Richard E. Buller

Tumor perfusion studies using fast magnetic resonance imaging technique in advanced cervical cancer: A new noninvasive predictive assay

PURPOSE This study investigated sequential changes in tumor blood supply using magnetic resonance (MR) perfusion imaging and assessed their significance in the prediction of outcome of patients with advanced cervical cancer. The purpose of this project was to devise a simple, noninvasive method to predict early signs of treatment failure in advanced cervical cancer treated with conventional radiation therapy. METHODS AND MATERIALS Sixty-eight MR perfusion studies were performed prospectively in 17 patients with squamous carcinomas (14) and adenocarcinomas (3) of the cervix, Stages bulky IB (1), IIB (5), IIIA (1), IIIB (8), and IVA (1), and recurrent (1). Four sequential studies were obtained in each patient: immediately before radiation therapy (pretherapy), after a dose of 20-22 Gy/ approximately 2 weeks (early therapy), after a dose of 40-45 Gy/ approximately 4-5 weeks (midtherapy), and 4-6 weeks after completion of therapy (follow-up). Perfusion imaging of the tumor was obtained at 3-s intervals in the sagittal plane. A bolus of 0.1 mmol/kg of MR contrast material (gadoteridol) was injected intravenously 30 s after beginning image acquisition at a rate of 9 ml/s using a power injector. Time/signal-intensity curves to reflect the onset, slope, and relative signal intensity (rSI) of contrast enhancement in the tumor region were generated. Median follow-up was 8 months (range 3-18 months). RESULTS Tumors with a higher tissue perfusion (rSI > or = 2.8) in the pretherapy and early therapy (20-22 Gy) studies had a lower incidence of local recurrence than those with a rSI of < 2.8, but this was not statistically significant (13% vs. 67%; p = 0.05). An increase in tumor perfusion early during therapy (20-22 Gy), particularly to an rSI of > or = 2.8, was the strongest predictor of local recurrence (0% vs. 78%; p = 0.002). However, pelvic examination during early therapy (20-22 Gy) commonly showed no appreciable tumor regression. The slope of the time/signal-intensity curve obtained before and during radiation therapy also correlated with local recurrence. Follow-up perfusion studies did not provide information to predict recurrence. CONCLUSION These preliminary results suggest that two simple MR perfusion studies before and early in therapy can offer important information on treatment outcome within the first 2 weeks of radiation therapy before response is evident by clinical examination. High tumor perfusion before therapy and increasing or persistent high perfusion early during the course of therapy appear to be favorable signs. High perfusion suggests a high blood and oxygen supply to the tumor. The increase in tumor perfusion seen in some patients early during radiation therapy suggests improved oxygenation of previously hypoxic cells following early cell kill. Radiation therapy is more effective in eradicating these tumors, resulting in improved local control. Our technique may be helpful in identifying early-while more aggressive therapy can still be implemented-those patients who respond poorly to conventional radiation therapy.

A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer

Purpose: To determine the safety, gene transfer, host immune response, and pharmacokinetics of a replication-deficient adenovirus encoding human, recombinant, wild-type p53 (SCH 58500) delivered into the peritoneal cavity (i.p.) alone and sequentially in combination with platinum-based chemotherapy, of patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer containing aberrant or mutant p53. Methods: SCH 58500 was administered i.p. to three groups of patients with heavily pretreated recurrent disease. Group 1 (n=17) received a single dose of SCH 58500 escalated from 7.5×1010 to 7.5×1012 particles. Group 2 (n=9) received two or three doses of SCH 58500 given alone for one cycle, and then with chemotherapy for two cycles. The SCH 58500 dose was further escalated to 2.5×1013 particles/dose in group 2. A third group (n=15) received a 5-day regimen of SCH 58500 given at 7.5×1013 particles/dose per day i.p. alone for cycle 1 and then with intravenous carboplatin/paclitaxel chemotherapy for cycles 2 and 3. Results: No dose-limiting toxicity resulted from the delivery of 236/287 (82.2%) planned doses of SCH 58500. Fever, hypotension abdominal complaints, nausea, and vomiting were the most common adverse events. Vector-specific transgene expression in tumor was documented by RT-PCR in cells from both ascitic fluid and tissue biopsies. Despite marked increases in serum adenoviral antibody titers, transgene expression was measurable in 17 of 20 samples obtained after two or three cycles of SCH 58500. Vector was detectable in peritoneal fluid by 24 hours and persisted for as long as 7 days whereas none was detected in urine or stool. There was poor correlation between CT scans and CA125 responses. CA125 responses, defined as a greater than 50% decrement in serum CA125 from baseline, were documented in 8 of 16 women who completed three cycles of the multidose regimen. Conclusion: CT scans are not a valid measure of response to i.p. SCH 58500 due to extensive adenoviral-induced inflammatory changes. Intraperitoneal SCH 58500 is safe, well tolerated, and combined with platinum-based chemotherapy can be associated with a significant reduction of serum CA125 in heavily pretreated patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer.

Vascular endothelial growth factor and social support in patients with ovarian carcinoma

The modulation of immunologic activities relevant to cancer by behavioral factors, such as stress, depression, and social support, is well documented. However, associations of behavioral factors with cytokines involved in tumor angiogenesis have not been studied. Vascular endothelial growth factor (VEGF) is a key cytokine that is capable of stimulating tumor angiogenesis, and it has been associated with poorer survival in patients with ovarian carcinoma. VEGF is modulated by a variety of behaviorally sensitive factors, including sympathetic activation. This study examined relationships of social support and depressive symptoms with VEGF levels in preoperative patients with ovarian carcinoma.

Computed tomography in endometrial carcinoma

Objective To determine the value of computed tomography (CT) scans for preoperatively detecting extrauterine-nodal disease and postoperative recurrent disease in patients with endometrial cancer. Methods We reviewed records of 702 women with primary endometrial carcinoma that was diagnosed between 1979 and 1993. Preoperative CT findings were compared with pathologic findings to assess nodal disease. The yield of postoperative CT was reviewed in clinically suspicious and routine settings. Results Among 492 women eligible for analysis, 178 (36%) had a total 326 CT scans. Among 56 women who had preoperative CT scans and lymph node samplings, positive and negative predictive values for nodal involvement were 50% and 94%, respectively, and sensitivity and specificity were 57% and 92%, respectively. Preoperative CT findings altered treatment plans in only six patients (8%). Forty-five asymptomatic women had 73 routine CT scans, and recurrence was diagnosed by CT in only two (4.4%). Thirty-seven women had CT scans for suspicion of recurrence, which was confirmed in 17 (46%). Kaplan-Meyer analysis showed no survival advantage in women with subclinical recurrences diagnosed by CT scan. Conclusion Routine preoperative CT scanning rarely alters treatment and is a poor predictor of nodal disease. Computed tomography in the postoperative period might be helpful for detection and follow-up of recurrent disease, but there was no difference in survival when subclinical recurrence was found by CT. Thus, CT scanning of any woman with endometrial cancer should be discouraged unless it is to evaluate symptoms.

Value of preoperative CA 125 level in the management of uterine cancer and prediction of clinical outcome.

Objective To enhance cost-effective management of uterine cancer by predicting the likelihood of extrauterine disease and survival on the basis of preoperative parameters. Methods A retrospective review of preoperative CA 125 levels from 210 women with endometrial carcinoma was performed. The relationship of preoperative CA 125 levels to various preoperative and postoperative histopathologic factors was investigated. Methods Elevated CA 125 (greater than 35 U/mL) correlated (P < .05) with higher stage, higher grade, increased depth of myometrial invasion, positive cytology, pelvic or para-aortic lymph node metastases, and reduced actuarial survival (P < .001). Multivariate analysis of preoperative factors showed that an elevated CA 125 level was the most important predictor for poor survival (P < .001). Moreover, a preoperative CA 125 level greater than 65 U/mL was the most significant predictor of extrauterine disease and carried a 6.5-fold higher risk (95% confidence interval 2.5, 17.1). A logistic model to predict extrauterine disease was developed. The model has a sensitivity of 62%, specificity of 91%, positive predictive value of 69%, and negative predictive value of 88%. Conclusion A CA 125 level should be included as part of the preoperative workup for all patients with uterine cancer. Patients with a preoperative CA 125 level less than or equal to 20 U/mL should be considered as candidates for vaginal hysterectomy unless unfavorable histology or a high-grade (grade II or III) tumor is present. In our series, this approach would have eliminated 24% of the abdominal staging procedures, with a risk of less than 3% for extrauterine disease, while lowering treatment-related morbidity and cutting costs in the treatment of this common female cancer.

PREOPERATIVE CA 125 LEVELS: AN INDEPENDENT PROGNOSTIC FACTOR FOR EPITHELIAL OVARIAN CANCER

OBJECTIVE To estimate the association of preoperative CA 125 levels with outcome in primary ovarian cancer patients. METHODS One hundred forty‐two patients with epithelial ovarian cancer, who had a serum CA 125 level drawn before surgery, were retrospectively evaluated. The relationship of preoperative CA 125 levels and various preoperative and postoperative variables was evaluated. CA 125 levels were determined using a solid‐phase immunoassay. RESULTS The median CA 125 value for all patients was 582 U/mL (range 7–52,930 U/mL). Preoperative CA 125 values did not correlate with increasing age (P = .40), but were found to be significantly associated with serous histology compared with other histology (median CA 125 of 870 versus 334 U/mL, P = .02), high‐stage (III/IV) compared with low‐stage (median CA 125 of 893 versus 174 U/mL, P < .001), high tumor grade (3) compared with grade 1 or 2 (median CA 125 of 928 versus 323 U/mL, P < .001), and the presence of ascites compared with absence of ascites (median CA 125 of 893 versus 220 U/mL, P < .001). Suboptimal cytoreduction (more than 1 cm residual) was associated with significantly higher CA 125 levels (1067 U/mL) compared with individuals with optimal cytoreduction (399 U/mL, P < .001). Preoperative CA 125 values less than 500 U/mL had a positive predictive value for optimal cytoreduction of 82%, but a poor negative predictive value of 48%. After adjusting for covariates, there was a significant association between CA 125 levels and disease‐specific survival. As preoperative CA 125 levels increased, the risk of death increased except at the highest values of CA 125. CONCLUSION Preoperative CA 125 is an independent risk factor for death due to disease in ovarian cancer, but not a reliable predictor of optimal cytoreduction.

Quality of life and mood in women with gynecologic cancer: A one year prospective study

Quality of life (QOL) and mood were prospectively investigated during the first year of treatment among women with gynecologic cancers. Relationships of coping styles to QOL and mood were examined.

Primary ovarian sarcoma: Analysis of prognostic variables and the role of surgical cytoreduction

Data regarding the value of cytoreduction and cell histology in ovarian sarcomas are limited. The goal of this study was to assess the value of surgical cytoreduction, preoperative CA 125 levels, stage, histology, and platinum‐based chemotherapy in the primary treatment of ovarian sarcomas.

Obesity and prognosis in endometrial cancer.

OBJECTIVE We tested the null hypothesis that morbid obesity as measured by the Quetelet index has no influence on survival in endometrial cancer. STUDY DESIGN A retrospective study of 492 women with endometrial carcinoma was performed. Age, height, weight, Quetelet index, stage, cell type, grade, node status, peritoneal cytologic findings, and depth of myometrial invasion were analyzed for influence on survival. RESULTS Mean Quetelet index was 34 (range 16 to 89). Quetelet index was < 30 in 45% of patients, 30 to 40 in 33%, and > 40 in 22%. Five percent of those with a Quetelet index > 40 had positive nodes, but 64% of patients with a Quetelet index > 40 did not have lymph node sampling done. Lack of sampling of lymph nodes in the entire group had no adverse effect on survival. In a proportional hazards regression model for time from diagnosis to death from disease, grade, node status, myometrial invasion, and stage had highly significant effects. When Quetelet index was analyzed as a continuous variable, as Quetelet index increased, time to recurrence was significantly increased (p = 0.0136), and significance was approached for survival (p = 0.0645). Quetelet index was strongly related to grade (p = 0.013), depth of myometrial invasion (p = 0.031), negative cytologic findings (p = 0.004), and stage (p = 0.011) with obese patients having better differentiated, less invasive tumors of lower stage with negative washings. CONCLUSIONS Morbid obesity positively affects survival in endometrial carcinoma. This effect is accounted for by the association of obesity with less aggressive disease. Morbid obesity is not associated with increased death from other causes. Lack of sampling of negative lymph nodes does not adversely affect survival.

Preservation of the saphenous vein during inguinal lymphadenectomy decreases morbidity in patients with carcinoma of the vulva

Traditional inguinal lymphadenectomy includes the removal of a portion of the saphenous vein. The authors hypothesized that preserving the saphenous vein would decrease morbidity without affecting treatment outcome.