Andrea Maneo

Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer.

BACKGROUND Stage Ib and IIa cervical carcinoma can be cured by radical surgery or radiotherapy. These two procedures are equally effective, but differ in associated morbidity and type of complications. In this prospective randomised trial of radiotherapy versus surgery, our aim was to assess the 5-year survival and the rate and pattern of complications and recurrences associated with each treatment. METHODS Between September, 1986, and December, 1991, 469 women with newly diagnosed stage Ib and IIa cervical carcinoma were referred to our institute. 343 eligible patients were randomised: 172 to surgery and 171 to radical radiotherapy. Adjuvant radiotherapy was delivered after surgery for women with surgical stage pT2b or greater, less than 3 mm of safe cervical stroma, cut-through, or positive nodes. The primary outcome measures were 5-year survival and the rate of complications. The analysis of survival and recurrence was by intention to treat and analysis of complications was by treatment delivered. FINDINGS 170 patients in the surgery group and 167 in the radiotherapy group were included in the intention-to-treat analysis; scheduled treatment was delivered to 169 and 158 women, respectively, 62 of 114 women with cervical diameters of 4 cm or smaller and 46 of 55 with diameters larger than 4 cm received adjuvant therapy. After a median follow-up of 87 (range 57-120) months, 5-year overall and disease-free survival were identical in the surgery and radiotherapy groups (83% and 74%, respectively, for both groups), 86 women developed recurrent disease: 42 (25%) in the surgery group and 44 (26%) in the radiotherapy group. Significant factors for survival in univariate and multivariate analyses were: cervical diameter, positive lymphangiography, and adeno-carcinomatous histotype. 48 (28%) surgery-group patients had severe morbidity compared with 19 (12%) radiotherapy-group patients (p = 0.0004). INTERPRETATION There is no treatment of choice for early-stage cervical carcinoma in terms of overall or disease-free survival. The combination of surgery and radiotherapy has the worst morbidity, especially urological complications. The optimum therapy for each patient should take account of clinical factors such as menopausal status, age, medical illness, histological type, and cervical diameter to yield the best cure with minimum complications.

Class II versus Class III Radical Hysterectomy in Stage IB–IIA Cervical Cancer: A Prospective Randomized Study

OBJECTIVE The objective of this study was to determine the role of the extent of the radicality in the treatment of stage IB-IIA cervical carcinoma with respect to survival, pattern of relapse, and morbidity. METHODS Two-hundred forty-three patients with cervical carcinoma (FIGO stages IB and IIa) were enrolled in a prospective randomized study comparing two types of radical hysterectomy (Piver-Rutledge-Smith class II and class III) between April 1987 and December 1993, and 238 are evaluable. Disease-free survival, overall survival, pattern of recurrences, and morbidity were the endpoints of this study. RESULTS Mean operative time was significantly (P = 0. 05) shorter in the group of patients undergoing class II hysterectomy (135 min vs 180 min), whereas mean blood loss (530 ml vs 580 ml) and number of patients requiring transfusions (35% vs 43%) were similar in the two arms of treatment. Complications unrelated to the extent of the surgical dissection and mean postoperative stay were similar in the two arms of treatment. Late morbidity was significantly lower in patients in the class II arm (especially urologic morbidity, 13% vs 28%). Postoperative radiotherapy was administered to 64 patients (54%) in class II and to 65 patients (55%) in the class III arm. Recurrence rate (24% class II vs 26% class III) and number of patients dead of disease (18% class II vs 20% class III) were not significantly different in the two groups of treatment. Overall 5-year survival was 81 and 77% and disease-free survival was 75 and 73%, respectively. Multivariate analysis confirms that survival does not depend on the type of operation. CONCLUSIONS Class II and class III radical hysterectomies are equally effective in surgical treatment of cervical carcinoma, but the former is associated with a lesser degree of late complications.

Conservative surgery for Stage I ovarian carcinoma in women of childbearing age

Objective To assess the results of a policy of tailored conservative surgical management for young women with stage I ovarian carcinomas.

Neoadjuvant chemotherapy and conservative surgery for stage IB1 cervical cancer

OBJECTIVES To assess the effectiveness of chemo-surgical conservative therapy for stage IB1 cervical tumors in patients desiring to preserve fertility. METHODS From 1995 to April 2007 51 nulliparous patients with tumor <or=3 cm, aged <or=40 years with no uterine and lymphnode neoplastic involvement were evaluated. Three courses with cisplatin 75 mg/m(2), paclitaxel 175 mg/m(2) and ifosfamide 5 g/m(2) (epirubicin 80 mg/m(2) in adenocarcinoma) were followed by cold-knife conization and pelvic lymphadenectomy. When intraoperative frozen section revealed massive neoplastic cervical persistence a radical total hysterectomy was performed. RESULTS Thirty women (59%) did not accept the conservative approach. In the remaining 21 patients median age was 30 years and median tumor size was 15 mm (range 10-30 mm). Adenocarcinoma was present in 12 cases (57%) and indifferentiated neoplasia in 10 (48%). Following neoadjuvant treatment, pathological complete response was observed in 5 cases, in situ or microinvasive residue in 12 and stromal invasion >3 mm in 4. Four women deemed ineligible for conservative surgery after chemotherapy and one refusing to preserve her genital apparatus underwent radical hysterectomy. After a median follow-up of 69 months no relapses were observed. Nine women attempted to conceive: ten pregnancies occurred in 6 patients and 9 live babies have been born, while one woman experienced a first-trimester miscarriage. CONCLUSIONS The high rate of pathological response confirms the effectiveness of the preoperative treatment for reducing the tumor volume allowing the removal only of a cervical cone instead of the entire cervix with cardinal ligaments as needed by radical trachelectomy. Successful pregnancies are possible after such integration.

Cancer of the cervix, FIGO stages IB and IIA: patterns of local growth and paracervical extension.

The relationship between patterns of local growth and paracervical extension of cervical cancer was evaluated in operative specimens of 230 patients with squamous cell carcinoma FIGO stage IB and IIA who were primarily treated, between January 1989 and December 1993, by abdominal radical hysterectomy with pelvic lymphadenectomy. Twelve cervical giant sections, each representing an area of 30°, including the corresponding paracervical tissues (lateral parametria, vesicocervical ligaments, and uterosacral ligaments), were made parallel to the cervical canal, and serial horizontal step sections at 3 µm were cut. Cervical carcinoma spread endocervically equally in all directions; higher frequencies were observed in the front and back cervical quadrants (about 28%) than in the lateral ones (about 22%) (P = NS). The corresponding tumor extension beyond the cervix was into the vesicocervical ligaments (anterior parametria) and the vesicocervical septum in about 23% of cases, into the uterosacral ligaments (posterior parametria) and the rectovaginal septum in about 15% of cases, and into right and left lateral parametria in about 28% and 34% cases, respectively. Paracervical extension (26%) was significantly related to the maximum depth of stromal invasion (χ2 = 19.11; P < 0.01), minimum thickness of uninvolved fibromuscular cervical stroma (χ2 = 32.34; P < 0.01), lymphatic invasion (χ2 = 17.91; P < 0.01), pelvic lymph node metastases, (χ2 = 48.37; P < 0.01) and tumor size (χ2 = 26.38; P < 0.01). Furthermore, involvement of anterior and posterior paracervical tissues was related to high percentages of the minimum thickness of unaffected cervical stroma in the corresponding front (92%) and back (88%) quadrants, whereas these percentages were much lower (30%) in lateral cervical quadrants with carcinomatous extension to lateral parametria. These patterns of growth suggest that surgery is only radical with respect to lateral parametria in the treatment of cervical cancer.

Simple conization and lymphadenectomy for the conservative treatment of stage IB1 cervical cancer. An Italian experience.

OBJECTIVES Simple conization represents a plausible treatment scheme for managing stage IA1-2 tumors conservatively. However its curative potential has not been widely exploited as regards stage IB1 lesions. Recent studies suggest that, in selected circumstances, patients with stage IB1 disease undergoing radical hysterectomy could have been safely cured by simple hysterectomy and even by cervical conization. METHODS Patients with stage IB1 cervical cancer desiring conservative management underwent simple conization and pelvic lymphadenectomy in three Italian institutes. RESULTS Thirty-six women received the conservative treatment since 1995 to 2010. Median age was 31 (range 24-40) years and median tumor size was 11.7 mm (range 8-25 mm). Adenocarcinoma was present in 12 cases (33%) and grade 3 neoplasia in 5 (14%). Lymph-vascular space involvement was detected in five patients (14%). Eleven had already a child while two had experienced an early abortion and a fetal loss at second trimester. After a median follow-up of 66 months (range 6-168) only one pelvic lymphnodal relapse was observed. Twenty-one pregnancies occurred in 17 patients and 14 live babies have been born (two preterm at 27 and 32 weeks) while one is ongoing. Three first-trimester miscarriages, one second-trimester fetal loss, an ectopic pregnancy and a termination of pregnancy have been recorded. Five patients decided to undergo hysterectomy after 3-12 years after conservative therapy: in one residual microinvasive adenocarcinoma was found. CONCLUSIONS Cervical conization represents a feasible conservative management of stage IB1 cervical cancer and shows a low risk of relapse, provided that patients are selected carefully. Conization would be suitable to treat stage IB lesions smaller than 15-20mm. with pathologic negative lymphnodes.

Class I versus class III radical hysterectomy in stage IB1-IIA cervical cancer. A prospective randomized study

OBJECTIVE The standard treatment for stage IB-IIA cervical cancer over the past three decades has been the Piver-Rutledge type III radical hysterectomy. This surgery implies a high rate of urologic morbidity. The objective was to determine the role of class I radical hysterectomy compared to class III radical hysterectomy in terms of morbidity, overall survival, DFS and patterns of relapse in patients undergoing primary surgery. MATERIALS AND METHODS 125 patients with stage IB1 and IIA cervical cancer ≤ 4 cm were randomized between type I and type III hysterectomy. Clinical, pathologic and follow-up data were prospectively collected. Adjuvant radiotherapy was administered when indicated. Univariate and multivariate analyses were carried out. RESULTS Sixty-two patients were randomized to class I surgery and 63 to class III. No significant differences were observed regarding pathologic findings and adjuvant treatment. Morbidity rates were higher after class III surgery (84% versus 45%). Pelvic recurrences were equal in both groups (8 cases each one). Fifteen-year overall survival rate was 90 and 74% respectively (p = 0.11) and 76 and 80% when cervical size is ≤ 3 cm (p = 0.88). CONCLUSIONS There are no significant differences in terms of both recurrence rate and overall survival among patients with stage IB-IIA cervical cancer undergoing simple extrafascial hysterectomy (class I) or radical hysterectomy (class III). Morbidity is proportional to the extent of radicality. These data confirm the need of tailoring the extent of resection to the characteristics of the cervical neoplasia and open new interesting pathways to upcoming protocols for the conservative management of these tumors.

Concurrent carboplatin/5-fluorouracil and radiotherapy for recurrent cervical carcinoma

BACKGROUND Results of salvage therapy in patients with carcinoma of the uterine cervix recurrent after surgery have been dismal even when the disease was apparently confined to the pelvis. Concurrent chemoradiation is one of the several avenues being investigated to improve these results. PATIENTS AND METHODS Thirty-five women with recurrent cervical carcinoma were enrolled in the trial. Twenty-eight patients (80%) had disease limited to the central pelvis (ten), lateral pelvis (fourteen) and vagina (four) and seven had paraortic metastases. Patients were treated with a combination of external radiotherapy (50-70 Gy) along with three cycles of 5-fluorouracil (1000 mg/m2/24-hour continuous infusion days 1-4) and carboplatin (75 mg/m2 in bolus days 1-4). RESULTS Treatment was well tolerated, with 30 patients (86%) completing the protocol as planned. Acute toxicity was severe but manageable; 11 patients (31%) experienced grades 3-4 acute toxicity. Late morbidity occurred in five patients (14%). Overall response rate was 74% (11 partial responses and 15 complete). After a median follow-up of 27 months (range 18-90), 13 patients (37%) are alive without disease, 4 (11%) are alive with persistent disease and 18 (52%) are dead of their disease. Actuarial two-year survival rate for the series as a whole is 44% and three-year survival is 25%. Stage of the primary disease, site of recurrence, interval from the primary therapy to recurrence, lymph node involvement, ureterohydronephrosis at the time of recurrence and diameter of the relapse are the most significant factors for survival, while complete response is related to diameter and site of relapse and lymph node status at the time of relapse. CONCLUSION The acceptable toxicity, high response rate and satisfying survival would suggest that concomitant carboplatin/5-fluorouracil and radiotherapy is a safe and tolerable treatment for recurrent cervical carcinoma. Further studies are needed to demonstrate an eventual survival benefit of this type of chemoradiation over standard radiotherapy alone and to identify the subsets of patients who in particular might benefit from this.

Complete remission of brain metastases from ovarian carcinoma with carboplatin

Central nervous system involvement by epithelial ovarian carcinoma is rare. We report the case of a 49 year old woman with stage IV serous carcinoma of the ovary who developed multiple cerebral and cerebellar metastases 7 months after achieving complete response to platin-based chemotherapy. Eight courses of carboplatin (400 mg/m2) were administered and after the second cycle complete remission of the brain deposits occured. The treatment afforded rapid subjective and objective relief and was associated with a good quality of life. Abdominal recurrent disease was diagnosed 22 months after treatment for brain involvement. Paltin-based chemotherapy was reinstated, but the patient died from progressive adbominal disease without any sign of cerebral involvement and any neurological symptomatology. Carboplatin should be considered for the treatment of ovarian carcinoma metastatic to the brain.

Treatment of fallopian tube carcinoma with cyclophosphamide, adriamycin, and cisplatin.

Primary carcinoma of the fallopian tube is uncommon; optimal primary treatment is still not well defined, and little information is available about the efficacy of cisplatin-based combination chemotherapy. Thirty-eight patients with fallopian tube carcinoma were treated with cyclophosphamide (500 mg/m2), Adriamycin (50 mg/m2), and cisplatin (50 mg/m2) (CAP). Thirty-two patients received the combination chemotherapy as first-line treatment after cytoreductive surgery, whereas six subjects were treated for recurrent disease. The patients received a median of six cycles of therapy (range, four to nine). At the initiation of chemotherapy, 24 patients had measurable lesions. In this group of patients, 15 had a clinical complete response (CR), four had a partial response (PR), three had stable disease (SD), and two had progressive disease (PD) after chemotherapy. The overall clinical response rate (CR + PR) was 80%. Ten of the 14 CR patients who were submitted to second-look operation (SLO) were found free of disease, in pathologic complete response (pCR). Three pCR patients relapsed, and two of them died despite second-line treatment. Nine patients achieving PR, SD, and PD after first-line chemotherapy were further treated (five with chemotherapy, two with radiotherapy, two with progesteron), but none responded to second-line treatment and all died (median survival, 9 months). Fourteen patients without gross residual disease after cytoreductive surgery had no measurable lesions and were not evaluable for response. Seven of them had negative SLO and remain disease free. Three patients (two stage III and one stage II) who refused SLO relapsed 14, 16, and 26 months after completion of chemotherapy. The median survival for the entire group was 38 months, and the 5-year survival rate was 35%. The toxicity of the regimen was moderate. The CAP regimen appears to be active in primary fallopian tube carcinoma and yields response rates comparable to those reported for epithelial ovarian cancer.