A phase 1 dose-escalation study of intraperitoneal cisplatin, intravenous/intraperitoneal paclitaxel, bevacizumab, and olaparib for newly diagnosed ovarian cancer.

OBJECTIVE: We assessed the safety and maximum tolerated dose (MTD) of the poly ADP-ribose polymerase (PARP) inhibitor olaparib with intravenous (IV)/intraperitoneal (IP) cisplatin/paclitaxel and IV bevacizumab, followed by olaparib and bevacizumab maintenance, in patients with newly diagnosed ovarian cancer who had undergone primary debulking surgery. METHODS: Treatment included: (Cycles 1-6) Day 1, IV paclitaxel 135 mg/m2/3 h + (from Cycle 2 onward) bevacizumab 15 mg/kg; Day 2, IP cisplatin 75 mg/m2; Days 2-8, olaparib (50/100/200 mg BID); Day 8, IP paclitaxel 60 mg/m2 of a 21-day cycle. Maintenance (Cycles 7-22) included: olaparib 300 mg BID and bevacizumab 15 mg/kg Day 1. The primary endpoint was MTD of olaparib, chemotherapy, and bevacizumab. RESULTS: Seventeen women were treated (Cohort 1 [50 mg olaparib], 8 patients; Cohort 2 [100 mg], 3 patients; and Cohort 3 [200 mg], 6 patients). Median age was 57 years (47-73); 94% had stage III disease; 29% had a germline BRCA mutation. Two of 6 patients in Cohort 3 experienced a dose-limiting toxicity (DLT). Grade 3/4 toxicities included: neutropenia (56%), lymphopenia (31%), anemia (25%), and fatigue (19%). Most patients started (88%, 81%) and completed (75%, 50%) maintenance olaparib and bevacizumab, respectively; 36% of patients on olaparib maintenance required a dose reduction. Median PFS was 33 months (26.2-NA). CONCLUSIONS: The MTD of intermittently dosed olaparib with concurrent IV/IP cisplatin/paclitaxel and bevacizumab is 100 mg BID. Non-hematologic toxicities were predominantly low grade. One-third of patients on olaparib maintenance required dose reduction.

A multimodality triage algorithm to improve cytoreductive outcomes in patients undergoing primary debulking surgery for advanced ovarian cancer: A Memorial Sloan Kettering Cancer Center team ovary initiative.

OBJECTIVE: To describe outcomes using a multimodal algorithm to triage patients with advanced epithelial ovarian cancer (EOC) to primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT). METHODS: All patients with EOC treated at our institution from 04/2015-08/2018 were identified. We included patients without contraindication to PDS who underwent prospective calculation of a Resectability (R)-score. A low risk score for suboptimal cytoreduction was defined as ≤6, and a high risk score ≥7. Patients were triaged to laparotomy/PDS, laparoscopic evaluation of resectability (LSC), or NACT depending on R-score. RESULTS: Among 299 participants, 226 (76%) had a low risk score and 73 (24%) a high risk score. For patients with a low risk score, management included laparotomy/PDS, 181 (80%); LSC, 43 (19%) (with subsequent triage: PDS, 31; NACT, 12); and NACT, 2 (1%). For patients with a high risk score, management included laparotomy/PDS, 9 (12%); LSC, 51 (70%) (with subsequent triage: PDS, 28; NACT, 23); and NACT, 13 (18%). Overall, 83% underwent PDS, with a 75% CGR rate and 94% optimal cytoreduction rate. Use of the algorithm resulted in a 31% LSC rate and a 6% rate of suboptimal PDS. CONCLUSIONS: The multimodal algorithm led to excellent surgical results; 94% of patients achieved an optimal resection, with a very low rate of suboptimal cytoreduction.

Models to predict outcomes after primary debulking surgery: Independent validation of models to predict suboptimal cytoreduction and gross residual disease.

OBJECTIVE: Treatment planning requires accurate estimation of surgical complexity (SC) and residual disease (RD) at primary debulking surgery (PDS) for advanced ovarian cancer (OC). We sought to independently validate two published computed tomography (CT) prediction models. METHODS: We included stage IIIC/IV OC patients who underwent PDS from 2003 to 2011. Two prediction models which included imaging and clinical variables to predict RD > 1 and any gross RD, respectively, were applied to our cohort. Two radiologists scored CTs. Discrimination was estimated using the c-index and calibration were assessed by comparing the observed and predicted estimates. RESULTS: The validation cohort consisted of 276 patients; median age of the cohort was 64 years old and majority had serous histology. The validation and model development cohorts were similar in terms of baseline characteristics, however the RD rates differed between cohorts (9.4% vs 25.4% had RD >1 cm; 50.7% vs. 66.6% had gross RD). Model 1, the model to predict RD >1 cm, did not validate well. The c-index of 0.653 for the validation cohort was lower than reported in the development cohort (0.758) and the model over-predicted the proportion with RD >1 cm. The second model to predict gross RD had excellent discrimination with a c-index of 0.762. CONCLUSIONS: We are able to validate a CT model to predict presence of gross RD in an independent center; the separate model to predict RD >1 cm did not validate. Application of the model to predict gross RD can help with clinical decision making in advanced ovarian cancer.

A multicenter assessment of the ability of preoperative computed tomography scan and CA-125 to predict gross residual disease at primary debulking for advanced epithelial ovarian cancer.

OBJECTIVE: To assess the ability of preoperative computed tomography scan and CA-125 to predict gross residual disease (RD) at primary cytoreduction in advanced ovarian cancer. METHODS: A prospective, non-randomized, multicenter trial of patients who underwent primary debulking for stage III-IV epithelial ovarian cancer previously identified 9 criteria associated with suboptimal (>1cm residual) cytoreduction. This is a secondary post-hoc analysis looking at the ability to predict any RD. Four clinical and 18 radiologic criteria were assessed, and a multivariate model predictive of RD was developed. RESULTS: From 7/2001-12/2012, 350 patients met eligibility criteria. The complete gross resection rate was 33%. On multivariate analysis, 3 clinical and 8 radiologic criteria were significantly associated with the presence of any RD: age≥60years (OR=1.5); CA-125≥600U/mL (OR=1.3); ASA 3-4 (OR=1.6); lesions in the root of the superior mesenteric artery (OR=4.1), splenic hilum/ligaments (OR=1.4), lesser sac >1cm (OR=2.2), gastrohepatic ligament/porta hepatis (OR=1.4), gallbladder fossa/intersegmental fissure (OR=2); suprarenal retroperitoneal lymph nodes (OR=1.3); small bowel adhesions/thickening (OR=1.1); and moderate-severe ascites (OR=2.2). All ORs were significant with p<0.01. A 'predictive score' was assigned to each criterion based on its multivariate OR, and the rate of having any RD for patients who had a total score of 0-2, 3-5, 6-8, and ≥9 was 45%, 68%, 87%, and 96%, respectively. CONCLUSIONS: We identified 11 criteria associated with RD, and developed a predictive model in which the rate of having any RD was directly proportional to a predictive score. This model may be helpful in treatment planning.

Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a prospective cohort study.

Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. Rivaroxaban was approved in 2012 for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but no prior studies have been reported specifically evaluating the efficacy and safety of rivaroxaban for cancer-associated thrombosis (CAT). Under a Quality Assessment Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT and now report a validation analysis of our first 200 patients. A 200 patient cohort with CAT (PE or symptomatic, proximal DVT), whose full course of anticoagulation was with rivaroxaban, were accrued. In competing risk analysis, primary endpoints at 6 months included new or recurrent PE or symptomatic proximal lower extremity DVT, major bleeding, clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. In competing risk analysis, the 6 months cumulative incidence of new or recurrent VTE was 4.4 % (95 % CI = 1.4-7.4 %), major bleeding was 2.2 % (95 % CI = 0-4.2 %) and all-cause mortality 17.6 % (95 % CI = 11.7-23.0 %). In this cohort of 200 patients with active cancer and CAT the rates of new or recurrent VTE and major bleeding were comparable to the cancer subgroup analysis from the EINSTEIN studies. The results of our Clinical Pathway provide guidance on Rivaroxaban use for treatment of CAT, and suggest that safety and efficacy is preserved, compared with past-published experience with LMWH.

Is It Time to Centralize Ovarian Cancer Care in the United States?

PURPOSE: The purpose of this article was to broadly review the most up-to-date information pertaining to the centralization of ovarian cancer care in the United States (US) and worldwide. METHODS: Much of the present literature pertaining to disparities in, and centralization of, ovarian cancer care in the US and internationally was reviewed, and specifically included original research and review articles. RESULTS: Data show improved optimal debulking rates, National Comprehensive Cancer Network (NCCN) guideline adherence, and overall survival rates in higher-volume, more specialized hospitals, and amongst higher-volume providers. CONCLUSIONS: Patients with invasive epithelial ovarian cancer, especially those with higher stages (III and IV), are better served by centralized care in high-volume hospitals and by high-volume physicians, who adhere to NCCN guidelines wherever possible. More research is needed to determine the policy changes that can increase NCCN guideline adherence in low-volume hospitals and low-provider caseload scenarios. Policy and future research should be aimed at increasing patient access, either directly or indirectly, to high-volume hospital and high-volume providers, especially amongst Medicare, lower socioeconomic status, and minority patients.

A multicenter prospective trial evaluating the ability of preoperative computed tomography scan and serum CA-125 to predict suboptimal cytoreduction at primary debulking surgery for advanced ovarian, fallopian tube, and peritoneal cancer.

OBJECTIVE: To assess the ability of preoperative computed tomography (CT) scan of the abdomen/pelvis and serum CA-125 to predict suboptimal (>1cm residual disease) primary cytoreduction in advanced ovarian, fallopian tube, and peritoneal cancer. METHODS: This was a prospective, non-randomized, multicenter trial of patients who underwent primary cytoreduction for stage III-IV ovarian, fallopian tube, and peritoneal cancer. A CT scan of the abdomen/pelvis and serum CA-125 were obtained within 35 and 14 days before surgery, respectively. Four clinical and 20 radiologic criteria were assessed. RESULTS: From 7/2001 to 12/2012, 669 patients were enrolled; 350 met eligibility criteria. The optimal debulking rate was 75%. On multivariate analysis, three clinical and six radiologic criteria were significantly associated with suboptimal debulking: age ≥ 60 years (p=0.01); CA-125 ≥ 500 U/mL (p<0.001); ASA 3-4 (p<0.001); suprarenal retroperitoneal lymph nodes >1cm (p<0.001); diffuse small bowel adhesions/thickening (p<0.001); and lesions >1cm in the small bowel mesentery (p=0.03), root of the superior mesenteric artery (p=0.003), perisplenic area (p<0.001), and lesser sac (p<0.001). A 'predictive value score' was assigned for each criterion, and the suboptimal debulking rates of patients who had a total score of 0, 1-2, 3-4, 5-6, 7-8, and ≥ 9 were 5%, 10%, 17%, 34%, 52%, and 74%, respectively. A prognostic model combining these nine factors had a predictive accuracy of 0.758. CONCLUSIONS: We identified nine criteria associated with suboptimal cytoreduction, and developed a predictive model in which the suboptimal rate was directly proportional to a predictive value score. These results may be helpful in pretreatment patient assessment.

Stage IB1 cervical cancer: role of preoperative MR imaging in selection of patients for fertility-sparing radical trachelectomy.

PURPOSE: To determine whether magnetic resonance (MR) imaging evaluation of key morphologic tumor characteristics can improve patient selection for radical trachelectomy. MATERIALS AND METHODS: The institutional review board approved and waived informed consent for this study of 62 patients (mean age, 32 years; age range, 23-42 years) with International Federation of Gynecology and Obstetrics stage IB1 cervical carcinoma who underwent attempted radical trachelectomy between November 2001 and January 2011 and had preoperative MR imaging. Retrospectively, two radiologists reviewed MR images for tumor presence and size, distance between tumor and internal os, and presence of deep cervical stromal invasion. Associations between MR imaging findings and surgery type were tested. RESULTS: Sensitivity and specificity of tumor detection were, respectively, 87% and 100% (reader 1) and 76% and 95% (reader 2). Six of six patients with negative cone biopsy margins and no tumor at postconization MR imaging were without tumor at trachelectomy pathologic analysis. Mean differences between MR imaging and histologic tumor sizes were 0.7 mm (range, -15 to 11 mm) for reader 1 and 2.2 mm (range, -9 to 15 mm) for reader 2. Sensitivities for deep cervical stromal invasion were 75% (reader 1) and 50% (reader 2). For each reader, nine of nine (100%) patients with tumor 5 mm or less from the internal os and three of five (60%) patients with tumor 6-9 mm from the internal os at MR imaging needed radical hysterectomy. For both readers, tumor size of 2 cm or larger (P < .001) and deep cervical stromal invasion (P ≤ .003) at MR imaging were associated with increased chance of radical hysterectomy. CONCLUSION: Pretrachelectomy MR imaging can help identify high-risk patients likely to need radical hysterectomy or confirm the absence of residual tumor in the cervix after a cone biopsy with negative margins.

Follow-up study of the correlation between postoperative computed tomographic scan and primary surgeon assessment in patients with advanced ovarian, tubal, or peritoneal carcinoma reported to have undergone primary surgical cytoreduction to residual disease of 1 cm or smaller.

INTRODUCTION: We previously reported a 52% correlation between the primary surgeon's assessment and the postoperative computed tomographic (CT) scan findings of residual disease in patients reported to have undergone cytoreduction to residual disease of 1 cm or smaller. This is a follow-up analysis of survival and prognostic factors for patients who had concordant and discordant postoperative CT scan findings. METHODS: Patients scheduled for primary cytoreductive surgery for presumed advanced ovarian carcinoma were offered enrollment in a prospective study evaluating the ability of preoperative CT scan to predict cytoreductive outcome. If cytoreduction to residual disease of 1 cm or smaller was reported, a CT scan was done 7 to 35 days postoperatively. The CT scan findings were graded by protocol radiologists using a qualitative analysis scale from 1 (normal) to 5 (definitely malignant). RESULTS: From January 2001 to September 2006, 285 patients were enrolled; 67 patients were eligible. Postoperative CT scans confirmed the primary surgeon's assessment of no residual disease larger than 1 cm in 38 cases (57%). In 29 cases (43%), the radiologist found residual disease larger than 1 cm and reported it as probably or definitely malignant. Comparing concordant versus discordant findings, there was no significant difference in median progression-free survival (21 vs 17 months; P = 0.365) or overall survival (60 vs 43 months; P = 0.146). Age (P = 0.040), stage (P = 0.038), and residual disease of 0.5 mm or smaller versus 0.6 to 1.0 cm (P = 0.018) were significant for overall survival on multivariate analysis. CONCLUSIONS: On this follow-up analysis, only age, stage, and residual disease were significant prognostic factors for overall survival. Discordant findings between the primary surgeon's assessment and the postoperative CT scan findings of residual disease was not an independent prognostic factor.

Rivaroxaban treatment of cancer-associated venous thromboembolism: Memorial Sloan Kettering Cancer Center institutional experience.

BACKGROUND: Low-molecular-weight heparin has been the preferred treatment of cancer-associated thrombosis (CAT); however, emerging data support the use of direct oral anticoagulants (DOACs). OBJECTIVES: The Memorial Sloan Kettering Cancer Center Clinical Pathway has served as the institutional guideline for the use of rivaroxaban to treat CAT since 2014. Key elements are to recommend against use of a DOAC in patients with active gastrointestinal (GI) or genitourinary tract lesions, and a prespecified dose reduction in the elderly (75+ years old). We present our institutional experience for treatment of CAT. METHODS: From January 2014 through September 2016, 1072 patients began rivaroxaban treatment for CAT; 91.9% had a solid tumor, 8.1% had hematologic malignancies, and 75% of patients with solid tumors had metastatic disease. All patients with CAT treated with rivaroxaban were included in this analysis, regardless of adherence to the Clinical Pathway. RESULTS: The 6-month cumulative incidence of recurrent venous thromboembolism and major bleeding were 4.2% (95% confidence interval [CI], 2.7%-5.7%) and 2.2% (95% CI, 1.1%-3.2%), respectively. The incidence of clinically relevant non-major bleeding leading to discontinuation of rivaroxaban for at least 7 days was 5.5% (95% CI,  3.7%-7.1%), and 73.3% of major bleeds occurred in the GI tract. The 6-month cumulative mortality rate was 22.2% (95% CI, 19.4%-24.9%). The elderly had similar rates of recurrent thrombosis and bleeding as those aged under 75 years. CONCLUSION: Our institutional experience suggests that in appropriately selected patients, rivaroxaban may be used for treatment of CAT with promising safety and efficacy.

Romiplostim Treatment of Chemotherapy-Induced Thrombocytopenia.

PURPOSE: Chemotherapy-induced thrombocytopenia (CIT) leads to delay or reduction in cancer treatment. There is no approved treatment. METHODS: We conducted a phase II randomized trial of romiplostim versus untreated observation in patients with solid tumors with CIT. Before enrollment, patients had platelets less than 100,000/µL for at least 4 weeks, despite delay or dose reduction of chemotherapy. Patients received weekly titrated romiplostim with a target platelet count of 100,000/µL or more, or were monitored with usual care. The primary end point was correction of platelet count within 3 weeks. Twenty-three patients were treated in a randomization phase, and an additional 37 patients were treated in a single-arm, romiplostim phase. Resumption of chemotherapy without recurrent CIT was a secondary end point. RESULTS: The mean platelet count at enrollment was 62,000/µL. In the randomization phase, 14 of 15 romiplostim-treated patients (93%) experienced correction of their platelet count within 3 weeks, compared with one of eight control patients (12.5%; P < .001). Including all romiplostim-treated patients (N = 52), the mean platelet count at 2 weeks of treatment was 141,000/µL. The mean platelet count in the eight observation patients at 3 weeks was 57,000/µL. Forty-four patients who achieved platelet correction with romiplostim resumed chemotherapy with weekly romiplostim. Only three patients (6.8%) experienced recurrent reduction or delay of chemotherapy because of isolated CIT. CONCLUSION: This prospective trial evaluated treatment of CIT with romiplostim. Romiplostim is effective in correcting CIT, and maintenance allows for resumption of chemotherapy without recurrence of CIT in most patients.

Limitations of CT during PET/CT.

UNLABELLED: Our aim was to determine the diagnostic limitations of low-dose, unenhanced CT scans performed for anatomic reference and attenuation correction during PET/CT. METHODS: The Radiology Information System at our oncologic hospital was queried during the 9-mo period from July 2002 to April 2003 for patients with PET/CT scans and diagnostic enhanced CT within 2 wk of each other. One radiologist interpreted the CT portion of the PET/CT (CT(p)) unaware of the PET results and the associated enhanced diagnostic CT (CT(d)). A medical student compared this interpretation with the official report of the CT(d) and listed all discrepancies between reports. A separate radiologist compared CT(p) and CT(d) images and classified true discrepant findings as due to lack of intravenous contrast, arm-position artifact, lack of enteric contrast, low milliamperage (mA), and quality of lung images. RESULTS: Among 100 patients, the most common malignancies were lymphoma (n = 37), cancer of the colorectum (n = 31), and esophageal cancer (n = 15). Among 194 true discrepancies in which findings were missed at CT(p), causes were as follows: (a) lack of intravenous contrast (128/194, 66%), (b) arm-down artifact (17/194, 9%), (c) quality of lung images (26/194, 13%), (d) lack of enteric contrast (15/194, 8%), and (e) low mA (8/194, 4%). Discrepancies were seen most commonly in detecting lymphadenopathy and visceral metastases. CONCLUSION: Most missed findings on the unenhanced CT portion of the PET/CT scans were due to technical factors that could be altered. Discrepant findings would have led to altered management in only 2 patients, suggesting a role for limited repeat imaging to reduce radiation and use of valuable resources.

Prospective study of the correlation between postoperative computed tomography scan and primary surgeon assessment in patients with advanced ovarian, tubal, and peritoneal carcinoma reported to have undergone primary surgical cytoreduction to residual disease 1 cm or less.

PURPOSE: To compare surgeons' operative assessments of residual disease (RD) to those identified on postoperative computed tomography (CT) scans in patients with advanced ovarian carcinoma reported to have undergone optimal primary cytoreduction. PATIENTS AND METHODS: All patients at one of two institutions, who were scheduled to have primary surgery for presumed advanced ovarian cancer, were asked to consent to a postoperative CT scan if cytoreduction to < or = 1 cm RD was reported. CT scan findings were graded using a qualitative analysis scale from 1 (normal) to 5 (definitely malignant). RESULTS: From January 2001 to September 2006, 285 patients were enrolled. A total of 78 patients met eligibility criteria and had postoperative CT scans. In 41 cases (52%), postoperative scan findings correlated with the surgical report of no RD more than 1 cm, and in seven cases (9%), the CT findings were indeterminate. In 10 cases (13%), more than 1 cm RD was noted by the radiologist as probably malignant, and in 20 cases (26%), definitely malignant. In these 30 cases, the radiologically reported median largest residual mass was 1.9 cm (range, 1.1 to 5.1), with RD more than 1 cm reported most commonly in the right upper quadrant (15 patients [50%]) and central abdomen (nine patients [30%]). CONCLUSION: There was only a 52% correlation between surgeons' assessments and postoperative CT scan evaluations of RD in patients reported to have undergone optimal cytoreduction. Further study is required to determine whether this lack of correlation is due to rapid interval tumor regrowth, RD underestimated by the surgeons, and/or overestimated by the radiologists; and to determine the clinical implications of these discrepancies.

Prognostic nomogram for renal insufficiency after radical or partial nephrectomy.

PURPOSE: We analyzed prognostic factors to predict renal insufficiency after partial or radical nephrectomy. We developed and performed internal validations of a postoperative nomogram for this purpose. We used a prospectively updated renal tumor database of more than 1,500 patients. MATERIALS AND METHODS: From July 1989 to October 2003, 161 partial nephrectomies and 857 radical nephrectomies performed at Memorial Sloan-Kettering Cancer Center for renal cortical tumors were analyzed. Computerized tomography images were reviewed by a single radiologist. Kidney volume was calculated using the ellipsoid formula, V = L1 x L2 x L3 x pi/6, where V represents volume and L represents length. Renal insufficiency was defined by 2 serum creatinine values greater than 2.0 mg/dl at least 1 month postoperatively. Tumor histology was not an exclusion criterion and yet we excluded cases of bilateral synchronous disease. Prognostic variables were preoperative serum creatinine, American Society of Anesthesiologists score, percent change in kidney volume after surgery, and patient age and sex. RESULTS: Renal insufficiency was noted in 105 of the 857 patients with radical nephrectomy (12.3%) and in 6 of the 161 with partial nephrectomy (3.7%) studied. Patients had a median followup of 21.2 months (maximum 157.9). The 7-year probability of freedom from renal insufficiency in the cohort was 79.1% (95% CI 74.6 to 83.6). The nomogram was designed based on a Cox proportional hazards regression model. Following internal statistical validation nomogram predictions appeared accurate and discriminating with a concordance index of 0.835. CONCLUSIONS: A nomogram was developed that can predict the 7-year probability of renal insufficiency in patients undergoing radical or partial nephrectomy.