Risk of developing chronic myeloid neoplasms in well-differentiated thyroid cancer patients treated with radioactive iodine.

Exposure to ionizing radiation increases the risk of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but such risks are not known in well-differentiated thyroid cancer (WDTC) patients treated with radioactive iodine (RAI). A total of 148 215 WDTC patients were identified from Surveillance, Epidemiology and End Results registries between 1973 and 2014, of whom 54% underwent definitive thyroidectomy and 46% received adjuvant RAI. With a median follow-up of 6.6 years, 77 and 66 WDTC patients developed MDS and MPN, respectively. Excess absolute risks for MDS and MPN from RAI treatment when compared to background rates in the US population were 6.6 and 8.1 cases per 100 000 person-years, respectively. Compared to background population rates, relative risks of developing MDS (3.85 (95% confidence interval, 1.7-7.6); P=0.0005) and MPN (3.13 (1.1-6.8); P=0.012) were significantly elevated in the second and third year following adjuvant RAI therapy, but not after thyroidectomy alone. The increased risk was significantly associated with WDTC size ⩾2 cm or regional disease. Development of MDS was associated with shorter median overall survival in WDTC survivors (10.3 vs 22.5 years; P<0.001). These data suggest that RAI treatment for WDTC is associated with increased risk of MDS with short latency and poor survival.

Enteral nutrition during the treatment of head and neck carcinoma: is a percutaneous endoscopic gastrostomy tube preferable to a nasogastric tube?

BACKGROUND: Multimodality treatments for patients with squamous cell head and neck carcinoma often produce significant mucositis and dysphagia, mandating enteral nutritional support. Patient preference has resulted in the increasing use of percutaneous endoscopic gastrostomy (PEG) tubes rather than nasogastric (NG) tubes. Anecdotal observations of prolonged PEG dependence and of a need for pharyngoesophageal dilatation in PEG patients prompted a retrospective review of the use of both types of feeding tubes. METHODS: Patients who were treated on clinical trials of radiotherapy or chemoradiotherapy for squamous cell head and neck carcinoma between 1989 and 1997 were reviewed retrospectively. Data were gathered regarding demographics, primary tumor site, T and N classifications, and the need for feeding tube placement. In patients requiring feeding tubes, the type and duration of the feeding tube, the need for tracheostomy, the need for pharyngoesophageal dilatation, and the degree of mucositis and dysphagia at baseline and at 1 month, 3 months, 6 months, and 12 months after beginning treatment were recorded. Comparisons were then made between the NG and the PEG groups. RESULTS: Ninety-one feeding tubes were placed in 158 patients over the 8-year interval. A hypopharyngeal primary site, female gender, a T4 primary tumor, and treatment with chemoradiotherapy were predictive of a need for feeding tube placement. NG tubes were placed in 29 patients, and PEG tubes were placed in 62 patients. PEG patients had more dysphagia at 3 months (59% vs. 30%, respectively; P = 0.015) and at 6 months (30% vs. 8%, respectively; P = 0.029) than NG patients. The median tube duration was 28 weeks for PEG patients compared with 8 weeks for NG patients, (P < 0.001). Twenty-three percent of PEG patients needed pharyngoesophageal dilatation compared with 4% of NG patients (P = 0.022). These end points could not be correlated with age, stage, primary tumor site, or tracheostomy placement. CONCLUSIONS: Although patients treated for head and neck carcinoma find that the PEG tube is a more acceptable route for enteral nutrition than the NG tube, in the authors' experience, a PEG tube was required for longer periods of time and was associated with more persistent dysphagia and an increased need for pharyngoesophageal dilatation. A randomized prospective trial is needed to test these observations.

Resectable esophageal carcinoma: local control with neoadjuvant chemotherapy and radiation therapy.

PURPOSE: To evaluate the usefulness of neoadjuvant chemotherapy and radiation therapy before esophagectomy for invasive cancer of the esophagus or gastroesophageal junction (GEJ). MATERIALS AND METHODS: The authors conducted a retrospective analysis of 154 patients who underwent esophagectomy for invasive cancer between September 1, 1991, and December 31, 1995. The end points evaluated were overall, disease-free, local-regional relapse-free, and systemic relapse-free survival. RESULTS: Seventy of the 154 patients received neoadjuvant combined-modality therapy (CMT) consisting of concurrent cisplatin and fluorouracil administration and accelerated, hyperfractionated radiation therapy. The remaining 84 patients underwent immediate esophagectomy. With a median follow-up of 34.7 months, the 3-year overall, disease-free, and distant metastatic relapse-free survival rates were 38.0%, 41.9%, and 56.0%, respectively. Although neoadjuvant therapy did not appear to prevent distant metastases, there was a dramatic effect on local control. After CMT, the 5-year local control rate was 90% compared to 64% after surgery (P < .001). Tumors in the GEJ recurred more frequently (P = .01); however, multivariate analysis showed CMT was the only independent predictor of local control. Postoperative mortality was 15.7% after CMT versus 5.9% without CMT (P = .05). CONCLUSION: Local control of esophageal cancer is excellent following neoadjuvant chemotherapy and radiation therapy. However, the effects of CMT on overall and disease-free survival are less clear due to significant differences between the treatment groups.

Use of concurrent chemotherapy, accelerated fractionation radiation, and surgery for patients with esophageal carcinoma.

BACKGROUND: The results of a Phase II study of concurrent chemotherapy and accelerated fractionation radiation therapy followed by surgical resection for patients with both adenocarcinoma and squamous cell carcinoma of the esophagus are presented. Pretreatment and postinduction staging were correlated with pathologic findings at surgery to assess the role of surgical resection and the predictive value of noninvasive staging techniques. METHODS: Patients received 2 induction courses with 4-day continuous intravenous infusions of cisplatin (20 mg/m2/day) and 5-fluorouracil (1000 mg/m2/day) beginning on Day 1 and Day 21, concurrent with a split course of accelerated fractionation radiation (1.5 grays [Gy] twice daily, to a total dose of 45 Gy). All patients were subsequently referred for surgical resection. A single, identical postoperative course of chemotherapy and 24 Gy accelerated fractionation radiation was planned for patients with residual tumor at surgery. RESULTS: Seventy-four patients were entered on this study; 72 patients were considered eligible and evaluable. Induction toxicity included nausea (85%), increased dysphagia (90%), neutropenia (<1000/mm3) (43%), thrombocytopenia (<20,000/mm3) (10%), and reversible nephrotoxicity (8%). Sixty-seven patients (93%) underwent surgery, and 65 (90%) were found to have resectable tumors. Twelve of these patients (18%) died perioperatively, and 18 (27%) had no residual pathologic evidence of disease. Resolution of symptoms and normalization of radiographic studies, endoscopy, or esophageal ultrasound did not identify pathologic complete responders accurately. No patient completing induction therapy and surgery experienced a locoregional recurrence. The Kaplan-Meier 4-year projected recurrence free and overall survival rates were 49% and 44%, respectively. CONCLUSIONS: Although this regimen is feasible, there was significant preoperative toxicity and perioperative mortality. Nonetheless, the recurrence free and overall survival rates were encouraging. However, no staging tool can predict a pathologic complete response after induction therapy accurately, suggesting a continued need for surgical resection.

Efficacy of high-dose oral leucovorin and 5-fluorouracil in advanced colorectal carcinoma. Plasma and tissue pharmacokinetics.

Thirty-one evaluable patients with advanced colorectal cancer were treated with oral leucovorin (LV) 500 mg/m2, administered hourly in four divided doses weekly for 6 weeks. Six patients received intravenous 5-FU at 450 mg/m2 and the remainder at 600 mg/m2 weekly for 6 weeks. This schedule was repeated after a 2-week rest period without medication. None of the patients had received previous chemotherapy. The results of the study showed a overall complete remission (CR) and partial remission (PR) of 45%. All responding patients received the 600-mg/m2 dose of 5-FU. There were five CR and nine PR. An additional seven (23%) patients had stable disease. Two of the seven received the 450-mg/m2 dose of 5-FU and the remainder received 600 mg/m2. The median disease-free interval for CR patients exceeded 25 months, while the interval for PR patients was 11.8 months. The median survival for CR patients was over 26.7 months and 16.5 months for the PR patients. The median survival for stable patients was 9.5 months and 5.5 months for patients with progressive disease. Toxicity included diarrhea in 70% of patients, excess lacrimal secretion in 35%, and nausea and vomiting in 25% There were no treatment-related deaths in this group. The authors conclude from this Phase I study that the optimal 5-FU dose in 600 mg/m2 combined with high-dose oral leucovorin for the treatment of advanced colorectal carcinoma.

Treatment of advanced-stage colorectal adenocarcinoma with fluorouracil and high-dose leucovorin calcium: a pilot study.

Thirty-one evaluable patients with measurable advanced colorectal carcinoma were entered into a pilot study that used weekly fluorouracil (5-FU) at the dose of 600 mg/m2 by bolus infusion administered midway during a two-hour leucovorin calcium infusion of 500 mg/m2. This regimen was repeated weekly for six doses. Twenty-seven of these patients (87%) were considered to be refractory to prior 5-FU therapy and four (13%) were previously untreated. All 31 patients successfully completed at least one 6-week cycle of this regimen with acceptable toxicity. The combined complete (CR) and partial response (PR) rate was 45% with another 25% of patients remaining stable. The 95% confidence levels for the responding patients are 27.6% and 62.7%, respectively. The remaining 30% of the patients had all received prior 5-FU therapy and progressed. All of the responding patients and 80% of the patients with stable disease received two or more cycles of this regimen after a 3- to 4-week interval off therapy. The median time to disease progression was 16.1 months for responding patients and 6.7 months for those patients with stable disease. The median survival for the responders was 20.6 months and for those with stable disease 9.8 months. The median survival for the nonresponding patients was 3.9 months. Toxicity included diarrhea in 70% of patients, skin rash (erythema) in 10%, stomatitis in 15%, nausea and vomiting in 25%, and myelosuppression in 10%. This study confirms and extends previous observations that demonstrate the improved efficacy of 5-FU when used with high-dose leucovorin in advanced colorectal carcinoma.

Bioavailability of high-dose oral leucovorin.

Fifteen adult subjects comprised the study group; 2 were colon cancer patients. Total leucovorin (citrovorum factor; CF) doses of 200, 400, 800, and 1600 mg were equally subdivided and administered at 0, 1, 2, and 3 hours. Three of the subjects were fasting and the other 12 were not. Quantitation of serum L-CF by Pediococcus cerevisiae and total reduced folates (TRF) by radio-assay were performed in 10 samples from each subject drawn over a 12-hour period after initiation of CF dosing. The mean serum levels of L-CF remained greater than 0.1 microM at 3 hours and the TRF 3.5 microM at 5 hours, respectively, after termination of CF dosing in all subjects treated at the 800- and 1600-mg dose schedule. At all CF dosage schedules employed, peak serum concentrations were reached within 4 and 6 hours after initiation of oral CF. Peak TRF concentrations at the 200-, 400-, 800-, and 1600-mg doses were 3.42 +/- 0.65, 4.05 +/- 1.04, 4.81 +/- 0.14, and 5.11 +/- 1.81 microM, respectively. Peak L-CF levels at 200, 400, 800, and 1600 were 0.15 +/- 0.11, 0.21 +/- 0.14, 0.23 +/- 0.11, and 0.34 +/- 0.16 microM. Based upon these observations, the following conclusions were reached: 1) no significant differences were observed in serum concentrations of folates between the 800- and 1600-mg dose schedules; 2) at these doses serum concentrations of L-CF and TRF were achieved that warrant a phase I investigation of high-dose oral CF with standard dose FUra in patients with advanced colorectal carcinoma.