Joel I. Sorosky

Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study.

PURPOSE Vascular endothelial growth factor (VEGF) seems to be a promoter of tumor progression for epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC). We conducted a phase II trial to assess the efficacy and tolerability of single-agent bevacizumab, an anti-VEGF monoclonal antibody. PATIENTS AND METHODS Eligible patients had persistent or recurrent EOC/PPC after one to two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status of at least 2. Treatment consisted of bevacizumab 15 mg/kg intravenously every 21 days until disease progression or prohibitive toxicity. Primary end points were progression-free survival (PFS) at 6 months and clinical response. RESULTS The study consisted of 62 eligible and assessable patients, median age 57 years, 41 (66.1%) having received two prior regimens and 36 (58.1%) [CORRECTED] considered platinum resistant. Grade 3 adverse events at least possibly related to bevacizumab were hematologic (1), GI (3), hypertension (6), thromboembolism (1), allergy (2), hepatic (1), pain (3), coagulation (1), constitutional (1), and dyspnea (1). Grade 4 adverse events included pulmonary embolus (1), vomiting and constipation (1), and proteinuria (1). Thirteen patients (21.0%) experienced clinical responses (two complete, 11 partial; median response duration, 10 months), and 25 (40.3%) survived progression free for at least 6 months. Median PFS and overall survival were 4.7 and 17 months, respectively. There was no significant association of prior platinum sensitivity, age, number of prior chemotherapeutic regimens, or performance status with the hazard of progression or death. CONCLUSION Bevacizumab seems to be well tolerated and active in the second- and third-line treatment of patients with EOC/PPC and merits phase III investigation.

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.

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.

Social Support, Psychological Distress, and Natural Killer Cell Activity in Ovarian Cancer

PURPOSE Psychosocial stress has been related to impaired immunity in cancer patients. However, the extent to which these relationships exist in immune cells in the tumor microenvironment in humans has not been explored. We examined relationships among distress, social support, and natural killer (NK) cell activity in ovarian cancer patients in peripheral-blood mononuclear cells (PBMC), ascitic fluid, and tumor-infiltrating lymphocytes (TIL). PATIENTS AND METHODS Patients awaiting surgery for a pelvic mass suspected of being ovarian cancer completed psychological questionnaires and gave a presurgical sample of peripheral blood. Samples of tumor and ascites were taken during surgery, lymphocytes were then isolated, and NK cytotoxicity and percentage were determined. The final sample, which was confirmed by surgical diagnosis, included 42 patients with epithelial ovarian cancer and 23 patients with benign masses. RESULTS Peripheral NK cell activity was significantly lower among ovarian cancer patients than in patients with benign masses. Among ovarian cancer patients, NK cytotoxicity in TIL was significantly lower than in PBMC or ascitic fluid. Social support was related to higher NK cytotoxicity in PBMC and TIL, adjusting for stage. Distress was related to lower NK cytotoxicity in TIL. A multivariate model indicated independent associations of both distress and social support with NK cell activity in TIL. CONCLUSION Psychosocial factors, such as social support and distress, are associated with changes in the cellular immune response, not only in peripheral blood, but also at the tumor level. These relationships were more robust in TIL. These findings support the presence of stress influences in the tumor microenvironment.

Pixel analysis of MR perfusion imaging in predicting radiation therapy outcome in cervical cancer

The purpose of this study was to assess heterogeneity of tumor microcirculation determined by dynamic contrast‐enhanced magnetic resonance (MR) imaging and its prognostic value for tumor radiosensitivity and long‐term tumor control using pixel‐by‐pixel analysis of the dynamic contrast enhancement. Sixteen patients with advanced cervical cancer were examined with dynamic contrast‐enhanced MR imaging at the time of radiation therapy. Pixel‐by‐pixel statistical analysis of the ratio of post‐ to precontrast relative signal intensity (RSI) values in the tumor region was performed to generate pixel RSI distributions of dynamic enhancement patterns. Histogram parameters were correlated with subsequent tumor control based on long‐term cancer follow‐up (median follow‐up 4.6 years; range 3.8–5.2 years). The RSI distribution histograms showed a wide spectrum of heterogeneity in the dynamic enhancement pattern within the tumor. The quantity of low‐enhancement regions (10th percentile RSI < 2.5) significantly predicted subsequent tumor recurrence (88% vs. 0%, P = 0.0004). Discriminant analysis based on both 10th percentile RSI and pixel number (reflective of tumor size) further improved the prediction rate (100% correct prediction of subsequent tumor control vs. recurrence). These preliminary results suggest that quantification of the extent of poor vascularity regions within the tumor may be useful in predicting long‐term tumor control and treatment outcome in cervical cancer. J. Magn. Reson. Imaging 2000;12:1027–1033.

Phase II Trial of the Pegylated Liposomal Doxorubicin in Previously Treated Metastatic Endometrial Cancer: A Gynecologic Oncology Group Study

PURPOSE To determine whether pegylated liposomal doxorubicin (PLD) has antitumor activity in pretreated patients with persistent or recurrent endometrial carcinoma and to define the nature and degree of toxicity of PLD. PATIENTS AND METHODS Women with histologically documented recurrent or persistent measurable endometrial carcinoma and with failure of one prior treatment regardless of prior anthracycline therapy were enrolled. PLD was administered intravenously over a 1-hour period at a dose of 50 mg/m(2) every 4 weeks; the dosage was modified in accordance with observed toxicity. RESULTS Of 46 patients entered, 42 were assessable for response, as three were declared ineligible on central pathology review and one was not assessable for response. Forty had received prior chemotherapy, 11 hormonal therapy, and 29 radiation therapy. Doxorubicin had been given to 32 patients, carboplatin with paclitaxel to six, carboplatin to one, and fluorouracil to one. Four patients had partial responses lasting 1.1, 2.1, 3.3, and 5.4 months; the overall response rate was 9.5% (95% confidence interval, 2.7% to 22.6%). Three of these responses (in liver and in lymph node) occurred in patients who had progressed after doxorubicin with either paclitaxel or cisplatin. The median number of courses was 2.5 (range, one to 14). Toxicity was generally mild: only 25 patients experienced leukopenia, with a median WBC count of 2,900 (range, 800 to 3,900) at nadir. The only grade 4 toxicities were one episode each of esophagitis, hematuria, and vomiting. The median overall survival was 8.2 months. CONCLUSION PLD has only limited activity in pretreated advanced, recurrent endometrial cancer, but further trials in anthracycline-naive patients and in previously untreated patients are ongoing. Its toxicity profile should permit its use in combination with myelosuppressive drugs.

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.

Usefulness of tumor volumetry by magnetic resonance imaging in assessing response to radiation therapy in carcinoma of the uterine cervix

PURPOSE Clinical evaluation of tumor size in cervical cancer is often difficult, and clinical signs of radiation therapy failure may not be present until well after completion of treatment. The purpose of this study is to investigate early indicators of treatment response using magnetic resonance (MR) imaging for quantitative assessment of tumor volume and tumor regression rate before, during, and after radiation therapy. METHODS AND MATERIALS Thirty-four patients with cervical cancer Stages IB [5], IIB [8], IIIA [1], IIIB [14], IVA [3], IVB [1], and recurrent [2] were studied prospectively with four serial MR examinations obtained at the start of radiation therapy, at 2-2.5 weeks (20-24 Gy), at 4-5 weeks (40-50 Gy), and 1-2 months after treatment completion. Tumor volume was assessed by three-dimensional volumetric measurements using T2-weighted images of each MR examination. The volume regression rate was generated based on the four sequential MR studies. These findings were correlated with local control, metastasis rate, and disease-free survival. Median follow-up was 18 months (range: 9-43 months). RESULTS The tumor regression rate after a dose of 40-50 Gy correlated significantly with treatment outcome. The actuarial 2-year disease-free survival was 88.4% in patients with tumors regressing to < 20% of the initial volume compared with 45.4% in those with > or = 20% residual (p = 0.007). The incidence of local recurrence was 9.5% (2 out of 21) and 76.9% (10 out of 13), respectively (p < 0.001). Analysis by initial tumor volume showed that this observation was valid in patients with initial volumes between 40 and 100 cm3. Analysis by FIGO stage confirmed this observation in all patients except those with Stage IB. CONCLUSION Sequential tumor volumetry using MR imaging appears to be a sensitive measure of the responsiveness of cervical cancer to irradiation. Treatment response can be assessed as early as during the course of radiation therapy by measurement of initial tumor volume and regression rate at 40-50 Gy. In patients with large (> 40 cm3) and advanced (Stage > or = IIIA) tumors, this technique may be helpful in supplementing the clinical examination for response assessment. The identification of patients at high risk for treatment failure may ultimately lead to improved clinical outcome.

Detection and patterns of treatment failure in 300 consecutive cases of “early” endometrial cancer after primary surgery

From November 1977 to July 1987, 300 consecutive patients with endometrial carcinoma clinically confined to the uterine corpus underwent primary surgery consisting of at least abdominal hysterectomy and adnexectomy. Patients with aggressive disease characteristics received postoperative radiotherapy. Forty-seven patients (16%) demonstrated recurrent disease from 2 to 125 (median of 12.8) months after surgery. Forty-seven percent of the recurrences were detected within the first year following surgery and 70% by 2 years after hysterectomy. Of the 47 recurrences, 29 were at distant sites, 16 were within the pelvis, and 2 consisted of both local and distant recurrences. Patients treated with pelvic radiotherapy after hysterectomy were more likely to experience distant, rather than local recurrences. Only 7 of the 148 patients (5%) treated with postoperative radiotherapy recurred in the pelvis. Approximately half of the recurrences were detected in asymptomatic individuals; physical examination and chest X-ray were the most useful means to detect disease in patients without symptoms. The combination of history, physical examination, pap smear, and chest X ray detected all of the recurrences. Actuarial survivals at 12, 24, and 36 months after recurrence were 42, 24, and 17%, respectively. The site of recurrence, time interval of surgery to recurrence, and use of postoperative pelvic radiotherapy were statistically related to patient prognosis. The identification of patients at risk of recurrence and more effective adjuvant therapy need to be developed in order to decrease the frequency of recurrence. In order to substantially improve the survival of patients with recurrent disease, more sensitive methods of detection, as well as more effective salvage therapy, will be required.