Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities.

PURPOSE: Diethyldithiocarbamate (DDTC) blocks cisplatin-induced toxicities in animal models without inhibiting antitumor effects. DDTC chemoprotection was tested in a randomized, multicenter, double-blind comparison versus placebo (PB) in patients with lung or ovarian cancer. Primary end points were nephrotoxicity, ototoxicity, neuropathy, and completion of therapy. PATIENTS AND METHODS: Between April 1990 and February 1992, 221 patients were registered with small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), or ovarian cancer. Cisplatin (100 mg/m2) and cyclophosphamide (in ovarian cancer) or etoposide (in lung cancer) were administered with either DDTC (1.6 g/m2 over 4 hours) or PB intravenously, every 4 weeks for a planned six cycles. RESULTS: At an interim safety analysis, data were available for 195 patients from the combined lung and ovarian cancer populations (PB, 99 patients; DDTC, 96 patients). Withdrawal for chemotherapy-induced toxicities occurred in 9% of PB-treated patients and 23% of DDTC-treated patients (P = .008). The mean cisplatin delivered dose-intensity (DDI) was 23 mg/m2/wk on both arms. However, the mean cisplatin cumulative dose delivered (CDD) was 379 mg/m2 on the PB arm, compared with 247 mg/m2 on the DDTC arm (P = .0001). At the time of interim analysis, 28% of PB-treated patients had completed all six cycles of therapy, compared with only 6% of DDTC-treated patients (P < .001). Although, clinical hearing loss, neuropathy, emesis, and myelosuppression were equivalent in the two treatment arms, DDTC-treated patients had more nephrotoxicity as determined by changes in serum creatinine concentration. Toxicities related to DDTC infusion included transient hypertension, flushing, and hyperglycemia. DDTC did not compromise response rates in either tumor type. CONCLUSION: This study did not demonstrate a significant chemoprotective effect against cisplatin-induced toxicities with the DDTC dose schedule tested. Patients who received DDTC received lower cumulative doses of cisplatin, but were more likely to be withdrawn from treatment early due to chemotherapy-related toxicities.

Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer.

PURPOSE: To compare cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide as primary chemotherapy for stage III (suboptimal) and stage IV ovarian cancer. PATIENTS AND METHODS: Three hundred forty-two patients were randomly assigned to treatment with six courses of intravenous (i.v.) cisplatin 100 mg/m2 plus i.v. cyclophosphamide 600 mg/m2, or i.v. carboplatin 300 mg/m2 plus i.v. cyclophosphamide 600 mg/m2. RESULTS: The estimated median survivals were 17.4 and 20.0 months for the cisplatin and carboplatin study arms, respectively. The null hypothesis of a 30% survival superiority with the cisplatin arm was rejected at the P = .02 level. Clinical response rates were 52% for the cisplatin arm and 61% for the carboplatin arm. Pathologic complete response rates were similar for both study arms. There was less thrombocytopenia on the cisplatin arm (P less than .001); however, there was less nausea and emesis (P less than or equal to .001 for courses 1 to 5), renal toxicity (P less than .001), anemia (P = .01), hearing loss (P less than .001), tinnitus (P = .01), neuromuscular toxicities (P = .001), and alopecia (P less than .001) on the carboplatin arm. CONCLUSION: Carboplatin-cyclophosphamide proved to have a significantly better therapeutic index than cisplatin-cyclophosphamide in patients with stage III (suboptimal) and stage IV ovarian cancer.

Analysis of residual disease following preoperative radiotherapy versus initial surgery in endometrial carcinoma.

A clinicopathologic study of residual disease following pre-operative radiotherapy (RT) in 67 patients and initial surgery in 40 patients with early invasive endometrial carcinoma is presented. In 10%, extrauterine spread was found at operation. In 10% of patients, the histologic type, and in 19% the grade of tumor, differed between the curettage and hysterectomy specimens. Pre-op RT altered the depth of myometrial invasion and frequency of vascular invasion, but there was no evidence that irradiation itself affected the histologic type or grade of tumor. The patients with residual tumor after pre-op RT had significantly more cancer-related deaths than those without residual disease. The high risk factors were deep myometrial invasion and residual disease outside the uterus. Vascular invasion did not affect the prognosis in this series. The importance of surgical-pathologic staging by initial surgery is discussed.

Spontaneous occurrence of synergistic bacterial gangrene following external pelvic irradiation.

A case of spontaneous synergistic bacterial gangrene occurring after external pelvic irradiation is presented in a 25-year-old woman with invasive cervical cancer. Treatment consisted of aggressive antibiotic therapy and extensive excision and debridement followed by split-thickness skin grafting. Both recovery and cosmetic results were satisfactory. The pathophysiology, predisposing factors, and treatment modalities are presented.

Histologic grade and prognosis of carcinoma of the cervix.

A histologic grading system based on tumor differentiation was applied in a study of 122 patients with stage IB and IIA squamous cell carcinoma of the uterine cervix. In general, the more dedifferentiated the primary tumor, the more bulky the primary lesion and the higher the incidence of pelvic node metastasis. Following treatment, patients with undifferentiated tumors had a higher incidence of tumor recurrence a lower 2-year survival rate than those with well or moderately differentiated lesions. These findings suggest that histologic grading is an important adjunct to the clinical evaluation of cervical cancer.

'Abnormal' Papanicolaou smears and colposcopy in pregnancy: ante- and post-partum findings.

Abnormal Papanicolaou smears and colposcopic findings suggesting human Papilloma virus (HPV) infection and cervical intraepithelial neoplasia (CIN) may occur during pregnancy. Condylomata acuminata often grow rapidly during pregnancy and may regress spontaneously following delivery. However, the post-partum outcome of the untreated ante-partum abnormal cytologic smear and colposcopy has not been defined clearly. Seventy-three pregnant patients were examined by colposcopy because of genital warts and/or abnormal Papanicolaou smears. Cytologic, colposcopic and histologic re-evaluation was conducted after delivery. Only one of the patients had a normal ante-partum colposcopic examination. This number increased to 15 after delivery. Forty-one patients had normal post-partum cytologic smears, but only 13 had normal histology. Abnormal post-partum cytology was highly predictive of abnormal colposcopy and histology. In contrast, normal post-partum cytology was not very accurate in predicting normal colposcopy and histology. It is concluded that a few pregnant patients may have partial regression of clinical HPV infection and abnormal cytology and colposcopy after delivery. However, the majority will continue to have abnormal findings 4 months following delivery in spite of normal post-partum cytology and even colposcopy.

The prognostic significance of vascular channel involvement and deep stromal penetration in early cervical carcinoma.

Eighty-eight patients with FIGO Stage Ib and IIa squamous cell carcinoma of the cervix underwent radical hysterectomy with pelvic and paraaortic lymphadenectomy. The records and histopathologic material were reviewed to determine the prognostic significance of vascular channel involvement and deep stromal penetration by tumor. Seventy-four patients (84%) were alive and free of disease for more than 2 years and 14 (16%) developed recurrent carcinoma within that time. A positive correlation was found between depth of stromal penetration by tumor and the degree of vascular channel involvement (p less than 0.05). Vascular involvement in itself did not significantly affect nodal status, survival or the rate of recurrence. Depth of penetration was associated with a higher incidence of positive nodes (p less than 0.05). There was a trend towards a lower survival rate and a higher recurrence rate in patients with deep stromal penetration as compared to those with superficial tumors. Microscopic nodal disease increased the rate of recurrence and had an adverse effect on survival. The combination of deep tumor penetration and positive nodes in the same patient was associated with the highest recurrence rate and the lowest survival (p less than 0.05). Nodal status was a more significant prognostic indicator than depth of tumor penetration because patients with deeply penetrating tumors and positive nodes had more than twice the recurrence rate than did patients with deep tumors and negative nodes. Postoperative radiation therapy was beneficial to patients whose tumors demonstrated deep stromal penetration and microscopic metastases to pelvic lymph nodes.

Randomized comparison of cisplatin plus epirubicin or doxorubicin for advanced epithelial ovarian carcinoma. A multicenter trial.

Stage III and IV epithelial ovarian cancer patients were prospectively randomized to receive eight courses of 60 mg/m2 of cisplatin plus either 75 mg/m2 of epirubicin (62 patients) or 60 mg/m2 of doxorubicin (54 patients). Clinical response rates for cisplatin/epirubicin of 42% [15% complete response (CR) and 27% partial response (PR)] and for cisplatin/doxorubicin of 55% (24% CR and 31% PR) were not statistically different (p = 0.14). The negative second look rate was 35% (10/29) for cisplatin/doxorubicin and 17% (5/30) for cisplatin/epirubicin (p = 0.12). The progression-free interval for cisplatin/epirubicin (13 months) was not statistically different (p = 0.09) from that for cisplatin/doxorubicin (19 months). The median survivals for cisplatin/epirubicin (756 days) and cisplatin/doxorubicin (739 days) were similar (p = 0.70). Cardiotoxicity was greater for the cisplatin/doxorubicin group (p = 0.0003). With similar survival and less cardiotoxicity, the cisplatin/epirubicin regimen had the more favorable therapeutic index.

Glassy cell carcinoma of the uterine cervix. An ultrastructural study and review.

Glassy cell carcinoma is an unusual neoplasm of the uterine cervix that accounts for 1% to 2% of all cervical malignant neoplasms. Although it seems to have a distinct histologic appearance, it has generally not been recognized, as indicated by the extremely small number of cases reported in the literature. Previous studies have indicated an aggressive behavior, a poor response to irradiation and surgery, and a tendency to widespread metastases. It occurs in a younger age group (mean age, 41 years) than other cervical neoplasms and often has been associated with pregnancy. The histogenesis is not known, but electron microscopic examination of one case we studied, and review of one previously described case, demonstrate that it is an adenosquamous carcinoma. The need to define this neoplasm better will be satisfied only by additional, thorough histologic and clinical studies.

Gynecologic surgery in the aged.

Aged women, those over 75 years, experience a high incidence of nearly all gynecologic neoplasms as well as associated chronic medical illnesses. In this study, 773 women underwent major surgery, while 711 underwent minor procedures. Fifty-two patients (3.5%) were 75 years of age or older. Forty-three of the 52 (83%) had a total of 119 associated medical complications. Eighty-nine surgical procedures were performed. A total of 17 postoperative complications occurred in 15 patients. Thirty-eight patients (73%) had no postoperative complications. One patient died because of infarction of the bowel diagnosed within 30 days of her primary surgical procedure. The aged patients in this study did well postoperatively with routine preoperative medical evaluation and postoperative care. Same-day admission and surgery did not increase morbidity. Aged patients can safely undergo major pelvic and abdominal surgery at a community medical center if one manages their associated medical conditions in a routine manner similar to that utilized in younger patients with similar problems. The associated medical complications and not age per se should be the deciding factor.

Endosalpingiosis as a source of psammoma bodies in a Papanicolaou smear. A case report.

Psammoma bodies are concentric, laminated structures produced by cross-sectioning the tips of calcified papillary formations and are usually associated with papillary carcinoma of the thyroid gland, meningiomas and serous papillary tumors of the ovary. These structures have occasionally been seen in cytologic smears obtained from women with endometrial or ovarian carcinoma. A woman had Papanicolaou smears that continued to show psammoma bodies for over two years, eventually leading to a hysterectomy. Even though the presence of psammoma bodies on a Papanicolaou smear should always alert the physician to the possibility of ovarian carcinoma, leading to a thorough search for this malignancy, a variety of benign conditions, such as endosalpingiosis, may also be associated with this finding.

Hysteroscopy may transport malignant cells into the peritoneal cavity. Case report.

The purpose of this report is to caution against the use of hysteroscopy at the time of uterine curettage performed in women with postmenopausal bleeding suspected of having endometrial carcinoma. A 63 year old postmenopausal woman had endometrial carcinoma diagnosed by hysteroscopically guided curettage. At the time of hysterectomy three weeks later, malignant cells were found in pelvic washings. Although a causal relationship between hysteroscopy and malignant peritoneal cytology cannot be postulated, we believe that hysterescopy should be used with caution in the work up of postmenopausal bleeding.

Endometrial adenocarcinoma: therapeutic impact of preoperative histopathologic examination of endometrial tissue.

Adenocarcinoma of the endometrium is diagnosed by the histologic evaluation of endometrial tissue. In stage I disease, five-year survival depends upon a number of prognostic factors. Histologic grade and type of carcinoma are most important. The need for pelvic and para-aortic lymphadenectomy is often based on the preoperative histologic grade and type of tumor. The purpose of this study was: 1) to compare preoperative histology of endometrial carcinoma to that found at hysterectomy, 2) to determine if preoperative histology can accurately predict depth of myometrial invasion or extra-uterine spread, 3) to determine whether para-aortic lymphadenectomy could be deleted based only on the preoperative finding of well differentiated carcinoma. In 19 (28%) of the 68 patients studied, the histologic grade or pattern at hysterectomy was different from that found preoperatively. In seven (13%) of the 52 "good prognosis" patients with grades 1 and 2 preoperative histology, hysterectomy revealed a more serious histologic type. Three of the seven (43%) had extrauterine spread. In the 16 "poor prognosis" patients with preoperative grade 3 or papillary serous/clear cell carcinoma, 14 (88%) had a similar histologic pattern at hysterectomy. Three of these patients had metastatic disease. Depth of myometrial invasion could not be predicted by preoperative histology even though the data suggested that extrauterine spread could. Clinical stage I endometrial carcinoma, grade 1 or 2, should not be treated without para-aortic nodal sampling based only on a supposedly favorable preoperative histologic pattern. Confirmed para-aortic nodal disease will alter the fields of post-operative radiation therapy should that become necessary. In these patients, however, pelvic lymphadenectomy is not justified.2 +

Stage IB carcinoma of the cervix: are all staging tests and procedures necessary?

The prognostic value and cost effectiveness of generally recommended ancillary tests and staging procedures in 115 patients with clinical Stage IB carcinoma of the cervix were retrospectively reviewed. All 112 intravenous pyelograms, 108 barium enemas, 102 cystoscopies and 98 sigmoidoscopies were normal. No malignant cells were found in pelvic washings. Of 111 patients who had paraaortic lymph node biopsies, only one had a positive node. This node was grossly enlarged and clinically suspicious. Paraaortic lymph node status was not influenced by tumor grade, prior conization, lymphovascular space involvement, depth of stromal invasion, positive pelvic lymph nodes or number of paraaortic nodes biopsied. The tests evaluated in this study are unnecessary and should no longer be performed in patients with clinical Stage IB carcinoma of the cervix. In addition, paraaortic lymph node biopsies in the absence of clinically suspicious nodes are not warranted. Eliminating these tests and procedures would result in substantial savings in health care cost.

Ovarian cancer. Current outlook on this deadly disease.

The lifetime risk of ovarian cancer in the US population is about 1.4%. The risk is increased in women who have a strong family history of the disease. Unfortunately, no accurate screening tests are available. Transvaginal sonography and CA-125 determinations can be valuable in selected patients. Attempts at prevention with oral contraceptive use and indicated or prophylactic oophorectomy should be seriously considered. Conservative treatment is appropriate in selected patients with early-stage ovarian cancer. However, because the majority of patients present with advanced disease, maximum cytoreductive surgery followed by chemotherapy is usually required. Such an approach results in a high incidence of initial clinical remission and can prolong survival to 2 or 3 years. Eventually, however, relapse and death often occur in spite of additional therapy. Another operation may be needed for secondary cytoreduction or palliation. Bowel obstruction, recurrent ascites, and pleural effusion are often terminal events.