroperitoneal MMMT. This case and the review of the literature illustrate the importance of surgical treatment. However, there are no evidence-based guidelines for the systemic management of these tumors.

Robotic Splenectomy for Isolated Splenic Recurrence of Endometrial Adenocarcinoma

Study ObjectiveTo demonstrate management of a rare case of an isolated intraparenchymal splenic metastasis of endometrial cancer with robotic-assisted surgery. DesignCase report (Canadian Task Force Classification III). SettingA 55-year-old patient with a history of endometrial cancer was found to have a splenic lesion on a follow-up examination. She underwent surgical staging, involving total hysterectomy, bilateral salpingo-oopherectomy, pelvic lymphadenectomy, and peritoneal washing, in 2014, and the final pathological findings showed an endometrioid endometrial adenocarcinoma, International Federation of Gynecology and Obstetrics stage IB G2. Multidisciplinary counseling was provided, and the patient opted for strict medical surveillance. At 20 months after the primary treatment, the patient experienced a vaginal cuff recurrence and refused radiation therapy. She instead underwent robotic surgery, followed by 6 cycles of carboplatin 6 AUC and paclitaxel 175 mg/m2. Seventeen months later, a positron emission tomography/computed tomography scan revealed a 3-cm intraparenchymal lesion of the spleen, and robotic splenectomy was scheduled. The Institutional Review Board approved this study. InterventionThe operative time was 90 minutes, and blood loss was <50 mL. The operation was performed successfully, with no intraoperative and postoperative complications. Histopathological analysis showed a 3-cm intraparenchymal splenic lesion. The patient was discharged on day +2, and 46 days later started adjuvant chemotherapy based on carboplatin 6 AUC and doxorubicin (Caelyx) 30 mg/m2. At a 2-month follow-up, the patient was disease-free and in good general condition. ConclusionThis case demonstrates the successful robotic management of recurrent endometrial cancer.

445P - Phase II study of efficacy of bevacizumab plus chemotherapy in management of malignant pleural effusion in non-squamous non-small cell lung cancer patients with malignant pleural effusion (MPE) unsuccessfully controlled by tube drainage or pleurodesis (NEJ-13-2 trial)

Background: Prospective and retrospective studies on intrapleural therapy of malignant pleural effusion (MPE) have reported that the success rate for controlling pleural effusion is 50% at 2.5 months. When pleurodesis is unsuccessful, the lung is not fully expanded after drainage before receiving effective chemotherapy. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of MPE. Here, a multicenter phase II trial was conducted to evaluate bevacizumab therapy in non-squamous NSCLC patients with unsuccessful management of MPE. Methods: Non-squamous NSCLC patients with MPE who had received unsuccessful tube drainage or pleurodesis received chemotherapy with bevacizumab (15 mg/kg) every 3 weeks. The primary endpoint was pleural effusion control rate (PECR), defined as the percentage of patients without reaccumulation of MPE for 8 weeks. The secondary endpoint was pleural Progression-free survival (PPFS), defined as PFS without reaccumulation of MPE. Results: Fifteen of 20 patients entered received a median of 4 cycles of carboplatin plus paclitaxel or pemetrexed including maintenance therapy with bevacizumab. The PECR was 80% of treated patients. PPFS was 16.6 months. The response rate and disease control rate were 45% and 80%, respectively, and the median PFS and overall survival (OS) were 9.8 months and 19.6 months, respectively. The patients with high VEGF (<1000pg/ml) in MPE had shorter PPFS (P = 0.01) and OS (P < 0.01). Toxicities of grade ≥3 included neutropenia (50.0%), thrombocytopenia (10.0%), proteinuria (10.0%) and hypertension (2.0%). Global QOL score investigated by EORTC QLQ-C30 favored in the patients without reaccumulation of MPE. Conclusions: The combination of bevacizumab with chemotherapy demonstrated efficacy with acceptable toxicities as a standard therapy in controlling MPE in patients with non-squamous NSCLC whose MPE was unsuccessfully controlled by tube drainage or pleurodesis. Clinical trial indentification: trial protocol number (NIH or European equivalent) is UMIN000006868. The release data is 10/12/2011. Legal entity responsible for the study: North East Japan Study Group Funding: None Disclosure: Y. Hosomi: Research funding from Chugai, MSD, Boheringer and Astrazeneca, H. Okamoto: Reserch funding from Chugai MSD Taiho AstraZeneca, Merck, Eli Lilly, Bristol and Astellas. K. Hagiwara: Patents, Royalties from LSI Medience, K. Kubota: Research funding from Chugai, Astrazeneca, Bheringer and Lilly. A. Gemma: Research fundung from Astrazeneca, Taiho, Chugai, MSD, Lilly and Bheringer. All other authors have declared no conflicts of interest.

A Phase 2 Dose and Volume De-escalation Trial for High- and Low-Risk HPV+ Oropharynx Cancer: Efficacy, Toxicity, and Dosimetric Analyses

In this prospective phase II de-escalation study, we used induction chemotherapy to identify favorable HPV+ oropharyngeal cancer (OPC) pts, including those with high-risk tumors, and applied significantly lower radiation or chemoradiation doses than previously reported. Pts with HPV+ OPC were classified as low-risk (≤T3, ≤N2B, ≤10 PYH) or high-risk (T4 or ≥N2C or >10 PYH). Pts received 3 cycles of carboplatin (AUC 6, D1) and nab-paclitaxel (100 mg/m2, D1/8/15). 1) Low-risk pts with ≥50% response received low-dose radiotherapy alone to 50 Gy (RT50). 2) Low-risk pts with 30-50% response OR high-risk pts with ≥50% response received low-dose chemoradiotherapy to 45 Gy (CRT45). 3) All other ( = poor response) pts received regular-dose chemoradiotherapy to 75 Gy (CRT75). All pts also received de-escalated RT volumes limited to the first echelon of uninvolved nodes. RT50 was delivered in 2 Gy/fx once daily. CRT arms consisted of paclitaxel, 5-FU, hydroxyurea, and 1.5 Gy twice daily RT every other week. Primary site biopsy and neck dissection were performed only after de-escalated treatment (RT50, CRT45) for pathologic confirmation. The primary endpoint was 2-year PFS. Secondary endpoints included pathologic complete response (pCR) rate and toxicity. Sixty-two pts were enrolled. Twenty-eight pts (45.2%) were low-risk and 34 pts (54.8%) were high-risk. A total of 71.4% of low-risk pts received RT50 and 21.4% received CRT45. 70.6% of high-risk pts received CRT45. The pCR rate was 94.4% after RT50 and 92.3% after CRT45. Median follow-up is 1 year. The 2-year PFS and OS were both 100% for low-risk pts, and 91.6% and 97.0% for high-risk pts. Mean dose to all OARs was significantly reduced as shown in the table below. Significant decrease in the rates of grade ≥3 mucositis (15.8% RT50, 46.4% CRT45, 60.0% CRT75, P = .033) and grade ≥3 dermatitis (0% RT50, 21.4% CRT45, 30.0% CRT75, P = .056) were observed. PEG-tube dependency was improved at 3 months (0% RT50, 14.8% CRT45, 70.0% CRT75, P<.001) and 6 months (0% RT50, 3.7% CRT45, 20.0% CRT75, P = .066) post-treatment. Favorable response to induction chemotherapy appears to be a powerful biomarker for dose and volume de-escalation with 50 Gy RT or 45 Gy CRT. Outstanding survival and high pCR rates suggest that completion neck dissection may not be necessary. Benefits in OAR sparing translated to significantly improved toxicity and functional outcomes.Abstract 290; Table 1OAR ─ Mean Dose (Gy)RT50CRT45CRT75ANOVA P-valueIpsilateral Parotid29.927.341.7<.001Contralateral Parotid14.715.624.3.001Ipsilateral Submandibular51.446.077.1<.001Contralateral Submandibular40.937.961.6<.001Pharyngeal Constrictor45.038.062.4<.001Larynx40.534.754.2<.001Oral Cavity26.424.543.9<.001 Open table in a new tab

Body weight, hemoglobin, and absolute neutrophil count in patients with advanced-stage epithelial ovarian cancer who received chemotherapy: A single-center study

The side effects of chemotherapy, a treatment modality of ovarian cancer, can disrupt overall treatment. To date, the clinical and laboratory profiles of ovarian cancer patients during chemotherapy have not been investigated. This study aimed to elucidate the clinical and laboratory profiles of patients with advanced-stage epithelial ovarian cancer who received chemotherapy in Dr. Cipto Mangunkusumo Hospital, including body mass index (BMI), hemoglobin (Hb), and absolute neutrophil count (ANC). To generate these clinical and laboratory profiles, we collected secondary data from the medical records of advanced-stage epithelial ovarian cancer patients who received six cycles of carboplatin and paclitaxel chemotherapy. We enrolled 23 patients with advanced-stage epithelial ovarian cancer patients who received six cycles of chemotherapy. Mean patient BMI before and after chemotherapy was 22.86 kg/m2 and 21.78 kg/m2, respectively. Hb levels before chemotherapy were 8–13 g/dl, with Hb < 10 g/dl in one patient (4.35%) and Hb ≥ 10 g/dl in 22 patients (95.65%). Mean ANC was 5845.6 ± 3325.0. An average of 24.65% of patients experienced anemia after each cycle of chemotherapy. Mean ANC before chemotherapy was 3.5582 ± 3.3250. An average of 26.81% of patients had ANC <1500 after each cycle of chemotherapy; no patients had ANC <1500 before chemotherapy initiation. After six cycles of chemotherapy, three patients (13.04%) had mild neutropenia, four patients (17.39%) had moderate neutropenia, and one patient (4.35%) had severe neutropenia. Of the 22 patients with Hb ≥ 10 g/dl before chemotherapy, 16 (72.72%) experienced a decrease in ANC during chemotherapy. Of the 20 patients (60.87%) with normal BMI or higher, 14 experienced a decrease in ANC during chemotherapy. The mean patient body weight decreased after six cycles of chemotherapy. Hb and ANC were persistently decreased in approximately a quarter of the 23 subjects. The decrease in ANC was not influenced by initial Hb and BMI.

Primary Fallopian Tube Carcinoma Presenting with Isolated Controlateral Inguinal Lymphadenopathy

Primary fallopian tube carcinoma is a rare tumor accounting for <1% of all female genital tract cancers. Presentation primarily as inguinal lymphadenopathy alone is rare. We report a case of a 57-year postmenopausal woman who presented with seven months history of swelling in the right groin, excised and confirmed to be metastatic adenocarcinoma. CA-125 was elevated with a value of 960 U/ml. An exploratory laparoscopy was done, with total abdominal hysterectomy, omentectomy, and appendicectomy, without lymph node dissection. Uterus, right fallopian tube, and ovaries were normal. The left fallopian tube was distended with a mass of 6x5 cm. Histology of left fallopian tube revealed high-grade adenocarcinoma with malignant peritoneal cytology. Histology of right fallopian tube and other structures was normal. The patient received four cycles of adjuvant carboplatin plus taxol with good biological and radiological response. She was referred to our institute for a second look surgery and lymph node dissection. Two months after the end of chemotherapy, she underwent the second surgery consisting of a pelvic, para-aortic and right inguinal lymphadenectomy with a sample from the left inguinal node. There were two metastatic nodes. The patient received six other cycles of carboplatin plus taxol. At present, she remains well, and CA-125 is normal. Fallopian tube adenocarcinoma rarely presents as metastatic inguinal lymphadenectomy. The management of this malignancy is generally the same as epithelial ovarian cancer.