•A two-tier system (limited- or extensive-stage) has been used for small cell neuroendocrine carcinomas of the cervix.•Concordance probability estimates found that the 2018 FIGO staging system ...predicted outcome better than the two-tier system.•38% of patients had metastases at initial diagnosis, and an additional 38% at subsequent recurrence.•38 patients (60%) had brain imaging: 1 (3%) had brain metastasis at diagnosis and 8 (21%) at subsequent recurrence.•Providers should have a low threshold for brain imaging in patients with advanced disease or neurologic symptoms.
To describe characteristics and outcomes of patients with small cell neuroendocrine carcinoma of the cervix (SCNCC) and determine the staging system most predictive of outcome—the two-tier (limited-stage LS vs. extensive-stage ES) or International Federation of Gynecology and Obstetrics (FIGO) staging system.
Patients with SCNCC evaluated at our institution from 1/1/1990–6/30/2021 were included. Medical records were reviewed for variables of interest. Appropriate statistical tests were performed to determine associations. Survival curves were created using the Kaplan-Meier method. Concordance probability estimates (CPEs) were calculated to evaluate the prediction probability of the staging systems.
Of 63 patients, 41 had LS and 22 ES SCNCC. Patients with ES disease were significantly older than those with LS disease (median, 54 and 37 years, respectively; p < 0.001). Smoking status, race, and history of HPV were not associated with stage or outcomes. Forty-eight patients had metastatic disease (24 50% at initial diagnosis). The most common first sites of metastasis were lung (n = 20/48, 42%), lymph nodes (n = 19/48, 40%), and liver (n = 13/48, 27%). Nine patients had brain metastasis (8 symptomatic at recurrence; 1 asymptomatic at initial diagnosis). Both staging systems were associated with progression-free and overall survival. Adjusted CPE found the FIGO staging system was more predictive of outcomes than the two-tier staging system.
Providers should have a low threshold to obtain brain imaging for patients with SCNCC, especially in the presence of visceral metastases. FIGO staging should be used to classify SCNCC. Further research is necessary to understand prognostic factors of this rare disease.
The purpose of this study was to evaluate the toxicity and pharmacodynamic behavior of the novel proteasome inhibitor PS341 administered as a twice weekly i.v. bolus for 2 weeks, followed by a 1-week ...recovery period in patients with advanced solid tumor malignancies.
In this Phase I trial, 43 patients were treated with PS341 in doses ranging from 0.13 to 1.56 mg/m2/dose. A standard Phase I design was used. Pharmacodynamic studies were performed to access 20S proteasome activity.
Forty-three patients were treated with 89 cycles of PS341. Patients were heavily pretreated. Dose-limiting toxicities on this schedule were diarrhea and sensory neurotoxicity. Other side effects seen were fatigue, fever, anorexia, nausea, vomiting, rash, pruritus, and headache. There was no dose-limiting hematological toxicity. A dose-related inhibition of 20S proteasome activity with increasing dose of PS341 was seen. There was one major response in a patient with refractory non-small cell lung carcinoma.
Given the results of this trial, it is safe and reasonable to recommend treatment with PS341 on the schedule used in this trial at 1.56 mg/m2/dose in Phase II trials. Particular care should be taken with patients with preexisting neuropathy. Further testing in Phase II trials is warranted.
Objective. To determine the impact of the incorporation of extensive upper abdominal debulking procedures on the rates of optimal primary cytoreduction and complications in stages IIIC and IV ...epithelial ovarian, fallopian tube, and primary peritoneal carcinomas.
Methods. Two groups of patients were identified for comparison. Group 1, the control group, consisted of 70 consecutive patients who underwent “standard” primary cytoreductive surgery before May 2000. Group 2, the study group, was composed of 70 consecutive patients who underwent surgery after January 2001, during which time, a more comprehensive debulking of upper abdominal disease was used, including diaphragm stripping/resection, splenectomy, distal pancreatectomy, liver resection, resection of porta hepatis tumor, and cholecystectomy.
Results. The median age of the entire cohort was 60 years (range, 36–88 years). The majority had stage IIIC disease (86%) and serous histology (76%). Optimal cytoreduction (residual disease ≤1 cm) rates were 50% for group 1 and 76% for group 2 (
P < 0.01). Patients in group 2 were more likely to have undergone extensive procedure(s) (27% versus 3%;
P < 0.001). Operative time and estimated blood loss were greater in group 2 than group 1 (264 versus 174 min, 880 versus 460 cc, respectively;
P < 0.001 for both). Complication rates and length of hospitalization were not significantly different between the two groups.
Conclusion. The use of extensive upper abdominal surgical procedures significantly increased the rate of optimal primary cytoreduction. Although operative time and estimated blood loss were increased, the rate of major complications and length of hospitalization remained the same.
Intraperitoneal (IP) cisplatin and intravenous (IV) or IP paclitaxel constitute a standard therapy for optimally debulked ovarian cancer. Bevacizumab prolongs progression-free survival (PFS) when ...included in first-line IV chemotherapy. In this study, the safety and feasibility of adding bevacizumab to a first-line IP regimen were assessed.
Treatment was as follows: paclitaxel 135 mg/m(2) IV over 3 hours day 1, cisplatin 75 mg/m(2) IP day 2, and paclitaxel 60 mg/m(2) IP day 8. Bevacizumab 15 mg/kg IV was given after paclitaxel on day 1 beginning in cycle 2. After six cycles of chemotherapy, bevacizumab was given every 3 weeks for 17 additional treatments. The primary end point was safety and tolerability determined by whether 60% of patients completed six cycles of IV/IP chemotherapy.
Of 41 treated patients, 30 (73%) received six cycles of IV/IP chemotherapy and 35 (85%) received at least four cycles. Three (27%) of those who discontinued chemotherapy did so because of complications related to bevacizumab (hypertension, n = 2; perforation, n = 1). Grades 3 to 4 toxicities included neutropenia (34%), vasovagal syncope (10%), hypertension (7%), nausea/vomiting (7%), hypomagnesemia (7%), and abdominal pain (7%). There were three grade 3 small bowel obstructions (7%) during cycles 3, 9, and 15. One patient died following rectosigmoid anastomotic dehiscence during cycle 4. Estimated median PFS is 28.6 months (95% CI, 19.1 to 38.9 months). Three patients (7%) had IP port malfunction.
The addition of bevacizumab to this IP regimen is feasible; however, bevacizumab may increase the risk of bowel obstruction/perforation. The observed median PFS is similar to that seen with IP/IV chemotherapy alone.
Abstract Objective Repeated exposure to carboplatin can lead to hypersensitivity reactions during retreatment with carboplatin. This may prevent its further use in platinum-sensitive ovarian cancer ...patients. At our institution, an increasing proportion of patients are prophylactically converted to an extended schedule of infusion after 8 cycles of carboplatin. We sought to determine whether an incrementally increasing, extended 3-hour infusion of carboplatin with appropriate premedication was associated with a lower rate of hypersensitivity reactions compared to the standard 30-minute schedule in sequentially treated patients. Methods We performed a retrospective electronic medical record review of patients with recurrent ovarian cancer retreated with carboplatin at our institution from January 1998 to December 2008. Results Seven hundred and seventy-seven patients with relapsed ovarian, fallopian tube, or primary peritoneal cancer were retreated with carboplatin and met study inclusion criteria. Of these, 117 (17%) developed hypersensitivity reactions during second-line or greater carboplatin-based treatment for recurrent disease. Only 6 (3.4%) of the 174 patients who received the extended schedule developed hypersensitivity reactions (0% grade 4; 50% grade 3) compared to 111 (21%) of 533 patients in the standard schedule group (13% grade 4; 77% grade 3). The first hypersensitivity episode occurred after a median of 16 platinum (carboplatin and cisplatin) treatments in the extended group compared to 9 in the standard group. Using the Fisher exact test, there was an association with a reduced incidence of hypersensitivity reactions with the extended infusion schedule ( P < 0.001). Conclusion Our data suggest appropriate premedication and prophylactic conversion to an extended infusion during carboplatin retreatment may reduce hypersensitivity reactions.
Abstract Objective GOG study 172 demonstrated improved progression-free (PFS) and overall (OS) survival for patients with stage III optimally debulked ovarian and peritoneal carcinoma treated with ...IV/IP paclitaxel and IP cisplatin compared to standard IV therapy. The inpatient administration, toxicity profile, and limited completion rate have been blamed for the lack of acceptance and widespread use of this regimen. We sought to evaluate the PFS, OS, toxicity, and completion rate of a modified outpatient IP regimen. Methods Using a prospectively maintained database, we evaluated the outcomes of patients who underwent primary optimal cytoreduction for stage III ovarian, tubal, or peritoneal carcinoma followed by IV/IP chemotherapy from 1/05-3/09. Our modified regimen was as follows: IV paclitaxel (135 mg/m2 ) over 3 h on day 1, IP cisplatin (75 mg/m2 ) on day 2, and IP paclitaxel (60 mg/m2 ) on day 8, given every 21 days for 6 cycles. Results We identified 102 patients who initiated the modified IV/IP regimen and completed chemotherapy. The median follow-up was 43 months. The median age at diagnosis was 57 years (range, 23–76). Primary disease site was: ovary, 77 (75%); fallopian tube, 13 (13%); peritoneum, 12 (12%). FIGO stage was: IIIA, 8 (8%); IIIB, 4 (4%); IIIC, 90 (88%). Residual disease after cytoreduction was: none, 58 (57%); ≤ 1 cm, 44 (43%). The most frequent grade 3/4 toxicities were: neutropenia, 12 (12%); gastrointestinal, 8 (8%); neurologic, 6 (6%). Eighty-two (80%) of 102 patients completed 4 or more cycles of IV/IP therapy; 56 (55%) completed all 6 cycles. The median PFS and OS were 29 and 67 months, respectively. Conclusions By modifying the GOG 172 treatment regimen, convenience, toxicity, and tolerability appear improved, with survival outcomes similar to those of GOG 172. This modified IV/IP regimen warrants further study.
BackgroundThis phase I dose escalation trial evaluated the feasibility of production, safety, maximum tolerated dose, and preliminary efficacy of autologous T cells sensitized with peptides encoding ...Wilms’ tumor protein 1 (WT1) administered alone or following lymphodepleting chemotherapy, in the treatment of patients with recurrent WT1+ ovarian, primary peritoneal, or fallopian tube carcinomas.MethodsA 3+3 dose escalation design was used to determine dose-limiting toxicity (DLT). In cohort I, patients received WT1-sensitized T cells dosed at 5×106/m2 (level I) without cyclophosphamide lymphodepletion. In cohorts II–IV, patients received lymphodepleting chemotherapy (a single intravenous dose of cyclophosphamide 750 mg/m2), 2 days prior to the first intravenous infusion of WT1-sensitized T cells administered at escalating doses (2×107/m2 (level II), 5×107/m2 (level III), and 1×108/m2 (level IV)).ResultsTwelve patients aged 23–72 years, with a median of 7 prior therapies (range 4–14), were treated on the study. No DLT was observed, even at the highest dose level of 1×108/m2 WT1-sensitized T cells tested. Common adverse events reported were grade 1–2 fatigue, fever, nausea, and headache. Median progression-free survival (PFS) was 1.8 months (95% CI, 0.8 to 2.6); 1 year PFS rate 8.3% (95% CI, 0.5 to 31.1). Median overall survival (OS) was 11.0 months (95% CI, 1.1 to 22.6); OS at 1 year was 41.7% (95% CI, 15.2% to 66.5%). Best response was stable disease in one patient (n=1) and progressive disease in the others (n=11). We observed a transient increase in the frequencies of WT1-specific cytotoxic T lymphocyte precursors (CTLp) in the peripheral blood of 9 of the 12 patients following WT1-sensitized T-cell infusion.ConclusionWe demonstrated the safety of administration of WT1-sensitized T cells and the short-term increase in the WT1 CTLp. However, at the low doses evaluated we did not observe therapeutic activity in recurrent ovarian cancer. In this heavily pretreated population, we encountered challenges in generating sufficient numbers of WT1-reactive cytotoxic T cells. Future studies employing WT1-specific T cells generated from lymphocytes are warranted but should be done earlier in the disease course and prior to intensive myelosuppressive therapy.Trial registration numberNCT00562640.One-sentence summaryThe authors describe the first human application of autologous WT1-sensitized T cells in the treatment of patients with recurrent ovarian, primary peritoneal, and fallopian tube carcinomas.
The cancer-testis antigen NY-ESO-1 is expressed by >40% of advanced epithelial ovarian cancers and is a promising immunotherapeutic target. In this study, we describe the effects of vaccination with ...the HLA-A*0201-restricted NY-ESO-1b peptide on patients with epithelial ovarian cancer in high-risk first remission.
After primary surgery and chemotherapy, high-risk epithelial ovarian cancer patients in first clinical remission received NY-ESO-1b peptide and Montanide every 3 weeks for five vaccinations. Tumor expression was evaluated by immunohistochemistry. Toxicity was monitored using National Cancer Institute Common Toxicity Criteria Scale Version 2. NY-ESO-1 specific humoral immunity (ELISA), T-cell immunity (tetramer and ELISPOT), and delayed-type hypersensitivity were assessed on weeks 0, 1, 4, 7, 10, 13, and 16.
Treatment-related adverse events included grade 1 fatigue, anemia, pruritus, myalgias, and hyperthyroidism and grade 2 hypothyroidism. There were no grade 3/grade 4 adverse events. Three of four patients (75%) with NY-ESO-1-positive tumor showed T-cell immunity by tetramer (0.6-9.5%) and ELISPOT (range, 35-260 spots). Four of five patients (80%) with NY-ESO-1-negative tumor showed T-cell immunity by tetramer (1.0-12.1%) and/or ELISPOT (range, 35-400 spots). With a median follow-up of 11.3 months, six of nine patients (67%) have recurred, with a median progression-free survival of 13 months (95% confidence interval, 11.2 months-not reached). Three of nine patients remain in complete clinical remission at 25, 38, and 52 months.
Vaccination of high-risk HLA-A*0201-positive epithelial ovarian cancer patients with NY-ESO-1b and Montanide has minimal toxicity and induces specific T-cell immunity in patients with both NY-ESO-1-positive and NY-ESO-1-negative tumors. Additional study is warranted.
Hypersensitivity with repeated exposure to platinum agents is common and can preclude continued treatment, even in patients with disease that remains platinum sensitive. We sought to compare the ...effects of prophylactic, extended carboplatin infusion versus standard infusion on the rate of carboplatin hypersensitivity reactions (HSRs) in women with recurrent ovarian cancer.
This was a single-institution, randomized, nonblinded trial comparing a graded, 3-hour extended infusion of carboplatin with a standard 30-minute infusion in patients with recurrent ovarian cancer who were enrolled from January 2011 to April 2015. The study was designed to detect a decrease in the HSR rate from 20% (standard infusion) to 5% (extended infusion) assuming a type 1 error of 10% and power of 80% using a 1-sided test.
Of 146 enrolled patients, 114 were evaluable. Fifteen (13%) had an HSR-11% (6/56) in the extended-infusion and 16% (9/58) in the standard-infusion groups (P = 0.582). Planned treatment completion was achieved in 50 (89%) of 56 patients and 49 (84%) of 58 patients, respectively. Of 25 patients who received single-agent carboplatin, 8 (32%) had an HSR (53% of all patients who had an HSR 8/15). Of 23 patients who received carboplatin with gemcitabine, 4 (17%) had an HSR (27% of all patients who had an HSR 4/15). Of 8 patients who received carboplatin with paclitaxel, 3 (38%) had an HSR (20% of all patients who had an HSR 3/15). There were no HSRs with pegylated liposomal doxorubicin, the most commonly given concurrent chemotherapy (46% of all patients).
A prophylactic, extended carboplatin infusion was not associated with a decreased HSR rate. The overall low HSR rate suggests that premedication may help reduce HSRs.
Abstract Objective Determine the safety and efficacy of cetuximab plus paclitaxel and carboplatin as initial treatment of stage III/IV ovarian cancer. Methods An initial intravenous IV dose of ...cetuximab (400 mg/m2 ) was administered over 120 min followed by weekly IV infusions of cetuximab (250 mg/m2 ) administered over 60 min. Paclitaxel (175 mg/m2 ) and carboplatin (area under the curve AUC of 6) were administered IV every 21 days for 6 cycles. The order of administration was cetuximab followed by paclitaxel and then carboplatin. Patients achieving a clinical complete response after 6 cycles were eligible to continue weekly cetuximab for 6 months or until toxicity or disease progression. Safety was evaluated using NCI Common Toxicity Criteria version 2.0. Progression-free survival (PFS) at 18 months was determined and compared with historical controls. Results Forty-one patients were enrolled in this study; 40 received treatment and were evaluable for toxicity, and 38 were evaluable for PFS. Grade 3/4 treatment-related toxicities included febrile neutropenia (12.5%), rash (2.5%), hypersensitivity reaction (7.5%), and hypomagnesemia (12.5%). Common grade 1/2 toxicities attributed to cetuximab included acneiform rash (82.5%), hirsutism (7.5%) or abnormal hair growth (25%), and nail disorders (22.5%), which in 3 cases resulted in the patient's discontinuation from the study. Median PFS was 14.4 months, and PFS at 18 months was 38.8%. Conclusions The combination of cetuximab with paclitaxel and carboplatin is adequately tolerated as primary therapy for ovarian cancer but did not demonstrate prolongation of PFS when compared to historical data.
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