Indications for primary and secondary exenterations in patients with cervical cancer

OBJECTIVE: Fifty years after the introduction of exenterative surgery in gynecologic oncology, the indication for primary and secondary exenteration is controversially discussed in cervical cancer patients. In addition, the term "palliative exenteration" is not precisely defined. We evaluate the role of primary exenteration in patients with stage IVA cervical cancer and the role of secondary palliative exenteration. METHODS: The study retrospectively analyzed surgical and oncologic data of 55 patients who underwent exenterative surgery in the Department of Gynecology at the University of Jena between February 1998 and January 2004. Primary surgery was performed in 20 patients with laparoscopically confirmed stage IVA cervical cancer, while 35 patients with recurrent cervical cancer underwent secondary exenteration. Fifty-one had total, 3 posterior and 1 anterior exenteration. Survival was analyzed in relation to the patient's age, indication (primary versus secondary, curative versus palliative), previous therapy (operation, radiation, chemotherapy, radiochemotherapy), histology, resection margins, pelvic nodal involvement, time interval from primary therapy to recurrence, type of exenteration and adjuvant therapy. Early and late postoperative complications as well as perioperative mortality were reviewed. RESULTS: The overall cumulative survival of all patients after exenteration was 36.8% at 5 years with 52.5% in the primary group and 26.7% in the recurrent one (p=0.0472). Complications were noted in 56.9% of patients, most commonly fistulas or gastrointestinal complications. Operative mortality was 5.5%. Survival correlated significantly with the time interval between primary treatment and recurrence (within 1-2 years 16.8% five-year survival, 2-5 years 28%, >5 years 83.2%, p=0.0105) as well as with curative or palliative intention (2-year survival rate of 60% in patients with curative intent, 10.5% in those with palliative intent, p=0.0001) and with tumor-free resection margins (2-year survival of 10.2% for positive margins, 5-year survival of 55.2% for negatives ones, p=0.0057). The age, the type of exenteration, the histologic type and the metastatic spread to pelvic lymph nodes had no significant influence on long-term survival. CONCLUSION: In patients with histopathologically confirmed stage IVA cervical cancer primary, exenteration is a valid alternative to primary chemoradiation. In patients with persistent or recurrent tumor limited to the pelvis, secondary exenteration should be offered in the absence of other therapeutic options. Palliative and curative attempts can best be differentiated by the resection margin status.     

A phase II study of apatinib in patients with recurrent epithelial ovarian cancer

Objective

Antiangiogenic treatments have been implicated to play a major role in epithelial ovarian cancer (EOC). Apatinib, a novel oral antiangiogenic agent targeting vascular endothelial growth factor receptor (VEGFR2), is currently being studied in different tumor types and is already used in gastric adenocarcinoma. This study was performed to assess the efficacy and safety of apatinib in patients with recurrent, pretreated EOC.

A phase II clinical trial of topotecan and carboplatin in patients with newly diagnosed advanced epithelial ovarian cancer

A phase II clinical trial conducted to evaluate the efficacy and tolerability of topotecan and carboplatin as first-line therapy for women with advanced epithelial ovarian cancer was the objective of this study. Patients had histologically confirmed ovarian epithelial cancer with at least one measurable lesion. Patients received topotecan 1.5 mg/m(2) on days 1-3 and carboplatin at an area under the curve (AUC) of 5 on day 3 every 21 days for six cycles. All 42 patients enrolled were evaluable for response and toxicity. Median number of cycles delivered was six. Overall response rate was 71%, with 19 clinical complete responses (45%) and 11 clinical partial responses (26%). Median survival time was 47 months and 5-year survival was 42%. Myelosuppression was the predominant toxicity, with grade 3 or 4 neutropenia occurring in 100% of patients. However, this toxicity was transient and easily manageable; no patients experienced febrile neutropenia. The combination of topotecan and carboplatin is active in advanced epithelial ovarian cancer. Delay of therapy by 1 week or topotecan dose reduction to 1.25 mg/m(2) is the first-choice option to reduce topotecan toxicity without affecting the efficacy. Moreover, a chemotherapy regimen using weekly topotecan, which is currently being tested, should be considered.     

Indications and long-term clinical outcomes in 282 patients with pelvic exenteration for advanced or recurrent cervical cancer

Objective

The aim of this study was to summarize the clinical experience at our clinic with pelvic exenteration as a treatment for cervical cancer with special regard to the indications and outcomes of specific patient groups.

Methods

Medical records of 282 women who underwent pelvic exenteration to treat cervical cancer were analyzed.

Results

In total, 70 patients (25%) underwent primary exenteration, and 212 (75%) underwent secondary exenteration. Exenteration was anterior for 14 (5%) patients, posterior for 6 (2%) and total for 262 (93%). The overall survival (OS) of the 282 patients was 41% at 5 years and 37% at 10 years. The disease-free survival at 5 years was 61%. For 133 patients for whom pelvic exenteration was a curative procedure, the OS was 64% at 5 years and 57% at 10 years. For cases of pelvic exenteration as a palliative intervention, the OS was 19% at 5 years and 18% at 10 years. No difference was seen in the OS at 5 years between patients who received primary and secondary operations. No significant difference in the OS was found regardless of whether the patients had positive pelvic lymph nodes, whereas in cases of paraaortic lymph node metastasis, the OS was significantly lower. Out of all of the procedures, 139 (49%) involved no perioperative or postoperative complications. One major complication was reported for 72 (26%) patients, two complications occurred for 42 patients (15%) and more than three complications were noted for 29 (10%) patients.

Conclusion

Pelvic exenteration is an effective technique with a high percentage of long-term survivors. To the best of our knowledge, our study involves the largest published number of patients treated with pelvic exenteration for a single gynecological cancer and shows that previous contraindications for pelvic exenteration, such as lymph node metastasis (especially when confined to the pelvic lymph nodes), older age or palliative intent, should be reconsidered.     

Tamoxifen in patients with advanced epithelial ovarian cancer

Tamoxifen was administered to 30 patients with persistent or recurrent epithelial ovarian cancer following initial plantinum-based chemotherapy. Two complete remissions (lasting 41 months and 12 months, respectively) were documented (6.6%), while 10 patients (33.3%) had stabilization of disease for a mean duration of 11.5 months. Tamoxifen was not associated with any significant toxicity and is a reasonable therapeutic option for patients with persistent or recurrent ovarian cancer, although it is only associated with modest activity. This paper reviews our experience with tamoxifen and summarizes the world literature.     

A phase II study of gemcitabine in combination with tanespimycin in advanced epithelial ovarian and primary peritoneal carcinoma

Objective

To evaluate the efficacy and biological effects of the gemcitabine/tanespimycin combination in patients with advanced ovarian and peritoneal cancer. To assess the effect of tanespimycin on tumor cells, levels of the chaperone proteins HSP90 and HSP70 were examined in peripheral blood mononuclear cells (PBMC) and paired tumor biopsy lysates.

Methods

Two-cohort phase II clinical trial. Patients were grouped according to prior gemcitabine therapy. All participants received tanespimycin 154 mg/m² on days 1 and 9 of cycle 1 and days 2 and 9 of subsequent cycles. Patients also received gemcitabine 750 mg/m² on day 8 of the first treatment cycle and days 1 and 8 of subsequent cycles.

Results

The tanespimycin/gemcitabine combination induced a partial response in 1 gemcitabine naïve patient and no partial responses in gemcitabine resistant patients. Stable disease was seen in 6 patients (2 gemcitabine naïve and 4 gemcitabine resistant). The most common toxicities were hematologic (anemia and neutropenia) as well as nausea and vomiting. Immunoblotting demonstrated limited upregulation of HSP70 but little or no change in levels of most client proteins in PBMC and paired tumor samples.

Conclusions

Although well tolerated, the tanespimycin/gemcitabine combination exhibited limited anticancer activity in patients with advanced epithelial ovarian and primary peritoneal carcinoma, perhaps because of failure to significantly downregulate the client proteins at clinically achievable exposures.     

Intraperitoneal treatment with the trifunctional bispecific antibody Catumaxomab in patients with platinum-resistant epithelial ovarian cancer: a phase IIa study of the AGO Study Group

Objective

The aim of this study was to select the best catumaxomab regimen for further investigation in ovarian cancer based on confirmed tumour response.

Methods

Randomised open-label phase IIa study in women with platinum-resistant or -refractory epithelial ovarian cancer. Catumaxomab (6-hour intraperitoneal infusion on days 0, 3, 7 and 10) was administered at a low (10, 10, 10 and 10 μg) or high dose (10, 20, 50 and 100 μg). Responders were patients with either a complete (CR) or partial (PR) response.

Results

Forty-five patients were randomised to receive either low dose (23) or high dose (22). There were no responders in the low-dose versus one patient (5%) in the high-dose group with a PR. In the low-dose group, two patients (9%) had stable disease compared with five patients (23%) in the high-dose group. Catumaxomab was well tolerated and there was no difference between the dose groups in the incidence of treatment-induced adverse events, the most common of which were gastrointestinal and injection-site reactions.

Conclusion

Catumaxomab had modest activity in platinum-resistant ovarian cancer. The high-dose regimen was associated with a slightly better therapeutic index than the low dose regimen.     

A phase II study of gemcitabine,carboplatin and bevacizumab for the treatment of platinum-sensitive recurrent ovarian cancer

Purpose

The doublet gemcitabine and carboplatin is effective for the treatment of recurrent ovarian cancer, while multi-agent chemotherapy with bevacizumab may add additional benefit. This phase II study tested the efficacy and safety of a biweekly gemcitabine, carboplatin, and bevacizumab combination in patients with platinum-sensitive recurrent ovarian, peritoneal, or tubal cancer (ROC).

Patients and methods

Eligible patients received concurrent gemcitabine 1000 mg/m², carboplatin area under the curve 3, and bevacizumab 10 mg/kg administered intravenously on days 1 and 15 every 28 days for six cycles or up to 24 cycles if clinical benefit occurred. The primary end points were progression-free survival (PFS) by RECIST, and safety; the secondary end points were objective response rates and overall survival.

Results

Overall, 45 patients were enrolled. The median PFS was 13.3 months (95% CI, 11.3 to 15.3). The objective response rate was 69%. Grade 4 hematologic toxicities included neutropenia (27%) and thrombocytopenia (2%). Grades 3 and 4 non-hematologic toxicities included fatigue (18%), pain (9%), and nausea/vomiting (4%). There were 2 episodes of cerebrovascular accidents, 2 noted DVTs, and no episodes of bowel perforation. Median OS was 36.1 months (95% CI, 26.7 to 45.5).

Conclusion

Biweekly gemcitabine, carboplatin, and bevacizumab were an effective regimen in recurrent ovarian cancer, with comparable toxicity to recently reported day 1 gemcitabine, carboplatin, bevacizumab, and day 8 gemcitabine. Response rate and PFS are improved from reported outcomes of the gemcitabine carboplatin doublet. The degree to which biweekly dosing may present a more rationale schedule for this triplet should be evaluated further.     

A phase II evaluation of Temozolomide in patients with recurrent epithelial ovarian cancer

OBJECTIVES: To assess the antitumor activity of Temozolomide, a novel alkylating agent, in patients with persistent or recurrent ovarian or primary peritoneal carcinoma who have failed other second-line chemotherapy agents. To identify the nature and degree of toxicity of Temozolomide in this group of patients. METHODS: Temozolomide was administered orally at an initial dose of 150 mg/m(2) daily for 5 days, every 4 weeks. If the initial course was tolerated without dose-limiting toxicity, then the dose was increased to 200 mg/m(2). Patients were evaluated for response and toxicity. RESULTS: Fifteen patients were enrolled and evaluated. The median number of prior treatment regimens was 3. Hematologic toxicity was encountered in 26% of patients and was manageable. There were no complete or partial responses. One patient had stable disease with significant improvement in her performance status while on treatment. CONCLUSION: This dose and schedule of Temozolomide had insignificant activity in this heavily pretreated group of patients with persistent or recurrent ovarian or primary peritoneal carcinoma.     

Sorafenib as a third line therapy in patients with epithelial ovarian cancer or primary peritoneal cancer: a phase II study

Purpose

New agents are required for the patients with epithelial ovarian cancer (EOC) who progress after first and second line of the treatment. Tumor vasculature targeted agents are potentially active in EOC. We aimed to assess the activity of sorafenib in patients with recurrent EOC who had received two prior therapies.

Patients and methods

A phase II non-randomized, open-label, single-arm study aimed to assess the efficacy, safety and tolerance of sorafenib monotherapy as a third line therapy in patients with EOC or primary peritoneal cancer (PPC). Sorafenib was administered as 400 mg twice daily on days 1–28 of each 4-week cycle. The primary end point of the study was to demonstrate the progression free survival (PFS).

Results

Eleven patients were enrolled. The median number of cycles was two. Among the 11 patients eligible for efficacy analysis, no patients experienced a partial response or complete response or stable disease lasting longer than 6 months according to RECIST criteria. Thus, the trial stopped at the end of the first stage of study design. The median PFS was 2.00 months (95% CI, 1,80–3,90). The median OS was 11.78 months (95% CI, 7.66 to 15.39). There were no grade 4 toxicities and few grade 3 toxicities.

Conclusion

Sorafenib fails to achieve sufficient objective response or sustained disease stabilization as third-line treatment for EOC.     

Transforming growth factor-alpha levels in the serum and ascites of patients with advanced epithelial ovarian cancer

A variety of cytokines have been identified to play a role in ovarian cancer. In this pilot study, we sought to determine whether transforming growth factor-alpha (TGF-alpha) was detectable in the serum and ascites of women with advanced stage epithelial ovarian cancer. TGF-alpha was measured using an enzyme-linked immunosorbent assay and was present in 18 of 25 control sera. Prior to treatment for stage III or IV epithelial ovarian cancer, 18 patients had undetectable serum levels of TGF-alpha, while 18 had values ranging from 10.6 to 531.7 pg/ml. The group with undetectable levels had a 6-month greater median survival; detectable TGF-alpha might be a negative prognostic indicator. In a separate group undergoing second-look laparotomy, differences in median TGF-alpha values versus controls and the primary study group approached significance. TGF-alpha was detected in significantly more control peritoneal fluid samples than in patient ascites. A larger study is warranted.     

Cytoreductive surgery for patients with recurrent epithelial ovarian carcinoma

OBJECTIVE: This study aims to identify favorable preoperative characteristics and examine the impact of secondary cytoreductive surgery on survival for patients with recurrent epithelial ovarian carcinoma. METHODS: Patients who underwent cytoreductive surgery for recurrent epithelial ovarian cancer were identified in our surgical database for the period 1988-2004. Patient charts were reviewed and data collected regarding patient demographics, surgical management, preoperative evaluation, perioperative complications, and oncologic outcome. RESULTS: Eighty-five patients met eligibility criteria. Preoperative factors that correlated with improved survival were disease-free interval of greater than 12 months (p<0.01) and residual disease after primary surgery of <2 cm (p<0.02). Other preoperative factors evaluated but not found significant included radiographic findings, physical findings, previous histology, stage, grade, previous chemotherapy, prior recurrence, and serum CA-125 level. Optimal resection to <1 cm residual disease was achieved in 86% of patients who had secondary cytoreduction. Small bowel and colon resection for cytoreduction occurred in 7% and 51% of patients, respectively. Operative complications occurred in 14% and postoperative complications occurred in 21% of patients. The median survival of patients who were optimally cytoreduced to <1 cm was 30 months compared to 17 months for patients with residual disease>or=1 cm (p<0.05). Operative factors that were evaluated and did not significantly effect survival were location of recurrence, presence of ascites, and extent of recurrence. Recurrent or progressive disease occurred in 75% of patients during follow-up. CONCLUSION: When selecting patients for secondary cytoreduction, the most significant preoperative factors are disease-free interval and success of a prior cytoreductive effort. Once secondary cytoreductive surgery is attempted, the most important factor for improved survival is optimal cytoreduction. Of equal importance is counseling regarding the significant risk for bowel surgery, colostomy, and complications.     

A phase II study of biweekly administration of paclitaxel in patients with recurrent epithelial ovarian cancer

Abstract. Lorenz E, Hagen B, Himmelmann A, Kjørstad K, Onsrud M, Tingelstad S, Gundersen G. A phase II study of biweekly administration of paclitaxel in patients with recurrent epithelial ovarian cancer.
The purpose of this study was to assess the efficacy and toxicity of single agent paclitaxel administered biweekly to patients with relapse of epithelial ovarian cancer previously treated with platinum-based regimen. Forty patients received an initial paclitaxel dose of 134 mg/m² administered intravenously over three hours every two weeks.
283 cycles were given. All 40 patients were evaluable for toxicity, which mainly consisted of granulocytopenia, myalgia/arthralgia, and peripheral neuropathy. Two patients developed severe hypersensitivity reactions. Dose escalation was possible by one level in 11 patients and by two levels in 12 patients, dose reductions were not necessary. Thirty-five patients were evaluated for response. Five obtained complete response (14%), eight obtained partial response (23%), and nine had stable disease (26%), while 11 patients showed progression (31%). The overall response rate was 37% (95% confidence interval 22–57%). The median duration of responses (complete and partial) was six months. Overall median time to progression and overall median survival for eligible patients ( n = 35) was 4.3 months and 11 months, respectively.
We conclude that biweekly administration of paclitaxel in recurrent epithelial ovarian carcinoma was active with manageable toxicity.     

A multicenter phase II study of the cryptophycin analog LY355703 in patients with platinum-resistant ovarian cancer

LY355703 is a synthetic product structurally related to the cryptophycin family isolated from the blue-green algae, which exerts a potent destabilization of microtubules during mitosis. This study was performed to determine the activity of LY355703 in patients with platinum-resistant advanced ovarian cancer and to characterize its toxicity profile. Twenty-six patients were enrolled in this study. Resistant disease was defined as a platinum-free interval of <6 months from primary treatment or rechallenge. LY355703 (1.5 mg/m(2)) was administered intravenously on days 1 and 8, every 3 weeks, infused over 2 h. From 24 patients evaluable for response, three partial responses (12.5%) and seven disease stabilizations were registered (29.2%), for an overall clinical benefit of 41.7%. Fourteen patients (58.3%) experienced a progression of the disease during treatment. Among the 25 patients evaluable for toxicity, two episodes of grade 3 anemia (8%); one, grade 3 thrombocytopenia (4%); one, grade 4 elevation of creatinine (4%); and one, grade 3 hyperbilirubinemia (4%) were reported. LY355703 has a modest activity in patients with platinum-resistant advanced ovarian cancer. Nevertheless, the considerable rate of disease stabilization in the absence of serious adverse events in this poor-prognosis study population suggests that this novel cryptophycin may deserve further investigation in this setting.     

A phase II evaluation of tirapazamine plus cisplatin in the treatment of recurrent platinum-sensitive ovarian or primary peritoneal cancer: a Gynecologic Oncology Group study

OBJECTIVES: To estimate the anti-tumor activity, nature and degree of toxicity of tirapazamine in combination with cisplatin in patients with recurrent platinum-sensitive ovarian or primary peritoneal cancers. METHODS: Eligible consenting patients had to have recurrent epithelial ovarian or primary peritoneal carcinoma with measurable disease. Patients were not allowed to have received any additional cytotoxic chemotherapy for management of recurrent or persistent disease, including re-treatment with initial chemotherapy regimens. Patients must have been platinum-sensitive, meaning a treatment-free interval of >6 months after response to a platinum-based regimen. The RECIST criteria were used for parameters of response. Tirapazamine was administered at a dose of 390 mg/m2 IV over 2 h followed 1 h later by cisplatin 60 mg/m2 IV every 3 weeks until disease progression or adverse effects prohibited further therapy. RESULTS.: Between June 2001 and February 2004, 65 patients were entered onto this study by 27 institutions; one patient was excluded due to ineligible tumor type. Twenty-six patients (41%) received six or more cycles of therapy; however, 16 (25%) received one course of therapy (mainly due to side effects or patient request). There were six (9%) complete responders and 28 (44%) partial responders for a total response rate of 53%. Only two patients (3%) developed increasing disease on this protocol, and response could not be assessed in 18 patients (28%). The median progression-free and overall survival for all patients is 10.9 and 26.4 months, respectively. The regimen did not cause major hematologic toxicity, however, it did cause frequent constitutional (23%) and gastrointestinal (mostly nausea/vomiting) (44%) grade 3 or 4 toxicity. CONCLUSIONS: The combination of tirapazamine and cisplatin has definite activity in the treatment of recurrent platinum-sensitive ovarian or primary peritoneal cancer. However, toxicity, primarily non-hematologic, was substantial. Reducing the toxicity of a tirapazamine-platinum combination should be pursued in future trials.     

Phase II study of bevacizumab and pemetrexed for recurrent or persistent epithelial ovarian,fallopian tube or primary peritoneal cancer

Objective

We aimed to evaluate the efficacy and safety of combination bevacizumab/pemetrexed for the treatment of recurrent epithelial ovarian cancer (EOC).

Methods

Platinum-sensitive or -resistant patients with recurrent or persistent EOC were eligible if they had received up to 2 prior chemotherapy regimens, including a platinum/taxane regimen without prior bevacizumab. Pemetrexed 500 mg/m² IV and bevacizumab 15 mg/kg IV were administered every 3 weeks. The primary endpoint was 6-month progression-free survival (PFS); other endpoints included toxicities, PFS and overall survival (OS).

Results

Thirty-four patients received a median of 7 treatment cycles (range, 2–26). Median follow-up was 25.7 months (range, 3.0–47.2). Six month progression-free survival (PFS) was 56% (95% CI: 38–71). The following response rates were documented (%; 95% CI): 0 complete response, 14 partial responses (41%; 25–59), 18 stable disease (53%; 35–70) and 2 progressive disease (6%; 1–20). Median PFS was 7.9 months (95% CI, 4.6–10.9), with a median OS of 25.7 months (95% CI, 15.4–29.8). Twenty-two patients (64.7%) had a platinum-free interval (PFI) of > 6 months prior to enrollment. Grade 3–4 hematologic toxicities included neutropenia (50%), leukopenia (26%), thrombocytopenia (12%) and anemia (9%). Non-hematologic grade 3–4 toxicities included metabolic (29%), constitutional (18%), pain (18%) and gastrointestinal (15%). Two patients developed hematologic malignancies within one year of treatment.

Conclusions

Combination bevacizumab/pemetrexed is an active option for both platinum-sensitive and -resistant recurrent EOC. Further investigation of cost and novel toxicities associated with this regimen may be warranted.     

Phase II study of gemcitabine in recurrent platinum-and paclitaxel-resistant ovarian cancer

OBJECTIVE: To determine the activity and tolerability of gemcitabine in the palliative treatment of ovarian cancer. METHODS: Patients affected by ovarian cancer, and with progressive disease after treatment with platinum/paclitaxel-based chemotherapy, were enrolled into this phase II study. Gemcitabine, 1000 mg/m(2), was administered on days 1, 8, and 15, by 30-min intravenous infusion. Cycles were repeated every 28 days. RESULTS: Fifty patients were enrolled. All the patients were platinum and/or paclitaxel resistant (median number of previous regimens, 2; range, 1-5). Median platinum-free interval was 3 (range, 1-11) months and median paclitaxel-free interval was 6 (range, 1-36) months. A total of 210 courses were evaluable for toxicity, with a median number of four cycles administered per patient (range, 1-10). A grade 3 or 4 hematological toxicity was observed in 27 patients (54%) (anemia grade 3, 16%; grade 4, 2%; neutropenia grade 3, 24%; grade 4, 18%; thrombocytopenia grade 3, 8%; grade 4, 0%). A 20-50% dose reduction was required for 36 patients (72%, 55% of cycles). Blood transfusions were necessary for 15 patients (30%), while 2 (4%) were treated with erythropoetin. Granulocyte colony-stimulating factor was necessary in 4 patients (8%). Nonhematological toxicity was mild and manageable. Only 4 patients (8%) experienced a grade 3 hepatic toxicity (elevated liver enzymes). Forty-one patients (82%) are, so far, evaluable for response. Among them, 7 partial responses (17%; 95% confidence interval [CI], 6-29), 15 disease stabilizations (>16 weeks) (36.6%; 95% CI, 21.9-51.3), and 19 progressions (46.3%; 95% CI, 31.0-61.6) have been registered. An overall clinical benefit was observed in 53.7% of patients. Thirteen patients (31.7%) had a time-to-progression exceeding 24 weeks. CONCLUSIONS: This study confirms the activity and safety of gemcitabine in heavily pretreated patients with recurrent ovarian cancer.