Rachelle Lanciano

Reducing Uncertainties About the Effects of Chemoradiotherapy for Cervical Cancer : A Systematic Review and Meta-Analysis of Individual Patient Data From 18 Randomized Trials

BACKGROUND After a 1999 National Cancer Institute (NCI) clinical alert was issued, chemoradiotherapy has become widely used in treating women with cervical cancer. Two subsequent systematic reviews found that interpretation of the benefits was complicated, and some important clinical questions were unanswered. PATIENTS AND METHODS We initiated a meta-analysis seeking updated individual patient data from all randomized trials to assess the effect of chemoradiotherapy on all outcomes. We prespecified analyses to investigate whether the effect of chemoradiotherapy differed by trial or patient characteristics. RESULTS On the basis of 13 trials that compared chemoradiotherapy versus the same radiotherapy, there was a 6% improvement in 5-year survival with chemoradiotherapy (hazard ratio [HR] = 0.81, P < .001). A larger survival benefit was seen for the two trials in which chemotherapy was administered after chemoradiotherapy. There was a significant survival benefit for both the group of trials that used platinum-based (HR = 0.83, P = .017) and non-platinum-based (HR = 0.77, P = .009) chemoradiotherapy, but no evidence of a difference in the size of the benefit by radiotherapy or chemotherapy dose or scheduling was seen. Chemoradiotherapy also reduced local and distant recurrence and progression and improved disease-free survival. There was a suggestion of a difference in the size of the survival benefit with tumor stage, but not across other patient subgroups. Acute hematologic and GI toxicity was increased with chemoradiotherapy, but data were too sparse for an analysis of late toxicity. CONCLUSION These results endorse the recommendations of the NCI alert, but also demonstrate their applicability to all women and a benefit of non-platinum-based chemoradiotherapy. Furthermore, although these results suggest an additional benefit from adjuvant chemotherapy, this requires testing in randomized trials.

Randomized Comparison of Weekly Cisplatin or Protracted Venous Infusion of Fluorouracil in Combination With Pelvic Radiation in Advanced Cervix Cancer: A Gynecologic Oncology Group Study

PURPOSE Concurrent chemoradiotherapy is the standard of care for locally advanced cervix cancer; the optimal chemotherapy regimen is not yet defined. This trial was designed to compare the outcome of protracted venous infusion (PVI) fluorouracil (FU) with standard weekly cisplatin and concurrent radiation therapy (RT). PATIENTS AND METHODS Patients with stage IIB, IIIB, and IVA cervical cancer with clinically negative aortic nodes were eligible. Pelvic RT dose was 45 Gy with a parametrial boost to involved sides of 5.4 to 9 Gy, and high- or low-dose rate intracavitary brachytherapy. Standard therapy was weekly cisplatin 40 mg/m2, and experimental therapy was PVI FU 225 mg/m2/d for 5 d/wk for six cycles during RT. RESULTS The study was closed prematurely when a planned interim futility analysis indicated that PVI FU/RT had a higher treatment failure rate (35% higher) and would, most likely, not result in an improvement in progression-free survival compared with weekly cisplatin/RT. The PVI FU/RT arm continues to show a higher risk of treatment failure (relative risk [RR] unadjusted, 1.29) and a higher mortality rate (RR unadjusted, 1.37). There was no difference in pelvic treatment failure between regimens, but there was an increase in the failure rate at distant sites in the PVI FU arm. CONCLUSION In this study, PVI FU does not show improved outcome over weekly cisplatin. Future research should explore combinations of FU with cisplatin, new radiosensitizers, and active drugs combined with RT to reduce the high rate of pelvic and distant treatment failure still seen in advanced cervix cancer.

Surgical versus radiographic determination of para-aortic lymph node metastases before chemoradiation for locally advanced cervical carcinoma: a Gynecologic Oncology Group Study.

Patients with cervical cancer who had negative para‐aortic lymph nodes (PALNs) identified by pretreatment surgical staging were compared with patients who had only radiographic exclusion of PALN metastases before they received treatment with pelvic radiation and brachytherapy (RT) plus cisplatin (C)‐based chemotherapy.

A Phase II Study of Concurrent Carboplatin and Paclitaxel and Thoracic Radiotherapy for Completely Resected Stage II and IIIA Non-small Cell Lung Cancer

Background: To determine the feasibility of combining concurrent carboplatin/paclitaxel and thoracic radiotherapy (TRT) for completely resected stage II and IIIA non-small cell lung cancer. Methods: Eligibility stipulated gross total resections with involved lymph nodes (N1 or N2), pathologic stage II or IIIA non-small cell lung cancer. TRT consisted of 50.4 Gy in 28 fractions with a boost of 10.8 Gy for extranodal extension (ENE) or 16.2 Gy for involved surgical margins. Chemotherapy was administered every 3 weeks: carboplatin (area under the curve of 5) and paclitaxel (175 mg/m2) during TRT for two cycles, with doses increased to an area under the curve of 7.5 and 225 mg/m2, respectively, for two cycles after TRT. Cox multivariate regression analysis was used to confirm independent predictors of outcome among clinical and treatment-related factors: age, T stage, N stage, presence of ENE, presence of involved surgical margins, histopathology. Results: Between April 1997 and March 2001, 42 patients were enrolled. Two patients were deemed ineligible due to having T4 disease, leaving 40 patients for analysis. Ninety-two percent (37/40) of patients had T1 or T2 disease; 60% (24/40) had N2 disease. Nine patients (22.5%) had ENE and 15% (six patients) had involved surgical margins. At a median follow up of 37 months (range, 3–103; median, 68 months for living patients), the 2- and 5-year Kaplan–Meier estimates of local regional control, freedom from distant metastasis, freedom from brain metastasis, and overall survival were 92% and 88%, 77% and 59%, 87% and 71% and 72% and 44%, respectively. Fourteen patients developed distant metastasis as the initial site of failure, eight of whom had brain metastasis. Brain metastasis was the only site of failure in four of the eight patients. Multivariate regression analysis demonstrated that the only independent predictor of overall survival was histology (p = 0.02). Patients with adenocarcinoma had a 5-year overall survival of 28% versus 68% for all other cell types. There were no independent predictors of distant metastases or brain metastases on multivariate regression analysis. Treatment was tolerated reasonably well: 92% of patients (37/40) received the planned doses of TRT; 67% of patients (27/40) received all four cycles of chemotherapy. Five patients developed grade 3 esophagitis, and three patients experienced grade 3 pneumonitis. Two patients experienced grade 5 toxicity. One was treatment related due to a patient who developed grade 3 esophagitis who developed an aspiration pneumonia that progressed to acute respiratory distress syndrome. Conclusions: Our results support the Radiation Therapy Oncology Group 97-05 findings and suggest that with new and better tolerated chemotherapy regimens the strategy of concurrent TRT and chemotherapy after completely resected stage II and IIIA non-small cell lung cancer should be further explored.

The Efficacy and Safety of Once-Daily Kytril® (Granisetron Hydrochloride) Tablets in the Prophylaxis of Nausea and Emesis Following Fractionated Upper Abdominal Radiotherapy

This multicenter, randomized, double-blind study compared the efficacy and safety of once-daily oral granisetron 2 mg (n = 134) and placebo (n = 126) as prophylaxis for nausea and emesis in patients receiving upper abdominal fractionated radiotherapy. Patients were scheduled to receive 10–30 fractions of radiotherapy; granisetron (two 1-mg tablets) or placebo was administered 1 hr before radiotherapy on each scheduled treatment day. Treatment comparisons were made at 24 hr and at 10 and 20 fractions. Patients treated with granisetron experienced greater emetic control than those treated with placebo as evidenced by median times to first emesis (35 vs. 9 days, p < 0.001) and first nausea (11 vs. 1 day, p < 0.001). Overall endpoint analysis showed that proportionally more granisetron than placebo patients were emesis free (57.5% vs. 42.1%, p = 0.0047) and nausea free (30.6% vs. 16.7%, p = 0.0042). Furthermore, 25% more granisetron-treated than placebo-treated patients were emesis free and 20% more were nausea free on at least 80% of study treatment days. The most commonly reported adverse experiences in granisetron-treated patients were diarrhea, asthenia, and constipation. These findings demonstrate that a once-daily, 2-mg dose of oral granisetron is well tolerated and significantly more effective than placebo in preventing nausea and emesis induced by fractionated radiotherapy to the upper abdomen.

Retrospective analysis of concomitant Cisplatin during radiation in patients aged 55 years or older for treatment of advanced cervical cancer: a gynecologic oncology group study.

Hypothesis: Patients with stages II to IVa cervical cancer aged 55 years or older were compared with patients younger than 55 years who received weekly cisplatin during pelvic radiation for differences in chemoradiation administration, toxicity, and outcome. Methods: Retrospective review included patients enrolled on Gynecologic Oncology Group trial Nos. 120 and 165 (n = 335) who received weekly cisplatin (40 mg/m2) during pelvic irradiation (40.8-50.1 Gy) followed by intracavitary brachytherapy (30-40 Gy). Results: For all 335 patients, 53% completed 6 cycles of chemotherapy during radiation with no observed difference in frequency among patients younger than 55 years or 55 years or older (P = 0.616). Excess hematological but not genitourinary toxicity was seen in patients 55 years or older. At 5 years, 56% of patients younger than 55 years were predicted to be alive and disease-free compared with 55% of those aged 55 years or older (P = 0.629). A 5-year survival was 60% in patients younger than 55 years as compared with 56% in patients aged 55 years or older (P = 0.265). Conclusions: Patients aged 55 years or older with locally advanced cervical cancer undergoing concurrent weekly cisplatin with pelvic radiation on cooperative group clinical trials achieve similar progression-free and overall survivals as younger patients. Disparity was not observed in the seriousness or frequency of treatment-related sequelae.

Impact of hydronephrosis on outcome of stage IIIB cervical cancer patients with disease limited to the pelvis, treated with radiation and concurrent chemotherapy: A Gynecologic Oncology Group study

OBJECTIVES To estimate the significance of hydronephrosis and impact of ureteral obstruction relief on outcome in patients with stage IIIB cervical cancer treated with radiation and concurrent chemotherapy. METHODS We retrospectively studied stage IIIB cervical cancer patients treated on GOG trials 56, 85, 120 and 165 evaluating radiation and concurrent chemotherapy. Eligible patient records were reviewed to assess the presence of hydronephrosis and treatment of ureteral obstruction. Patients were classified into three groups; no hydronephrosis, hydronephrosis relieved from ureteral obstruction via stent or percutaneous nephrostomy and hydronephrosis without treatment of ureteral obstruction. RESULTS 539 stage IIIB patients were studied. Hydronephrosis was present in 238 (44.2%). Patient age, race, and tumor characteristics (size, histology and grade) were not significantly different between patients with or without hydronephrosis. Patients with hydronephrosis received similar doses of radiation and cisplatin-based chemotherapy. Both overall and progression-free survival were worse with hydronephrosis (log-rank test p value=0.0189 and 0.0186, respectively). Univariable analysis identified five prognostic factors; pelvic nodal metastasis (p=0.0001), tumor diameter (p=0.0007), cisplatin-based concurrent chemoradiation (p=0.0031), hydronephrosis (p=0.0189), and performance status (p=0.0359). Hydronephrosis was associated with worse performance status (p<0.001). On multivariable analysis hydronephrosis was not a significant prognostic factor. Ureteral obstruction relief occurred for 88% of patients and was associated with improved survival. CONCLUSION In patients with stage IIIB cervical cancer restricted to the pelvis, hydronephrosis at presentation is a significant but not independent prognostic factor associated with poor performance status and poorer survival. Relief of ureteral obstruction is correlated with improved outcome.

Smoking behavior in women with locally advanced cervical carcinoma: a Gynecologic Oncology Group study

OBJECTIVE The purpose of this study was to assess cigarette use and environmental smoke exposure in women with cervical cancer. STUDY DESIGN Smoking behavior was recorded prospectively in a clinical trial of women with locally advanced cervical carcinoma. RESULTS Of 315 participants, 133 women (42%) were current smokers; 72 women (23%) were former smokers, and 110 women (35%) were never smokers. Current smokers began smoking earlier (16 vs 18 years; P = .009), for more years (29 vs 24 years; P = .005), and in greater amounts (20 vs 11 cigarettes/d; P < .001) than former smokers. Active smokers lived more often with another smoker (63.3%), compared with former smokers (35.0%; P < .001) or never-smokers (28.7%; P < .001). Agreement between self-report and urine cotinine level was high (kappa = 0.872; P < .001). A significant decrease in cotinine level during treatment occurred in 5.2% of current smokers. CONCLUSION Prevalence of smoking and tobacco consumption was twice that of the North American female population. Few smokers quit or decreased consumption during treatment.

CURRENT DEVELOPMENTS IN THE TREATMENT OF NEWLY DIAGNOSED CERVICAL CANCER

The International Federation of Gynecology and Obstetrics (FIGO) staging of cervical cancer relies on physical examination. However, surgical staging, which helps determine the extent of invasion of lymph nodes by cancer, is currently used more widely to define the need for additional therapies. Examples of these additional treatments include high-dose-rate brachytherapy techniques, extension of radiotherapy fields, surgery, concurrent chemotherapy and radiotherapy, and neoadjuvant chemotherapy prior to surgery. Currently there are many ongoing randomized studies that strive to define the risk-to-benefit ratio of these additional therapies.

Outcome of stage IVA cervical cancer patients with disease limited to the pelvis in the era of chemoradiation: A Gynecologic Oncology Group study

OBJECTIVES To evaluate the outcome of stage IVA cervical cancer treated with radiation and concurrent cisplatin-based chemotherapy. METHODS We conducted a retrospective study of stage IVA cervical cancer patients from four trials (Gynecologic Oncology Group protocols 56, 85, 120, and 165) treated with radiotherapy with or without concurrent cisplatin-based chemotherapy. Patient records were reviewed for demographic and tumor features, treatment, and progression-free survival (PFS) and overall survival (OS). Stage IVA patients were compared to stage IIIB patients from these same studies. RESULTS Among the 51 stage IVA patients studied, 92% were stage IVA on the basis of bladder involvement. The median PFS was 10.1 months (95% CI=6.3-14.5 months) and median OS was 21.2 months (95% CI=13.3-30.5 months). The 3 year survival was 32%. On univariate analysis, only advanced age was associated with OS (p=0.0115) but age had only marginal effect on PFS (p=0.083). Pathologic proven pelvic nodal metastasis was of marginal significance for both PFS and OS, p=0.059 and 0.064, respectively. Despite similar patient characteristics, the use of cisplatin-based chemotherapy had no impact on PFS or OS but was underpowered to address this question. When compared to stage IIIB patients, stage IVA patients had a poorer performance status (p=0.0231), larger tumor size (p=0.0302), and more frequent bilateral parametrial involvement (0.0063). CONCLUSION Patients with stage IVA disease had poor median survival of only 21 months with only 32% 3 year survival. Stage IVA patients have larger tumor size, more bilateral parametrial involvement, and poorer survival when compared to stage IIIB patients.