A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: A Gynecologic Oncology Group study.

PURPOSE: From 1979 to 1984, 356 eligible patients with advanced or recurrent endometrial carcinoma no longer amenable to therapy with surgery, radiotherapy, or progestins were treated with doxorubicin alone or doxorubicin in combination with cyclophosphamide. PATIENTS AND METHODS: Patients were randomized to receive doxorubicin 60 mg/m2 intravenously (i.v.) with or without cyclophosphamide 500 mg/m2 i.v. every 3 weeks for eight drug courses. All patients had received prior therapy with progestins with subsequent progression of disease. No patients had received prior therapy with cytotoxic drugs. Of 356 patients, 300 had measurable disease. RESULTS: Among 132 patients treated with doxorubicin alone, there were seven complete responses (5%), 22 partial responses (17%), 73 with stable disease (55%), and 30 with increasing disease within 2 months of study entry (23%). For the 144 patients who received the combination, there were 18 complete responses (13%), 25 partial responses (17%), 75 with stable disease (52%), and 26 with increasing disease (18%). The median progression-free interval for those patients who received doxorubicin alone was 3.2 months, while it was 3.9 months for those who received the combination. The median survival duration for doxorubicin patients was 6.7 months, while it was 7.3 months for the combination patients. None of the unadjusted estimates of treatment differences are statistically significant. Prognostic features that had an impact on outcome included one factor associated with an increased likelihood of response (presence of measurable lung metastases) and four features associated with a poorer survival (poor performance status [PS] of 2 or 3, high pathologic grade, and presence of liver metastases or other intraabdominal disease). If these features are taken into account in multivariate analyses, there is no statistically significant evidence for differences in response rates (relative odds of response, 1.58; P = .06, one-tailed test), and survival duration is slightly longer in the combination regimen (17% reduction in death rate; P = .048). CONCLUSION: The combination of doxorubicin plus cyclophosphamide thus appears to offer a small advantage over doxorubicin alone in the management of endometrial carcinoma at the expense of more frequent and severe myelosuppression and gastrointestinal toxicity.

Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study.

The Gynecologic Oncology Group has conducted a randomized prospective trial comparing cisplatin 50 mg/m2 every 21 days (regimen 1), 100 mg/m2 every 21 days (regimen 2), and cisplatin 20 mg/m2 for five consecutive days repeated every 21 days (regimen 3). Four hundred ninety-seven evaluable patients have been accrued on this study. The response rates were 20.7%, 31.4%, and 25.0%, for regimens 1, 2, and 3, respectively; the complete remission rates were 10.0%, 12.7%, and 8.6% for regimens 1, 2, and 3, respectively. The median duration of response ranged from 3.9 to 4.8 months, the median progression-free interval from 3.7 to 4.6 months, and the median survival time from 6.1 to 7.1 months. The difference in response rates for regimens 1 and 2 is statistically significant (P = .015) but less than the magnitude originally considered clinically significant. The differences in complete remission rates, response duration, progression-free interval, and survival times are not statistically significant. The following types of toxicity were observed: serum creatinine level greater than 2 mg/dL and/or BUN level greater than 40 mg/dL was 7%, 14%, and 17% on regimens 1, 2, and 3, respectively; leukocyte count less than 4,000/microL was 27%, 44%, and 41% on regimens 1, 2, and 3, respectively. Nausea and vomiting occurred in 74 patients (83%). The regimen consisting of a 100-mg/m2 single dose has produced a statistically significant higher response rate than the 50 mg/m2 regimen while producing no appreciable differences in complete remission rate, response duration, progression-free interval, or survival. In addition, the higher dose regimen was associated with greater myelosuppression and nephrotoxicity.

A randomized comparative trial of carboplatin and iproplatin in advanced squamous carcinoma of the uterine cervix: a Gynecologic Oncology Group study.

A total of 394 patients with advanced, measurable squamous carcinoma of the uterine cervix and no prior chemotherapy were randomized to therapy with either carboplatin or iproplatin. There were 23 patients ineligible for the study and 10 patients who were not evaluable; the remaining 361 patients were evaluable for response and adverse effects. Randomization was well balanced for age, performance status, and prior therapy. Both platinum analogs were given every 28 days with starting doses of 400 mg/m2 for carboplatin (340 mg/m2 if the patient underwent prior radiation) and 270 mg/m2 for iproplatin (230 mg/m2 if the patient underwent prior radiation). These doses are equivalent to cisplatin doses of 75 to 100 mg/m2. Hematologic toxicity was dose-limiting, among which thrombocytopenia was slightly more common than leukopenia. Gastrointestinal toxicity was also prominent with both agents; however, iproplatin was significantly more toxic than carboplatin (P less than .001). Renal, otic, and peripheral nervous system toxicities were absent or infrequent with both analogs. No electrolyte abnormalities were observed. The percentage of planned dosages that were actually administered was 100% of carboplatin doses and 85% of iproplatin doses (P less than .0001). The reduction in iproplatin dose was apparently due to gastrointestinal toxicity. Response rates were similar for both agents (15% for carboplatin, 11% for iproplatin) and appear to be inferior to those noted with the parent compound, cisplatin.

Spontaneous release of interleukin-6 by primary cultures of lymphoid and tumor cell populations purified from human ovarian carcinoma.

Interleukin-6 (IL-6) is a cytokine that has been implicated as a growth factor in human ovarian carcinoma, yet the in vivo source of IL-6 in patients remains undefined. We measured IL-6 by ELISA in cell-free ascites (CFA) of 19 patients with ovarian carcinoma. IL-6 was detectable in all samples (mean level 3.3 ng/ml). To identify the cellular source of IL-6, we measured this cytokine by ELISA in 24-48 h supernatants of cultured lymphocyte-, macrophage-, and tumor cell-enriched populations purified from three solid ovarian carcinomas by centrifugal elutriation. All cell populations spontaneously released IL-6; however, tumor cells and tumor-associated macrophage released levels of IL-6 that greatly exceeded those released by tumor-associated lymphocytes. Kinetic studies revealed that IL-6 was detectable at 6 h and that levels increased in all cultures examined over a 48 h time course. These data suggest that both tumor and infiltrating host cells may be the source of the high levels of IL-6 found in carcinomatous ascites. Furthermore, although all three cell types examined may contribute to IL-6 production in patients with ovarian carcinoma, tumor cells are perhaps the most clinically significant source.

Management of uncorrected exstrophy of the bladder in women.

A 28-year-old Hispanic woman presented with uncorrected exstrophy of the bladder and accompanying defects of the external genitalia. These defects were corrected in a single operation. The objectives of the operation and the rationale for choosing the specific methods used are discussed in detail.

Skinning vulvectomy for the treatment of multifocal vulvar intraepithelial neoplasia.

Of 108 women treated for vulvar intraepithelial neoplasia between 1977 and 1984 at the Irvine Medical Center, University of California, and the Memorial Medical Center of Long Beach, Women's Hospital, 48 with multifocal and/or widespread lesions underwent skinning vulvectomy and split thickness skin graft reconstruction. Six women in the skinning vulvectomy sample had early stromal invasion in the vulvectomy specimen. Recurrences at intervals of four to 87 months occurred in 13 patients undergoing this procedure. The risk of recurrence did not appear to be related to the status of the surgical margins because seven of 22 patients with involved margins experienced recurrence compared with six of 26 with uninvolved margins.

Primary invasive carcinoma of the vagina.

A retrospective review was conducted of 53 women with invasive carcinoma of the vagina and without documented exposure to diethylstilbestrol who were seen at the University of California Irvine Medical Center, Long Beach Memorial Medical Center, and Saddleback Memorial Medical Center from 1976-1988. Forty-seven (89%) had squamous cell carcinoma and six (11%) adenocarcinoma. Thirty-seven (70%) were treated with whole-pelvis irradiation and brachytherapy, nine with surgery alone, and the other seven with a combination of treatments. The crude and corrected 2-year survival rates for the entire group were 47 and 69%, respectively. Those with previous pelvic surgery were more likely to develop serious treatment-related complications. There was a statistically significant correlation between previous hysterectomy and the diagnosis of primary invasive carcinoma of the vagina after the onset of symptoms. Women diagnosed during routine examination, before symptom onset, tended to have a survival advantage. All women, including those who have had hysterectomy, should be counseled to continue gynecologic cancer surveillance regardless of age.

Mixed mesodermal sarcoma of the ovary.

Three cases of mixed mesodermal sarcoma (MMS) are reported and a review of 90 cases from the English literature is presented. All cases were analyzed with regard to clinical features, prognosis, and therapeutic efficacy. The histogenesis of these rare tumors is discussed and a new classification of ovarian sarcomas is proposed. MMS usually afflicts the postmenopausal women and occurs more often in the nulliparous female. The disease is usually advanced (Stage III) when diagnosed and thus provides a difficult challenge to any postoperative therapy.

Chemotherapeutic retroconversion of immature teratoma of the ovary.

There has been a growing interest in treating malignant germ cell tumors of the ovary with adjuvant chemotherapy following appropriate surgery. This is a report of 3 patients treated in this manner. Of interest is the finding in all 3 patients of residual mature metastatic teratomatous tissue representing many tissue types. The concept of possible chemotherapeutic "retroconversion" or "in situ destruction" of immature tissue may be the mechanism for this result. All patients are alive and presumably well at the time of this report.

Ifosfamide treatment of recurrent or metastatic endometrial stromal sarcomas previously unexposed to chemotherapy: a study of the Gynecologic Oncology Group.

OBJECTIVE: To determine the effectiveness and toxicity of ifosfamide chemotherapy in women with metastatic or recurrent endometrial stromal sarcomas unexposed to other chemotherapy. METHODS: In a prospective, multi-institutional phase II study conducted by the Gynecology Oncology Group, the starting dose of ifosfamide was 1.5 g/m2 given daily intravenously (i.v.) for 5 days (reduced to 1.2 g/m2 daily in patients who had previously received radiotherapy). Mesna (2 mercaptoethane sodium sulfonate) was given i.v. immediately and at 4 and 8 hours after the administration of ifosfamide. Each dose of mesna was 20% of the total daily dose of ifosfamide. Patients were treated every 3 weeks if blood counts permitted. Therapy was discontinued if there was progression of the cancer or unacceptable toxicity. RESULTS: Twenty-two patients were entered into this study. One was excluded from analysis because of the wrong histologic type, leaving 21 evaluable for response and toxicity. Gynecologic Oncology Group grade 3 or 4 granulocytopenia occurred in four patients (19%), and one patient each experienced Gynecologic Oncology Group grade 4 anemia and genitourinary toxicity. Three patients experienced complete tumor responses and four had partial responses, for an overall response rate of 33.3%. CONCLUSION: Ifosfamide is active in the therapy of women with chemotherapy-naive metastatic or recurrent endometrial stromal sarcomas.

Early evaluation of the urinary tract following radical hysterectomy: structure and function relationships.

One hundred ten consecutive patients with invasive gynecologic cancers, treated by radical hysterectomy at The University of California, Irvine Medical Center, underwent early postoperative intravenous pyelogram (IVP). An abnormal early postoperative IVP did not predict subsequent urinary tract dysfunction (anatomical defect or disrupted voiding pattern) at 3 months, which occurred in 29% of the patients, nor did it detect any unsuspected fistulas or ureteral obstruction that persisted beyond the 3-month follow-up. Urinary tract dysfunction was not significantly associated with tumor volume, operative blood loss, or the type of radical hysterectomy performed. However, the inability to remove a suprapubic catheter before the 21st postoperative day was associated with a significant increase in urinary tract dysfunction at 3 months (P less than .03). We conclude that, in the absence of intraoperative urinary tract injury or clinical symptoms suggesting fistula or ureteral obstruction, the routine use of postoperative IVP should be abandoned.

Surgical treatment of unexpected invasive cervical cancer found at total hysterectomy.

OBJECTIVE: To determine the proper management of patients found to have invasive cancer of the cervix on pathologic examination of a uterus removed for benign indications. METHODS: We report 18 patients undergoing hysterectomy who were found to have cervical cancer with invasion deeper than 3 mm and/or lymph-vascular space involvement. None had gross residual tumor following simple hysterectomy. All patients underwent a second operation. Seventeen women underwent a radical parametrectomy, upper vaginectomy, and pelvic lymphadenectomy; one had pelvic and periaortic lymphadenectomy alone because of bilateral grossly positive obturator nodes. RESULTS: Median follow-up was 72 months. One of the 15 women without residual disease or nodal involvement at second operation had pelvic recurrence 66 months after therapy. Three patients with disease identified at radical surgery underwent tailored postoperative pelvic radiation, and two of these had pelvic recurrence. The overall actuarial 5-year survival for the 18 patients was 89%. Operative morbidity was comparable to that of patients undergoing primary radical hysterectomy. CONCLUSION: This study confirms that patients with unexpected invasive cervical cancer found at total hysterectomy can undergo radical re-operation with low morbidity and excellent cure rates.

Effects of early postoperative chemotherapy on wound healing.

Wound complications were investigated in 100 patients undergoing chemotherapy for epithelial ovarian cancer and compared with wound complications in patients with other gynecologic malignancy who did not receive chemotherapy but were operated on by the same gynecologic oncologists. The incidence of wound complications in the chemotherapy-treated population was 11%. Complications developed with equal frequency regardless of when postoperative chemotherapy was initiated. Thus, chemotherapy did not increase the risk of wound complications despite efforts to begin chemotherapy as soon as possible after cytoreductive surgery. Low postoperative albumin levels (P less than .01), postoperative hemoglobin of 10 g/dL or less (P less than .02), advanced stage of disease (P less than .004), and electrocautery use (P less than .05) were all risk factors for development of wound complications, whereas the frequency of bowel resection and type of fascial or skin closure did not adversely influence the risk. Patients who received chemotherapy and developed wound breakdown actually healed faster than our control population. They healed at the same rate as did obstetric and gynecologic patients from the literature. Because delays in administering chemotherapy postoperatively have been associated with decreased survival, we recommend that chemotherapy for advanced-stage epithelial cancer not be delayed solely because of concern for wound healing.

Conservative surgical management of dysgerminoma concomitant with pregnancy.

Three cases of pure dysgerminoma concomitant with pregnancy were managed by conservative surgery and term delivery. One woman with advanced disease received chemotherapy for the last trimester. Tumor response, measured by normalization of the serum tumor markers CA 125 and lactic dehydrogenase, was confirmed by magnetic resonance imaging.

A prospective randomized comparison of methotrexate, dactinomycin, and chlorambucil versus methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine in "poor prognosis" metastatic gestational trophoblastic disease: a Gynecologic Oncology Group study.

In 1981, the Gynecologic Oncology Group initiated a prospective randomized study in which patients with poor-prognosis gestational trophoblastic disease received either standard MAC chemotherapy (methotrexate, dactinomycin, and chlorambucil) or the modified CHAMOMA regimen (methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine). The protocol was closed in May 1986 because the modified CHAMOMA regimen was significantly more toxic and possibly less effective. There were 42 patients entered, with 22 receiving MAC and 20 receiving modified CHAMOMA. There have been six deaths due to disease in the modified CHAMOMA group and none in the MAC group. Five MAC failures and one modified CHAMOMA failure have been rescued by surgery and/or chemotherapy. All six of the patients who died on the modified CHAMOMA regimen had developed disease following a previous term pregnancy, but none had prior chemotherapy. All seven patients who were treated for gestational trophoblastic disease after term pregnancy in the MAC group were cured of disease. With the modified CHAMOMA regimen, 44% of patients had life-threatening hematologic toxicity, as compared with only 9% of the MAC patients. Thus, the standard MAC regimen appears to be at least equally effective and much less toxic than the modified CHAMOMA regimen, indicating a more favorable therapeutic index.

Surgically treated, early-stage neuroendocrine small-cell cervical carcinoma.

Fourteen patients with stage IB or IIA neuroendocrine small-cell cervical cancer were treated either by operation alone or operation in combination with postoperative radiotherapy at the University of California, Irvine Medical Center, and Memorial Medical Center of Long Beach, between January 1979 and February 1986. Patients were included in the study only if they met characteristic light and electron microscopic criteria for neuroendocrine small-cell cancer. Thirteen patients underwent radical hysterectomy and one a simple hysterectomy. All patients underwent pelvic lymphadenectomy, with 57% found to have nodal metastases. Twelve of 14 patients are dead of disease eight to 31 months after treatment, and the two living patients had recurrence at 38 and 44 months. One is without evidence of disease 18 months after radiation for a pelvic recurrence, and the other has survived five months after recurrence without treatment. The interval from treatment to recurrence was substantially longer in patients with tumors up to 2 cm in diameter as compared with those greater than 2 cm. Despite the early stage of cancer in these patients, the dismal outcome indicates that traditional modes of therapy for cervical cancer are not effective in cases of neuroendocrine small-cell carcinoma.

Relationship of serum CA125 and lipid-associated sialic acid tumor-associated antigen levels to the disease status of patients with gynecologic malignancies.

Serum samples obtained from 133 patients with gynecologic malignancies were assayed for two tumor-associated antigen markers: CA125, an ovarian marker, and lipid-associated sialic acid, a nonspecific marker. In the patient population, there were 77 papillary serous and 19 unspecified ovarian adenocarcinomas, and 24 miscellaneous ovarian carcinomas. Thirteen patients had nonovarian malignancies. Sixty-nine percent (74 of 108) of the patients with known disease had abnormal CA125 levels, whereas only 32% (20 of 63) had abnormal lipid-associated sialic acid levels. Changes in CA125 serum levels reflected the disease status of the patients for whom there were serial serum samples. Normal levels of CA125 corresponded to no evidence of disease in 100% (six of six) surgically evaluated patients and 75% (30 of 40) of clinically evaluated patients. Changes in CA125 levels from normal to abnormal corresponded to disease progression in 80% (12 of 15) of the patients. Decreases in CA125 levels from abnormal to normal corresponded to complete clinical response in 55% (11 of 20), and partial clinical response in 45% (nine of 20). No such correlations were available for lipid-associated sialic acid antigen levels. For tumors that express CA125 antigen, serum levels appear to be a good marker for the extent of malignant gynecologic disease. Levels of CA125 that rose from normal to abnormal were usually associated with recurrent disease.

Integrated external and interstitial radiation therapy for primary carcinoma of the vagina.

Twenty-seven patients with the diagnosis of primary carcinoma of the vagina were treated by definitive radiotherapy. Twenty-three patients received a combination of external and interstitial iridium-192 implant irradiation and four patients received only interstitial irradiation. Twenty-one patients had squamous cell carcinoma and six had adenocarcinoma. All patients were staged according to the FIGO classification. More than 70% of patients had relatively advanced local disease and conventional intracavitary irradiation was unsuitable. Local tumor control was observed in 85% (23 of 27 patients), and 56% of the patients remain alive and free of disease for a median follow-up period of 50 months to a maximum follow-up period of 84 months. Fifteen percent of the patients suffered from treatment-related complications.

Malignant germ cell tumors of the ovary.

OBJECTIVE: To evaluate the efficacy of adjuvant therapy for ovarian germ cell tumors. METHODS: We reviewed records of women who had malignant germ cell tumors of the ovary from 1977-1997. RESULTS: Seventy-two women had surgical resections of malignant ovarian germ cell tumors and most received adjuvant therapy. Fifty-six women (78%) presented with stage I disease, and 16 (22%) had more advanced disease. Tumor subtypes included dysgerminoma (n = 20), yolk sac tumor (n = 8), immature teratoma (n = 29) and mixed germ cell tumor (n = 15). Surgical management of the 56 with stage I disease consisted of total abdominal hysterectomy, bilateral salpingo-oophorectomy, and extensive surgical staging in ten women, whereas a conservative surgical approach, consisting of unilateral adnexectomy with or without comprehensive surgical staging, was adopted in later years (n = 46). Fifty-six women were treated with postoperative chemotherapy, predominantly platinum-based regimens. The 5-year actuarial survival rate was 93%. None of the 36 women who presented after 1984 have died of disease. CONCLUSION: These data confirmed that platinum-based adjuvant treatments allow most women with ovarian germ cell malignancies to have conservative surgery without compromising survival.

Laparoscopy in the evaluation of gynecologic cancer.

Laparoscopy was used to evaluate 60 patients with a variety of known or suspected gynecologic neoplasms. Diagnostic laparoscopy was performed on 18 patients to confirm benign or malignant pelvic masses or to confirm peritoneal carcinomatosis. Ten of these 18 patients (56%) were found to have unresectable carcinomatosis or benign disease which did not require further surgery. Staging laparoscopy was performed on 13 patients of which 3 had clinically unsuspected intraperitoneal spread of their disease. Surveillance laparoscopy was performed on 29 patients to determine the remission, regression, or progression of their disease following treatment; 8 (27%) had progressive or unresectable persistent disease. Despite the fact that the study comprised a high-risk group of previously operated on or irradiated patients, there was only one major complication. There was, however, a 10% incidence of laparoscopic failure from inadequate visualization. Twenty-one of the study patients (35%) were spared a laparotomy by the use of laparoscopy. The findings of this investigation help to identify those gynecologic oncology patients who should benefit most from the use of laparoscopy as an adjunct to the diagnosis, staging, or surveillance of intraabdominal malignant tumors.