Gillian Thomas

Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials.

BACKGROUND Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer. METHODS Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups. FINDINGS Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42). INTERPRETATION Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits. FUNDING German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

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.

The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix

It is unclear whether blood transfusion can overcome the negative impact of anemia before or during radiotherapy (RT) in patients with carcinoma of the cervix. The objective of this retrospective study was to examine the impact of anemia and blood transfusion on 605 patients with carcinoma of the cervix treated with radical RT at 7 centers across Canada in 1989, 1990, and 1992.

Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group.

PURPOSE To determine the feasibility of using preoperative chemoradiotherapy to avert the need for more radical surgery for patients with T3 primary tumors, or the need for pelvic exenteration for patients with T4 primary tumors, not amenable to resection by standard radical vulvectomy. METHODS AND MATERIALS Seventy-three evaluable patients with clinical Stage III-IV squamous cell vulvar carcinoma were enrolled in this prospective, multi-institutional trial. Treatment consisted of a planned split course of concurrent cisplatin/5-fluorouracil and radiation therapy followed by surgical excision of the residual primary tumor plus bilateral inguinal-femoral lymph node dissection. Radiation therapy was delivered to the primary tumor volume via anterior-posterior-posterior-anterior (AP-PA) fields in 170-cGy fractions to a dose of 4760 cGy. Patients with inoperable groin nodes received chemoradiation to the primary vulvar tumor, inguinal-femoral and lower pelvic lymph nodes. RESULTS Seven patients did not undergo a post-treatment surgical procedure: deteriorating medical condition (2 patients); other medical condition (1 patient); unresectable residual tumor (2 patients); patient refusal (2 patients). Following chemoradiotherapy, 33/71 (46.5%) patients had no visible vulvar cancer at the time of planned surgery and 38/71 (53.5%) had gross residual cancer at the time of operation. Five of the latter 38 patients had positive resection margins and underwent: further radiation therapy to the vulva (3 patients); wide local excision and vaginectomy necessitating colostomy (1 patient); no further therapy (1 patient). Using this strategy of preoperative, split-course, twice-daily radiation combined with cisplatin plus 5-fluorouracil chemotherapy, only 2/71 (2.8%) had residual unresectable disease. In only three patients was it not possible to preserve urinary and/or gastrointestinal continence. Toxicity was acceptable, with acute cutaneous reactions to chemoradiotherapy and surgical wound complications being the most common adverse effects. CONCLUSION Preoperative chemoradiotherapy in advanced squamous cell carcinoma of the vulva is feasible, and may reduce the need for more radical surgery including primary pelvic exenteration.

Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy.

The results of treating anal canal carcinoma by radical external beam radiation alone (RT) or by combined 5‐fluorouracil, mitomycin C and radiation (FUMIR), were compared in nonrandomized groups of patients treated in a single center. In each treatment regimen, surgery was reserved for those patients with residual carcinoma. The uncorrected 5‐year survival rate in each group was approximately 70%, but primary tumor control was achieved in 93% (28/30) with FUMIR compared to 60% (15/25) treated with RT. Acute hematologic and enterocolic toxicity with uninterrupted external beam radiation courses of 5000 cGy in 4 weeks plus chemotherapy led to the adoption of split‐course treatment. Serious late toxicity requiring surgical intervention occurred in 3 of 25 following RT, and in 5 of 30 following FUMIR. Colostomies were needed as part of treatment for residual carcinoma or for the management of treatment‐related toxicity in 11 of 25 treated by RT and have been required to date in 4 of 30 treated by FUMIR. The improvement in the primary tumor control rate and the reduction in the number of patients requiring colostomy when compared with the results of RT favor combined chemotherapy and radiation as the initial treatment for anal canal carcinoma.

Radical Radiotherapy for Muscle Invasive Transitional Cell Carcinoma of the Bladder: Failure Analysis

Patients with muscle invasive carcinoma of the bladder treated with radical radiation were prospectively documented and followed in an attempt to identify prognostic factors predictive of the response to treatment. Data on 121 consecutive patients treated with radical radiation between 1981 and 1985 are presented. Over-all actuarial survival of the patient population (median age 70 years) was 31.6% at 5 years and cause-specific survival was 44.8%. At analysis 33 of 121 patients (27.3%) were alive with preserved bladder function. Independent prognostic factors for cause-specific survival and for complete response with radical radiation were tumor configuration, hemoglobin level and clinical stage. The rate free of local relapse was significantly influenced by stage and presence of coexistent carcinoma in situ. The study suggests that factors other than stage and grade influence prognosis in invasive bladder cancer and should be considered in interpreting treatment results.

Retroperitoneal Lymphadenectomy for Testis Tumor with Nerve Sparing for Ejaculation

The principal morbidity of retroperitoneal lymphadenectomy is the potential loss of ejaculation and, therefore, fertility owing to damage of the retroperitoneal sympathetic nerves that form the superior hypogastric plexus. We describe the results of our retroperitoneal lymphadenectomy when individual nerves from the sympathetic ganglia are identified and preserved while still performing a thorough bilateral retroperitoneal lymphadenectomy. The nerve-sparing procedure was technically feasible in 20 of 30 consecutive patients and it was only impractical with extensive gross disease. Of the 20 patients 18 (90 per cent) ejaculate, including 8 with bulky (5 cm. or more) residual retroperitoneal disease who underwent a successful nerve-sparing operation. All 12 patients (100 per cent) with nonbulky disease ejaculate. With short followup, no retroperitoneal recurrences have been detected. This technique is an alternative to limited dissection designed to spare nerves using boundaries based on the patterns of metastatic involvement.

Early Invasive Cervical Cancer: Tumor Delineation by Magnetic Resonance Imaging, Computed Tomography, and Clinical Examination, Verified by Pathologic Results, in the ACRIN 6651/GOG 183 Intergroup Study

PURPOSE To compare magnetic resonance imaging (MRI), computed tomography (CT), and clinical examination for delineating early cervical cancer and for measuring tumor size. PATIENTS AND METHODS A 25-center study enrolled 208 patients with biopsy-proven invasive cervical cancer for MRI and CT before attempted curative radical hysterectomy. Each imaging study was interpreted prospectively by one onsite radiologist and retrospectively by four independent offsite radiologists, who were all blinded to surgical, histopathologic, and other imaging findings. Likelihood of cervical stromal and uterine body involvement was rated on a 5-point scale. Tumor size measurements were attempted in three axes. Surgical pathology was the standard of reference. RESULTS Neither MRI nor CT was accurate for evaluating cervical stroma. For uterine body involvement, the area under the receiver operating characteristic curve was higher for MRI than for CT for both prospective (0.80 v 0.66, respectively; P = .01) and retrospective (0.68 v 0.57, respectively; P = .02) readings. Retrospective readers could measure diameter by CT in 35% to 73% of patients and by MRI in 79% to 94% of patients. Prospective readers had the highest Spearman correlation coefficient with pathologic measurement for MRI (r(s) = 0.54), followed by CT (r(s) = 0.45) and clinical examination (r(s) = 0.37; P < .0001 for all). Spearman correlation of multiobserver diameter measurements for MRI (r(s) = 0.58; P < .0001) was double that for CT (r(s) = 0.27; P = .03). CONCLUSION In patients with cervical cancer, MRI is superior to CT and clinical examination for evaluating uterine body involvement and measuring tumor size, but no method was accurate for evaluating cervical stroma.

Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study

PURPOSE To determine if patients with carcinoma of the vulva, with N2/N3 lymph nodes, could undergo resection of the lymph nodes and primary tumor following preoperative chemo-radiation. METHODS AND MATERILAS: Fifty-two patients were entered in the study, but six patients did not meet the criteria of the protocol and were excluded. The remaining 46 patients are the subject of this report. Patients underwent a split course of radiation, 4760 cGy to the primary and lymph nodes, with concurrent chemotherapy, cisplatin/5-FU, followed by surgery. RESULTS Four patients did not complete the chemo-radiation, because three expired and one refused to complete the treatment. Four patients who completed chemo-radiation did not undergo surgery, because two of them died of non-cancer-related causes, and in the other two patients, the nodes remained unresectable. Following chemo-radiation, the disease in the lymph nodes became resectable in 38/40 patients. Two patients who completed the course of chemo-radiation did not undergo surgery as per protocol because of pulmonary metastasis. One underwent radical vulvectomy and unilateral node dissection and the other radical vulvectomy only. The specimen of the lymph nodes was histologically negative in 15/37 patients. Nineteen patients developed recurrent and/or metastatic disease. The sites of failure were as follows: primary area only, 9; lymph node area only, 1; primary area and distant metastasis, 1; distant metastasis only, 8. Local control of the disease in the lymph nodes was achieved in 36/37 and in the primary area in 29/38 of the patients. Twenty patients are alive and disease-free, and five have expired without evidence of recurrence or metastasis. Two patients died of treatment-related complications. CONCLUSION High resectability and local control rates of the lymph nodes were obtained in patients with carcinoma of the vulva with N2/N3 nodes treated preoperatively with chemo-radiation.

Adenocarcinoma: A unique cervical cancer

Adenocarcinoma of the cervix constitutes only approximately 20% of all cervical carcinomas; therefore, specific Level 1 evidence to guide patient management is lacking. Most trials have included this histologic subtype but in insufficient numbers to do more than generate hypotheses from subset analyses. As a consequence, our understanding of the natural history and optimal management of adenocarcinoma of the cervix is limited. The optimal management of adenocarcinoma of the cervix continues to be a subject of debate among practitioners as to whether or not it should be different from squamous cell carcinoma and what would constitute this management. The purpose of this review was to give an overview of the current knowledge on adenocarcinoma of the cervix and its differences from squamous cell carcinoma with regard to risk factors, prognosis, survival rates, patterns of recurrence, and response to treatment. This article will focus on possible specific therapeutic directions to explore in the management of locally advanced adenocarcinomas.