Wesley C. Fowler

Randomized Comparison of Fluorouracil Plus Cisplatin Versus Hydroxyurea as an Adjunct to Radiation Therapy in Stage IIB-IVA Carcinoma of the Cervix With Negative Para-Aortic Lymph Nodes: A Gynecologic Oncology Group and Southwest Oncology Group Study

PURPOSE In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities. METHODS All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU. RESULTS Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018). CONCLUSION This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.

Carcinoma of the cervix treated with radiation therapy I. A multi‐variate analysis of prognostic variables in the gynecologic oncology group

Between 1977 and 1985, the Gynecologic Oncology Group (GOG) conducted three clinical trials in locally advanced carcinoma of the cervix, clinical Stages I to IVA as classified by the International Federation of Gynecology and Obstetrics (FIGO). All 626 patients had primary carcinoma of the cervix and underwent operative assessment of the para‐aortic (PA) lymph nodes. Patients received standardized external radiation therapy to the pelvis or to the pelvis and PA lymph nodes followed by one or two brachytherapy applications. To date, no statistically significant differences in progression‐free interval (PFI) or survival time have been identified between the randomization treatment arms on any of these studies. Basic similarities among these studies led us to pool these data to identify patient characterisitcs and tumor characteristics associated with an increased risk of treatment failure. Multi‐variate analysis showed patient age, performance status (PS), PA lymph node status, tumor size, and pelvic node status to be significantly associated with PFI. When modeling for survival, all these factors and clinical stage and bilateral extension were significant.

A comparative study of 3 surgical methods for hysterectomy with staging for endometrial cancer: robotic assistance, laparoscopy, laparotomy

OBJECTIVE The purpose of this study was to compare outcomes in women who underwent endometrial cancer staging by different surgical techniques. STUDY DESIGN Three hundred twenty-two women underwent endometrial cancer staging: 138 by laparotomy (TAH); 81 by laparoscopy (TLH) and 103 by robotic technique (TRH). RESULTS The TRH cohort had a higher body mass index than the TLH cohort (P = .0008). Lymph node yield was highest for TRH (P < .0001); hospital stay (P < .0001) and estimated blood loss (P < .0001) were lowest for this cohort. Operative time was longest for TLH (213.4 minutes) followed by TRH (191.2 minutes) and TAH (146.5 minutes; P < .0001. Postoperative complication rates were lower for TRH, compared with TAH (5.9% vs 29.7%; P < .0001). Conversion rates for the robotic and laparoscopic groups were similar. CONCLUSION TRH with staging is feasible and preferable over TAH and may be preferable over TLH in women with endometrial cancer. Further study is necessary to determine long-term oncologic outcomes.

A prospective surgical pathological study of stage I squamous carcinoma of the cervix: A Gynecologic Oncology Group study

Thirty-three institutions collaborating in the Gynecologic Oncology Group gathered surgical and pathological data on 1125 patients with primary, previously untreated, histologically confirmed stage I cervical carcinoma with more than 3 mm of invasion who were selected to undergo radical hysterectomy and paraaortic and pelvic lymphadenectomy. Of the 940 eligible, evaluable patients, 732 had squamous carcinoma. Of the study group, 87 (12%) did not undergo radical hysterectomy because of gross disease beyond the uterus or microscopic aortic node involvement documented at exploratory laparotomy. Among the 645 patients undergoing pelvic and paraaortic lymphadenectomy and radical hysterectomy, five risk factors were significantly associated with microscopic pelvic lymph node metastasis: depth of invasion (P = 0.0001), parametrial involvement (P = 0.0001), capillary-lymphatic space invasion (P = 0.0001), tumor grade (P = 0.01), and gross versus occult primary tumor (P = 0.009). The factors identified as independent risk factors for pelvic lymph node metastasis by multivariate analysis were capillary-lymphatic space involvement (P less than 0.0001), depth of invasion (P less than 0.0001), parametrial involvement (P = 0.0005), and age (P = 0.02). The model was used to predict the chance of a patient having nodal metastasis for any combination of risk factors.

A case-control study of robot-assisted type III radical hysterectomy with pelvic lymph node dissection compared with open radical hysterectomy

OBJECTIVE The purpose of this study was to compare robotically assisted hysterectomy (RAH) with open (ORH) type III radical hysterectomy in the treatment of early-stage cervical cancer. STUDY DESIGN The outcomes of 51 consecutive patients who underwent RAH were compared with the outcomes of 49 patients who underwent ORH. RESULTS There were no differences with regard to patient demographics. There were significant differences between the groups with regard to operative blood loss (P < .0001), operative time (P = .0002), and lymph node retrieval (P = .0003), all of which were in favor of the RAH cohort. All patients with RAH were discharged on postoperative day 1, compared with a 3.2-day average hospitalization for the cohort with ORH. The incidence of postoperative complications was 7.8% and 16.3% for the RAH and ORH cohorts, respectively (P = .35). CONCLUSION Robotic type III radical hysterectomy with pelvic node dissection is feasible and may be preferable over open radical hysterectomy in patients with early-stage cervical cancer. Further study will determine procedure generalizability and long-term oncologic outcomes.

Carcinoma of the cervix, stage III: results of radiation therapy

From April 1969 through December 1980, 203 patients with Stage III epidermoid carcinoma of the cervix were treated with radiation therapy with curative intent. The disease‐free survival at 2, 5, and 10 years was 50%, 33%, and 27%, respectively. The survival was better for patients with Stage IIIB disease than for those with Stage IIIA disease. Eighty‐eight patients were treated with external beam therapy only, and 115 received external beam and brachytherapy. The disease‐free survival was better for the combination therapy group initially, but this difference was not sustained beyond 5 years. One hundred eight patients experienced recurrence within the irradiated field, for a locoregional recurrence rate of 53%. Twenty‐seven patients had complications (13%). The complications were mild in 13 patients, moderate in 4 patients, and severe in 10 patients. A study was made of the relationship of the dose to Point A and the occurrence of complications. Similar analyses were made of the bladder and rectal doses and the subsequent occurrence of urinary and intestinal complications. In these analyses, the mean dose to Point A and the critical organs was higher for the groups of patients with complications than for those patients without complications. This relationship was also observed when the patients were stratified for treatment with either external beam plus brachytherapy or external beam therapy alone.

Treatment of recurrent or advanced uterine sarcoma. A randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group).

Recurrent or metastatic uterine sarcoma represents an ominous and aggressive form of malignant disease. In an attempt to define a beneficial treatment program, we compared treatment with doxorubicin (A) 60 mg/m2 versus a combination of doxorubicin 60 mg/m2 and cyclophosphamide 500 mg/m (CA), each regimen given every 3 weeks. Of 132 patients entered on study, 104 were eligible; 50 received A and 54 CA. Pretreatment characteristics were similar, and no patient had received prior chemotherapy. The proportion of complete responses (CR) + partial responses (PR) for measurable disease patients was 5 of 26 (19%) for both A and CA. Multivariate analysis done on progression‐free interval (PFI) and survival (S) showed CA to be of no benefit over A (PFI, P = 0.22; S, P = 0.55). For both A and CA patients, measurable disease (PFI, P = 0.002; S, P = 0.02, respectively), performance status (PFI, P = 0.004; S, P = 0.0002; respectively), and sites of residual disease (PFI, P = 0.008; S, P = 0.003, respectively) were detected as prognostic variables. Conversely, histologic type, age, and recurrence status (primary versus recurrent at entry) were not prognostic indicators. These data indicate no significant benefit of CA versus A alone in patients with uterine sarcoma.

Carcinoma of the cervix: Analysis of bladder and rectal radiation dose and complications

From April 1969 through December 1980, 527 patients with epidermoid carcinoma of the cervix received radical radiation therapy at North Carolina Memorial Hospital (NCMH). The treatment was designed to deliver a combined dose (external beam plus intracavitary) of 7000-8000 cGy to Point A and 5000-6500 cGy to the pelvic lymph nodes depending upon the stage of the disease. The maximum dose to the bladder and to the rectum were calculated from the orthogonal intracavitary placement films with contrast material in these organs. Thirty-three cases of cystitis and fifty-eight cases of proctitis were recorded. The mean bladder dose for the group of patients with cystitis was higher, 6661 +/- 1309 cGy, than that for the patients without cystitis, 6298 +/- 1305 cGy, p = .19. The risk of cystitis increased as a function of bladder dose ranging from 3% for patients receiving less than or equal to 5000 cGy to the bladder to 12% for patients receiving greater than or equal to 8001 cGy to the bladder. A similar correlation was also found for rectal dose and proctitis. The mean rectal dose for the group of patients with proctitis was higher, 6907 +/- 981 cGy, than that for the patients without proctitis, 6381 +/- 1290 cGy, p = .003. The risk of proctitis increased as a function of rectal dose ranging from 2% for patients receiving less than or equal to 5000 cGy to the rectum to 18% for patients receiving greater than or equal to 8001 cGy to the rectum. A study of the severity of the cystitis as a function of bladder dose revealed a relationship between bladder dose and the severity of the complication (Grade I cystitis = 6600 +/- 1318 cGy vs Grade III cystitis = 6856 +/- 853 cGy). A dose-response relationship was found between the rectal dose and the severity of the complication (Grade I proctitis = 6810 +/- 906 cGy vs Grade III proctitis = 6997 +/- 1137 cGy). This relationship was statistically significant, p = .003. While there was no difference in the frequency of cystitis as a function of dose to the whole pelvis, the risk of proctitis did increase with increasing doses of external beam to the whole pelvis. It ranged from 3% for patients who received 2000 cGy or less to the whole pelvis to 14% for patients who received greater than 4000 cGy to the whole pelvis, p = .02.

Vulvar intraepithelial neoplasia III: occult cancer and the impact of margin status on recurrence

Objective To determine the impact of margin status on disease recurrence and the incidence of occult cancer in women diagnosed with vulvar intraepithelial neoplasia (VIN) III and treated with surgical excision. Methods Between 1989 and 1995, 73 women were diagnosed preoperatively with VIN III by vulvar biopsy and were treated with surgical resection. Patients were examined postoperatively, and recurrence was diagnosed when a biopsy of suspicious lesions confirmed VIN III. Results The mean age was 45 years; 81% of the patients were white, and 18% were black. Eighty-two percent of the women had used tobacco, 56% had prior cervical dysplasia, and 37% had prior genital warts. An underlying squamous vulvar cancer was found in 22% of patients at initial treatment for VIN III. Fifty-nine women had follow-up of at least 7 months. Of these, 66% (39 of 59) had positive surgical margins, 31% (18 of 59) had negative margins and 3% had unknown margins (two of 59). With positive margins, 46% (18 of 39) suffered recurrent disease; with negative margins, only 17% (three of 18) had recurrent disease (P = .03). Multifocal disease and a history of genital warts also correlated with VIN III recurrence (P = .03 for both). Conclusion A significant number of women diagnosed initially with VIN III on a vulvar biopsy harbored occult vulvar cancer. Recurrences were almost threefold higher when margins were positive for residual VIN III. We conclude that surgical resection is an appropriate method of treatment of VIN III for both diagnostic and therapeutic purposes.

A randomized comparison of a rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: A gynecologic oncology group study

In this study, 331 patients with advanced or recurrent squamous cell carcinoma of the cervix no longer amenable to control with surgery or radiotherapy were randomized to receive cisplatin 50 mg/m2 as either a continuous infusion over 24 hr or a more rapid infusion at a rate of 1 mg/min. Antiemetic therapy was standardized for the initial course of both regimens as metoclopramide 60 mg at the time of and at 3 and 6 hours after initiation of cisplatin. The overall frequency of objective regression of disease was 18%; the response rate in each regimen was essentially identical. The continuous infusion regimen was associated with a significantly greater percentage of patients who experienced no nausea and vomiting (34% versus 18%, P = 0.002). Other adverse effects included nephrotoxicity, peripheral neuropathy, myelosuppression, and ototoxicity. Both the frequency and severity of these were essentially the same for each regimen.