Charles Levenback

Pelvic Radiation with Concurrent Chemotherapy Compared with Pelvic and Para-Aortic Radiation for High-Risk Cervical Cancer

BACKGROUND AND METHODS We compared the effect of radiotherapy to a pelvic and para-aortic field with that of pelvic radiation and concurrent chemotherapy with fluorouracil and cisplatin in women with advanced cervical cancer. Between 1990 and 1997, 403 women with advanced cervical cancer confined to the pelvis (stages IIB through IVA or stage IB or IIa with a tumor diameter of at least 5 cm or involvement of pelvic lymph nodes) were randomly assigned to receive either 45 Gy of radiation to the pelvis and para-aortic lymph nodes or 45 Gy of radiation to the pelvis alone plus two cycles of fluorouracil and cisplatin (days 1 through 5 and days 22 through 26 of radiation). Patients were then to receive one or two applications of low-dose-rate intracavitary radiation, with a third cycle of chemotherapy planned for the second intracavitary procedure in the combined-therapy group. RESULTS Of the 403 eligible patients, 193 in each group could be evaluated. The median duration of follow-up was 43 months. Estimated cumulative rates of survival at five years were 73 percent among patients treated with radiotherapy and chemotherapy and 58 percent among patients treated with radiotherapy alone (P=0.004). Cumulative rates of disease-free survival at five years were 67 percent among patients in the combined-therapy group and 40 percent among patients in the radiotherapy group (P<0.001). The rates of both distant metastases (P<0.001) and locoregional recurrences (P<0.001) were significantly higher among patients treated with radiotherapy alone. The seriousness of side effects was similar in the two groups, with a higher rate of reversible hematologic effects in the combined-therapy group. CONCLUSIONS The addition of chemotherapy with fluorouracil and cisplatin to treatment with external-beam and intracavitary radiation significantly improved survival among women with locally advanced cervical cancer.

Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: An update of Radiation Therapy Oncology Group Trial (RTOG) 90-01

PURPOSE To report mature results of a randomized trial that compared extended-field radiotherapy (EFRT) versus pelvic radiotherapy with concomitant fluorouracil and cisplatin (CTRT) in women with locoregionally advanced carcinomas of the uterine cervix. PATIENTS AND METHODS Four hundred three women with cervical cancer were randomly assigned to receive either EFRT or CTRT. Patients were eligible if they had stage IIB to IVA disease, stage IB to IIA disease with a tumor diameter > or = 5 cm, or positive pelvic lymph nodes. Patients were stratified by stage and by method of lymph node evaluation. RESULTS The median follow-up time for 228 surviving patients was 6.6 years. The overall survival rate for patients treated with CTRT was significantly greater than that for patients treated with EFRT (67% v 41% at 8 years; P <.0001). There was an overall reduction in the risk of disease recurrence of 51% (95% CI, 36% to 66%) for patients who received CTRT. Patients with stage IB to IIB disease who received CTRT had better overall and disease-free survival than those treated with EFRT (P <.0001); 116 patients with stage III to IVA disease had better disease-free survival (P =.05) and a trend toward better overall survival (P =.07) if they were randomly assigned to CTRT. The rate of serious late complications of treatment was similar for the two treatment arms. CONCLUSION Mature analysis confirms that the addition of fluorouracil and cisplatin to radiotherapy significantly improved the survival rate of women with locally advanced cervical cancer without increasing the rate of late treatment-related side effects.

Quality of Life and Sexual Functioning in Cervical Cancer Survivors

PURPOSE To compare quality of life and sexual functioning in cervical cancer survivors treated with either radical hysterectomy and lymph node dissection or radiotherapy. METHODS Women were interviewed at least 5 years after initial treatment for cervical cancer. Eligible women had squamous cell tumors smaller than 6 cm at diagnosis, were currently disease-free, and had either undergone surgery or radiotherapy, but not both. The two treatment groups were then compared using univariate analysis and multivariate linear regression with a control group of age- and race-matched women with no history of cancer. RESULTS One hundred fourteen patients (37 surgery, 37 radiotherapy, 40 controls) were included for analysis. When compared with surgery patients and controls using univariate analysis, radiation patients had significantly poorer scores on standardized questionnaires measuring health-related quality of life (physical and mental health), psychosocial distress and sexual functioning. The disparity in sexual function remained significant in a multivariate analysis. Univariate and multivariate analyses did not show significant differences between radical hysterectomy patients and controls on any of the outcome measures. CONCLUSION Cervical cancer survivors treated with radiotherapy had worse sexual functioning than did those treated with radical hysterectomy and lymph node dissection. In contrast, these data suggest that cervical cancer survivors treated with surgery alone can expect overall quality of life and sexual function not unlike that of peers without a history of cancer.

Lymphatic Mapping and Sentinel Node Identification in Patients With Cervix Cancer Undergoing Radical Hysterectomy and Pelvic Lymphadenectomy

PURPOSE The purpose of this study was to determine the feasibility of sentinel node identification in patients with invasive cervix cancer undergoing radical hysterectomy and pelvic lymphadenectomy using preoperative and intraoperative lymphatic mapping. PATIENTS AND METHODS Thirty-nine patients at two institutions were enrolled onto this institutional review board-approved study. All underwent preoperative lymphoscintigraphy and intraoperative lymphatic mapping with blue dye and a handheld gamma probe. Radical hysterectomy was aborted in four patients because metastatic disease was discovered on frozen section analysis of the sentinel node. RESULTS Preoperative lymphoscintigraphy revealed at least one sentinel node in 33 patients (85%), including 21 (55%) with bilateral sentinel nodes. All 39 patients had at least one sentinel node identified intraoperatively. Eighty percent of sentinel nodes were in three pelvic locations: iliac, obturator, and parametrial (in descending order of frequency). The remaining sentinel nodes were in the common iliac and para-aortic nodal basins. A total of 132 nodes were identified clinically as sentinel nodes; 65 (49%) were both blue and hot, 35 (27%) were blue only, and 32 (24%) were hot only. Eight patients (21%) had metastatic disease. In five of these patients, sentinel nodes were the only positive lymph nodes. One patient had false-negative sentinel nodes. She had four microscopically positive parametrial nodes that were resected in continuity with the uterus. The sensitivity of the sentinel node was 87.5% and the negative predictive value was 97%. CONCLUSION Preoperative lymphoscintigraphy and intraoperative lymphatic mapping were highly successful at identifying sentinel nodes in patients undergoing radical hysterectomy.

Correlation of Smoking History and Other Patient Characteristics With Major Complications of Pelvic Radiation Therapy for Cervical Cancer

PURPOSE The purpose of this study was to identify patient-related factors that influence the risk of serious late complications of pelvic radiation therapy. PATIENTS AND METHODS The records of 3,489 patients treated with radiation therapy for International Federation of Gynecology and Obstetrics stage I or II carcinoma of the cervix were reviewed for information about patient characteristics, treatment details, and outcomes. Any complication occurring or persisting more than 3 months after treatment that required hospitalization, transfusion, or an operation or caused severe symptoms or the patients death was considered a major late complication. Complication rates were calculated actuarially. The median duration of follow-up was 85 months, and 99% of patients were followed for at least 3 years or until they died. RESULTS Heavy smoking was the strongest independent predictor of overall complications (multivariate hazard ratio, 2.30; 95% confidence interval [CI], 1.84 to 2.87). The most striking influence of smoking was on the incidence of small bowel complications (hazard ratio for smokers of one or more packs per day, 3.25; 95% CI, 2.21 to 4.78). Hispanics had a significantly lower rate of small bowel complications than whites, and blacks had higher rates of bladder and rectal complications than whites. Thin women had an increased risk of gastrointestinal complications, and obese women were more likely to have serious bladder complications. CONCLUSION Complications of pelvic radiation therapy are strongly correlated with smoking, race, and other patient characteristics. These factors should be considered before the results of clinical studies are generalized to different cultural and racial groups.

Lymphatic Mapping and Sentinel Lymph Node Biopsy in Women With Squamous Cell Carcinoma of the Vulva: A Gynecologic Oncology Group Study

PURPOSE To determine the safety of sentinel lymph node biopsy as a replacement for inguinal femoral lymphadenectomy in selected women with vulvar cancer. PATIENTS AND METHODS Eligible women had squamous cell carcinoma, at least 1-mm invasion, and tumor size ≥ 2 cm and ≤ 6 cm. The primary tumor was limited to the vulva, and there were no groin lymph nodes that were clinically suggestive of cancer. All women underwent intraoperative lymphatic mapping, sentinel lymph node biopsy, and inguinal femoral lymphadenectomy. Histologic ultra staging of the sentinel lymph node was prescribed. RESULTS In all, 452 women underwent the planned procedures, and 418 had at least one sentinel lymph node identified. There were 132 node-positive women, including 11 (8.3%) with false-negative nodes. Twenty-three percent of the true-positive patients were detected by immunohistochemical analysis of the sentinel lymph node. The sensitivity was 91.7% (90% lower confidence bound, 86.7%) and the false-negative predictive value (1-negative predictive value) was 3.7% (90% upper confidence bound, 6.1%). In women with tumor less than 4 cm, the false-negative predictive value was 2.0% (90% upper confidence bound, 4.5%). CONCLUSION Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva.

A Phase III Randomized Clinical Trial Comparing Laparoscopic or Robotic Radical Hysterectomy with Abdominal Radical Hysterectomy in Patients with Early Stage Cervical Cancer

STUDY OBJECTIVE Cervical cancer is a significant health problem in countries of the developing world. Although case series suggest advantages of total laparoscopic radical hysterectomy (TLRH) compared with total abdominal radical hysterectomy (TARH), no randomized controlled trial is currently available to establish TLRH as the new standard treatment. In this study, TLRH or total robotic radical hysterectomy (TRRH) will be performed without a vaginally assisted portion of the procedure. DESIGN A biphasic randomized controlled trial was designed to test feasibility of recruitment and equivalence in regard to disease-free survival (Canadian Task Force classification I). SETTING Tertiary referral hospital. PATIENTS Patients with histologically confirmed invasive squamous cell carcinoma or adenocarcinoma of the cervix, stage IA1 (with lymphovascular space invasion), IA2, and IB1 are eligible. INTERVENTIONS During the first phase, 100 patients will be randomized (1:1) to receive either TLRH/TRRH or TARH, with the primary end point being the rate of enrollment. During the second phase, recruitment will be extended by another 640 patients in a 1:1 TLRH/TRRH:TARH allocation, to determine equivalence with respect to disease-free survival with 80% power and alpha=0.05. MEASUREMENTS AND MAIN RESULTS Equivalence will be assumed if the difference in disease-free survival does not exceed 7% at 4 years. Secondary outcomes include treatment-related morbidity, costs and cost effectiveness, patterns of recurrence, quality of life, pelvic floor function, feasibility of intraoperative sentinel node sampling, and overall survival. All data from this multicenter study will be entered using online electronic case report forms, allowing real-time assessment of data completeness and patient follow-up. CONCLUSION This prospective trial aims to show the equivalence of a TLRH/TRRH versus TARH approach for patients with early stage cervical cancer following a 2-phase protocol. This trial was developed and designed with the input and approval of the members of the Gynecologic Oncology Committee from the American Association of Gynecologic Laparoscopists.

Treatment of poor-prognosis sex cord-stromal tumors of the ovary with the combination of bleomycin, etoposide, and cisplatin

Objective To investigate the clinical activity of the combination of bleomycin, etoposide, and cisplatin for metastatic ovarian sex cord-stromal, cord-stromal tumors of all types and poorly differentiated Sertoli-Leydig cell tumors confined to the ovary. Methods The regimen was administered as follows: bleomycin 10–15 mg/day by continuous intravenous (IV) infusion on days 1–3; etoposide 100 mg/m2 IV per day on days 1–3; cisplatin 100 mg/m2 IV on day. 1. End points for analysis included response, progression-free survival, and survival. Results Nine patients were entered in this trial. The median age was 37 years (range 12–69). Histologic types included adult granulosa cell tumor in five patients, juvenile granulosa cell tumor in one, poorly differentiated Sertoli-Leydig cell tumor in two, and mixed tumor in one. Stage distribution was as follows: stage Ia, two: stage IIc, one; stage IIc, one; recurrent, five. Of the six patients with measurable disease, two (33%) had a complete response (one surgical and one clinical), and three (50%) had a partial response, for an overall response rate of 83%l; one patient had no response. Toxicity was acceptable; two patients had mild bleomycin pulmonary toxicity. Of the three patients with nonmeasurable disease, one relapsed, one developed progressive disease, and one remains in remission. Of the seven patients with metastatic disease, only one (14%) had a durable remission. Median progression-free survival was 14 months. Median survival time was 28 months. At the time of analysis, two patients alive disease-free, three were alive with disease, and four were dead of disease. Conclusion Although the overall response rate to the combination of bleomycin, etoposide, and cisplatin was high, the regimen apparently lacks durable activity in this groups of tumors. More active drugs and modalities should continue to be investigated.

Uterine papillary serous carcinoma (UPSC) treated with cisplatin, doxorubicin, and cyclophosphamide (PAC)

Uterine papillary serous carcinoma (UPSC) is an aggressive malignancy that accounts for a disproportionate number of intraabdominal failures among endometrial carcinoma patients. The histologic appearance and tendency toward intraabdominal spread resemble those of papillary serous adenocarcinoma of the ovary. Because approximately 70% of untreated ovarian carcinoma patients respond to platinum-based chemotherapy, it has been suggested that UPSC patients might respond to similar treatment regimens. Twenty patients with UPSC were treated with cisplatin, doxorubicin (Adriamycin), cyclophosphamide (PAC) chemotherapy between January 1982 and December 1989. They included 9 patients with advanced primary disease, 5 with recurrence, and 6 who received PAC as adjuvant therapy. Patients received a mean of five cycles of PAC. Only 2 of 11 patients with measurable disease greater than 2 cm achieved complete clinical responses of 12 and 31 months duration; there were no partial responses. Actuarial 5-year survival for all patients was 23%. The mean progression-free interval was 9 months. Patients with clinical stages I or II disease had a higher survival rate than those with stage III or IV disease (P = 0.003). Survival did not correlate with depth of myometrial invasion (P = 0.81) or size of residual tumor following initial surgery (P = 0.16). Estrogen or progesterone receptors were detected in 10 of 11 tumors tested. Seven of 9 patients tested had elevated serum levels of CA-125 (greater than 35 U/ml). Correlation between CA-125 value and clinical course was demonstrated in 3 of 5 patients who had serial measurements. Of all patients, 3 are currently alive; 1 has documented disease. Moderate to severe toxicity was seen in 14 patients (70%). There was one possible treatment-related death from cardiomyopathy. UPSC, despite its histologic and clinical similarities to ovarian carcinoma, was relatively resistant to PAC chemotherapy in this mixed group of patients.

Parametrial involvement in radical hysterectomy specimens for women with early-stage cervical cancer

OBJECTIVE: To estimate the incidence of parametrial involvement and to evaluate factors associated with parametrial spread in women with early-stage cervical cancer and to identify a cohort of patients at low risk for parametrial spread who may benefit from less radical surgery. METHODS: We reviewed all patients who underwent radical hysterectomy and pelvic lymphadenectomy for invasive cervical cancer between 1990 and 2006. All women with squamous, adenocarcinoma, or adenosquamous disease, stage IA2–IB1, who underwent completed radical hysterectomy were included in the analysis. Normally distributed continuous variables were compared using Student’s t-test for independent samples to analyze the outcome of positive or negative parametrial involvement. RESULTS: Three hundred fifty patients met the inclusion criteria. Overall, 27 women (7.7%) had parametrial involvement. The majority of specimens with parametrial involvement (52%) had tumor spread through direct microscopic extension. Patients with parametrial involvement were more likely to have a primary tumor size larger than 2 cm (larger than 2 cm: 14%, smaller than 2 cm: 4%, P=.001), higher histologic grade (grade 3: 12%, grades 1 and 2: 3%, P=.01), lymphovascular space invasion (positive: 12%, negative: 3%, P=.002), and metastasis to the pelvic lymph nodes (positive: 31%, negative: 4%, P<.001). One hundred twenty-five women (36%) had squamous, adenocarcinoma, or adenosquamous lesions, all grades, with primary tumor size 2 cm or smaller and no lymphovascular space invasion. In this group of patients, there was no pathologic evidence of parametrial involvement. CONCLUSION: We were able to retrospectively identify a cohort of women with early-stage cervical cancer who were at very low risk for parametrial involvement. If prospective application of these findings confirms our results, less radical surgery—such as simple hysterectomy, simple trachelectomy, or conization—with pelvic lymphadenectomy may be a reasonable therapeutic option for women with primary tumors 2 cm or smaller and no lymphovascular space invasion. LEVEL OF EVIDENCE: III