A phase II trial of thalidomide in patients with refractory uterine carcinosarcoma and correlation with biomarkers of angiogenesis: A Gynecologic Oncology Group study

Objectives

To evaluate the efficacy and adverse events of thalidomide in previously-treated, measurable, persistent or recurrent carcinosarcoma of the uterus, and to explore associations between angiogenic markers with patient demographics and clinical outcome.

Methods

Eligible, consenting patients were treated until disease progression or toxicity intervened with daily starting dose of 200 mg thalidomide/day that was increased by 200 mg every 2 weeks to a target dose of 1000 mg/day. Endpoints included progression-free survival (PFS) ≥ 6 months (primary), toxicity, response, overall PFS and survival. Pre- and post-treatment plasma were evaluated for a panel of angiogenic biomarkers and assessed against clinical outcomes.

Results

Of 55 enrolled patients, 45 were evaluable for toxicity and survival. Two patients (4%; 90% CI 1-13%) experienced a partial response, and 8 (18%; 90% CI 9-30%) had PFS ≥ 6 months. Median PFS was 1.9 months and median survival was 5.9 months. Grade 2-3 sensory neuropathy was noted in 6 patients, and 4, 3, and 3 patients experienced grade 3 sedation, fatigue, and constipation, respectively. Three patients had grade 4 adverse events (2 thromboembolic, 1 anemia). High pre-treatment VEGFA levels were associated with poorer PFS and survival.

Conclusions

Treatment with thalidomide met the protocol specified goal of prolonging PFS at 6 months. However, based on results with newer agents, the activity was insufficient to support further investigation. Association between pre-treatment VEGFA and prognosis in this population supports further evaluation of anti-angiogenic therapies in uterine carcinosarcoma.     

Locally advanced adenocarcinoma and adenosquamous carcinomas of the cervix compared to squamous cell carcinomas of the cervix in Gynecologic Oncology Group trials of cisplatin-based chemoradiation

Objective

Conflicting results have been reported for adeno- and adenosquamous carcinomas of the cervix with respect to their response to therapy and prognosis. The current study sought to evaluate impact of adeno- and adenosquamous histology in the randomized trials of primary cisplatin-based chemoradiation for locally advanced cervical cancer.

Methods

Patients with adeno- and adenosquamous cervical carcinomas were retrospectively studied and compared to squamous cell carcinomas in GOG trials of chemoradiation.

Results

Among 1671 enrolled in clinical trials of chemoradiation, 182 adeno- and adenosquamous carcinomas were identified (10.9%). A higher percentage of adeno- and adenosquamous carcinomas were stage IB₂ (27.5% versus 20.0%) and fewer had stage IIIB (21.4% versus 28.6%). The mean tumor size was larger for squamous than adeno- and adenosquamous. Adeno- and adenosquamous carcinomas were more often poorly differentiated (46.2% versus 26.8%). When treated with radiation therapy alone, the 70 patients with adeno- and adenosquamous carcinoma of the cervix showed a statistically poorer overall survival (p = 0.0499) compared to the 647 patients with squamous cell carcinoma of the cervix. However, when treated with radiation therapy with concurrent cisplatin-based chemotherapy, the 112 patients with adeno- and adenosquamous carcinomas had a similar overall survival (p = 0.459) compared the 842 patients with squamous cell carcinoma. Adverse effects to treatment were similar across histologies.

Conclusion

Adeno- and adenosquamous carcinomas of the cervix are associated with worse overall survival when treated with radiation alone but with similar progression-free and overall survival compared to squamous cell carcinomas of the cervix when treated with cisplatin based chemoradiation.     

A randomized phase III trial of IV carboplatin and paclitaxel × 3 courses followed by observation versus weekly maintenance low-dose paclitaxel in patients with early-stage ovarian carcinoma: a Gynecologic Oncology Group Study

Objective

To compare the recurrence-free interval (RFI) and safety profile in patients with completely resected high-risk early-stage ovarian cancer treated with intravenous (IV) carboplatin and paclitaxel with or without maintenance low-dose paclitaxel for 24 weeks.

Methods

Eligibility was limited to patients with stage IA/B (grade 3 or clear cell), all IC or II epithelial ovarian cancer. All patients were to receive carboplatin AUC 6 and paclitaxel 175 mg/m² q3 weeks × 3 courses with random assignment to either observation or maintenance paclitaxel 40 mg/m²/week × 24 weeks. Recurrence required clinical or radiological evidence of new tumor.

Results

There were 571 patients enrolled onto this study, of whom 29 were deemed ineligible due to inappropriate stage or pathology, leaving 542 patients. At least 3 cycles of treatment were administered to 524/542 (97%) of patients, and among those assigned to maintenance paclitaxel, 80% completed the regimen. The incidence of grade 2 or worse peripheral neuropathy (15.5% vs. 6%), infection/fever (19.9% vs. 8.7%), and dermatologic events (70.8% vs. 52.1%) was higher on the maintenance regimen (p < 0.001). The cumulative probability of recurring within 5 years for the maintenance paclitaxel regimen is 20% vs. 23% for surveillance (hazard ratio 0.807; 95% CI: 0.565-1.15). The probability of surviving 5 years was 85.4% and 86.2%, respectively.

Conclusion

Maintenance paclitaxel at 40 mg/m²/week × 24 weeks added to standard dose AUC6 and paclitaxel 175 mg/m² × 3 doses provides no significant increase in RFI.     

Efficacy of contemporary chemotherapy in stage IIIC endometrial cancer: A histologic dichotomy

Background

Treatment failures in stage IIIC endometrial carcinoma (EC) are predominantly due to occult extrapelvic metastases (EPM). The impact of chemotherapy on occult EPM was investigated according to grade (G), G1/2EC vs G3EC.

Methods

All surgical-stage IIIC EC cases from January 1, 1999, through December 31, 2008, from Mayo Clinic were included. Patient-, disease-, and treatment-specific risk factors were assessed for association with overall survival, cause-specific survival, and extrapelvic disease-free survival (DFS) using Cox proportional hazards regression.

Results

109 cases met criteria, with 92 (84%) having systematic lymphadenectomy (> 10 pelvic and > 5 paraaortic lymph nodes resected). In patients with documented recurrence sites, occult EPM accounted for 88%. Among G1/2EC cases (n = 48), the sole independent predictor of extrapelvic DFS was grade 2 histology (hazard ratio [HR], 0.28; 95% CI, 0.08–0.91; P = .03) while receipt of adjuvant chemotherapy approached significance (HR 0.13; 95% CI, 0.02, 1.01; P = .0511). The 5-year extrapelvic DFS with and without adjuvant chemotherapy was 93% and 54%, respectively (log-rank, P = .02). Among G3EC (n = 61), the sole independent predictor of extrapelvic DFS was lymphovascular space involvement (HR, 2.63; 95% CI, 1.16–5.97; P = .02). Adjuvant chemotherapy did not affect occult EPM in G3EC; the 5-year extrapelvic DFS for G3EC with and without adjuvant chemotherapy was 43% and 42%, respectively (log-rank, P = .91).

Conclusions

Chemotherapy improves extrapelvic DFS for stage IIIC G1/2EC but not stage IIIC G3EC. Future efforts should focus on prospectively assessing the impact of chemotherapy on DFS in G3EC and developing innovative phase I and II trials of novel systemic therapies for advanced G3EC.     

Papillary serous carcinoma in ovaries of normal size: a clinicopathologic study of 20 cases and comparison with extraovarian peritoneal papillary serous carcinoma

OBJECTIVE: The aim of this study was to compare the clinicopathological features of papillary serous carcinoma in ovaries of normal size and primary peritoneal carcinoma (PPC). METHODS: Among 167 patients diagnosed with advanced primary serous ovarian carcinoma over a 9-year period, 20 patients with a normal ovarian size (not larger than 4 cm in the longest diameter) were selected for this study after a review of the pathologic materials. The clinicopathological characteristics of the patients were compared with those of seven patients with PPC, diagnosed using the GOG criteria during the same period. RESULTS: All the patients with ovarian carcinoma and five of seven PPC patients had small ovarian tumors. There were few significantly different features between the two groups. The patients with ovarian carcinoma were younger than those with PPC (median age of 52 vs. 64 years, P=0.007) and tended to have a lower baseline CA125 level (median value of 937 vs. 2870 U/mL, P=0.097), less severe omental involvement (P=0.057), and a more complete response to adjuvant chemotherapy (89% vs. 57%, P=0.064). CONCLUSIONS: Although the sample size was small, there was no meaningful difference between patients with papillary serous carcinoma in ovaries of normal size and PPC. Therefore, further studies will be needed to determine the relevance of the GOG rules in distinguishing between the two groups.     

RhoB mediates antitumor synergy of combined ixabepilone and sunitinib in human ovarian serous cancer

Objective

The aim was to evaluate antitumor activity of the combination of ixabepilone and sunitinib in pre-clinical models of chemotherapy naïve and refractory epithelial ovarian tumors, and to investigate the mechanism of synergy of such drug combination.

Methods

HOVTAX2 cell line was derived from a metastatic serous papillary epithelial ovarian tumor (EOC) and a paclitaxel-resistant derivative was established. Dose response curves for ixabepilone and sunitinib were generated and synergy was determined using combination indexes. The molecular mechanism of antitumor synergy was examined using shRNA silencing.

Results

The combination of ixabepilone and sunitinib demonstrated robust antitumor synergy in naïve and paclitaxel-resistant HOVTAX2 cell lines due to increased apoptosis. The GTPase, RhoB, was synergistically upregulated in cells treated with ixabepilone and sunitinib. Using shRNA, RhoB was demonstrated to mediate antitumor synergy. These results were validated in two other EOC cell lines.

Conclusions

Ixabepilone plus sunitinib demonstrated antitumor synergy via RhoB in naïve and paclitaxel-resistant cells resulting in apoptosis. This study demonstrates a novel mechanism of action leading to antitumor synergy and provides ‘proof-of-principle’ for combining molecular targeted agents with cytotoxic chemotherapy to improve antitumor efficacy. RhoB could be envisioned as an early biomarker of response to therapy in a planned Phase II clinical trial to assess the efficacy of ixabepilone combined with a receptor tyrosine kinase inhibitor such as sunitinib. To the best of our knowledge, this is the first demonstration of antitumor synergy between these two classes of drugs in EOC and the pivotal role of RhoB in this synergy.     

Histological grading in a large series of advanced stage ovarian carcinomas by three widely used grading systems: consistent lack of prognostic significance. A translational research subprotocol of a prospective randomized phase III study (AGO-OVAR 3 protocol)

While there is no doubt that histologic grading is applicable in early stage ovarian carcinoma, it is still in controversial discussion concerning advanced stage ovarian carcinoma. It was the aim of this study to assess the three most widely used grading systems for ovarian carcinoma in terms of prognostic significance, concordance rates, and reproducibility in a large number of advanced stage ovarian carcinomas of all types after standardized chemotherapy. Representative hematoxylin and eosin slides from 334 cases of stage IIB–IV ovarian carcinoma (prospective randomized, multi-center, phase III study) were used. The first round was grading of all cases according to FIGO, GOG, and Silverberg by one author. The second round (after 1 year) was 30 randomly selected cases graded by three authors. None of the three grading systems was prognostically significant (FIGO p = 0.38; GOG p = 0.70; Silverberg p = 0.92). The concordance rates between the three systems were as follows: FIGO/GOG 95.5%, κ = 0.929; Silverberg/FIGO 69.9%, κ = 0.533; Silverberg/GOG 66.8%, κ = 0,481. Grading of advanced stage ovarian carcinomas was of no value for estimation of prognosis in this homogeneously treated patient group. Alternative methods should be defined, which might help to separate patients with high risk of tumor progression from others with low risk.     

原发性腹膜癌与卵巢浆液性腺癌临床生物学行为和肿瘤标志物的比较

目的 探讨原发性腹膜癌与卵巢浆液性腺癌的临床生物学行为和肿瘤标志物的表达及异同点。方法 回顾性分析24例原发性腹膜癌及79例卵巢浆液性腺癌的临床资料。并比较两者雌、孕激素受体（ER、RR）、细胞角蛋白CK，和抑癌基因P53表达的异同。结果 原发性腹膜癌组主诉下腹胀的比例、CA125值、腹水量及腹水中癌细胞检出率均高于卵巢浆液性腺癌组（P〈0．05）。结论 原发性腹膜癌临床生物学行为和组织学来源与卵巢浆液性腺癌相似。前者盆腹腔病变比较弥散和广泛，CA125值、腹水量及腹水中脱落癌细胞检出率均高于后者。两类病人手术和化疗方式相同．其结果相似。     

CA125 regression in ovarian cancer patients treated with intravenous versus intraperitoneal platinum-based chemotherapy: a gynecologic oncology group study

Objective

CA125 is a non-specific marker of peritoneal irritation which has the potential for false elevation during intraperitoneal treatment. The purpose of this study is to identify the rate of CA125 regression during intraperitoneal (IP) versus intravenous (IV) chemotherapy for ovarian cancer.

Methods

GOG 114, a randomized control trial evaluating IP and IV treatment, includes an intensive CA125 measurement schema with weekly CA125 levels until ≤ 35 units/ml for both IP- and IV-treated patients. Rate of CA125 normalization, median CA125 values for each treatment cycle, as well as clinical and pathologic features were compared between the treatment groups. Baseline CA125 levels and rate of CA125 decline were evaluated with respect to overall survival.

Results

CA125 data were available for 223 patients who received IV cisplatin/paclitaxel and for 231 patients who received IV carboplatin followed by IP cisplatin/paclitaxel. Standard prognostic criteria and baseline CA125 values were similar between the treatment groups. For treatment cycles in which IP-treatment was administered, there was no statistically significant difference in CA125 levels between IV- and IP-treated patients. The rate of CA125 normalization was similar between IV- and IP-treated patients (p = 0.55). Patients with low pre-chemotherapy CA125 levels which rapidly declined during treatment demonstrated a survival advantage (p < 0.0001).

Conclusions

No difference in CA125 decline was identified between IP- and IV-treated patients undergoing a weekly CA125 monitoring schedule. This data supports the utilization of standard CA125 response criteria in the therapeutic monitoring for patients receiving IP treatment.