Marco Marinaccio

Topotecan Compared With No Therapy After Response to Surgery and Carboplatin/Paclitaxel in Patients With Ovarian Cancer: Multicenter Italian Trials in Ovarian Cancer (MITO-1) Randomized Study

PURPOSE Topotecan is an active second-line treatment for advanced ovarian cancer. Its efficacy as consolidation treatment after first-line standard chemotherapy is unknown. PATIENTS AND METHODS To investigate whether topotecan (1.5 mg/m(2) on days 1 through 5, four cycles, every 3 weeks) prolonged progression-free survival (PFS) for patients responding to standard carboplatin (area under the curve 5) and paclitaxel (175 mg/m(2) administered as a 3-hour infusion in six cycles; CP), a multicenter phase III study was performed with an 80% power to detect a 50% prolongation of median PFS. Patients were registered at diagnosis and randomized after the end of CP. RESULTS Two hundred seventy-three patients were randomly assigned (topotecan, n = 137; observation, n = 136), with a median age of 56 years. Stage at diagnosis was advanced in three fourths of patients (stage III in 65% of patients; stage IV in 10%); after primary surgery, 46% had no residual disease and 20% were optimally debulked. After CP, 87% reached a clinical complete response, and 13% achieved a partial response. Neutropenia (grade 3/4 in 58% of the patients) and thrombocytopenia (grade 3 in 21%; grade 4 in 3%) were the most frequent toxicities attributed to topotecan. There was no statistically significant difference in PFS between the arms (P =.83; log-rank test): median PFS was 18.2 months in the topotecan arm and 28.4 in the control arm. Hazard ratio of progression for patients receiving topotecan was 1.18 (95% CI, 0.86 to 1.63) after adjustment for residual disease, interval debulking surgery, and response to CP. CONCLUSION The present analysis indicates that consolidation with topotecan does not improve PFS for patients with advanced ovarian cancer who respond to initial chemotherapy with carboplatin and paclitaxel.

Residual neurotoxicity in ovarian cancer patients in clinical remission after first-line chemotherapy with carboplatin and paclitaxel: The Multicenter Italian Trial in Ovarian cancer (MITO-4) retrospective study

BackgroundCarboplatin/paclitaxel is the chemotherapy of choice for advanced ovarian cancer, both in first line and in platinum-sensitive recurrence. Although a significant proportion of patients have some neurotoxicity during treatment, the long-term outcome of chemotherapy-induced neuropathy has been scantly studied. We retrospectively assessed the prevalence of residual neuropathy in a cohort of patients in clinical remission after first-line carboplatin/paclitaxel for advanced ovarian cancer.Methods120 patients have been included in this study (101 participating in a multicentre phase III trial evaluating the efficacy of consolidation treatment with topotecan, and 19 treated at the National Cancer Institute of Naples after the end of the trial). All patients received carboplatin (AUC 5) plus paclitaxel (175 mg/m2) every 3 weeks for 6 cycles, completing treatment between 1998 and 2003. Data were collected between May and September 2004. Residual sensory and motor neurotoxicity were coded according to the National Cancer Institute – Common Toxicity Criteria.Results55 patients (46%) did not experience any grade of neurological toxicity during chemotherapy and of these none had signs of neuropathy during follow-up. The other 65 patients (54%) had chemotherapy-induced neurotoxicity during treatment and follow-up data are available for 60 of them. Fourteen out of 60 patients (23%) referred residual neuropathy at the most recent follow-up visit, after a median follow up of 18 months (range, 7–58 months): 12 patients had grade 1 and 2 patients grade 2 peripheral sensory neuropathy; 3 patients also had grade 1 motor neuropathy. The remaining 46/60 patients (77%) had no residual neuropathy at the moment of interview: recovery from neurotoxicity had occurred in the first 2 months after the end of chemotherapy in 22 (37%), between 2 and 6 months in 15 (25%), or after more than 6 months in 9 patients (15%). Considering all 120 treated patients, there was a 15% probability of persistent neurological toxicity 6 months after the end of chemotherapy.ConclusionA significant proportion of patients with advanced ovarian cancer treated with first-line carboplatin/paclitaxel suffer long-term residual neuropathy. This issue should be carefully taken into account before considering re-treatment with the same agents in sensitive recurrent disease.Carboplatin/paclitaxel is the chemotherapy of choice for advanced ovarian cancer, both in first line and in platinum-sensitive recurrence. Although a significant proportion of patients have some neurotoxicity during treatment, the long-term outcome of chemotherapy-induced neuropathy has been scantly studied. We retrospectively assessed the prevalence of residual neuropathy in a cohort of patients in clinical remission after first-line carboplatin/paclitaxel for advanced ovarian cancer. 120 patients have been included in this study (101 participating in a multicentre phase III trial evaluating the efficacy of consolidation treatment with topotecan, and 19 treated at the National Cancer Institute of Naples after the end of the trial). All patients received carboplatin (AUC 5) plus paclitaxel (175 mg/m2) every 3 weeks for 6 cycles, completing treatment between 1998 and 2003. Data were collected between May and September 2004. Residual sensory and motor neurotoxicity were coded according to the National Cancer Institute – Common Toxicity Criteria. 55 patients (46%) did not experience any grade of neurological toxicity during chemotherapy and of these none had signs of neuropathy during follow-up. The other 65 patients (54%) had chemotherapy-induced neurotoxicity during treatment and follow-up data are available for 60 of them. Fourteen out of 60 patients (23%) referred residual neuropathy at the most recent follow-up visit, after a median follow up of 18 months (range, 7–58 months): 12 patients had grade 1 and 2 patients grade 2 peripheral sensory neuropathy; 3 patients also had grade 1 motor neuropathy. The remaining 46/60 patients (77%) had no residual neuropathy at the moment of interview: recovery from neurotoxicity had occurred in the first 2 months after the end of chemotherapy in 22 (37%), between 2 and 6 months in 15 (25%), or after more than 6 months in 9 patients (15%). Considering all 120 treated patients, there was a 15% probability of persistent neurological toxicity 6 months after the end of chemotherapy. A significant proportion of patients with advanced ovarian cancer treated with first-line carboplatin/paclitaxel suffer long-term residual neuropathy. This issue should be carefully taken into account before considering re-treatment with the same agents in sensitive recurrent disease.

Long-term follow-up is crucial after treatment for granulosa cell tumours of the ovary

Objective:The aim of this study is to evaluate the long-term outcome of granulosa cell tumour (GCT) of the ovary in a large series of patients treated in MITO centres (Multicentre Italian Trials in Ovarian Cancer) and to define prognostic parameters for relapse and survival.Methods:A retrospective multi-institutional review of patients with GCTs of the ovary treated or referred to MITO centres was conducted. Surgical outcome, intraoperative and pathological findings and follow-up data were analysed. Kaplan–Meier and Cox proportional hazards analyses were used to determine the predictors for survival and recurrence.Results:A total of 97 patients with primary GCT of the ovary were identified. The median follow-up period was 88 months (range 6–498). Of these, 33 patients had at least one episode of disease recurrence, with a median time to recurrence of 53 months (range 9–332). Also, 47% of recurrences occurred after 5 years from initial diagnosis. At multivariate analysis, age and stage were independent poor prognostic indicators for survival; surgical treatment outside MITO centres and incomplete surgical staging retained significant predictive value for recurrence in both univariate and multivariate analyses.Conclusions:This study confirms the generally favourable prognosis of GCTs of the ovary, with 5-year overall survival approaching 97%. Nevertheless, prognosis after 20 years was significantly poorer, with 20-year survival rate of 66.8% and a global mortality of 30–35. These findings support the need for lifelong follow-up even in early-stage GCT.

Chronic Endometritis Due to Common Bacteria Is Prevalent in Women With Recurrent Miscarriage as Confirmed by Improved Pregnancy Outcome After Antibiotic Treatment

Recurrent miscarriage (RM) is defined as 3 or more miscarriages before 20 weeks’ pregnancy. In recent years, interest has been focused on chronic endometritis (CE), a subtle inflammation thought to be associated with RM. We aimed to evaluate the relationships between CE and RM. The records of 360 women with unexplained RM were retrospectively analyzed. Data from hysteroscopy, endometrial histology, endometrial culture, and polymerase chain reaction for chlamydia, performed before and after antibiotic treatment for CE, were analyzed. The occurrence of successful pregnancies within 1 year after treatment was also evaluated. Results showed that 208 (57.8%) women with RM showed CE at hysteroscopy; 190 (91.3%), positive at hysteroscopy, were also positive at histology, and 142 (68.3%) had positive cultures. Common bacteria were found in 110 (77.5%) patients. Mycoplasma and Ureaplasma were found in 36 (25.3%) patients and Chlamydia in 18 patients (12.7%). In 102 (71%) women, antibiogram-based antibiotic treatment normalized hysteroscopy, histology, and cultures (group 1); while in 40 (28.2%) patients, CE was still present at hysteroscopy (group 2). In 16 of the 66 patients positive at hysteroscopy, but not at cultures, the hysteroscopy becomes normal (group 3) after a Centers for Disease Control and Prevention-based therapy; while in 50 women, CE was still present (group 4). One year after treatment, group 1 showed a significantly higher number of pregnancies (78.4%) compared to group 2 (17.5%; P < .001) and group 4 (15.3%; P = .005). The CE is frequent in women with RM. Antibiotic treatment seems to be associated with an improved reproductive outcome.

Ovarian Sertoli-Leydig cell tumors. A retrospective MITO study

OBJECTIVE To evaluate clinicopathologic features and to investigate the outcome of patients with ovarian Sertoli-Leydig cell tumors (SLCTs). METHODS Data concerning 21 patients treated in 11 MITO centers were retrospectively reviewed. RESULTS Median age was 37 (range 16-76). FIGO stage was: 17 (81%) IA, 1 (4.8%) IC, 1 (4.8%) IIB and 2 (9.5%) IIIC. Five patients (23.8%) had G1 tumor, ten (47.6%) had G2, and six (28.6%) had G3. Fertility-sparing operation was performed in 11 patients, while hysterectomy with bilateral salpingo-oophorectomy was executed in 10 patients; five patients received adjuvant chemotherapy (G2-3). Seven patients (33.3%) relapsed with a median time to recurrence of 14 months. Six recurrent patients had G2-3 disease, while one had G1. Four patients had stage IA disease, one IC and 2 stage IIIC. Patients with stage IA disease did not receive adjuvant chemotherapy. Two patients had pelvic recurrence, 4 abdominal (one with lymph nodal involvement), one on the contralateral ovary and the trocar access. Five patients underwent salvage surgery plus chemotherapy, while one received only salvage chemotherapy and one palliation. Five patients died of disease, four had received first treatment not in a MITO center. 5 year overall survival was 100% for patients with G1 disease and 77.8% for G2-3. 5 year overall survival was 92.3% for stage I and 33.3% for stage>I. CONCLUSIONS The prognosis of patients with grade 1 SLCT is excellent without adjuvant chemotherapy. Patients with advanced stage or grade 2-3 tumors appear to benefit from postoperative chemotherapy.

Reliability of diagnostic fluid hysteroscopy in the assessment of cervical invasion by endometrial carcinoma: A comparative study with transvaginal sonography and MRI ☆

OBJECTIVE This study aimed at comparing the reliability of diagnostic fluid hysteroscopy, transvaginal sonography (TVS), and magnetic resonance imaging (MRI) to assess pre-operatively the presence of cervical involvement by endometrial carcinoma. METHODS Cervical involvement was assessed by diagnostic fluid mini-hysteroscopy, TVS and MRI before surgery in 100 patients with histological diagnosis of endometrial carcinoma. Results were compared with pathological examination on surgical specimen. The sensitivity, the specificity, the positive and negative predictive values, the accuracy, the positive and negative likelihood ratios (LR) of the three techniques for recognizing the cervical involvement by the carcinoma were calculated. RESULTS At histology cervical involvement was found in 15 cases. Compared to TVS and MRI, hysteroscopy showed the highest sensitivity (0.53, 0.67 and 0.93, respectively). The specificity of MRI was significantly higher than both hysteroscopy and TVS (0.95, 0.88 and 0.82, respectively). The diagnostic accuracy of hysteroscopy (0.89) and MRI (0.91) was similar and significantly higher than TVS (0.78). The LR for a positive result of MRI was 14.16, that was 2.08 and 4.68 times higher than that of hysteroscopy and TVS, respectively. CONCLUSIONS In conclusion, this study demonstrates that in women with endometrial carcinoma the exclusion of cervical canal involvement at hysteroscopy is more reliable than at MRI and TVS while MRI is the most reliable technique for predicting cervical involvement. In the pre-surgical work-up of patients affected by endometrial carcinoma hysteroscopy and MRI are both useful for staging and planning the correct surgical strategy.

Surgical and medical treatment of clear cell ovarian cancer: results from the multicenter Italian Trials in Ovarian Cancer (MITO) 9 retrospective study

Objective: Clear cell ovarian carcinoma has a poorer prognosis compared with other histological subtypes. Materials and Methods: The Multicenter Italian Trials in Ovarian Cancer (MITO) 9 study retrospectively assessed an Italian cohort of patients with clear cell ovarian cancer observed in the years 1991-2007 in 20 Italian centers. Results: A total of 240 patients with ovarian cancer were analyzed. Forty-five percent of the patients had stage I disease. In 62.9%, clear cell histology was pure, whereas in the other cases, a mixed population was evident. Most of the cases underwent standard surgery, whereas in 7.1% of the patients, a fertility-sparing surgery was given. Lymphadenectomy was performed in 47.9% (115/240) of the patients (54.3% in stages I and II; 39.2% in advanced stage). Most of the patients were treated with platinum-based chemotherapy including paclitaxel in 52.9%. Disease-free survival was longer in patients undergoing lymphadenectomy at surgery (P = 0.0001), both in early stages (P = 0.0258) and in stage III and IV diseases (P = 0.0037). The impact of lymphadenectomy was also evident on overall survival in patients with advanced-stage disease. At multivariate analysis, lymphadenectomy (done vs not done) and stage (I and II vs III and IV) were independently associated with longer disease-free and overall survival, whereas front-line chemotherapy (with vs without taxanes) was not significant. Conclusion: This analysis suggests that lymphadenectomy has a strong prognostic role for clear cell ovarian cancer influencing disease-free survival and overall survival. The addition of paclitaxel to platinum-based chemotherapy does not affect the outcome.

Trabectedin as single agent in the salvage treatment of heavily treated ovarian cancer patients: A retrospective, multicenter study

OBJECTIVE The aim of this multicenter, retrospective study was to evaluate the efficacy and the safety of single agent Trabectedin (ET-743, Yondelis) in very heavily treated, relapsed ovarian cancer (ROC) patients. PATIENTS AND METHODS Response to treatment was classified according to RECIST criteria. Progression-free (PFS), and overall survival (OS) were also assessed. RESULTS 98 patients were analyzed (originally 67 platinum sensitive, and 31 platinum refractory/resistant). Median number of previous regimens was 4 (range: 1-6). In the whole population, overall response rate (ORR) was 27.5%; stable disease (SD) was observed in 33 patients (33.6%), and clinical benefit was achieved in 60 cases (61.2%). ORR was 38.6% in fully platinum sensitive population, and 26.1% in partially platinum sensitive patients. In platinum refractory/resistant disease, ORR was 12.9%. Overall, median PFS and OS were 5, and 13 months, respectively. Patients responding to Trabectedin showed a more favorable PFS (median = 9 months) than patients with SD (median = 6 months), or progression (median = 2 months). Median OS of responding patients was 18 months compared to 14 months in SD patients, and 9 months in progressing patients. Grade 3-4 neutropenia was observed in 17 (17.3%) patients. Transient and non-cumulative Grade 3-4 AST and ALT level elevation was found in 7 (7.1%), and 13 (13.3%) cases, respectively. There was 1 case of Grade 3, and 1 case of Grade 4 cardiac toxicity. CONCLUSIONS Trabectedin, as a single agent, retains its efficacy in terms of rate of ORR and clinical benefit in heavily treated ROC patients, especially in the group of platinum sensitive disease.

Microbiological findings in endometrial specimen: our experience.

PurposeCollection of an endometrial specimen for investigating infectious agents in the endometrial cavity is an invasive technique that is at times difficult and painful. In order to avoid the need for endometrial sampling in the cases of suspected or evident endometrial pathology, the aim of this study is to investigate the reliability of cervical cultures for detecting infectious agents present at the endometrial level, comparing the results between cervical cultures and endometrial cultures in women with clinical signs of endometrial inflammation.MethodsIn a prospective diagnostic study, in the period from January 2009 to October 2010, we enrolled 404 women referred to the Department of Obstetrics and Gynecology for diagnostic hysteroscopy. All the patients underwent cervical and endometrial sampling. Cultures for common bacteria, Neisseria gonorrhoeae, yeast, and Ureaplasma urealyticum were performed.ResultsThe most frequent infectious agents detected at the endometrial level were common bacteria, which accounted for 69% of all cases. In particular, streptococci were found in 27% of cases, and bacteria from intestinal flora (Enterococcus faecalis and Escherichia coli) was recovered in 31% of cases. U. urealyticum was detected in 10% and Mycoplasma in only one patient (0.2% of cases). No cases of N. gonorrhoeae were found.ConclusionsCervical culture has a low concordance with endometrial culture. In fact in only 33% of cases was the microorganism found in the cervix the same as that found in the endometrium. These results infer that an endometrial culture is a useful investigative tool for determining the microorganisms in endometrial pathology.

Brain metastases in patients with EOC: Clinico-pathological and prognostic factors. A multicentric retrospective analysis from the MITO group (MITO 19)

BACKGROUND Brain metastases (BM) from epithelial ovarian cancer (EOC) are considered a rare and unfavourable event. There is no consensus regarding the best management of these patients. METHODS A multicenter retrospective analysis of patients with BM from EOC treated between 1997 and 2014 in 18 institutions of the MITO (Multicenter Italian Trials in Ovarian cancer) group was conducted. Univariate and multivariate analysis were performed. RESULTS A total of 174 women were identified as having BM from EOC. The median time interval between primary diagnosis of EOC and occurrence of BM was 26months (range 2-129months). The median overall survival from primary EOC diagnosis was 48months (95% CI 39.5-56.4months) and from diagnosis of BM was 12months (95% CI 9.6-14.3months). The majority of enrolled women (81.7%) were classified as sensitive to platinum-based chemotherapy. Four variables were significantly associated with poor overall survival in multivariate analysis: multiple BM [HR: 1.86 (95% CI: 1.22-2.84)], presence of extracranial disease [HR: 1.77 (95% CI: 1.11-2.83)] age [HR: 1.74 (95% CI: 1.17-2.59)], and monotherapy [HR: 2.57 (95% CI: 1.64-3.86)]. On the contrary, residual tumor at primary surgery, FIGO stage at primary diagnosis and platinum sensitivity were found to have no significant impact on survival from diagnosis of brain lesions. CONCLUSIONS Our results suggest that BM is a rare and late manifestation of EOC, with a 12-month life-span expectation. Multiple approach is a positive independent prognostic factor and should be proposed to carefully selected patients.