James V. Fiorica

Randomized Phase III Trial of Cisplatin With or Without Topotecan in Carcinoma of the Uterine Cervix: A Gynecologic Oncology Group Study

PURPOSE On the basis of reported activity of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or topotecan plus cisplatin in advanced cervix cancer, we undertook a randomized trial comparing these combinations versus cisplatin alone, to determine whether survival is improved with either combination compared with cisplatin alone, and to compare toxicities and quality of life (QOL) among the regimens. PATIENTS AND METHODS Eligible patients were randomly allocated to receive cisplatin 50 mg/m(2) every 3 weeks (CPT); cisplatin 50 mg/m(2) day 1 plus topotecan 0.75 mg/m(2) days 1 to 3 every 3 weeks (CT); or methotrexate 30 mg/m(2) days 1, 15, and 22, vinblastine 3 mg/m(2) days 2, 15, and 22, doxorubicin 30 mg/m(2) day 2, and cisplatin 70 mg/m(2) day 2 every 4 weeks (MVAC). Survival was the primary end point; response rate and progression-free survival (PFS) were secondary end points. QOL data are reported separately. RESULTS The MVAC arm was closed by the Data Safety Monitoring Board after four treatment-related deaths occurred among 63 patients, and is not included in this analysis. Two hundred ninety-four patients enrolled onto the remaining regimens: 146 to CPT and 147 to CT. Grade 3 to 4 hematologic toxicity was more common with CT. Patients receiving CT had statistically superior outcomes to those receiving CPT, with median overall survival of 9.4 and 6.5 months (P = .017), median PFS of 4.6 and 2.9 months (P = .014), and response rates of 27% and 13%, respectively. CONCLUSION This is the first randomized phase III trial to demonstrate a survival advantage for combination chemotherapy over cisplatin alone in advanced cervix cancer.

Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: A Gynecologic Oncology Group study

PURPOSE This study evaluated efficacy of single-agent trastuzumab against advanced or recurrent HER2-positive endometrial carcinoma (EC), and explored predictors for HER2 amplification. PATIENTS AND METHODS Eligible patients had measurable stage III, IV, or recurrent EC. There was no limit on prior therapy although total prior doxorubicin dose was limited to 320 mg/m(2). Tumors were required to have HER2 overexpression (2+ or 3+ immunohistochemical staining) or HER2 amplification (FISH HER2/CEP 17 ratio >2.0). Trastuzumab was administered intravenously at a dose of 4 mg/kg in week 1, then 2 mg/kg weekly until disease progression. The primary endpoint was tumor response. RESULTS Of the 286 tumors centrally screened by LabCorp, 33 (11.5%) were HER2-amplified. Three of 8 clear (38%) cell carcinomas and 7 of 25 serous carcinomas (28%) screened exhibited HER2 amplification compared with 7% (2/29) of endometrioid adenocarcinomas. HER2 overexpression was correlated with HER2 amplification (r=0.459; p<0.0001). Thirty-four women were enrolled; 1 was excluded (refused treatment); and 18 had tumors with known HER2 amplification. No major tumor responses were observed. Twelve women experienced stable disease, 18 had increasing disease, and 3 were indeterminate for tumor response. Neither HER2 overexpression nor HER2 amplification appeared to be associated with progression-free survival or overall survival. CONCLUSION Trastuzumab as a single agent did not demonstrate activity against endometrial carcinomas with HER2 overexpression or HER2 amplification, although full planned accrual of women with HER2 amplified tumors was not achieved due to slow recruitment. Serous and clear cell endometrial carcinomas appear to be more likely to demonstrate HER2 amplification.

Invasive carcinoma of the vulva

Four hundred fifteen patients who had invasive carcinoma of the vulva were treated with primary surgery from July 1, 1955, through June 30, 1989. Three hundred seventy-six (90%) of the patients had squamous carcinoma. Two hundred fourteen patients (52%) had radical vulvectomy with inguinofemoral lymphadenectomy. Twenty-four patients (6%) underwent radical vulvectomy with pelvic exenteration for advanced disease, and 55 patients (13%) had nonradical operations. The remaining 122 patients (29%) underwent radical vulvectomy, inguinofemoral lymphadenectomy, and pelvic lymphadenectomy. The primary morbidity was associated with lymphedema (8.6%) and groin wound breakdown (54%). No intraoperative deaths occurred among the 415 patients treated surgically, but there were 17 deaths (4%) within 28 days of operation. The absolute 5-year survival rate was 85% in patients with negative inguinofemoral lymph nodes and 39% when these lymph nodes were positive for metastatic carcinoma. The overall absolute 5-year survival rate was 67%.

Upper vaginectomy for in situ and occult, superficially invasive carcinoma of the vagina

Between Aug. 1, 1985, and July 31, 1990, 32 patients underwent upper vaginectomy for grade 3 vaginal intraepithelial neoplasia. Thirty-one of these patients had undergone hysterectomy, 25 because of cervical neoplasia. Fourteen patients had undergone treatment for vaginal intraepithelial neoplasia. Nine (28%) had invasive cancer on final pathologic examination. Among the remaining 23 patients, recurrence of vaginal neoplasia developed in four (17%), with a mean time to recurrence of 78 weeks, and one was found to have superficial invasion at the time of recurrence. The remaining 19 patients remain alive with no evidence of recurrent disease at a mean follow-up interval of 152 weeks. In our patients upper vaginectomy was efficacious for the diagnosis of occult invasive carcinoma of the vagina and for the treatment of in situ and superficially invasive carcinoma of the vagina.

Further experience with radiation therapy and concomitant intravenous chemotherapy in advanced carcinoma of the lower female genital tract.

Sixty-seven patients with advanced carcinoma of the lower female genital tract (cervix, vagina, and vulva) were treated with radiation and concomitant intravenous cisplatin and/or 5-fluorouracil. Fifty-seven patients (85%) responded completely clinically. Thirty-five (61%) complete responders recurred with a median time to recurrence of 6 months. Twenty-six of the thirty-five patients who recurred had some component of local failure. The 22 complete responders who have not recurred have been followed a median of 13 months. Acute toxicity was minimal, with only 6 patients requiring interruption of therapy. Nine (13%) patients developed severe late complications and eight required surgery. The actuarial 5-year survival is 22%. This treatment regimen is disappointing in terms of both survival and local control.

Concurrent Chemoradiation for Cervical Cancer.

The current practice of treating cervical cancer with surgery or radiation alone has been challenged by the recent information from the National Cancer Institute regarding concurrent chemoradiation for cervical cancer. Results from each of five randomized phase III trials show an overall survival advantage of 30% — plus acceptable toxicity — for cisplatin-based therapy given concurrently with radiation therapy (Table). The patient populations in these studies included women with FIGO stages IB2-IVA cervical cancer treated with primary radiotherapy and women with FIGO stage I-IIA disease with poor prognostic factors (metastatic disease in pelvic lymph nodes, parametrial disease, or positive surgical margins) at the time of primary surgery. Although the trials varied in terms of stage of disease, dose of radiation, and schedule of cisplatin and radiation, they all demonstrated significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% with concurrent chemoradiation. Based on these results, strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.

Ovarian management at the time of radical hysterectomy for cancer of the cervix

Ovarian management at the time of radical hysterectomy for cervical cancer was reviewed retrospectively over a 7-year period. All patients had early-stage cancer except three who had stage IIB disease. Approximately 80% of patients had squamous cancer and 20% adenocarcinoma or adenosquamous carcinoma. The mean age was 44, and 24% of patients were 35 or younger. Ninety-nine patients had their ovaries removed. None of the ovaries contained metastatic disease including 22 patients with adenocarcinoma or adenosquamous carcinoma. Of the 17 patients with retained ovaries 14 had transposition into the paracolic gutters. Only one of the 14 patients with transposed ovaries developed symptoms of ovarian failure. No patients with retained ovaries developed metastatic disease or required reoperation secondary to new ovarian pathology. It is our opinion that normal ovaries can be preserved in young women at the time of radical hysterectomy for early cervical cancer regardless of histologic type.

Adenocarcinoma of the Endometrium: An Institutional Review.

BACKGROUND: Many oncologists regard endometrial cancer as a relatively benign and easily treatable gynecologic tumor. Inadequate care can result in poor outcomes. METHODS: The authors review the epidemiology and pathology of the disease, and they compare disease characteristics and outcomes of FIGO staging with their own 11-year experience at a tertiary referral center. RESULTS: Patients referred to tertiary referral centers tend to present with more advanced stages of disease than those reported by FIGO, although the profile of histologic types is similar. CONCLUSIONS: Prevention and early detection of endometrial cancer can minimize the impact of this disease. Complete staging and tumor removal including extrafascial hysterectomy with bilateral salpingo-oophorectomy, pelvic lymphadenectomy, and selective paraaortic lymphadenectomy are the cornerstones of surgical therapy.

Lymphoscintigraphy in vulvar cancer: a pilot study.

Abstract This pilot study was undertaken to correlate the patterns of lymphatic drainage demonstrated by vulvar lymphoscintigraphy with the clinical and pathologic findings of the inguinofemoral lymph nodes in patients with vulvar cancer. Ten patients were studied with the radionuclide Technetium-antimony trisulfide colloid (Tc 99m ASC) using a perilesional technique. Images were obtained at 2–4 hr postinjection. Four of the six patients with central lesions or lesions that crossed the midline had bilateral groin uptake, and two had unilateral uptake to the side on which the lesion was predominantly located. Three of these patients, each with suspicious groin nodes bilaterally, had metastatic nodal disease, two unilateral and one bilateral, in whom the uptake was bilateral and unilateral, respectively. Three of the four patients with unilateral lesions had ipsilateral groin drainage only and one had no drainage. Three underwent a bilateral lymphadenectomy and none had metastasis. The pattern of Tc 99m ASC uptake was not predictive of metastatic nodal disease. In two of the three patients with unilateral groin recurrence the side of recurrence was the same as that demonstrated on lymphoscintigraphy, and in the third case there was bilateral drainage. Further data are needed to determine the role of lymphoscintigraphy in the management of vulvar cancer.

Interstitial radiotherapy for the treatment of advanced orrecurrent vulvar and distal vaginal malignancy

Summary From March 1, 1985 to April 30, 1988 10 patients with locally advanced primary orrecurrent vulvar or distal vaginal malignancy were managed with interstitial radiotherapy with or without teletherapy. One patient died of complications of a total pelvic exenteration for radionecrosis 8 months after completion of radiotherapy. The remaining nine patients were alive at a mean follow-up of 28 months (14 to 50 months). Recurrent disease developed within a bed of severe radionecrosis in two patients at 13 and 47 months after completion of radiotherapy. The remaining seven patients have remained without evidence of recurrent disease. Of the 10 total patients severe radionecrosis developed in six at a median of 8.5 months (6 to 26 months) after radiotherapy. We conclude from our data that the use of interstitial needles, mainly combined with external radiotherapy, for the treatment of locally advanced primary or recurrent vulvar and introital malignancy is highly effective but also highly morbid