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No randomised trials have addressed the value of systematic aortic and pelvic lymphadenectomy (SL) in ovarian cancer macroscopically confined to the pelvis. This study was conducted to investigate the role of SL compared with lymph nodes sampling (CONTROL) in the management of early stage ovarian cancer. A total of 268 eligible patients with macroscopically intrapelvic ovarian carcinoma were randomised to SL (N=138) or CONTROL (N=130). The primary objective was to compare the proportion of patients with retroperitoneal nodal involvement between the two groups. Median operating time was longer and more patients required blood transfusions in the SL arm than the CONTROL arm (240 vs 150 min, P

The question of whether platinum-based adjuvant chemotherapy can improve outcomes in patients with early-stage epithelial ovarian cancer is an important one. We carried out a multicenter, open randomized trial to determine whether adjuvant chemotherapy would improve overall survival and prolong recurrence-free survival in women with early-stage epithelial ovarian cancer.

A series of meta-analyses of randomised controlled trials raised the question of whether the three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) was more or less effective than optimal-dose single-agent carboplatin for women with advanced ovarian cancer.

Background: Hematopoietic toxicity of high-dose carboplatin (HD-CBDCA) chemotherapy can be managed effectively with autologous blood cell support, but no conclusive data are available on its the neuro- and ototoxicity. Patients and methods: We determined the neuro- and ototoxicity of HD-CBDCA in 10 patients affected by advanced ovarian cancer. HD-CBDCA was delivered as 24-hour continous infusion or as 5-day schedules. Each patient underwent an extended clinical and instrumental neurological and otological evaluation before, during and after treatment. Results: After HD-CBDCA only I patient had a clinically-evident peripheral neuropathy, while 3 additional patients had only distal paresthesias. Neurophysiological examination evidenced mild, although diffuse, sensory nerve impairment. Motor nerve impairment war also occasionally observed All the sensory and motor pathological changes had a favorable course during the follow-up period. Ototoxicity was more severe than neurotoxicity and, in one case it was dose-limiting and audiologic impairment tended to remain constant also in the follow-up period. Conclusions: HD-CBDCA treatment can be tolerated by most of the patients, but careful monitoring of neuro- and, especially, ototoxicity should be planned

Background: From 1983 to 1990, 271 consecutive patients with stage I ovarian cancer entered two randomised trials, aimed at assessing the role of adjuvant chemotherapy after radical surgery in early stages of ovarian cancer.Trial I compared cisplatin (50 mg/m2 with repeated courses every 28 days for 6 cycles) to no further therapy in F.I.G.O.stage la & b Grade U-IH patients; trial II compared cisplatin (same dose and schedule) to 32P in Ian & bii and Ic patients Methods: Both studies were multicentric and centrally randomized. Treatment was allocated by phone and stratified by center. All patients satisfying major eligibility criteria (histological diagnosis of ovarian carcinoma, correct F.I.G.O. stage and grade, no previous neoplasms) were analysed according to treatment allocated by randomisation. Results: With a median observation time of 16 months, cisplatin significantly reduced the relapse rate by 65% (HR = 0.35; 95% CI = 0.14-0.89, p = 0.028; Cox Model) in trial I and 61% (HR = 0.39; 95% CI = 0.19-0.77, p = 0.007; Cox Model) in trial II. Survival was not significantly different (trial I - Kaplan-Meier overall 5-year survival: cisplatin = 88%, control = 82%, HR = 1.15; 95% CI = 0.44 - 2.98; p = 0.773; Cox Model); trial II - overall 5-year survival: cisplatin = 81%, 32P = 79%, HR = 0.72; 95% CI = 0.37-1.43; p = 0.354; Cox model). In both studies the risk of dying after relapse increased for patients originally randomized to the cisplatin arms: in trial I, 6 of 7 patients in the cisplatin relapsed arm and died of tumor compared with 8 of 14 patients in the control arm. In trial II, 11 of 12 patients on cisplatin, and 18 of 26 on 32P succumbed to tumor recurrence. Conclusion: Adjuvant cisplatin treatment in early ovarian cancer significantly prevents relapse in comparison to 32P in Stage IC patients or to no immediate treatment in earlier Stage women. The impact of cisplatin adjuvant treatment on survival remains, however, unclear. © 1995 Kluwer Academic Publishers.

Batimastat (also known as BB-94) is a synthetic matrix metalloproteinase inhibitor that has shown antineoplastic and antiangiogenic activity in various tumor models. In this study, two human ovarian carcinoma (HOC) xenografts (HOC22 and HOC8) were used to investigate the effect of batimastat on the antineoplastic activity of cisplatin. Both xenografts produced ascites and solid lesions in the peritoneal cavity of nude mice. HOC cells were inoculated i.p. in nude mice, and treatment was started at different stages of the disease. Batimastat was administered alone or concurrently with or subsequent to cisplatin therapy. In all of the protocols, the response of HOC xenografts was confirmed by cytological analysis of ascites and histological examination of the organs in the peritoneal cavity. Treatment of nude mice bearing early-stage (3 days after tumor implantation) HOC22 or HOC8 with cisplatin or batimastat alone delayed tumor growth and increased the survival time of the mice, although all animals eventually died. In contrast, treatment with batimastat (60 mg/kg i.p. every other day, for a total of eight injections) concomitantly with cisplatin (4 mg/kg i.v., every 7 days for a total of three injections) completely prevented growth and spread of both xenografts, and all animals were alive and healthy on day 200. The potentiation of cisplatin's activity by batimastat was dose dependent and was observed in the treatment of both advanced (7 days after tumor inoculation) and late-stage (20 days after inoculation) tumor. The administration of batimastat following cisplatin therapy also led to significant improvement in the survival of mice compared to treatment with cisplatin alone. These results suggest a potentiation of the antineoplastic activity of cisplatin by batimastat and support the use of the two agents in combination in the treatment of ovarian cancer patients.

Background: The objective of this study is to evaluate the safety of fertility-sparing surgery (FSS) for early-stage epithelial ovarian cancer (EOC). Methods: A retrospective analysis was performed to identify patients treated for early-stage EOC and to compare the clinical outcomes of patients treated with FSS and radical surgery (RS). Results: A total of 1031 patients were treated at two Institutions, 242 with FSS (group A) and 789 with RS (group B). Median duration of follow-up was 11.9 years. At univariate analyses, FSS was associated with decreased risk of relapse (P=0.002) and of tumour-related death (P=0.001). Multivariate analysis did not confirm the independent positive role of FSS neither on relapse-free interval (RFI) nor on cancer-specific survival (CSS). Tumour grade was associated with shorter RFI (P

Objective Neoadjuvant chemotherapy (NACT) is a valid treatment option for women with locally advanced cervical cancer (LACC). This study aims to evaluate the impact of sociodemographic factors, clinical factors, and NACT regimens on survival endpoints. The role of pathological response to NACT as a surrogate endpoint of survival was also assessed. Materials and Methods Retrospective analysis of consecutive sample data from women with LACC (stages Ib2-IVa) who underwent NACT followed by radical surgery was performed. Response was classified as optimal response (including complete response and optimal partial response), suboptimal partial response, stable disease, and progressive disease. Results Four hundred forty-six women who had undergone surgery from 1992 to 2011 were analyzed. The overall optimal response was 35.4%. At a median follow-up of 12.7 years, 165 women (37.0%) experienced recurrence or died. Increase in patient age at surgery, International Federation of Gynecology and Obstetrics stage III/IV versus stage Ib2, and lymph-node positivity versus negativity seemed to impact negatively on survival, whereas neoadjuvant platinum-Taxol–containing regimens (compared with platinum-based regimens) improved survival. Response to NACT could be considered a surrogate endpoint of survival. Conclusions Age, International Federation of Gynecology and Obstetrics stage III/IV, lymph-node involvement, and type of NACT administered have a significant impact on survival. Response to NACT is a good surrogate endpoint of survival in patients with LACC.

Human papillomaviruses (HPVs) are necessary, but not sufficient, for the development of cervical cancer (CC). Human β-herpesviruses (β-HHVs) have been suggested as possible cofactors in the oncogenesis of CC. In this cross-sectional study, the prevalence and possible association of cytomegalovirus (CMV), HHV-6 and -7 with HPV presence was investigated by quantitative real-time PCR assays in cervical samples obtained from 208 italian women. The two most common high-risk HPV types found were 31 and 16. Overall, the positive rates for CMV, HHV-6 and HHV-7 were 66%, 25%, and 6%, respectively. In particular, the prevalence of CMV was found to be extremely high irrespective of either the cytological category or HPV positivity. The prevalence of HHV-6 DNA was significantly higher in high-grade squamous intraepithelial lesions (HSIL) respect to normal women (P

Objectives . To evaluate the risk of the laparoscopic approach to patients with borderline ovarian tumors compared to the laparotomic management. Methods . We treated or followed in our institution 479 women with borderline ovarian tumor. Sixty-two patients had fertility-sparing surgery followed by restaging or follow-up intervention: 30 operated by laparoscopy, 32 by laparotomy. Restaging surgery was performed in five cases and second-look surgery in 57. Results . The diameter of the cyst is significantly lower in patients treated by laparoscopy, especially in women who underwent cystectomy (4.7 cm) compared to oophorectomy (10 cm, P = 0.008). Rupture of the cyst and stage IC were more frequent in the laparoscopic group. After a median follow-up of 61 months for the laparoscopic group and 77 months for the laparotomic group, we observed 11 patients (37%) with persistent disease after primary laparoscopy (adnexa, five cases; peritoneal implants, three cases; both patterns, three cases). After primary laparotomy, no patients showed early persistence of tumor, and ovarian relapses were diagnosed in seven women (22%) 33–138 months after laparotomy. The univariate analysis for the risk of neoplastic persistence after primary laparoscopy shows that patients with cysts greater than 5 cm have a higher risk (odds ratio 9.7, P = 0.02) compared to smaller cysts. No other factors proved significant, but the odds ratios for patients with serous tumor (5.8), stage IC (2.0), and those undergoing cystectomy (1.9) suggest a relationship to the probability of persistence. Conclusion . Laparoscopic treatment in borderline ovarian tumors should be reserved to masses not greater than 5 cm. When conservative therapy is desired, the entire affected ovary should be removed. If the neoplasia is bilateral, cystectomy could be allowed in women who wish to preserve fertility, although they are at high risk of relapse.

Sarcoma botryoides of the cervix is an extremely rare tumour and seems to be associated with a better prognosis than its vaginal counterpart. Recent studies have suggested that it is possible to limit surgery to local excision in stage I cases. We report three cases of young subjects treated successfully with polypectomy or diathermy loop excision followed by adjuvant chemotherapy. One patient had a local recurrence which was treated with further local excision. All subjects remain alive without evidence of recurrence and with normal menstrual function 36, 38 and 38 months following initial diagnosis. A conservative surgical approach to early cervical sarcoma botryoides is possible. The efficacy of adjuvant chemotherapy and the regimen of choice still need to be investigated. © 1999 Cancer Research Campaign

Objective Treatment of locally invasive cervical cancer diagnosed during pregnancy in women who desire to retain their pregnancy is a major challenge to physicians. Neoadjuvant chemotherapy followed by radical hysterectomy has been reported to be an attractive option to delay delivery until fetal viability has been reached. Methods Between 1994 and 2009 9 patients were treated at San Gerardo Hospital (Monza, Italy) for cervical cancer during pregnancy. Results FIGO stage was IB1 in four patients and IB2 in five. Tumor diameter ranged between 20 and 70mm. After neoadjuvant platinum-based chemotherapy partial response was achieved in 5 patients, while 4 had a stable disease. One patient received a second-line chemotherapy during pregnancy due to progressive disease, achieving a partial response. Median duration of therapy delay until cesarean section was 16weeks. Between 30 and 36weeks of gestation all patients underwent cesarean section. Piver II radical hysterectomy with pelvic lymphadenectomy was performed. Two children had mild perinatal morbidities and were discharged in good conditions after 14 and 40days. Three patients received adjuvant therapy for pathological risk factors. Four patients relapsed (44%) and two of them (23%) died because of tumor progression. Conclusion During pregnancy, the oncological outcome of cervical cancer patients is similar to non-pregnant ones. Chemotherapy does not seem to affect fetal health and development, even if longer follow-up is required. Therefore, neoadjuvant chemotherapy for the treatment of locally invasive cervical cancer during pregnancy seems to be a reasonable option for delay definitive treatment until fetal viability is obtained.

Background The efficacy and tolerability of the regimen containing paclitaxel and cisplatin (TP) in the neo-adjuvant treatment of locally advanced squamous cell cervical cancer are unknown. The TIP regimen (TP plus ifosfamide) showed high efficacy but high toxicity and it is used as an internal control. Patients and methods In all, 154 patients were randomized to TP (paclitaxel 175 mg/m2 + cisplatin 75 mg/m2; n = 80) or TIP (TP + ifosfamide 5 g/m2; n = 74), three cycles, followed by radical surgery. Pathological response to chemotherapy was classified as optimal [no residual tumor (complete response) or residual disease with ≤3 mm stromal invasion (PR1)] or suboptimal response. Results Patient characteristics (TP/TIP): stage IB2 (56%/64%), IIA (18%/14%), IIB (20%/19%), III–IVA (5%/4%) and median age (42 years/45 years). The optimal response rate in the TP group was 25%, 95% confidence interval (CI) = 16% to 37% and 43%, 95% CI = 31% to 55% in the TIP group. Grades 3–4 leukopenia (6%/53%) and neutropenia (26%/76%) were significantly more frequent on TIP. Conclusion TP performance was below expectation since the lower 95% confidence limit of the optimal response rate failed to reach the prespecified minimum requirement of efficacy, i.e. 22%. The TIP regimen confirmed its activity but was associated with higher haematological toxicity than TP.

A cross-sectional study was carried out in a population of North Italy to determine the prevalence of eight oncogenic human papillomavirus (HPV) types most commonly found in cervical carcinoma and to study the relationship between HPV DNA loads and severity of disease. A total of 597 cervical samples obtained from patients with pathological findings (n = 472) and from women with normal cytology (n = 125) were analyzed by means of normalized Real-time PCR assays to quantify HPV-16, -18, -31, -45, and -33 group (including -33, -52, -58, -67); the normalization of oncogenic HPV viral load was carried out by quantitation of a single copy gene. The two most common oncogenic HPV types found were 16 and 31 (24.3% and 22.9% of pathological samples, respectively); multiple infections were demonstrated in 22% of pathological samples. Overall, the HPV total viral load was found to increase with increasing severity of associated lesions, although a stronger association was observed only for HPV-31 and HPV-16 (gamma = 0.49 and 0.41, respectively) as compared to HPV-18 and -33 group (gamma = 0.19 and 0.02, respectively). However, we found that high levels of HPV-31 or 33 group DNA could be prognostic of minor oncogenic risk for high-grade squamous intraepithelial lesions (H-SIL) (age adjusted odds ratio [AORs] = 1.57 and 1.26, respectively) than HPV-16 and HPV-18 (AORs = 30 and 8, respectively). The AORs also increased with HPV total viral load and reached a maximum of AORs = 15.7. Thus, HPV load is a type-dependent risk marker for the development of H-SIL.

Objective: To evaluate the surgical management of ovarian germ-cell tumors treated at a single institution during the last decade. Methods: One hundred twenty-nine patients affected by ovarian germ-cell tumors were studied retrospectively for their surgical management. Fifty-seven patients were affected by dysgerminoma, 39 by non-dysgerminoma, and 33 by pure immature teratoma. Seventy-nine patients were stage I according to International Federation of Gynecology and Obstetrics criteria, with five first referred at recurrence, 11 at stage II, 35 at stage III, and four at stage IV. Results: Fertility-sparing surgery was performed in 108 of 129 patients. Eighty-five of 100 referred patients underwent surgical or radiologic restaging, with an increase in staging in 16 cases. Three patients with immature teratoma underwent second laparotomy for a growing mass. Thirty-one patients underwent second-look surgery, with positive findings in four cases. Three patients did not respond to chemotherapy, and ten had a recurrence after complete response or surveillance. Six patients died of tumor, with an overall survival of 96% (mean follow-up time 55 months). Conclusion: Fertility-sparing surgery is warranted in all ovarian germ-cell tumors because it does not affect recurrence rate or survival. Extensive tumor-reductive surgery is advisable only in immature teratoma patients and is not necessary for other histologic types. Restaging can be useful in selected cases, but the administration of effective chemotherapy, when needed, seems to be more important. The usefulness of second-look surgery is marginal.

The feasibility of conservative surgery and the role of postoperative adjuvant therapy are still controversial issues in the management of early ovarian cancer. Data on 99 patients below the age of 40 with stage I ovarian cancer are reported and conservative surgery was performed in 56 (56%) patients (36 stage Ia, 1 stage Ib, and 19 stage Ic). Relapse occurred in 3 stage Ia (grades 1, 2, and 3) patients, but only 1 occurrence was in the residual ovary and the patient was rescued by surgery. The other 2 patients who relapsed in distant sites died as a result of their tumors. Seventeen patients who desired to become pregnant did so for a total of 25 conceptions. These data support the possibility of some extension of the traditional conservative approach. Only two randomized studies so far have tested cisplatin as an adjuvant treatment of early disease. A Norwegian trial compared cisplatin to 32P in stage I-III ovarian cancer without residual tumor after primary surgery and found no difference in survival. An Italian study compared cisplatin to observation in stage Ia and Ib grade 2 and 3 tumors and cisplatin to 32P in stage Ic patients. While disease-free survival was statically longer in cisplatin-treated patients of both groups, no difference in survival could be detected. These results supported the design of a currently ongoing multicenter trial testing platinum-based therapy soon after surgery or at time of relapse.

A case-control study was conducted on 91 cases with histologically-confirmed borderline ovarian tumours and 237 control subjects in hospital for acute non-gynaecological, hormonal or neoplastic disease. Women reporting three or more births, compared to nulliparae, had a relative risk (RR) estimate of 0.6, but this finding was not statistically significant (95% confidence interval (CI): 0.2-1.4). The risk of borderline tumours increased, although not significantly, with later age at first birth: compared to women reporting first birth at age 24 or before, the RRs were 1.3 and 1.7 in those reporting respectively their first birth at age 25-29 and 30 years or more. No significant relationship emerged between borderline ovarian cancer and age at menarche, menopausal status and lifelong menstrual pattern. Cases tended to report a later age at menopause than controls, but the trend in risk was not statistically significant. Nine cases (9.9%) and 68 controls (24.9%) reported oral contraceptive use: compared with never users the multivariate RR for ever users was 0.3, and the risk dropped with duration of use to 0.2 in users for two years or more (chi 2 (1) trend = 12.70, p less than 0.001). This study provides epidemiological evidence of a pathogenetic continuum between borderline and invasive ovarian tumours.Researchers compared 91 women with histologically confirmed borderline ovarian tumors at the University of Milan with 237 women (controls) admitted to Ospedale Maggiore in Milan, Italy for acute nongynecological, nonhormonal and nonneoplastic conditions to learn more about the epidemiology of borderline ovarian tumors. Oral contraceptives (OC) users had about a 70% lower risk of borderline ovarian tumors than nonOC users (relative risk ¿RR¿=0.3). In fact, the RR fell significantly to 0.2 for women who used OCs for at least 2 years (p.001). Further the risk of borderline ovarian tumors increased significantly as the age of women at the time of 1st birth increased (RR=1.8 for 25-29 year olds and RR=2.5 for =or 30 year olds; p=.02 [Mantel-Haenszel technique]). Women who experienced at least 1 induced abortion were less likely to have borderline ovarian tumors than those who had never experienced an induced abortion (RR=0.2). This may be because these women were of high fertility which agreed with the finding of lower risk in women of parity =or 3 (RR=0.7; p=0.23 insignificant). A higher risk was associated with late age at menopause, but the association was insignificant (RR=around 50 years old). Since the sample size was small due to the rarity of borderline ovarian tumors, one should interpret these results which caution. Nevertheless they supported the incessant ovulation hypothesis in ovarian carcinogenesis where the more exposure to ovulation or ovulatory cycles the greater the chance of ovarian neoplasms. Therefore they suggested an epidemiological continuum between various grades of malignancy of epithelial ovarian neoplasms.

Expression of HLA-DR antigens by purified preparations of human ovarian carcinoma cells freshly isolated from surgical specimens was examined in parallel with the capacity of tumor cells to elicit a blastogenic response from autologous lymphocytes in mixed lymphocyte-tumor culture (MLTC) assay. Of 21 tumor preparations, 11 (52%) reacted with monoclonal antibodies 279 and/or 949 specific for a monomorphic determinant of HLA-DR antigens, with heterogeneous positivity, ranging between 30% and 95%. In this series of patients positive MLTC occurred in 8/21 individual experiments. The HLA-DR expression was proportionally similar in tumors giving positive MLTC (4/8 = 50%) and negative MLTC (7/13 = 53%). The lack of correlation between DR expression on tumor cells and stimulatory activity in autologous MLTC and the fact that DR-negative tumors could induce lymphocyte stimulation, support the hypothesis that blastogenesis occurs upon recognition of tumor-associated antigens, different from DR molecules, possibly tumor-specific antigens.