Refractory Epithelial Ovarian Carcinoma Research Articles

Patient self-reporting of tolerability using PRO-CTCAE in a randomized double-blind, placebo-controlled phase II trial comparing gemcitabine in combination with adavosertib or placebo in patients with platinum resistant or refractory epithelial ovarian carcinoma

BackgroundA double-blind, randomized, placebo-controlled, phase 2 trial assessed gemcitabine in combination with the wee1 inhibitor adavosertib or placebo in platinum resistant or refractory high grade serous ovarian cancer (HGSOC), demonstrating improved progression free and overall survival favouring the adavosertib/gemcitabine arm. An exploratory objective of the study included the PRO-CTCAE assessment, to capture self-reporting of frequency, severity and/or interference of symptomatic adverse events (syAEs). MethodsPRO-CTCAE items at baseline, days 1 and 15 of each cycle and off treatment, were completed in two centres, with the objective of characterizing syAEs in the first three months of therapy. The maximum post-baseline score proportion for each syAE was tabulated per patient. The 12-week area under the curve (AUC12w) as a measure of syAE over-time and incremental AUC12w (iAUC12w) for adjustment to baseline syAEs. ResultsSixty-one patients were approached for PRO-CTCAE surveys and 55 were evaluable. Among patients with HGSOC, 28 received gemcitabine/adavosertib (arm A) and 19 gemcitabine/placebo (arm B). Survey completion rates were high. The proportion of participants with positive (≥1) PRO-CTCAE scores was higher for difficulty swallowing with gemcitabine/adavosertib (arm A 35.7% vs arm B 5.3%, p = 0.02). The high score (≥3) syAEs showed more frequent diarrhea with gemcitabine/adavosertib (arm A 25% vs arm B 0%, p = 0.03). The proportions of worsening syAEs over time were higher in patients receiving gemcitabine/adavosertib for difficulty swallowing (arm A 35.7% vs arm B 5.3%; p = 0.03) and fatigue severity (arm A 71.43% vs arm B 42.1%; p = 0.04). ConclusionsThe longitudinal assessment of patient self-reported tolerability showed greater difficulty swallowing and fatigue severity in patients receiving gemcitabine/adavosertib, compared to gemcitabine/placebo. PRO-CTCAE provides complementary and objective assessment of drug tolerability from a patient's perspective.

Quality of life, vascular endothelial growth factor inhibition, and survival outcomes with combination oral metronomic therapy in platinum refractory epithelial ovarian carcinoma: Results from a randomized study.

6048 Background: Patients with recurrent and refractory epithelial ovarian cancer (EOC) have dismal outcomes. We evaluated a combination of oral metronomic therapy in platinum refractory EOC vis-à-vis angiogenic marker expression and its impact on patient reported outcomes. Methods: Between October 2017 and September 2019, 75 patients were randomized to receive etoposide (VP-16) (50 mg daily for 14 days) cyclophosphamide (50 mg daily for 28 days) (Arm A, n = 38) or etoposide (VP-16) (50 mg daily for 14 days) cyclophosphamide (50 mg daily for 28 days) and pazopanib (400 mg daily 28 days) every 28 days (Arm B, n = 37). Eligibility criteria included histopathological diagnosis of EOC, platinum refractory disease and ECOG performance status 0-2. Primary endpoint was serological progression free survival (PFS) as defined by Rustin criteria. Quality of Life (QoL) (evaluated using the EORTC QLQC30 and OV 28 questionnaires) and serum vascular endothelial growth factor (VEGF) were ascertained at baseline and after 3rd and 6th cycle. Intention to treat analysis was done. Results: Baseline characteristics were well matched in 2 arms. At a median follow up 14.4 months (95% CI 13.2-15.7), the median serological PFS is better for patients in Arm B 5.1 months (95%CI 3.13-10.33) compared to 3.4 months (95%CI 3-6.53) in arm A ( P= 0.045). Median overall survival (OS) is not reached in arm B versus 11.2 months (95%CI 5.66-NR) in arm A (P= 0.032). Disease progression was seen in 42.1% (n = 16) in Arm A versus 40.5 %(n = 15) in arm B ( P= 0.40). Sixteen patients are maintaining response. Mucositis (29.7% n = 11) and fatigue (13.5%, n = 5) were more in the pazopanib-containing arm ( P= 0.36). Serum VEGF demonstrated significant decline with subsequent cycles of therapy {median values (range): Arm A, baseline; 466.0 pg/mL(123.9-1930) vs. 6 cycles; 92.05pg/ mL(42.34-279.5) P< 0.0001; Arm B, baseline; 382.0 pg/mL(49.44-2054.0) vs 6 cycles; 119.7 pg/mL(18.20-367.5) P= 0.013} without any difference between the two arms ( P= 0.18). QoL symptom scales in both QLQC 30 and OV 28 questionnaires indicated small but significant improvement in pazopanib arm ( P= 0.02) without differences in global (p = 0.96) and physical functioning scales. ( P= 0.68). Conclusions: Addition of pazopanib to etoposide and cyclophosphamide resulted in improvement in serological PFS and OS with a well-tolerated toxicity profile and modest improvement in QoL.Serum VEGF expression requires validation in a larger cohort. Clinical trial information: CTRI/2017/10/010219.

891P - Weekly G-Csf Improves the Tolerability of Weekly Paclitaxel-Carboplatin. a Phase Ii Study of the Belgian Gynaecological Oncology Group (Bgog-Ov5)

ABSTRACT Aim: Weekly paclitaxel (60mg/m2) and carboplatin (AUC 2.7) (TCw) has been shown to be an effective treatment in patients with recurrent or advanced gynaecological cancer (Vandenput Int J Gyn Cancer 2012; Torfs Eur J Cancer 2012; Cadron Gynecol Oncol, 2013). The main toxicity of the regimen has been neutropenia grade (G) 3-4 and or neutropenic fever. Methods: In this prospective study 108 patients were needed to detect a 15% reduction in the occurrence of G3-4 neutropenia (a: 0.05; b: 0.95) compared with the historical incidence of 84%, by using prophylactic filgrastim on day 5 of each of the 18 weekly planned courses. The main inclusion criteria were: measurable disease, platin-resistant or refractory epithelial ovarian carcinoma (OC), or recurrent or advanced endometrial (EC) or cervical cancer (CC), and no prior weekly or dose-dense TC. Results: 108 (3 cohorts of ovarian, endometrial and cervical cancer of each 36 patients) were included by 12 BGOG centers between February 20, 2012 and March 14, 2013. The median number of prior chemotherapy lines was 3 for OC, 2 for EC and 1 for CC, respectively. The percentage of G3-4 neutropenia was 34% (CI: 26%-44%; p Conclusions: TCw with G-CSF support is feasible with an acceptable toxicity in patients with platin-resistant or –refractory OC, and advanced or recurrent EC or CC. The incidence of G3-4neutropenia is lower with the addition of weekly G-CSF compared with earlier studies without the addition of prophylactic G-CSF. Disclosure: All authors have declared no conflicts of interest.

Key role of topoisomerase I inhibitors in the treatment of recurrent and refractory epithelial ovarian carcinoma

Ovarian cancer remains one of the most difficult gynecologic cancers to treat, owing to its aggressive biology and high relapse rate, as well as the toxic side effects of available chemotherapeutic agents used to treat recurrent disease. Topoisomerase I inhibitors, including topotecan and irinotecan, are some of the most effective and tolerable treatment options for recurrent ovarian cancer. The ideal dosing, timing of administration, role in combination with other chemotherapies or biologics and potential role in up-front therapy remains an area of active research. This article reviews the mechanism of action of topoisomerase I inhibitors and the efficacy, dosing, schedule and toxicity for topotecan, irinotecan, 9-nitrocamptothecin, DX-8951 and 9-aminocamptothecin. Conclusions include a discussion of future avenues of research and ongoing projects.

Pegylated liposomal doxorubicin (Lipo-Dox®) for platinum-resistant or refractory epithelial ovarian carcinoma: A Taiwanese gynecologic oncology group study with long-term follow-up

Objectives. To evaluate the efficacy and safety of a distearoylphosphatidylcholine pegylated liposomal doxorubicin, Lipo-Dox®, in platinum-resistant or refractory epithelial ovarian cancer. Methods. A multicenter phase II trial enrolled women with platinum-resistant or refractory epithelial ovarian carcinoma and naïve to anthracycline. Eligible patients had either measurable tumor(s) or elevated serum CA 125 titer. Lipodox was initiated with a dose of 45 mg/m 2 at a 4-week interval with subsequent escalation or reduction. A total of six cycles were scheduled. Results. 29 patients, 20 with platinum-resistant and 9 with platinum refractory tumors, were enrolled. Lipo-Dox was given for an average of 4.6 cycles per patient with a total of 134 cycles. Among the 26 evaluable patients, one achieved CR, 5 PR and 9 SD. The overall response rate was 23.1% (95% CI, 6.8%–39.3%) with a median response duration of 11.6 weeks. 5 of the 6 responses were in patients with resistant disease. The median progression-free duration in the SD patients was 25.7 weeks. With a median follow-up of 13.8 months, the median progression-free and median overall survivals in the 26 patients were 5.4 months and 13.8 months, respectively. Hand–foot skin reaction occurred in 4.5% and skin pigmentation in 11.2% of all treatment cycles, all were Grade 1/2. Nausea and vomiting occurred in 14.2%, while anemia, leukopenia and thrombocytopenia occurred in 20.9%, 32.8% and 9% of cycle, respectively, and were mostly Grade 1 or 2. Conclusion. Lipo-Dox, the third liposome encapsulated doxorubicin, at 45 mg/m 2 every 4 weeks, is effective against recurrent, platinum-resistant epithelial ovarian cancers.

A combination of low-dose prolonged infusional gemcitabine and oral treosulfan in platinum- and taxane-refractory Mullerian carcinomas: A phase II study

5064 The GeT regimen - gemcitabine (dFdC) + treosulfan (TREO) - has been found to be active in metatastic melanoma and refractory epithelial ovarian carcinoma (EOC). However, the q3w regimen with dFdC at 1250mg/m2 day 1+8 and TREO at 5000 mg/m2 day 1 was associated with myelosuppression negatively influencing dose intensity and, consecutively, progression-free survival (PFS). Since maintaining cellular accumulation appears to be crucial for long-lasting responses, this phase II trial in platinum- and taxane refractory Mullerian carcinomas (MC) was set up using a modified q2w GeT protocol with dFdC at 450 mg/m2 (3 h infusion) day 1 and oral TREO at 1000 mg/m2 day 1–4. A total of 25 patients (pts) were included (EOC: n=24; papillary-serous endometrial carcinoma: n=1). Patients had failed a median of 2 prior Ctx (1: n=9; 2: n=6; 3: n=5; 4: n=2; 5: n=2) including platinum and paclitaxel in all, anthracyclines in 9 and topotecan or dFdC in either 4 pts. A total of 145 cycles were given with a median of 6 (range: 2–10). All pts had measurable or evaluable disease according to the RECIST and Rustin criteria, repectively. All treatments were evaluable for both toxicity and response. Anemia which was never therapy-limiting was frequent but exceeded NCI-CTC grade 2 in only 8/145 cycles (6%). Leukopenia > grade 2 was not observed. In one patient, interval prolongation was necessary due to febrile urinary tract infection. In another patient, treatment was terminated due to non-lethal pulmonary embolism. Other toxicities did not exceed NCI-CTC grade 1 nor did any other patient require hospitalization due to therapy-related toxicities. A total of 9 CR and 4 PR were recorded accounting for an objective response rate of 52%; 6 pts achieved SD and 6 pts progressed on GeT. The median progression-free survival was 29 weeks. Until now, only 5 pts have died, so that the median overall survival is not yet reached. Facing the intensive pre-treatment of the pts studied, it can be concluded that the modified GeT protocol is well tolerated and exhibits a promising clinical activity in MC refractory to both platinum and taxanes that warrants further exploration in large-scaled clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration L.a.n.c.e. Inc.

Long-term results and pharmacokinetics of high-dose paclitaxel in patients with refractory epithelial ovarian carcinoma.

The purpose of this study was to analyze the efficacy and toxicity of a high dose of paclitaxel in patients with ovarian cancer refractory to platinum chemotherapy. Another phase II study of hydroxyurea was run in the same patient population. Fifty patients with measurable ovarian cancer were entered on this phase II study at The University of Texas M. D. Anderson Cancer Center. Treatment consisted of 250 mg/m2 of paclitaxel given by continuous intravenous infusion over 24 h every 3 weeks. Patients with disease unresponsive to paclitaxel could then be crossed over to hydroxyurea, and vice versa. Twenty-five (53%) out of 47 evaluable patients had a response (two complete responses and 23 partial responses). Twelve (26%) patients had stable disease. The median survival was 11.3 months. The main toxic effect was neutropenia (98% of patients) with 28 (9%) episodes of neutropenic fever. Neutropenia required therapy with granulocyte colony-stimulating factor. Other side effects were alopecia (100%), anemia (98%), gastrointestinal problems (57%), stomatitis (27%), and neurotoxicity (55%). Paclitaxel administered at a high dose as a single agent proved to be very active in patients who had platinum-refractory ovarian cancer and was well tolerated. Further studies of high-dose paclitaxel in patients with ovarian carcinoma are indicated.

Palliative Benefit of External-Beam Radiation in the Management of Platinum Refractory Epithelial Ovarian Carcinoma

In vitrostudies and clinical experience have suggested that patients with platinum-refractory epithelial ovarian carcinoma exhibit cross-resistance to radiation. Salvage with radiation in these patients is rare. However, radiation is often utilized to palliate symptoms caused by these chemotherapy-resistant tumors. Forty-seven patients with platinum-refractory epithelial ovarian carcinoma were referred for palliative radiation and 33 (70%) were evaluable for response. One to four regimens of platinum-based chemotherapy (median 2.7) were given to each patient prior to radiation therapy. Of the 33 evaluable patients, 23 (69.7%) had a complete resolution of symptoms after radiation, 8 (24%) had a partial resolution, and 2 were unassessable because of unrelated medical complications. The median duration of response was 11 months (range 1–86) and closely approximated their survival. Thirteen of 33 patients (39%) obtained relief of symptoms for greater than 12 months, with 10 of 33 (30%) having symptoms controlled for 6 to 12 months. In only 10 patients (30%) was the duration of palliation less than or equal to 6 months. Four patients required reirradiation to the same area for recurrence of their symptom. External-beam radiation therapy can provide effective and durable palliation of symptoms in platinum-refractory epithelial ovarian carcinoma patients.

Exacerbation of Pseudogout by Granulocyte Colony-Stimulating Factor

Letters1 November 1996Exacerbation of Pseudogout by Granulocyte Colony-Stimulating FactorVictor Sandor, MD, Raffit Hassan, MD, and Elise Kohn, MDVictor Sandor, MDNational Cancer Institute Bethesda, MD 20892.Search for more papers by this author, Raffit Hassan, MDNational Cancer Institute Bethesda, MD 20892.Search for more papers by this author, and Elise Kohn, MDNational Cancer Institute Bethesda, MD 20892.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-125-9-199611010-00029 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:We report a case of reactivation of pseudogout by granulocyte colony-stimulating factor (G-CSF) in a patient receiving chemotherapy for ovarian cancer. To our knowledge, this is the first report of this side effect of G-CSF.A 70-year-old woman was treated with 9-aminocamptothecin (9-AC) on a National Cancer Institute phase II trial for refractory epithelial ovarian carcinoma. 9-Aminocamptothecin was administered in 14-day cycles at 47 µg/m2 body surface area per hour over 72 hours. Treatment with G-CSF (5 µg/kg) was started on day 5 of each cycle and was continued for 8 days. At evaluation for her third ...

Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma.

To determine the efficacy and toxicity of topotecan administered as a 5-day intravenous infusion in patients with advanced ovarian cancer refractory to cisplatin-based chemotherapy. Thirty patients with advanced epithelial ovarian cancer refractory to cisplatin-based chemotherapy received intravenous infusions of topotecan 1.5 mg/m2 delivered over 30 minutes each day for 5 days. A course was repeated every 21 days. The patient eligibility requirements included age > or = 18 years, Zubrod score < or = 2, measurable disease, adequate hepatic and renal function, neutrophil count > or = 1,500/microL, platelet count > or = 100,000/microL, and anticipated survival > or = 3 months. Twenty eight patients were assessable for response and toxicity. All patients were assessable for survival. The major toxicity from administration of topotecan at this dose schedule was myelosuppression; 21 patients required dose reductions. Four patients had neutropenic fever that required hospitalization, and seven patients required platelet transfusions. Maculopapular pruritic exanthema occurred in 20% of patients; gastrointestinal side effects were mild. No deaths were reported on the study. At dose levels of 1.5, 1.25, and 1.0 mg/m2, 61%, 31%, and 25% of patients, respectively, required dose reductions. Of 28 assessable patients, four (14%; 95% confidence interval [CI], 4% to 34%) achieved a partial response (PR) at a median of 1.4 months and lasting 8.9 months, and 17 had stable disease (SD). The overall median survival time was 10.0 months (95% CI, 8.1 to 13.5). Topotecan shows modest clinical activity against cisplatin-refractory ovarian cancer, although the dose-intensity is compromised by the depth of the granulocyte nadir and the duration of granulocytopenia. Further studies of topotecan may necessitate a reevaluation of optimal dose schedule, with the possible incorporation of multilineage cytokines, and its activity in taxane-resistant tumors.

Salvage Therapy for Recurrent and Refractory Ovarian Cancer with High-Dose Chemotherapy and Autologous Bone Marrow Support: A Gynecologic Oncology Group Pilot Study

Nine patients with recurrent or refractory epithelial ovarian carcinoma following previous chemotherapy were treated with high-dose carboplatin (300 mg/m2) and ifosfamide according to a dose escalation schedule (1.50, 1.75, 2.00 g/m2), each given intravenously daily for 5 days with autologous bone marrow support. Eight of the nine patients were evaluable for response. Five achieved complete response (CR), all of whom relapsed at 4, 5, 6, 8, and 23 months following treatment. Two partial responses persisted for 6 months, and one patient with stable disease progressed after 2 months and has since died of disease. The median duration of remission was 6 months. The treatment was well tolerated across the doses of ifosfamide with the exception of one treatment-related death which was due to acute renal failure and central nervous system toxicity from ifosfamide. It appears that the use of high-dose chemotherapy with autologous bone marrow support in the treatment of ovarian cancer produced a high rate of response of short duration in this small group of heavily pretreated women.

A phase II study of topotecan administered intravenously as 5 daily infusions every 21 days to women with refractory epithelial ovarian carcinoma

A phase II study of topotecan administered intravenously as 5 daily infusions every 21 days to women with refractory epithelial ovarian carcinoma

Sequentially administered ethinyl estradiol and medroxyprogesterone acetate in the treatment of refractory epithelial ovarian carcinoma in patients with positive estrogen receptors

The activity of sequentially administered hormonal therapy was investigated over 25 days in 25 patients with epithelial ovarian carcinoma who had estrogen receptor (ERc)-positive tumors. Patients received ethinyl estradiol (EE) (50 micrograms/d) on days 1 to 7 and medroxyprogesterone acetate (MPA) (400 mg/d) on days 8 to 25. Twenty-three patients completed one or more courses of treatment. There were no complete responses (CR). Four partial responses (PR) with durations of 9, 4, 3, and 1 months were seen. Two incomplete responses with durations of 6 and 4 months were also seen. Six patients had stable disease (SD), and 11 patients had progression. The overall response rate was 17% and may represent a modest improvement in response over those in previously published studies conducted with MPA alone. No significant toxic effects were noticed, and some patients reported an improved sense of well-being. However, two patients experienced depression with this treatment. The mean ERc values in responders, patients with SD, and nonresponders were 70.0, 36.7, and 47.9 fmol/mg cytosolic protein, respectively. Future studies of hormonal therapy in patients with ovarian carcinoma should attempt to identify more reliable indices for determining sensitivity to these agents.

Phase II trial of ifosfamide and mesna in refractory epithelial ovarian carcinoma

Phase II trial of ifosfamide and mesna in refractory epithelial ovarian carcinoma