Robert S. Mannel

Radiation myelitis: A complication of concurrent cisplatin and 5-fluorouracil chemotherapy with extended field radiotherapy for carcinoma of the uterine cervix

Radiation myelitis is a rare but serious complication of radiation therapy. The total dose of radiation to the spinal cord required to cause myelopathy is greater than 50 Gy when the treatment is administered in 25 or more fractions; however, recent evidence has suggested that the concurrent use of chemotherapy may decrease the tolerance of the spinal cord to radiation. This report describes a case of radiation myelitis in a patient after concomitant fluorouracil/cisplatin chemotherapy and extended field radiotherapy for stage IIA adenosquamous cell carcinoma of the uterine cervix metastatic to the para-aortic lymph nodes.

Simplified postoperative patient-controlled analgesia on a gynecologic oncology service

Twenty-nine women who underwent various abdominal operations for gynecologic malignancies self-administered postoperative analgesia by means of disposable Travenol Infusors with Patient Control Modules. Administration of morphine sulfate at a rate of 1 mg per injection and a maximum of 10 mg per hour via patient-controlled analgesia was judged satisfactory by all 29 patients. The mean dose rate administered ranged from 1.2 to 1.5 mg per hour per day during the first 3 days postoperatively. No respiratory depression occurred and excessive sedation was reported by only 2 patients after the first 24 hr postoperatively. If further surgeries were required, more than 90% of these patients would prefer patient-controlled analgesia to intramuscular injections.

Intraperitoneal cisplatin: Comparison of antitumor activity and toxicity as a function of solvent saline concentration

The use of increasing concentrations of NaCl in the solvent during administration of cisplatin is known to decrease nephrotoxicity, but its effect on antitumor activity is less certain. A murine tumor model employing the subrenal capsule assay was used to test the toxicity and antitumor activity of intraperitoneal cisplatin at different doses of the drug using varying concentrations of NaCl in the vehicle of administration. Toxicity (measured by LD50, weight loss, and nephrotoxicity) was significantly lower in mice treated with cisplatin prepared in 4.5% NaCl as compared to cisplatin prepared in distilled water (DW) or 0.9% NaCl. Administration of 4.5% NaCl subcutaneously along with intraperitoneal cisplatin prepared in DW failed to decrease toxicity. Despite lower toxicity, no decrease in antitumor activity could be demonstrated based on increasing concentrations of NaCl in the solvent during intraperitoneal therapy.

Use of a murine model for comparison of intravenous and intraperitoneal cisplatin in the treatment of microscopic ovarian cancer

The most effective method for the delivery of cisplatin chemotherapy in the treatment of epithelial ovarian cancer limited to the presence of microscopic intraperitoneal disease is a controversial issue. The use of intravenous (iv) versus intraperitoneal (ip) cisplatin was evaluated in a murine tumor model of human epithelial ovarian cancer. Using single dose cisplatin therapy for microscopic disease limited to positive cytology of abdominal disease and microscopic peritoneal involvement, ip therapy had significantly greater (P less than 0.001) survival time than iv therapy (28 +/- 1.6 days vs. 23 +/- 1.6 days, respectively). Once ascites and macroscopically evident intraperitoneal tumor became apparent, no difference could be found in survival time based on iv versus ip therapy (16 +/- 3 days for both groups); though both forms of therapy significantly (P less than 0.05) prolonged survival in mice with macroscopic disease when compared to control animals (13 +/- 1.2 days). The evidence presented implies that ip cisplatin therapy is significantly more effective than iv therapy when dealing with microscopic intraperitoneal disease.

Treatment of advanced and recurrent endometrial carcinoma: Correlation of patient response to hormonal and cytotoxic chemotherapy and the response predicted by the subrenal capsule chemosensitivity assay

The tumors from 38 patients with advanced or recurrent endometrial carcinoma were assayed by the subrenal capsule xenograft assay (SRCA) for sensitivity to hormonal and cytotoxic chemotherapy. Three patients initially received radiation therapy. All other patients received maximal surgical debulking followed by treatment with radiation therapy (5), and/or hormonal (19), and cytotoxic (30) chemotherapy. All the patients who received hormonal chemotherapy had progression of disease. There were 2 complete responses, 5 partial responses, and 26 disease progressions with cytotoxic chemotherapy; and 2 complete responses, 2 partial responses, and 5 disease progressions with radiation therapy. The SRCA was 100% predictive of the response of the tumors to hormonal therapy and had 75% sensitivity, 65% specificity, and 66% efficiency of the response of the tumors to cytotoxic chemotherapy. Laboratory assays of tumor response to radiation therapy were not measured. Those patients with early stage, well-differentiated tumors with no residual disease had the longest survival times. Absence of residual disease after the first surgery was the most important delineator of survival for all categories of patients.

A Phase II trial of intravenous bevacizumab, paclitaxel and intraperitoneal cisplatin followed by intravenous bevacizumab maintenance for treatment of stage II-III ovarian cancer

Objective: Acceptance of intraperitoneal (IP) chemotherapy has not been widespread with anticipated toxicity commonly cited as a limitation of this therapy. We evaluated a modified IP regimen with IV bevacizumab to determine feasibility and assess toxicities. Methods: A phase II study was conducted in patients with advanced ovarian cancer following cytoreduction to < 1cm residual disease. The primary aim was to evaluate feasibility as defined as completion of 6 cycles. Patients received IV paclitaxel 135 mg/m2 and IV bevacizumab 15 mg/kg (cycle 2-6) on day 1 followed by cisplatin 75 mg/m2 IP day 2, repeated every 21 days x 6 cycles. Following primary therapy, patients received IV bevacizumab 15 mg/kg maintenance q21 days x 12 cycles. The FACT GOG NTX tool was used to prospectively monitor neuropathy scores over treatment. Results: 20 evaluable patients are presented including 85% with stage III disease, and 75% with no gross residual. 85% received 6 cycles of IP therapy and 77% of these received all 12 cycles of maintenance. Scores for neuropathy worsened through cycle 6, peaked at 9 and improved by 18. Toxicity was acceptable with neutropenia the most common grade 3-4 adverse event, and 8 patients experienced grade 2-3 neuropathy. With a median follow-up of 63 months, the median PFS and OS is 50 and 71 months respectively. Conclusions: Adding IV bevacizumab to a modified IP regimen is feasible. As compared to GOG 172, the lower cisplatin dose and omission of day 8 IP paclitaxel may allow a higher completion rate. Despite modifications, neuropathy remains important issue in IP based cisplatin regimens. Correspondence to: Kathleen N. Moore, MD, Stephenson Oklahoma Cancer Center, 800 NE 10th St Oklahoma City, Oklahoma 73121, USA, Tel: 405-2718707; Fax: 405-271-2976, E-mail: kathleen-moore@ouhsc.edu Received: September 30, 2015; Accepted: October 22, 2015; Published: October 26, 2015 Introduction Ovarian cancer is the leading cause of death from gynecologic cancer in the United States [1]. The high death rate stems from late presentation and tumor that has spread beyond the ovary and throughout the peritoneal cavity at the time of diagnoses [2]. Three randomized clinical trials have demonstrated the superiority of intraperitoneal (IP) over intravenous (IV) platinum based chemotherapy in patients with optimally debulked advanced stage ovarian cancer [3-5] (Table 1). The most recent is Gynecologic Oncology Group (GOG) protocol 172; a phase III randomized trial comparing IV paclitaxel plus cisplatin versus IV paclitaxel (135 mg/m2 over 24 hours on day 1) plus IP cisplatin (100 mg/m2 on day 2) and IP paclitaxel (60 mg/m2on day 8) in patients with <1 cm residual disease. Both progression-free (PFS) (median, 18.3 vs. 23.8 months) and overall survival (OS) (median, 49.7 vs. 65.6 months) was significantly improved with the IP regimen [5]. Widespread acceptance of this IP regimen was not seen because of toxicities associated with the therapy [6]. Only 42% of women on the IP arm of GOG 172 received 6 cycles of therapy, and 49% received 3 or fewer cycles [5]. Patients who were randomized to the IP therapy group in GOG-172 had higher rates of adverse events for neurologic, gastrointestinal, metabolic, infection, febrile, and hematologic toxicities [6]. Parallel with the studies of IP therapies have been investigations of targeted therapies, specifically those that target angiogenesis. Phase II studies demonstrated single agent activity of the VEGF antibody, bevacizumab, [7-9] and two phase III studies in front-line therapy were initiated based on the premise that combining chemotherapy with bevacizumab or maintenance bevacizumab following chemotherapy would improve outcomes [10,11]. The pivotal phase III GOG 218 trial demonstrated progression-free survival (PFS) benefit in patients who received concurrent and maintenance bevacizumab compared with Lanneau GL (2015) A Phase II trial of intravenous bevacizumab, paclitaxel and intraperitoneal cisplatin followed by intravenous bevacizumab maintenance for treatment of stage II-III ovarian cancer Volume 1(3): 60-65 Clin Obstet Gynecol Reprod Med, 2015 doi: 10.15761/COGRM.1000117 chemotherapy alone (14.1 months vs. 10.3 months; hazard ratio (HR) 0.717, p<0.001). However, there was no difference in overall survival (OS) reported [10]. A subset analysis was performed on the patients with stage IV disease who received bevacizumab and did find an OS benefit of 40.6 compared to 32.8 months (HR=0.72; 95% CI 0.53-0.97) [12]. In parallel ICON 7 demonstrated an improvement in PFS (19 vs. 17.3 months; HR 0.81, p=0.004, no improvement in OS except in those with stage IV and sub-optimal residual disease who had a median OS of 39.7 vs. 30.3 months [13]. This study sought to enhance IP chemotherapy delivery by reducing toxicity as well as combine IP chemotherapy with IV bevacizumab which had not been widely reported at the time of study inception. We sought to evalute the feasibiltiy of administering a modification of the GOG 172 IP regimen with the addition of IV bevacizumab. Feasibility would be judged based on the ability to complete 6 cycles of therapy and on the toxicity profile of the regimen. Methods After institutional review board approval, an open label phase II study was conducted in patients with stage II-III ovarian (epithelial and carcinosarcoma), fallopian tube, or primary peritoneal cancers with residual disease ≤ 1 cm following initial CRS. The primary aim of the study was to evaluate the feasibility of delivering IP cisplatin with IV paclitaxel and IV bevacizumab as defined by the proportion of patients able to complete 6 cycles of the IP based treatment. Eligible patients had a GOG performance status of 0-1, normal baseline hematologic, renal, and hepatic laboratory values, and had a protein/urine creatinine ratio < 1.0. All patients were to be treated within 12 weeks of surgery. Patients with borderline tumors or stage IV disease were excluded. Patients with significant cardiovascular history, uncontrolled hypertension, or nonhealing wounds were excluded. IP ports were placed either at the time of initial surgery or as a secondary procedure using the recommended surgical approaches from the GOG surgical manual. Patients received IV paclitaxel 135 mg/m2 over 3 hours and IV bevacizumab 15 mg/kg (cycle 2-6) on day 1 followed by IP cisplatin 75 mg/m2 IP on day 2. Patients received standard hypersensitivity prophylaxis and anti-emetic medications. All patients received preand postcisplatin hydration on day 2 with 2 L normal saline administered IV over 2-4 hours. Cycles were administered every 21 days for a total of 6 cycles. Following completion of primary therapy, IV bevacizumab at 15 mg/kg IV was given as maintenance therapy every 21 days for 12 cycles or until disease progression or excessive toxicity. Patients were seen each cycle and toxicities were recorded and graded by the NCI common toxicity criteria version 3.0. In addition, the FACT-GOG/ NTX4 neuropathy assessement tool was administered at baseline, following cycles 3 and 6, then after every cycle during maintneance therapy [14]. Dose delays and modifications were used to manage significant neuropathy, neutropenia, or thrombocytopenia. Blood count recovery to an absolute neutrophil count (ANC) ≥1500/ mm3 and platelets ≥100,000/mm3 were required to treat for the subsequent cycle. Patients were removed from study if a delay of >3weeks was required. Patients were required to maintain a home log of their blood pressures and these were assessed prior to each treatment and used to assess whether bevacizumab would be administered. If blood pressure was ≤150 mm/≤90 mm Hg bevacizumab was continued. Grade 3 hypertension (HTN) was managed by use of anti-hypertensive medications and treatment delays, and grade 4 HTN required discontinuation of bevacizumab. Proteinuria was monitored prior to every cycle using the protein creatinine ratio, and were continued on treatment provided the ratio was <3.5. Statistics The GOG 172 study suggested that completion rates of 6 cycles of IP based therapy was ~ 40%. It was felt that improving the rate of successful completion to 80% would be clinically relevant. With a sample size of 20 patients, 13 or more completing therapy would exceed the historical rate of completion (40%) (95% CI 13/20: 40.7-84.6%). Patients were assessed each treatment cycle, then every 3 months for two years, then every 6 months for 3 years. Imaging studies were performed based on presence of symptoms, clinical findings, or rising CA125 levels. PFS was measured from start of treatment to disease progression and OS was measured from diagnosis to death or last follow up. Results From August 2007 to September 2008, 22 patients were enrolled in the study and 20 were evaluable for feasibility of completion of 6 cycles. Of the 20 evaluable patients, median age was 59 years, 85% had stage III disease, 60% had high-grade and 20% had low-grade serous tumors (Table 2). All patients underwent primary CRS and were left with <1 cm residual disease (75% no gross). During the cytotoxic treatment phase, 3 patients were unable to complete all 6 cycles of therapy. One patient had an IP port complication at cycle 4, another had persistent grade 3 neuropathy after cycle 4, and 1 patient received 5 cycles of IP based therapy but due to grade 3 abdominal pain with IP therapy received cycle 6 intravenously. Overall, Study PFS (median) OS (median) SWOG/GOG-104 Alberts et al. [4] 49 mo (IP) vs. 41 mo (IV), p=0.02 GOG-114/SWOG Markman et al. [3] 28 mo (IP) vs. 22 (IV), p= 0.01 63 mo (IP) vs. 52 (IV), p= 0.05 GOG-172 Armstrong et al. [5] 24 mo (IP) vs.18 (IV), p= 0.05 65.6 mo (IP) vs. 49.7 (IV), p= 0.03 Table 1. Phase III IP based clinical trials. Variable N= 20 N (%) %

Assessing the performance of quantitative image features on early stage prediction of treatment effectiveness for ovary cancer patients: a preliminary investigation

The objective of this study is to investigate the performance of global and local features to better estimate the characteristics of highly heterogeneous metastatic tumours, for accurately predicting the treatment effectiveness of the advanced stage ovarian cancer patients. In order to achieve this , a quantitative image analysis scheme was developed to estimate a total of 103 features from three different groups including shape and density, Wavelet, and Gray Level Difference Method (GLDM) features. Shape and density features are global features, which are directly applied on the entire target image; wavelet and GLDM features are local features, which are applied on the divided blocks of the target image. To assess the performance, the new scheme was applied on a retrospective dataset containing 120 recurrent and high grade ovary cancer patients. The results indicate that the three best performed features are skewness, root-mean-square (rms) and mean of local GLDM texture, indicating the importance of integrating local features. In addition, the averaged predicting performance are comparable among the three different categories. This investigation concluded that the local features contains at least as copious tumour heterogeneity information as the global features, which may be meaningful on improving the predicting performance of the quantitative image markers for the diagnosis and prognosis of ovary cancer patients.