Phase II trial on cisplatin-adriamycin-paclitaxel combination as neoadjuvant chemotherapy for locally advanced cervical adenocarcinoma.

OBJECTIVE: Neoadjuvant chemotherapy (NACT) followed by surgery is a different therapeutic approach to locally advanced cervical adenocarcinoma (LACA) and seems to offer specific advantages over chemoradiation. This phase II trial was designed to evaluate the toxicity and activity of NACT with cisplatin-adriamycin-paclitaxel (TAP) in patients with LACA. METHODS: Patients with International Federation of Gynecology and Obstetrics stage IB2-IIB uterine adenocarcinoma were treated with NACT TAP for 3 cycles. After the last cycle, patients underwent radical surgery with lymph node dissection. Pathological response was classified as no residual tumor (pCR), residual disease with less than 3-mm stromal invasion (pR1), or residual disease with more than 3-mm stromal invasion (pR2). RESULTS: Between 2003 and 2010, 30 women were enrolled. Fourteen complete clinical responses, 10 partial responses, and 6 stabilizations of disease were registered. Three patients achieved a pCR, 6 a pR1 response, and 21 a pR2 response. At a median follow-up of 45 months, progression-free survival and overall survival were 37 and 48 months, respectively. Hematologic toxicity was the most relevant adverse effect. CONCLUSIONS: The TAP combination seems to be feasible with an acceptable toxicity profile and a promising response rate for the treatment of LACA.

Class III NSRH: oncological outcome in 170 cervical cancer patients.

OBJECTIVE: To analyze local recurrence rate (LRR), morbidities and oncologic outcome of class III nerve-sparing radical hysterectomy. PATIENTS AND METHODS: 170 consecutive class III NSRH cases were performed. Nineteen patients were addressed directly to surgery whilst neoadjuvant chemotherapy was administered in 151 patients. The majority of patients had SCC (75%). The median follow-up was 31 months. RESULTS: The mean age was 50 [27-78] years. Mean post-operative hospital stay was 7 [3-16] days. 2 intraoperative complications occurred. Operating time and blood loss was similar to the state-of-the-art of conventional radical hysterectomy. Overall G3-4 complication rate was 8.2 % (14/170). Early G3-4 complication rate was 3.5% (6/170). Late G3-4 complication rate was: 4.7%. (8/170). Positive pelvic nodes were noted in 31 patients (18.2%). Vagina and parametrial involvement were present in 38 (22%) and 27 (15.8%) patients, respectively. LRR was 10% (17/170). The sites of relapse were: 12 pelvic, 5 vaginal. There were 9 patients DOD. The 2-year and 5-year DFS rates were 89% and 81%, respectively. Univariate and multivariate analysis identified vagina involvement and postoperative treatment as significant prognostic factors. CONCLUSIONS: The oncologic results of NSRH were similar to the state-of-the-art of conventional radical hysterectomy. Two years DFS in relation to FIGO stage of disease was 92.3, 89.2 and 86.1 % respectively for IB1, IB2, IIB comparable to literature data. The early and late complications rate related to autonomic injury was significantly lower. The nerve-sparing technique should be considered in all cervical cancer patients addressed to surgery.

Quality of life and sexual, bladder, and intestinal dysfunctions after class III nerve-sparing and class II radical hysterectomies: a questionnaire-based study.

BACKGROUND: To compare quality of life and bladder, intestinal, and sexual dysfunctions in 2 groups of patients undergoing different types of radical hysterectomies (RHs). METHODS: Patients with cervical cancer who underwent RH have been enrolled in a questionnaire-based study. Quality of life (QoL) and bladder, intestinal, and sexual dysfunctions were evaluated with the Functional Assessment of Cancer Therapy-Cervix (FACT-Cx). Patients were grouped according to the type of RH: group 1, class II RH and group 2, class III nerve-sparing RH (NSRH). RESULTS: Of 157 women included in the study, 127 filled out the questionnaire. Overall, QoL score assessed with the FACT questionnaire did not differ significantly between the 2 groups. The FACT subscales assessing physical, functional, emotional, and social well-being did not differ significantly between the 2 groups, whereas the FACT-Cx subscales assessing disease-related symptoms in group 2 patients showed a significantly worse score (72 vs 66; P = 0.03). Evaluating singularly the 15 items of the Cx subscales assessing disease-related symptoms, we did not find any significant difference between the 2 groups, but only Cx1 ("I am bothered by discharge or bleeding from my vagina") was significantly worse in group 2 patients. At univariate analysis, we found that NSRH and adjuvant radiotherapy (RT) impact negatively on the FACT-Cx subscales regarding pelvic visceral function. However, at multivariate analysis, only adjuvant RT impact negatively. CONCLUSIONS: Patients submitted to class III NSRH did not present worse QoL and pelvic visceral dysfunctions when compared with class II RH. The RT seems to be a factor impacting negatively on bladder and sexual function.

Trabectedin for women with ovarian carcinoma after treatment with platinum and taxanes fails.

PURPOSE: To assess the efficacy and toxicity of the marine-derived alkaloid trabectedin (ET-743) in patients with advanced ovarian cancer refractory to or experiencing disease relapse after platinum- and taxane-based chemotherapy. PATIENTS AND METHODS: Fifty-nine patients from four institutions either resistant (n = 30) or sensitive (n = 29) to prior platinum and taxanes were treated with a 3-hour infusion of trabectedin every 3 weeks. Patients were monitored weekly for toxicity and restaged every two cycles for response. Response was assessed according to Response Evaluation Criteria in Solid Tumors Group. RESULTS: The peer-reviewed objective response rate in platinum-sensitive patients was 43% (95% CI, 23% to 65%) with an estimated median time to progression of 7.9 months (95% CI, 7.5 to 14.1 months); in platinum-resistant patients two partial responses were observed. Responses were durable for up to 12.9 months (median, 5 months). The predominant toxicities at the recommended dose of 1,300 microg/m(2) were neutropenia, asthenia, and self-limited increase of aminotransferases never requiring treatment interruption. CONCLUSION: Trabectedin administered as a 3-hour infusion at 1,300 microg/m(2) is a safe new drug with promising activity in relapsed ovarian cancer, showing a 43% objective response rate in patients with platinum-sensitive disease, which favorably compares with other salvage treatments and warrants additional development either alone or in combination.

Implementation of laparoscopic approach for type B radical hysterectomy: a comparison with open surgical operations.

OBJECTIVE: To investigate the safety, feasibility and effectiveness of laparoscopic approach in the management patients undergoing modified radical hysterectomy for early stage cervical cancer. METHODS: Consecutive data of 157 women who had class II radical hysterectomy, for stage IA2 and stage IB1 <2 cm cervical cancer, were prospectively collected. Data of patients undergoing surgery via laparoscopy (LRH) were compared with those undergoing open surgical operations (RAH). A propensity-matched comparison (1:1) was carried out to minimize as possible selection biases. Post-operative complications were graded per the Clavien-Dindo classification. Five-year survival outcomes were assessed using Kaplan-Meier model. RESULTS: After the exclusion of 37 (23.5%) patients on the basis of propensity-matching, 60 patients undergoing LRH were compared with 60 patients undergoing RAH. No between-group differences in baseline, disease and pathological variables were observed (p > 0.05). Patients undergoing surgery via laparoscopy experienced longer operative time than patients undergoing RAH; while LRH correlated whit shorter length of hospitalization and lower blood loss in comparison to RAH. Intra- and post-operative complication rate was similar between groups (p = 1.00). The execution of LRH or RAH did not influence site of recurrence (p > 0.2) as well as survival outcomes, in term of 5-year disease-free (p = 0.29, log-rank test) and overall survivals (p = 0.50, log-rank test). CONCLUSION: Laparoscopic approach is a safe procedure, upholds the results of RAH, reducing invasiveness of open surgical operations. Further large prospective investigations are warranted.

Microinvasive squamous cell cervical carcinoma.

Several histologic tumor-related features are the key factors for further treatment planning in microinvasive cervical cancer (MIC) after conization. To better define the indications for conservative treatment of MIC we conducted a literature review for prognostic factors for MIC and we carried out a prospective observational study evaluating most important pathologic factors and the relationships between tumor and edges of the cone and incidence of recurrences. In our experience seven recurrences were observed. Two distinct groups of patients were identified with a clearance lower or higher of 10 and 8 mm for apical and lateral margin respectively. Depth of infiltration and even lymph-vascular involvement have been confirmed as the most important histologic parameters to be evaluated. Apical and lateral clearance of the tumor are significantly correlated with the recurrence rate. If an adequate lateral border of healthy tissue is present on the specimen, conization may be considered as definitive treatment of MIC.

Nerve-sparing radical hysterectomy: a pilot study.

Nerve-sparing radical hysterectomy has increasingly been used for cervical cancer, with less morbidity. We aimed with this study: i) to describe an alternative technique of nerve-sparing radical Piver III hysterectomy, using the CUSA, in which attention was given to the uterosacral ligament and cardinal ligament; ii) to evaluate the feasibility of this new nerve-sparing technique; iii) to describe the surgical anatomy of the autonomic nervous system; iv) to assess the early incidence of bladder dysfunction. Twelve consecutive patients with local-regional advanced cervical cancer were enrolled in the study on nerve-sparing radical hysterectomy with extended pelvic lymphadenectomy. The mean age was 44 years (range, 30-59), mean body mass index was 24 kg/m2 (range, 18-30), mean operating time was 217 mins (range, 195-240), and mean blood loss was 437 cc (range, 200-750). The average hospitalization time was 9 days (range, 5-15 days). Two patients presented pathologically positive parametrium. Two of 12 (17%) patients were discharged with self-catheterism. In the first outpatient follow-up, 1 patient had recovered spontaneous voiding. The nerve-sparing technique with CUSA can be an option to reduce radical hysterectomy-related morbidity. The technique proved to be feasible, with promising results in terms of preventing bladder dysfunction. An elevated body mass index and large tumors can impair the performance of the technique. Further studies clarifying neuroanatomy and neurophysiology of autonomic nervous structures, as well as a prospective controlled trial on nerve-sparing radical hysterectomy should be carried out to confirm our data.

Role of paclitaxel and cisplatin as the neoadjuvant treatment for locally advanced squamous cell carcinoma of the vulva.

OBJECTIVE: The therapeutic outcomes of patients with advanced vulvar cancer are poor. Multi-modality treatments including concurrent chemoradiation or different regimens of neoadjuvant chemotherapy (NACT), and surgery have been explored to reduce the extent of surgery and morbidity. The present single-institution trial aimed to evaluate the efficacy and toxicity of paclitaxel and cisplatin in locally advanced vulvar cancer. METHODS: From 2002 to 2009, 10 patients with stage III-IV locally advanced squamous cell carcinoma of the vulva were prospectively treated with 3 courses of paclitaxel-ifosfamide-cisplatin or paclitaxel-cisplatin. Nine of them subsequently underwent radical local excision or radical partial vulvectomy and bilateral inguino-femoral lymphadenectomy. RESULTS: The clinical response rate of all enrolled patients was 80%, whereas the pathological responses included 1 case with complete remission, 2 with persistent carcinoma in situ, and 6 invasive cancer cases with tumor shrinkage of more than 50%. Four patients had positive nodes. Forty percent of patients experienced grade 3-4 bone marrow toxicity, which was successfully managed with granulocyte-colony stimulating factor, even in cases of elderly patients. Median progression-free survival after surgery was 14 months (range, 5 to 44 months). Six of the 7 recurrent cases were local, and 3 of them were treated with salvage surgery while the other 3 received radiation with or without chemotherapy. After a median follow-up period of 40 months (range, 5 to 112 months), 55.5% of patients remained alive with no evidence of disease, including 2 long-term survivors after recurrence at 5 and 9 years. CONCLUSION: Based on the high response rate and manageable toxicity, NACT with paclitaxel and cisplatin with or without ifosfamide followed by surgery could be considered as a therapeutic option for locally advanced vulvar cancer.

Nerve-sparing radical hysterectomy in cervical cancer: evolution of concepts.

OBJECTIVES: This paper reviews the evolution of concepts concerning the nerve-sparing radical hysterectomy (NSRH) in cervical cancer. METHODS: Research studies published between 1991 and 2006 were reviewed. RESULTS: Significant progress has been made in understanding the neuroanatomy and the neurophysiology of autonomic pelvic plexus. The ideal surgical management of cervical cancer patients should be tailored on the basis of prognostic factors and quality of life. Within the discussion concerning the optimal level of radicality of hysterectomy, which is still controversial, the new concept of NSRH has to be considered in order to reduce morbidity without compromising the oncological disease control. Surgical strategies have been developed to spare the autonomic functions with promising results. CONCLUSIONS: To date, there is a growing body of data about NSRH in cervical cancer. However, there is not yet a consensus concerning to which part of uterine support ligaments a NS approach should be directed.

Clinical and pathological prognostic factors in squamous cell carcinoma of the vulva.

OBJECTIVE: The objective of this study was the prognostic analysis of clinicopathologic variables related to primary tumor and to lymph node metastases. METHODS: We retrospectively analyzed 389 cases of squamous cell carcinoma of the vulva. The following variables were studied: patients' age, diameter and location of the tumor, clinical tumor characteristics, depth of invasion, grade, lymphovascular space involvement (LVSI) and lymph node status. In the subset of 110 node positive patients, we evaluated number of positive nodes, laterality, extension of node dissection, lymph node chains involved, presence of extracapsular spread and rate of lymph node replacement. All variables with P value < 0.2 by the univariate analysis were successively subjected to multivariate analysis (Cox proportional hazard model). RESULTS: Among all the tumor-related variables age, clinical tumor characteristics, LVSI and lymph node status were found to be statistically significant predictors of survival for the log-rank test. On the basis of multivariate analysis, the nodal status was the most significant independent prognostic factor (hazard rate [HR]: 2.06; confidence interval [CI] 95%: 1.57-12.07) followed by LVSI (HR: 3.47; CI95%: 1.85-7.85). The independent prognostic factors among the variables relative to positive nodes were the percentage of nodal replacement (HR: 6.99; CI95%: 3.51-16.14) and the extracapsular spread (HR: 4.88; CI95%: 2.96-10.14). CONCLUSIONS: Lymph node status and nodal features, such as extracapsular spread and nodal replacement rate, were shown to be independent factors. These factors should be considered to identify high risk patients and in planning further adjuvant therapy.

Type II versus Type III nerve-sparing radical hysterectomy: comparison of lower urinary tract dysfunctions.

OBJECTIVES: According to our previous experience, Type III Nerve-sparing Radical hysterectomy (NSRH) for cervical cancer presented an acceptable urologic morbidity, without compromising radicality. The aim of this study was to compare Type NSRH with other types of RH in terms of incidence of early bladder dysfunctions and perioperative complications. METHODS: One hundred and ten patients with cervical cancer were submitted to Type II RH (group 1), Type III NSRH (group 2) and Type III RH (group 3). We assessed the postoperative early bladder function and complications. The follow-up period was 3 months. RESULTS: Group 1 had a significantly shorter duration of the surgery, minor mean blood loss and shorter mean length of postoperative stay when compared to groups 2 and 3. No intraoperative complications were reported in either of the groups. The groups did not differ significantly in terms of GIII/IV morbidity (group 1 = 10%, group 2 = 10% and group 3 = 15%, chi(2), P value: 0.65). Not even they differed in terms of urologic GI-IV morbidity (group 1 = 13%, group 2 = 15% and group 3 = 10%, chi(2), P value = 0.88). Groups 1 and 2 presented a prompt recover of bladder function, significantly different from that of group 3. There was a significant difference between the groups regarding the number of patients discharged with self-catheterism (group 1 = 0; group 2 and group 3 = 11; chi(2), P value << 0.05). CONCLUSIONS: The Type III NSRH seems to be comparable to Type II RH and superior to Type III RH in terms of early bladder dysfunctions.

Nerve-sparing radical hysterectomy: a surgical technique for preserving the autonomic hypogastric nerve.

OBJECTIVES: Recently, a nerve-sparing radical hysterectomy has been proposed for cervical cancer to reduce morbidity. The aim of this study is (i) to describe the surgical anatomy of the autonomic nervous system, (ii) to describe a new nerve-sparing technique for Piver III radical hysterectomy (RH) using the CUSA, in which greater attention was paid to the autonomic nervous pathway, and (iii) to assess the feasibility and the impact of this nerve-sparing technique on the incidence of early bladder dysfunctions. METHODS: Twenty-three patients with cervical cancer were submitted to nerve-sparing Piver III RH with pelvic lymphadenectomy. Postoperative assessment of bladder function consisted draining the bladder for 3 days using Foley catheterization. Then, we started draining the bladder every 3 h with a no. 10 French catheter to register the onset of spontaneous voiding and to assess the postvoid residual urine volume (PVR). RESULTS: The nerve-sparing technique were performed satisfactorily in all cases. The mean operating time was 219 min (range: 150-270). The mean blood loss was 489 ml (range: 200-800). The average period of hospitalization was 10 days (range: 5-16). Two (9%) patients were discharged with self-catheterization, and one of them recovered the ability to void her bladder spontaneously by the time of her first visit to the outpatient clinic. CONCLUSIONS: This nerve-sparing RH technique using the CUSA proved feasible, with promising results in terms of preventing early bladder dysfunction. The average time between surgery and the onset of spontaneous voiding was acceptable. Further prospective controlled studies are needed to confirm our data.

Gemcitabine combined with oxaliplatin (GEMOX) as second-line chemotherapy in patients with advanced ovarian cancer refractory or resistant to platinum and taxane.

OBJECTIVES: The aim of this multicenter feasibility study was to determine the toxicity profile and antitumor activity of the gemcitabine plus oxaliplatin combination as second-line treatment in platinum plus paclitaxel resistant/refractory advanced ovarian cancer. METHODS: Twenty patients received a 30-60-min infusion of gemcitabine a week for 2 weeks, followed by 120-180 min infusion of oxaliplatin every 3 weeks. The doses used were 1,000 and 130 mg/m(2), respectively. Seventeen cases (85% of the total) were platinum resistant and 3 (15%) were platinum refractory. RESULTS: Grade 3/4 thrombocytopenia occurred in 14/20 of cases (70%); there were no symptomatic cases. 2 patients required platelet transfusion and 8 patients received hydrocortisone. The dose- limiting toxicity was thrombocytopenia. Combined grade 3/4 neutropenia was observed in 8/20 (40%) of cases (no sepsis was registered). Five patients were treated with recombinant erythropoietin because of grade 3 anemia and 4 cases received G-CSF prophylactically from the first cycle. The overall response rate of the combination in terms of antitumor activity was 26% (95% CI = 9-51%). CONCLUSION: A combination of gemcitabine and oxaliplatin using this schedule gave rise to a moderate/severe toxicity profile and would be feasible only if growth factors were used and/or gemcitabine were administered at lower doses. The antitumor activity of the combination was insufficient reward for the resultant toxicity profile. However, equivalent to that of other drugs used in platinum refractory and resistant patients.