Adjuvant therapy for gallbladder carcinoma: the Mayo Clinic Experience.

PURPOSE: To analyze the effect of adjuvant chemoradiotherapy on gallbladder carcinoma. METHODS AND MATERIALS: We retrospectively reviewed the records from consecutive patients who underwent R0 resection of gallbladder carcinoma between January 1, 1985, and December 31, 2004. Patients had either Stage I (T1-T2N0M0) or Stage II (T3N0M0 or T1-T3N1M0) disease. Patients undergoing adjuvant therapy received 5-fluorouracil chemotherapy concurrently with radiotherapy (median dosage, 50.4 Gy in 28 fractions). Adverse prognostic factors and the effect of adjuvant treatment on overall survival (OS) were evaluated. RESULTS: A total of 73 patients were included in the analysis; of these, 25 received adjuvant chemoradiotherapy. On univariate analysis, no adverse prognostic factors for OS reached statistical significance, but trends were noted for Stage N1 vs. N0 (p = .06), Nx vs. N0 (p = .09), Stage T3 vs. T1-T2 (p = .06), and histologic findings other than adenocarcinoma (p = .13). The median OS for patients receiving adjuvant chemoradiotherapy vs. surgery alone was 4.8 years and 4.2 years, respectively (log-rank test, p = .56). However, a significantly greater percentage of patients receiving adjuvant chemoradiotherapy had Stage II disease (p <.001). In the multivariate Cox model, increasing T and N category and histologic findings other than adenocarcinoma were significant predictors of decreased OS. Additionally, adjuvant chemoradiotherapy was a significant predictor of improved OS after adjusting for these prognostic factors (hazard ratio for death, 0.3; 95% confidence interval, 0.13-0.69; p = .004). CONCLUSION: After adjusting for the stage parameters and histologic findings, our data suggest that adjuvant chemoradiotherapy might improve OS for patients with gallbladder cancer.

Comparison of treatment tolerance and outcomes in patients with cervical cancer treated with concurrent chemoradiotherapy in a prospective randomized trial or with standard treatment.

PURPOSE: To compare the treatment and outcomes of cervical cancer patients treated with concurrent chemoradiotherapy (CT-RT) in a multi-institutional trial or as standard care. PATIENTS AND METHODS: We reviewed the records of 302 patients treated with CT-RT for locoregionally confined, intact cervical cancer between 1990 and 2005. Of the 302 patients, 76 were treated using cisplatin and 5-fluorouracil (C/F) on Radiation Therapy Oncology Group protocol 90-01 (CT-RT(90-01)); 226 underwent CT-RT as standard care with either C/F [CT-RT(SC(C/F)); n = 115] or weekly cisplatin [CT-RT(SC(WC)); n = 111). RESULTS: The CT-RT(90-01) patients more often had tumors >or=6 cm and were less often diabetic than were the CT-RT(SC) patients. The CT-RT(SC(WC)) patients were more likely than the CT-RT(SC(C/F)) patients to be >or=60 years old or to have Stage III-IV disease. During treatment, CT-RT(SC(C/F)) patients experienced more Grade 2-3 neutropenia and were, therefore, less likely to receive 200 mg/m(2) cisplatin than were either CT-RT(SC(WC)) or CT-RT(90-01) patients (52% vs. 77% vs. 85%, respectively; p <0.001). At 5 years, the disease-specific survival rates were greater for patients treated with C/F [CT-RT(SC(C/F)), 75%; CT-RT(90-01), 79%] than for those treated with CT-RT(SC(WC)) (58%; p = 0.02). On multivariate analysis, C/F chemotherapy, cisplatin dose >or=200 mg/m(2), Stage I-II disease, and negative pelvic lymph nodes were independent predictors of improved disease-specific survival. CONCLUSIONS: Even within a large comprehensive cancer center, the high rates of chemotherapy completion achieved on a multi-institutional trial can be difficult to reproduce in standard practice. Although C/F toxicity was greater in the standard care patients, their outcomes were similar to those of patients treated with C/F on Radiation Therapy Oncology Group protocol 90-01.

Anemia in cervical cancer patients: implications for iron supplementation therapy.

Iron deficiency and tumor bleeding are common causes of anemia in cervical cancer. Anemia has a negative prognostic influence, and its correction is thought to improve prognosis; therefore, most patients are treated with either transfusion and/or erythropoietin. At present little is known about the value of iron stores replenishment to increase hemoglobin levels in this setting. Untreated cervical cancer patients with a hemoglobin <12 g/dL were randomized to intramuscular iron or to transfusion. Iron dose was calculated according to [weight (kg)x(15--actual Hb)x2.4]+500 and administered by injections of 200 mg daily. In both arms, patients who did not achieve at least 10 g/dL hemoglobin before or during chemoradiation were transfused. Patients received standard pelvic radiation plus six weekly doses of cisplatin. Hematic counts were performed before starting chemoradiation and weekly thereafter. Fifteen patients were studied; six were assigned to iron and nine to transfusion. Mean basal hemoglobin levels were 9.9 and 9.5 g/dL respectively. Total iron, saturation index, binding capacity, and ferritin were within normal limits, although there was a high variability among the patients. The mean total dose of iron administered was 1229 mg. Two weeks after randomization, hemoglobin increased to 10.9 and 10.2 g/dL respectively. At wk 1 of treatment and thereafter, levels were higher in the iron arm, in whom the values were close or higher than 12 g/dL (p=0.03). The median number of units transfused were 0 in the iron group and 2 in the transfusion (p=0.02) arm. Parenteral iron seems to be effective to increase hemoglobin in cervical cancer patients.

Cisplatin, fluorouracil, celecoxib, and RT in resectable esophageal cancer: preliminary results.

Esophageal cancer frequently expresses cyclooxygenase-2 (COX-2) enzyme. In preclinical studies, COX-2 inhibition results in decreased cell proliferation and potentiation of chemotherapy and radiation. We report preliminary results of a phase II study conducted by the Hoosier Oncology Group in patients with potentially resectable esophageal cancer. All patients received cisplatin at 75 mg/m2 given on days 1 and 29 and fluorouracil (5-FU) at 1000 mg/m2 on days 1 to 4 and 29 to 32 with radiation (50.4 Gy beginning on day 1). Celecoxib (Celebrex) was administered at 200 mg orally twice daily beginning on day 1 until surgery and then at 400 mg orally twice daily until disease progression or unexpected toxicities, or for a maximum of 5 years. Esophagectomy was performed 4 to 6 weeks after completion of chemoradiation. The primary study endpoint was pathologic complete response (pCR). Secondary endpoints included response rate, toxicity, overall survival, and correlation between COX-2 expression and pCR. Thirty-one patients were enrolled from March 2001 to July 2002. Respective grade 3/4 toxicities were experienced by 58%/19% of patients, and consisted of granulocytopenia (16%), nausea/vomiting (16%), esophagitis (10%), dehydration (10%), stomatitis (6%), and diarrhea (31%). Seven patients (24%) required initiation of enteral feedings. There have been seven deaths so far, resulting from postoperative complications (2), pulmonary embolism (1), pneumonia (1), and progressive disease (3). Of the 22 patients (71%) who underwent surgery, 5 had pCR (22%). We conclude that the addition of celecoxib to chemoradiation is well tolerated. The pCR rate of 22% in this study is similar to that reported with the use of preoperative chemoradiation in other trials. Further follow-up is necessary to assess the impact of maintenance therapy with celecoxib on overall survival.

Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma.

PURPOSE: This study was performed to evaluate the outcome of patients with gallbladder cancer who received postoperative concurrent chemotherapy and radiation therapy. METHODS AND MATERIALS: Curative resection followed by adjuvant combined modality therapy with external beam radiation therapy (EBRT) and chemotherapy was attempted in 21 consecutive gallbladder carcinoma (GBC) patients at the Mayo Clinic from 1985 through 1997. All patients received concurrent 5-fluorouracil during EBRT. EBRT fields encompassed the tumor bed and regional lymph nodes (median dose of 54 Gy in 1.8-2.0-Gy fractions). One patient received 15 Gy intraoperatively after EBRT. A retrospective analysis was performed for the end points of local control, distant failure, and overall survival. RESULTS: After maximal resection, 12 patients had no residual disease on pathologic evaluation, 5 had microscopic residual disease, and 4 had gross residual disease. One patient had Stage I disease, and 20 had Stage III-IV disease. With median follow-up of 5 years (range: 2.6-11.5 years), 5-year survival for the entire cohort was 33%. The 5-year survival rate of patients with Stage I-III disease was 65% vs. 0% for those with Stage IV disease (p < 0.02). For patients with no residual disease, 5-year survival was 64% vs. 0% for those with residual disease (p = 0.002). The median survival was 0.6, 1.4, and 5.1 years for patients with gross residual, microscopic residual, and no residual disease, respectively (p = 0.02). The 5-year local control rate for the entire cohort was 73%. Two-year local control rates were 0%, 80%, and 88% for patients with gross residual, microscopic residual, or no residual disease, respectively (p < 0.01). Five-year local control rates were 100% for the 6 patients who received total EBRT doses >54 Gy (microscopic residual, 3 patients; gross residual, 1 patient; negative but narrow margins, 2 patients) vs. 65% for the 15 who received a lower dose (3, gross residual; 2, microresidual; 10, negative margins). CONCLUSION: Patients with completely resected (negative margins) GBC followed by adjuvant EBRT plus 5-fluorouracil chemotherapy had a relatively favorable prognosis, with a 5-year survival rate of 64%. These results seem to be superior to historical surgical controls from the Mayo Clinic and other institutions, which report 5-year survival rates of approximately 33% with complete resection alone. Both tumor stage and extent of resection seemed to influence survival and local control. More aggressive measures using current cancer therapies and integration of new cancer treatment modalities will be required to favorably impact on the poor prognosis of patients with Stage IV or subtotally resected GBC. Additional investigation leading to earlier diagnosis is warranted, because most patients with GBC present with advanced disease.

Long-term follow-up of RTOG 92-10: cervical cancer with positive para-aortic lymph nodes.

PURPOSE: The purpose of this study was to evaluate the late toxicity and efficacy of twice-daily external irradiation to the pelvis and lumbar para-aortic region with brachytherapy and concurrent chemotherapy for carcinoma of the cervix with positive para-aortic lymph nodes. PATIENTS AND METHODS: This study was designed to administer twice-daily radiation doses of 1.2 Gy to the pelvis and lumbar para-aortic lymph nodes (simultaneously) at 4-6-h intervals, 5 days per week. The total external radiation doses were 24-48 Gy to the whole pelvis, 12-36 Gy parametrial boost, and 48 Gy to the lumbar para-aortic region with an additional boost to a total dose 54-58 Gy to the positive para-aortic lymph node(s). One or two intracavitary implants were performed to deliver a minimum total dose of 85 Gy to point A. Cisplatin (75 mg/m(2); Days 1, 22, and 43) and 5-fluorouracil (1,000 mg/m(2)/24 h x 4 consecutive days, beginning on Days 1, 22, and 43) were given for two or three cycles. RESULTS: Thirty patients with clinical Stages I-IV carcinoma of the cervix with biopsy-proven para-aortic lymph node metastases were enrolled in this study. Hyperfractionated external irradiation was completed in 87% (26 of 30). Brachytherapy was given in two implants to 47% (14 of 30) and in one implant to 33% (10 of 30); 13% (4 of 30) did not receive brachytherapy, 1 patient had three implants, and 1 had five high-dose-rate implants. Radiotherapy was completed per protocol in 70%. Three cycles of chemotherapy were given to 23% (7 of 30); 73% (22 of 30) received two cycles, and 1 patient did not receive chemotherapy. The acute toxicity from chemotherapy was Grade 1 in 3%, Grade 2 in 17%, Grade 3 in 48%, and Grade 4 in 28%. Acute toxicity from radiotherapy was Grade 1 in 7%, Grade 2 in 34%, Grade 3 in 21%, and Grade 4 in 28%. Late toxicity was Grade 1 in 10%, Grade 2 in 17%, Grade 3 in 7%, and Grade 4 in 17%. Grade 5 toxicity occurred in 1 patient during the course of therapy, but none had a late Grade 5 toxicity. The median follow-up time for the 7 patients alive at the time of last follow-up was 57 months. The overall survival estimates were 46% at 2 years and 29% at 4 years. The probability of local-regional failure was 40% at 1 year and 50% at 2 and 3 years. The probability of disease failure at any site was 46% at 1 year, 60% at 2 years, and 63% at 3 years. CONCLUSION: The results suggest that twice-daily external irradiation to the pelvis and lumbar para-aortic region with brachytherapy and concurrent chemotherapy resulted in an unacceptably high rate (17%, 5 of 29) of Grade 4 late toxicity. One patient died of acute complications of therapy. The survival estimates seem no better than standard fractionation irradiation without chemotherapy.

Role of nutrition support during induction chemoradiation therapy in esophageal cancer.

BACKGROUND: Preoperative chemoradiation therapy (CRT) potentially benefits a subgroup of patients with esophageal cancer. The ability to administer aggressive CRT may depend on the initial nutritional status and the ability to sustain nutrition during therapy. Parenteral nutrition support during CRT may lead to complications that limit its usefulness and negate any potential benefit. METHODS: Data were analyzed to evaluate the role of parenteral nutrition support (PNS) in patients receiving CRT. Forty-five consecutive patients with locoregional esophageal cancer, enrolled in a phase I/II trial of induction CRT, were analyzed. On the basis of the nutrition support received, two groups were defined as follows: group I (with PNS, n = 30) and group II (without PNS, n = 15). Results were compared in terms of chemotherapy (CT) dose tolerated, morbidity of CRT, response rates, and surgical outcome in groups with and without PNS. RESULTS: The two groups were comparable for demographic data, stage and site of disease, and performance status. There was no significant difference between the groups in the nutritional parameters (weight and serum albumin) before and after CRT. Group I patients received significantly more (% of total calculated dose) CT compared with group II (5-fluorouracil [5-FU], 86.4% vs 68.8%, p = .02; cisplatin [CDDP], 90.8% vs 78.2%, p = .05; and interferon alpha-2b [IFN-alpha], 95.4% vs 79.8%, p = .05, in groups I and II, respectively). Major (grade III/IV) adverse effects of CT were hematologic (group I, 93.3% vs group II, 86.6%, p = .59) and gastrointestinal (group I, 56.67% vs group II, 33.3%, p = .2). Postsurgical staging revealed complete response in 10 (22%) and a major response in 23 (51%) patients, although the response rates were similar in the two groups (group I, 76.6% vs group II, 66.6%, p = .8). Surgical morbidity (51.8% vs 61.5%, p = .73), mortality (7.4% vs 7.6%, p = 1.00), and hospital stay (22.5 vs 19.6 days, p = .63) were also similar in the two groups. CONCLUSIONS: PNS can be provided to these patients without an increased risk of CRT or resection-related morbidity. Although early and prolonged PNS facilitates administration of complete CRT doses, no benefit is derived from the administration of more CRT in the present regimen. The utility of PNS in this setting is unclear and, until further clarified, should not be applied routinely to this cohort of patients.

Metabolic alterations in implanted human tumors after combined radiation and hyperthermia therapy measured by in vivo 31P MRS.

The bioenergetics of human lung tumors grown subcutaneously in KSN nude mice, were studied in vivo using 31P NMR spectroscopy up to 27 days following radiotherapy and/or hyperthermia. Six tumors were treated with radiation (20 Gy, single fraction) and hyperthermia (44 degrees C, 10 min). There was a significant increase in the ratio of inorganic phosphate to beta-nucleoside triphosphate (Pi/beta-NTP) 24 h after radiation plus hyperthermia (p < .01), but a significant decrease 6 days after the treatment (p < .05) relative to untreated controls. Furthermore, the combined therapy produce significant acidosis at 24 h post therapy followed by significant alkalosis at 6 days compared to no treatment. This biphasic pattern was also significant in comparison with the pretreatment values of Pi/beta-NTP and pH. The combined therapy produced not only tumor decline at 24 h indicated by increased Pi/beta-NTP ratio and acidic pH shift, but also metabolic activation of tumor cells at 6 days indicated by decreased Pi/beta-NTP ratio and alkalotic pH shift. The tumor blood flow estimated by hydrogen ion clearance curves were completely depleted at 24 h and fully recovered to pretreatment level at 6 days. Reasonable close negative correlation between the blood flow and Pi/beta-NTP ratio (r = -0.59, p < .01) indicated that the two contrasting physiological states were closely related to tumor perfusion status. The 31P spectra of tumors following the combined therapy were concluded to demonstrate additive physiological effects of hyperthermia and radiation.