Stefano Greggi

Neoadjuvant Chemotherapy and Radical Surgery Versus Exclusive Radiotherapy in Locally Advanced Squamous Cell Cervical Cancer: Results From the Italian Multicenter Randomized Study

PURPOSE Neoadjuvant chemotherapy (NACT) and radical surgery (RS) have emerged as a possible alternative to conventional radiation therapy (RT) in locally advanced cervical carcinoma. In 1990, a phase III trial was undertaken to verify such a hypothesis in terms of survival and treatment-related morbidity. PATIENTS AND METHODS Patients with squamous cell, International Federation of Gynecology and Obstetrics stage IB2 to III cervical cancer were eligible for the study. They received cisplatin-based NACT followed by RS (type III to V radical hysterectomy plus systematic pelvic lymphadenectomy) (arm A) or external-beam RT (45 to 50 Gy) followed by brachyradiotherapy (20 to 30 Gy) (arm B). RESULTS Of 441 patients randomly assigned to NACT+RS or RT, eligibility was confirmed in 210 and 199 patients, respectively. Treatment was administered according to protocol in 76% of arm A patients and 72% of arm B patients. Adjuvant treatment was delivered in 48 operated patients (29%). There was no evidence for any significant excess of severe morbidity in one of the two arms. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 58.9% and 55.4% for arm A and 44.5% and 41.3% for arm B (P =.007 and P =.02), respectively. Subgroup survival analysis shows OS and PFS rates of 64.7% and 59.7% (stage IB2-IIB, NACT+RS), 46.4% and 46.7% (stage IB2-IIB, RT) (P =.005 andP =.02), 41.6% and 41.9% (stage III, NCAT+RS), 36.7% and 36.4% (stage III, RT) (P =.36 and P =.29), respectively. Treatment had a significant impact on OS and PFS. CONCLUSION Although significant only for the stage IB2 to IIB group, a survival benefit seems to be associated with the NACT+RS compared with conventional RT.

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.

Long-term effects of oral contraceptives on ovarian cancer risk.

Several epidemiologic studies have reported a protective effect of oral contraceptives (OCs) on ovarian cancer. However, there remain open issues, including better quantification of time‐related factors such as time since last use, age at first use and time since first use. We performed a collaborative reanalysis of 6 case‐control studies conducted between 1978 and 1999 in the United Kingdom, Greece and Italy, including a total of 2,768 incident, histologically confirmed cases of epithelial ovarian cancer and 6,274 hospital controls under age 70 years. A reduced risk of ovarian cancer was found for ever‐ compared to never‐users [odds ratio (OR) = 0.66, 95% confidence interval (CI) 0.56–0.79], and a stronger reduction was observed for women who had used OCs for ≥5 years (OR = 0.50, 95% CI 0.33–0.76) compared to those who had used them for <5 years. The protective effect of OCs on ovarian cancer was consistent across strata of age, parity, menopausal status and family history of breast or ovarian cancer. After allowance for duration of use, no other time factor was related to ovarian cancer risk: the reduced risk was similar for women who stopped OC use ≥20 years before compared to <10 years; likewise, no significant modification of risk reduction was observed for age at first OC use and time since first OC use. The present analysis indicates that, after taking into account duration of OC use, the OC protection from ovarian cancer persists for a long time after stopping use.

Carboplatin Plus Paclitaxel Versus Carboplatin Plus Pegylated Liposomal Doxorubicin As First-Line Treatment for Patients With Ovarian Cancer: The MITO-2 Randomized Phase III Trial

PURPOSE Carboplatin/paclitaxel is the standard first-line chemotherapy for patients with advanced ovarian cancer. Multicentre Italian Trials in Ovarian Cancer-2 (MITO-2), an academic multicenter phase III trial, tested whether carboplatin/pegylated liposomal doxorubicin (PLD) was more effective than standard chemotherapy. PATIENTS AND METHODS Chemotherapy-naive patients with stage IC to IV ovarian cancer (age ≤ 75 years; Eastern Cooperative Oncology Group performance status ≤ 2) were randomly assigned to carboplatin area under the curve (AUC) 5 plus paclitaxel 175 mg/m(2) or to carboplatin AUC 5 plus PLD 30 mg/m(2), every 3 weeks for six cycles. Primary end point was progression-free survival (PFS). With 632 events in 820 enrolled patients, the study would have 80% power to detect a 0.80 hazard ratio (HR) of PFS. RESULTS Eight hundred twenty patients were randomly assigned. Disease stages III and IV were prevalent. Occurrence of PFS events substantially slowed before obtaining the planned number. Therefore, in concert with the Independent Data Monitoring Committee, final analysis was performed with 556 events, after a median follow-up of 40 months. Median PFS times were 19.0 and 16.8 months with carboplatin/PLD and carboplatin/paclitaxel, respectively (HR, 0.95; 95% CI, 0.81 to 1.13; P = .58). Median overall survival times were 61.6 and 53.2 months with carboplatin/PLD and carboplatin/paclitaxel, respectively (HR, 0.89; 95% CI, 0.72 to 1.12; P = .32). Carboplatin/PLD produced a similar response rate but different toxicity (less neurotoxicity and alopecia but more hematologic adverse effects). There was no relevant difference in global quality of life after three and six cycles. CONCLUSION Carboplatin/PLD was not superior to carboplatin/paclitaxel, which remains the standard first-line chemotherapy for advanced ovarian cancer. However, given the observed CIs and the different toxicity, carboplatin/PLD could be considered an alternative to standard therapy.

Long-term survival following neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer

The aim of this study was to analyse the long-term survival and the relationships between prognostic factors at presentation, chemoresponsiveness and disease outcome in patients with locally advanced cervical cancer treated by neoadjuvant chemotherapy and radical surgery (RS). Two consecutive studies of neoadjuvant chemotherapy containing cisplatin, bleomycin plus/minus methotrexate followed by radical hysterectomy and systematic aortic and pelvic lymphadenectomy were carried out between January 1986 and September 1990 on 130 patients with > or = 4 cm stage IB2-III cervical cancer. Survival analysis was performed using the Kaplan and Meier test and Coxs multivariate regression analysis. 128 (98%) of the patients enrolled were evaluable for clinical response and survival, 83% (106) of the patients responded to chemotherapy, with a 15% complete response rate. Logistic regression analysis demonstrated that International Federation of Gynecology and Obstetrics (FIGO) stage, cervical tumour size, parametrial involvement and histotype are highly predictive of response. Responding patients underwent laparotomy, but 8% were not amenable for radical surgery. The 10-year survival estimates were 91%, 80% and 34.5% for stage IB2-IIA bulky, IIB and III, respectively (P < 0.001). After Coxs regression analysis, the parameters significantly associated with survival were the same factors predicting response to neoadjuvant chemotherapy. No stage IB2-IIA bulky patient has so far relapsed, while 12% stage IIB and 56% stage III patients recurred. The 10-year disease-free survival estimates are 91% and 44% for stage IB2-IIB and III, respectively (P < 0.001). Metastatic nodes and persistent tumour in the parametria were the only two independent factors for disease-free survival after multiple regression analysis. After a long-term follow-up (median follow-up 98 months (20-129+)), our results give new evidence of the prognostic value of response to neoadjuvant chemotherapy and of a possible therapeutic benefit of the sequential treatment adopted which, however, must be verified in a randomised setting.

Conservative treatment of early endometrial cancer: Preliminary results of a pilot study

OBJECTIVE This study evaluated the feasibility and efficacy of combined operative hysteroscopy (HSC) and hormone therapy as fertility-preserving treatment in a cohort of selected young women with early endometrial carcinoma (EC). METHODS Fourteen patients (median age 38 years, range 26-40) with FIGO stage IA (intramucous) EC wishing to preserve fertility were enrolled with the following inclusion criteria: age ≤40 years; no evidence of Lynch II syndrome; well-differentiated estrogen/progesterone receptor positive (ER+/PR+) endometrioid EC; no evidence of myoinvasion, multifocal tumor, node metastasis, ovarian mass; normal serum CA 125. Treatment consisted of hysteroscopic ablation of the lesion and the myometrial tissue below, followed by oral megestrol acetate (MA) 160 mg/day for 6 months (6 pts) or 52 mg levonorgestrel-medicated intrauterine device (LNG-IUD) for 12 months (8 pts). RESULTS With a median follow-up of 40 months (range 13-79), one patient recurred after 5 months from operative HSC and underwent definitive surgery, one patient showed an endometrial hyperplasia without atypia at the 3 and 6 month HSC control, with negative controls thereafter. Three patients have attempted to conceive and one of them conceived and term delivered a healthy baby. CONCLUSIONS Combined operative HSC and progestin therapy may have a role for safe and effective conservative management of early EC in selected patients wishing to preserve fertility.

High-dose cisplatin and bleomycin neoadjuvant chemotherapy plus radical surgery in locally advanced cervical carcinoma: A preliminary report

One course of chemotherapy containing cisplatin and bleomycin as a neoadjuvant treatment was given to 26 consecutive patients with previously untreated stage IB (bulky disease)-III cervical carcinoma and followed by radical surgery. After chemotherapy responses were detected in 23 patients (5 complete and 18 partial; overall, 88%) and permitted radical surgery in 21 cases (81%). Surgery consisted of type III-IV radical hysterectomy plus systematic para-aortic and pelvic lymphadenectomy. At histologic examination, complete responses were found in 5 (19%) and partial responses in 16 (62%) cases. The average number of lymph nodes removed was 61 (range, 38-118). A lower than expected incidence of lymph node metastases was detected (2/21, 9.5%). The chemotherapy-induced toxicity was mainly represented by nausea and vomiting. Chemotherapy did not seem to complicate surgery in these circumstances, even though moderate-degree postoperative complications occurred in 48% of cases. Eighteen months median follow-up time (range, 11-23) from hystological diagnosis has been reached in the operated patients, and no recurrences have been detected so far.

Human papillomavirus (HPV) genotypes and HPV16 variants and risk of adenocarcinoma and squamous cell carcinoma of the cervix

OBJECTIVE Human papillomavirus (HPV) genotypes have been extensively studied in uterine cervix squamous cell carcinoma and HPV16 variants have been found to be associated with increased cancer risk, but few reports have been published on genotype distribution and HPV16 variant prevalence in adenocarcinoma tumors. The objective of this study was to analyze viral genotypes and HPV16 intratypic variants in cervical adenocarcinoma and squamous cell carcinoma of Italian women. METHODS A total of 39 invasive adenocarcinoma and 132 squamous cell carcinoma were reviewed and classified according to the modified WHO classification. HPV sequences were detected by nested PCR, using the broad spectrum consensus-primer pairs MY09/MY11 and the GP5+/GP6+ system, and genotyped by nucleotide sequence analysis. The HPV16-positive cases were amplified with E6-specific oligonucleotides and amplimers subjected to direct nucleotide sequence for variant identification. RESULTS The prevalence rate of any HPV infection was 72% in adenocarcinoma, and 85% in cervical squamous cell carcinoma. Among the 140 HPV-positive cancer cases, a total of nine mucosal HPV genotypes (HPV16, 18, 31, 33, 35, 39, 45, 58, 82) epidemiologically classified as carcinogenic or probably carcinogenic viruses were identified. The HPV type 16 was the most common viral type representing 64% and 73% of all infections in adenocarcinoma and squamous cell carcinoma, respectively. The E6 nucleotide sequence analysis of HPV16 isolates allowed the identification of Asian American (AA) variants in 33% of adenocarcinoma and in 20% of squamous cell carcinoma suggesting their stronger association with cancer of glandular origin. CONCLUSION These results suggest that HPV16 has a high prevalence in both invasive adenocarcinoma and squamous cell carcinoma from Italian patients. Moreover this study confirms previous observations, summarized in a systematic review of the literature, on the increased cancer risk of HPV16 AA class in adenoglandular cancer, possibly related to their more oncogenic behavior compared to HPV16 European variants.

Food groups and endometrial cancer risk: a case-control study from Italy

OBJECTIVE Although several studies have been conducted on the relation between dietary habits and endometrial cancer risk, the evidence for specific food groups is still controversial. STUDY DESIGN We analyzed data from an Italian case-control study including 454 women with histologically confirmed endometrial cancer and 908 controls admitted to the same hospitals for acute, nonneoplastic conditions. Multivariate odds ratios (ORs) were obtained after allowance for major potential confounding factors. RESULTS A significant increase in risk was observed for red meat, with an OR of 2.07 for an increment of 1 serving per day. Inverse associations were observed for coffee (OR, 0.83), cereals (OR, 0.92), and vegetables (OR, 0.83). CONCLUSION Our results support the existence of a relation between dietary habits and endometrial cancer risk and in particular suggest that a diet rich in red meat and poor in vegetables may have an unfavorable effect.

ANALYSIS OF 138 CONSECUTIVE OVARIAN CANCER PATIENTS : INCIDENCE AND CHARACTERISTICS OF FAMILIAL CASES

Eight families with two or more first-degree relatives affected with ovarian carcinoma were identified among a series of 138 consecutive ovarian cancer patients. History of breast cancer was reported in six of the eight families. Five of 19 patients with familial cancer developed ovarian cancer as a second primary tumor following breast carcinoma, whereas only 6/130 sporadic cases had a previous history of breast cancer. No significant difference was detected in clinical and pathological features between sporadic and familial cases. However, in three high-risk families ovarian cancer tended to develop at a younger age compared with other familial cases and with sporadic occurrences, and nulliparity was less frequent in the familial group. These observations emphasize the need to take into account multiple factors-in addition to positive family history-for the evaluation of genetic predisposition to ovarian carcinoma.