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.

Ovarian metastases in early-stage cervical cancer (IA2-IIA): a multicenter retrospective study of 1965 patients (a Cooperative Task Force study).

This is a retrospective study of patients treated for early-stage cervical cancer to identify pathologic risk factors associated with ovarian metastases and, therefore, to establish when ovarian preservation can be performed without increasing the risk of relapse in order to improve the quality of life in premenopausal patients. Between 1982 and 2004, 1965 patients with FIGO stage IA2-IB-IIA cervical squamous cell carcinoma and nonsquamous histology types were surgically treated; 1695 (86%) patients underwent primary radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic node dissection, the remaining 270 patients (14%) had their ovaries preserved. The clinical records were reviewed for all patients and clinical features at presentation, the histopathology and follow-up data were recorded. Overall, ovarian metastases were diagnosed in 16 of 1695 patients, for an incidence rate of 0.9%. Univariate analysis shows age (45 years: P = 0.0079), FIGO stage (IB1-IIA 4 cm: P = 0.0133), histology (squamous vs nonsquamous, P = 0.0014), noninvolved peripheral stromal thickness (<3 vs >3 mm: P = 0.0001), lymphvascular space involvement (present vs absent, P = 0.0007), lymph node status (positive vs negative, P = 0.00009) to be statistically associated with the presence of ovarian metastases. Multivariate analysis shows only age (P = 0.0119), FIGO stage (P = 0.011), histology (P = 0.001), and unaffected peripheral stromal thickness (<3 mm: P = 0.037) to be independent risk factors for ovarian metastases. Based on the present data and on the data available in the literature, ovarian preservation could be safely performed in young patients with early-stage squamous cell carcinoma (histology as the most significant risk factor), with macroscopically normal ovaries, and with preserved peripheral unaffected cervical stroma.

[Treatment of stage IIIB cervical carcinoma. A comparison between radiotherapy, concurrent chemo-radiotherapy and neoadjuvant chemotherapy]. / Trattamento del carcinoma della cervice uterina stadio IIIB. Confronto tra radioterapia, chemio-radioterapia concomitante e chemioterapia neoadiuvante.

AIM: The aim of this study is to evaluate the effectiveness of radiation, concomitant chemoradiation and primary chemotherapy in the treatment of FIGO stage IIIB cervical carcinoma. METHODS: Between January 1981 and December 2001 94 women with stage IIIB FIGO cervical carcinoma were observed. Exclusive radiotherapy was administered in 30 cases (32%), radiotherapy and radiosensitizing chemotherapy in 20 cases (21%) and primary chemotherapy in 44 cases (47%); among the latter patients 2 (4%) developed neoplastic progression, 28 (64%) underwent surgery and 14 (32%) underwent radiotherapy. RESULTS: After a median follow-up of 69 months, 5-year overall survival of the 3 groups is respectively 23%, 36% and 26% (p=0.7). Total dose to point A greater than 60 Gy and the use of brachyradiotherapy are suggestive for a better outcome among women treated with radiation therapy (5-year overall survival 31% versus 18%, p=0.8 and 33% versus 23%, p=0.4, respectively). Radiologically assessed nodal status is the only statistically significant risk factor (p=0.001). Although not statistically significant, vaginal involvement is a relevant factor influencing survival (p=0.1). Women treated with concomitant chemoradiation showed a better 5-year disease-free survival (45%) when compared to the other treatment groups (radiation alone 27%, primary chemotherapy 30%, p=0.4). CONCLUSIONS: Primary chemotherapy, although useful to allow subsequent surgery, does not yield a survival advantage with respect to the irradiated patients. Among these, concomitant radiosensitizing chemotherapy is likely to improve the disease-free survival.

The clinical outcome of patients with stage Ia1 and Ia2 squamous cell carcinoma of the uterine cervix: a Cooperation Task Force (CTF) study.

PURPOSE OF INVESTIGATION: The objective of this retrospective multicenter study was to assess the clinical outcome of patients with microinvasive squamous cell carcinoma of the uterine cervix. METHODS: The hospital records of 166 patients with microinvasive squamous cell carcinoma of the uterine cervix were reviewed. All cases were retrospectively staged according the 1994 International Federation of Gynecology and Obstetrics (FIGO) nomenclature. One hundred and forty-three cases were in Stage Ia1 and 23 in Stage Ia2 disease. Surgery consisted of conization alone in 30 (18.1%) patients, total hysterectomy in 82 (49.4%), and radical hysterectomy in 54 (32.5%). All patients in whom conization was the definite treatment had Stage Ia1 disease and had cone margins negative for intraepithelial or invasive lesions. RESULTS: None of the 67 patients submitted to pelvic lymphadenectomy had histologically proven metastatic lymph nodes. Of the 166 patients, eight (4.8%) had an intraepithelial recurrence and four (2.4%) had an invasive recurrence. With regard to FIGO substage, disease recurred in nine (6.3%) out of 143 patients with Stage Ia1 and three (13.0%) out of 23 with Stage Ia2 cervical cancer. With regard to type of surgery, disease recurred in three (10.0%) out of the patients treated with conization alone, four (4.9%) out those who underwent total hysterectomy, and five (9.3%) out of those who underwent radical hysterectomy. It is worth noting that none of the 30 patients treated with conization alone had recurrent invasive cancer after a median follow-up of 45 months. However three (10%) of these patients developed a cervical intraepithelial neoplasia (CIN) III after 16, 33, and 94 months, respectively, from conization. CONCLUSIONS: Conization can represent the definite treatment for patients with Stage Ia1 squamous cell cervical cancer, if cone margins and apex are disease-free. For patients with Stage Ia2 cervical cancer extrafascial hysterectomy with pelvic lymphadenectomy might be an adequate standard therapy, although the need for lymph node dissection is questionable.

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.

Patterns of recurrence in patients with squamous cell carcinoma of the vulva. A multicenter CTF Study.

BACKGROUND: Invasive vulvar carcinoma is a rare disease with an incidence rate of 3-5% of all female genital neoplasms. The current study discusses the limited number of articles in the literature regarding the patterns of recurrence as well as the clinical outcome of patients with recurrent disease based on a consistent and consecutive series of cases. METHODS: A common clinical chart focusing on the study of patterns of recurrence was used in five Italian gynecologic institutions with uniform criteria of surgical nomenclature, pathologic variables, and sites of recurrence. Between 1980-1994, 502 cases of primary invasive squamous carcinoma of the vulva were registered consecutively, treated, and considered for this multicentered study. RESULTS: Of 502 patients, 187 (37.3%) developed a recurrence. Distribution of the recurrences by site was as follows: perineal, 53.4%; inguinal, 18.7%; pelvic, 5.7%; distant, 7.9%; and multiple, 14.2%. In a multivariate analysis, 3 characteristics appeared to be statistically correlated with the risk of recurrence: International Federation of Gynecology and Obstetrics Stage > II (P = 0.029), positive lymph nodes (P = 0.009), and vascular space invasion (P = 0.004). The 5-year survival rate was 60% for perineal recurrences, 27% for inguinal and pelvic recurrences, 15% for distant recurrences, and 14% for multiple recurrences. CONCLUSIONS: In the current study the prognostic factors found to have statistical significance as prognostic factors for risk of recurrence were tumor dimension, lymph node involvement, and stromal and vascular space invasion. The presence of inguinal lymph node metastases was predictive of multiple and distant recurrences with a low rate of incidence of isolated perineal recurrence (27%) compared with negative lymph node cases (57.5%). Survival analysis of recurrent disease showed that the surgical resection of local recurrences may provide acceptable results (51% at 5 years). This observation may justify a follow-up program aimed at identifying those patients with early local recurrence suitable for radical resection.

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.

Radical hysterectomy for recurrent or persistent cervical cancer following radiation therapy.

The objective of this paper was to determine the role of radical hysterectomy in persistent or recurrent cervical cancer after primary radiation therapy. Between 1982 and 1995, 34 patients underwent radical hysterectomy for persistent (n = 15) or recurrent (n = 19) cervical cancer after primary radiotherapy. Univariate analysis using log-rank comparison of survival curves was conducted to identify clinical and pathologic factors predictive of survival. The median tumor size at the time of recurrence or persistence was 3.2 cm (range 1-6 cm). 24 patients (70%) had recurrence limited to the uterine cervix; four (12%) had vaginal involvement and six (18%) had early parametrial involvement. No treatment-related deaths were observed. Eighteen major complications (grade III-IV) occurred in 15 cases (44%); 5 patients experienced a fistula. Mean follow-up time was 81 months (range 33-192 months). Recurrent disease was documented in 20 patients (59%), and median time to recurrence was 37 months (range 4-56 months). Fifteen patients (44%) are alive without evidence of disease at a median survival of 81 months (range 33-192), and 18 patients (53%) died of disease with a median survival of 22 months (range 7-106). One patient died of intercurrent disease. Actuarial 5-year survival rate for the whole group is 49%. Patients with FIGO stage IB-IIA at primary diagnosis, no clinical parametrial involvement, and small (

Molecular characterisation of a panel of human ovarian carcinoma xenografts.

In a panel of 16 human ovarian tumours transplanted in nude mice, the expression of genes involved in cell cycle regulation and in response to drug treatment were characterised. In the 16 tumours analysed we could not detect overexpression of Erb-B2 oncogene while expression of MDR1 mRNA was not detected in 11/15 samples and was low in 4/15 tumours. Only three tumours had mutations in the p53 gene exons 5-8 and one of these mutations did not result in any amino acid alteration. The levels of mRNA for cyclins A, D1 and E were heterogeneous with some tumours expressing high levels and others not expressing them at all. The same was found for the cyclin dependent kinases (CDK) CDK2 and CDK4 and for CDK inhibitors p21/WAF1, p27/KIP1 and p16/CDKN2. Two genes belonging to the nucleotide excision repair, ERCC1 and ERCC3 were detectable in all the samples examined, as were the genes MGMT and MAG, also involved in DNA repair. The data indicate a heterogeneity in the expression of genes considered to be involved in the cellular responses to cytotoxic drug treatment and indicate the possibility of using these tumour models to test specifically molecules with a defined mechanism of action.

Neoadjuvant chemotherapy to radiation and concurrent chemoradiation for locally advanced squamous cell carcinoma of the cervix: a review of the recent literature.

Radiotherapy is the standard treatment for locally advanced cervical cancer; nevertheless it fails to control disease progression within the irradiation fields in more than 40% of cases, particularly in patients with bulky tumor. Distant metastases are not infrequent in more advanced cases. Chemotherapy has been integrated with radiotherapy to improve local control and treat distant subclinical metastases. Schedules of combined treatment more frequently represented by neoadjuvant chemotherapy followed by radiation (NACT) and by concomitant chemotherapy and radiation (CT-RT). A review of the recent literature is presented. The role of NACT is controversial: high response rates are reported but doubtful advantages in terms of survival or local control have been shown. In randomized trials, hydroxyurea concomitant to radiation improves local control and survival, particularly in stage IIIB and IVA. Several randomized trials of concurrent chemoradiation with 5FU, cisplatin and mitomycin C are underway, but few have been published: no significative differences are reported in term of local control or survival. Acute toxicity is higher than in radiation alone, but usually manageable. For the analysis of late morbidity a longer follow-up is required. Large randomized trials of adequate radiotherapy versus concomitant chemoradiation are necessary to refine our understanding of the benefits of this integrated treatment.

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.

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. DESIGN: Retrospective study. PARTICIPANTS: Ninety-nine women aged 40 years or younger who underwent either primary surgery in our department or were referred after primary surgery performed elsewhere. METHODS: Of the 99 women in our study, 56 underwent fertility-sparing surgery and 43 more radical surgery. Minimal requirements for conservative management were adequate staging and complete information about the therapeutic options. Factors important in the choice of the treatment were, age, wish to preserve fertility, histologic type and grade, and the stage of the tumour. RESULTS: Conservative treatment was conducted in 84% of nulliparous and in 33% of parous women; 62% of grade 1 tumours, 48% of grade 2, and 50% of grade 3 were treated conservatively. With a median follow up of seven years, we observed five recurrences (9%) of carcinoma in women treated conservatively and five (12%) in those treated more radically. Two women (one in each treatment arm) were saved after recurrence. Two recurrences after conservative surgery involved the residual ovary (3.6%). Two women developed borderline tumour in the contralateral ovary and both were treated by surgery. CONCLUSION: After adequate staging and accurate information is given to the patient, conservative treatment may be safe in some women with early ovarian cancer. The risk of recurrence in the contralateral ovary is low. Conservative surgery may be also considered in some Stage I grade 3 tumours and in some women with stage JC tumours.

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.

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.

Second-look laparotomy in the management of fallopian tube carcinoma.

OBJECTIVE: To evaluate the role of second-look laparotomy following platinum-based combination chemotherapy in patients with fallopian tube carcinoma. METHODS: A retrospective chart review was conducted on 21 patients with tubal carcinoma who underwent second-look laparotomy following cytoreductive surgery and platinum-based combination chemotherapy. RESULTS: Thirteen patients (62%) were found to be free of disease at second-look operation. Neither stage nor grade were predictive of findings at second-look procedure. The absence of gross residual disease following primary surgery was the only predictor of disease-free status at second-look laparotomy (p < 0.01). With a mean follow-up of 49 months among the survivors, four (31%) of the patients with negative second-look laparotomy have had a recurrence. The median survival following a positive second-look laparotomy was 18 months (range 5-42 months). CONCLUSION: Second-look laparotomy provides useful prognostic information in patients with tubal carcinoma. The high rate of recurrent disease after negative second-look laparotomy, and the lack of an effective second-line treatment in patients with persistent disease, represent major criticisms of this procedure.

Concurrent carboplatin/5FU and radiotherapy compared to radiotherapy alone in locally advanced cervical carcinoma: a case-control study.

AIMS AND BACKGROUND: Despite the introduction of innovative techniques in radiotherapy (RT) delivery, no significant improvement in survival has been achieved in the last decades. Concurrent chemoradiation therapy (CRT) is one of the several avenues being explored to improve the results. METHODS AND STUDY DESIGN: Twenty-eight women with locally advanced squamous cell carcinoma of the uterine cervix were treated with CRT comprising a combination of external and intracavitary RT, along with 3 cycles of 5-fluorouracil (5-FU) and carboplatin. Toxicity, pelvic control rate and disease-free survival achieved in this group of patients were compared in a case-control study with those of a group of 28 patients with similar clinico-pathologic characteristics treated with radical RT alone at our institution. RESULTS: CRT was well tolerated, with 97% of the patients completing the protocol as planned. Acute toxicity, primarily hematologic, was significantly (P = 0.05) higher in the cases than in the controls (25% vs 3%). One treatment-related death occurred in a stage III patient in the CRT group. The median follow-up was 55 months (range, 20-156) in the RT group and 20 months (range, 14-46) in the CRT group. Pelvic control rate, disease-free survival and overall survival were not significantly different in the two groups. Estimated 5-year survival rate was 70% and 66% respectively for the RT and CRT group. CONCLUSIONS: Concomitant carboplatin/5-FU and radiotherapy is a safe and tolerable means of treatment for locally advanced cervical cancer. In our study, however, concurrent CRT did not result in a significant improvement in pelvic control rate or survival compared to standard conventional radiotherapy.

Paclitaxel induces significant changes in epidoxorubicin distribution in mice.

BACKGROUND: Inhibition of Pgp can affect the distribution and the pharmacokinetics of anthracyclines, causing marked changes in their toxicity. Since both paclitaxel and cremophor are substrates of Pgp, it was hypothesized that they could modify the pharmacokinetics of anthracyclines in a similar fashion. PURPOSE OF THE STUDY: To evaluate whether pretreatment of mice with cremophor or paclitaxel dissolved in cremophor could induce changes in the distribution of epidoxorubicin (EpiDx). MATERIALS AND METHODS: Male CDF1 mice were treated with ethanol or cremophor or paclitaxel and 30 min later with EpiDx (15 mg/kg i.v.). EpiDx serum and tissue levels were determined at several time points after EpiDx treatment by high pressure liquid chromotagraphy (HPLC) assay coupled with fluorimetric detection. RESULTS: Pretreatment with paclitaxel dissolved in cremophor induced a highly significant increase in EpiDx levels in all tissues examined including heart. At 8 h heart levels in mice treated with EpiDx alone, EpiDx and cremophor and EpiDx and paclitaxel were 8.3 micrograms/g, 10.9 micrograms/g and 16.7 micrograms/g (P < 0.01), respectively. Cremophor alone induced a similar increase in spleen EpiDx levels but had only a moderate effect on heart and lung EpiDx levels. Levels of doxorubicin (Dx) aglycone in kidney and liver of mice treated with paclitaxel and EpiDx were higher than those in mice treated with EpiDx alone. CONCLUSIONS: A pharmacokinetic interaction between paclitaxel and EpiDx was clearly demonstrated in mice. The much higher tissue levels of EpiDx after paclitaxel pretreatment may be the reason for the increased toxicity of EpiDx when administered soon after paclitaxel.

Concurrent preoperative chemotherapy with 5-fluorouracil and mitomycin C and radiotherapy (FUMIR) followed by limited surgery in locally advanced and recurrent vulvar carcinoma.

To prospectively evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy locally advanced or recurrent vulvar carcinoma, 58 patients referring for primary (41) or recurrent (17) disease received preoperative external radiotherapy to a dose of 54 Gy, divided into two courses with an interval of 2 weeks. 5-Fluorouracil (750 mg/m2 daily for 5 days) and mitomycin-C (15 mg/m2 single bolus) were given at the start of each cycle. Wide local excision and inguinal lymphadenectomy were planned after treatment. Eighty-nine percent of patients completed the chemoradiotherapeutic treatment, whereas 72% underwent surgery. Objective responses were observed in 80% of vulvar diseases and in 79% of groin metastases. Pathologic complete response of both the vulvar and inguinal disease was confirmed in 13 patients (31%). Early severe toxicity was recorded in 3 patients and severe worsening of performance status in 3. Three deaths occurred shortly after treatment and at least one is directly related to toxic effects. This treatment allows good control of locally advanced and recurrent vulvar cancer with acceptable side effects. Further follow-up is required to determine the long-term outcome and the effectiveness of the surgical procedure.

Salvage therapy with ifosfamide and mitoxantrone in advanced ovarian cancer.

OBJECTIVE: To evaluate the anti-tumour activity and toxicity of ifosfamide (5 g/m2 continuous infusion) and mitoxantrone (10 mg/m2) given in combination every 3 weeks in patients with ovarian cancer resistant to at least two previous regimens which included platinum. PATIENTS AND METHODS: Additional eligibility criteria were an ECOG performance status < or = 2 and measurable disease. Of 47 patients entered in the study, 8 were defined as platinum-resistant and 39 as potentially sensitive according to Markman's criteria. Thirty-five patients had also received paclitaxel as last treatment before entering this study. Tumour response was evaluated every three cycles. RESULTS: One complete and 11 partial responses were reported, for an overall response rate of 25% (95% CI: 14%-40%). Three of the partial responders were resistant to platinum. None of the 7 partial responders pretreated with taxol had responded to it. The overall median survival was 11 months. Neutropenia G4 was reported in 18 patients (42%) with hospitalisation because of febrile neutropenia in 3 of them. CONCLUSIONS: In patients with ovarian cancer failing at least 2 previous therapies including platinum, the combination of ifosfamide and mitoxantrone has shown an antitumour activity comparable to that of paclitaxel, with acceptable toxicity. Objective responses were reported also in patients failing paclitaxel, suggesting a lack of cross resistance.

Primary carcinoma of the fallopian tube. A retrospective analysis of 47 patients.

BACKGROUND: Fallopian tube carcinoma is a rare disease, and few data about prognostic factors are available in the literature. PATIENTS AND METHODS: The medical charts of 47 patients with primary carcinoma of the fallopian tube treated at our institution between 1982 and 1994 were reviewed. Age, stage, histologic grade, residual disease after surgery, peritoneal cytology and lymph-node involvement were evaluated for their prognostic impact in a univariate analysis. RESULTS: The mean age of the patients was 57.5 years and 19 of them (40%) had early-stage disease. Poorly differentiated tumors were diagnosed in 64% of the patients. Eleven of 20 patients (55%) submitted to surgical evaluation of lymph nodes had retroperitoneal involvement. Thirty-three patients received CAP chemotherapy following surgery, and the overall clinical response rate was 80%. Sixteen patients (34%) had recurrences within 8 to 50 months from diagnosis. Twenty patients (42.6%) are alive without disease, one patient is alive with tumor, and 26 patients (55.3%) died of the disease. The median survival for the group as a whole was 44 months, and the actuarial 5-year survival was 29%. In univariate analysis stage (I + II vs. III + IV), grade (G1 + G2 vs. G3) residual disease after surgery (less than 2 cm vs. greater than 2 cm). peritoneal cytology (negative vs. positive) and lymph-node metastases were all factors significantly affecting survival. CONCLUSIONS: Aggressive cytoreductive surgery followed by platin-based chemotherapy offer the possibility of long-term control of primary tubal carcinoma.