A phase I trial of concurrent sorafenib and stereotactic radiosurgery for patients with brain metastases.

We hypothesized that sorafenib (BAY 43-9006), an oral multi-kinase inhibitor, used in combination with SRS will improve overall intracranial control. This Phase I study assesses the safety, tolerability, and maximal tolerated dose of sorafenib administered with SRS to treat 1-4 brain metastases. This was an open label phase I dose escalation study with an expansion cohort. Eligible adults had 1-4 brain metastases from solid malignancies. Sorafenib was begun 5-7 days prior to SRS and continued for 14 days thereafter. Dose escalation of sorafenib was conducted via a "3 + 3" dose escalation design. Dose limiting toxicities (DLT) were determined 1 month after SRS and defined as ≥grade 3 neurologic toxicities. Twenty-three patients were enrolled. There were no DLTs at dose level 1 (400 mg per day) or dose level 2 (400 mg twice per day). An expansion cohort of 17 patients was treated at dose level 2. There were six grade 3 toxicities: hypertension (n = 2), rash (n = 1), lymphopenia (n = 1), hypokalemia (n = 1), fatigue (n = 1) and hand-foot syndrome (n = 1). All of these were attributable to sorafenib and not to the combination with SRS. The median time to CNS progression was 10 months, 1 year CNS progression-free survival was 46%, the median overall survival was 11.6 months and the 1 year overall survival was 46%. The use of sorafenib concurrent with SRS for the treatment of 1-4 brain metastases is safe and well tolerated at 400 mg twice a day. Our recommended phase II dose of concurrent sorafenib with SRS would be 400 mg twice daily.

Association between hospital case volume and the use of bronchoscopy and esophagoscopy during head and neck cancer diagnostic evaluation.

BACKGROUND: There are no clinical guidelines on best practices for the use of bronchoscopy and esophagoscopy in diagnosing head and neck cancer. This retrospective cohort study examined variation in the use of bronchoscopy and esophagoscopy across hospitals in Michigan. METHODS: A total of 17,828 patients were identified with head and neck cancer in the 2006 to 2010 Michigan State Ambulatory Surgery Databases. A hierarchical, mixed-effect logistic regression was used to examine whether a hospital's risk-adjusted rate of concurrent bronchoscopy or esophagoscopy was associated with its case volume (< 100, 100-999, or ≥ 1000 cases per hospital) for those undergoing diagnostic laryngoscopy. RESULTS: Of 9218 patients undergoing diagnostic laryngoscopy, 1191 (12.9%) received concurrent bronchoscopy and 1675 (18.2%) underwent concurrent esophagoscopy. The median hospital rate of bronchoscopy was 2.7% (range, 0%-61.1%), and low-volume (odds ratio [OR] = 27.1; 95% confidence interval [CI] = 1.9, 390.7) and medium-volume (OR = 28.1; 95% CI = 2.0, 399.0) hospitals were more likely to perform concurrent bronchoscopy compared to high-volume hospitals. The median hospital rate of esophagoscopy was 5.1% (range, 0%-47.1%), and low-volume (OR = 9.8; 95% CI = 1.5, 63.7) and medium-volume (OR = 8.5; 95% CI = 1.3, 55.0) hospitals were significantly more likely to perform concurrent esophagoscopy relative to high-volume hospitals. CONCLUSIONS: Patients with head and neck cancer who are undergoing diagnostic laryngoscopy are much more likely to undergo concurrent bronchoscopy and esophagoscopy at low- and medium-volume hospitals than at high-volume hospitals. Whether this represents overuse of concurrent procedures or appropriate care that leads to earlier diagnosis and better outcomes merits further investigation.

Phase II Trial of Paclitaxel/Cisplatin Followed by Surgery and Adjuvant Radiation Therapy and 5-Fluorouracil/Leucovorin for Gastric Cancer (ECOG E7296).

BACKGROUND: Randomized trials have shown an increase in survival with perioperative chemotherapy as well as with postoperative chemoradiation. It was hypothesized that combining induction chemotherapy with postoperative chemoradiation would be well tolerated and improve pathologic complete response. METHODS: Patients with resectable cancers of the stomach/gastroesophageal junction were eligible. Neoadjuvant chemotherapy consisted of 3 cycles of paclitaxel and cisplatin. Adjuvant therapy consisted of 1 cycle of 5-fluorouracil (FU) and leucovorin (LV) followed by chemoradiation (45 Gy with concurrent 5-FU/LV). Chemoradiation was followed by 2 additional cycles of 5-FU/LV. Response to neoadjuvant therapy was based on pathology. RESULTS: From 1999 to 2002, 38 eligible patients were enrolled; 35 completed induction chemotherapy, and 29 went on to surgery. Sixteen patients did not develop metastatic progression, 10 developed metastatic disease, and 12 were unevaluable. There were no pathologic complete responses after induction therapy. Twenty-five of 38 patients suffered grade 3-4 toxicities during induction paclitaxel/cisplatin. Six of the 7 patients who received postoperative therapy suffered grade 3-4 toxicities. Only 3 of 38 (7.9%) eligible patients completed all assigned treatment. The median overall survival was 1.6 years, and the 2-year survival was 40%. CONCLUSIONS: This regimen of neoadjuvant paclitaxel/cisplatin followed by postoperative 5-FU/LV-based chemoradiation did not have a high enough response rate and proved to be too toxic for further development.

Long-term follow-up of a Phase II trial of high-dose radiation with concurrent 5-fluorouracil and cisplatin in patients with anal cancer (ECOG E4292).

PURPOSE: Although chemoradiation using 5-fluorouracil (5-FU) and mitomycin-C (MMC) is the standard of care in the treatment of anal cancer, many patients are unable to tolerate MMC. This Phase II clinical trial was performed to determine whether cisplatin could replace MMC in the treatment of anal cancer. METHODS AND MATERIALS: Thirty-three patients with localized anal cancer were enrolled. One patient registered but never received any assigned therapy and was excluded from all analyses. Between February 1, 1993, and July 21, 1993, 19 patients were accrued to Cohort 1. Radiation consisted of 45 Gy to the primary tumor and pelvic nodes, followed by a boost to the primary and involved nodes to 59.4 Gy. A planned 2-week treatment break was used after 36 Gy. Concurrent chemotherapy consisted of 5-FU 1,000 mg/m(2)/day on Days 1 to 4 and cisplatin 75 mg/m(2) on Day 1. A second course of 5-FU and cisplatin was given after 36 Gy, when the patient resumed radiation therapy. Between April 4, 1996, and September 23, 1996, an additional 13 patients (Cohort 2) were accrued to the study and received the same treatment except without the planned treatment break. RESULTS: Complete response was seen in 78% (90% CI, 63-89) of patients and was higher in patients who did not get a planned treatment break (92% vs. 68%). The overall Grade 4 toxicity rate was 31%. One treatment-related death (Grade 5) occurred in a patient who developed sepsis. The 5-year overall survival was 69%. CONCLUSIONS: Radiation therapy, cisplatin, and 5-FU resulted in an overall objective response (complete response + partial response) of 97%. Although the 5-year progression-free survival was only 55%, the overall 5-year survival was 69%. Given the excellent salvage provided by surgery, this study affirms that cisplatin-based regimens may be an alternative for patients who cannot tolerate the severe hematologic toxicities associated with mitomycin-based chemoradiation regimens.

Ad libitum feeding decreases hospital stay for neonates after pyloromyotomy.

PURPOSE: The optimal feeding regimen for neonates after pyloromyotomy for hypertrophic pyloric stenosis (HPS) remains controversial. This study sought to compare ad libitum feeding to a Conventional feeding regimen with regard to time to full diet, length of hospital stay, and readmission rates. METHODS: A 6-month review of 36 consecutive patients who underwent pyloromyotomy for HPS was undertaken. Patients were fed in 1 of 2 ways according to specific surgeon preference. Conventional Regimen patients (n = 19) were kept nothing by mouth (NPO) for 6 hours after surgery and incrementally advanced to full feedings. ad libitum (n = 17) patients were kept NPO until fully reversed from anesthesia and then given full strength formula or breast milk. Discharge was considered when 2 feedings of 60 mL were tolerated. RESULTS: Twenty-eight males and 8 females with a mean age of 5.0 plus minus 1.7 (SD) weeks, gestational age of 39 plus minus 2.1 weeks, weight of 4.0 plus minus 0.9 kg, and operating time of 56 plus minus 12 minutes were studied. The interval from operating room to full diet was significantly less with ad libitum feeding than on the conventional regimen (20.3 plus minus 5.0 v. 25.4 plus minus 8.3 hours, P <.05). The Ad Libitum group also had a significantly decreased length of hospital stay (28.5 plus minus 8.9 hours v. 35.8 plus minus 11 hours; P <.05). There were no readmissions in either group. CONCLUSIONS: Ad libitum feedings decrease time to full diet and discharge without an increase in readmission rates. The estimated potential savings per patient using ad libitum feedings were $392.00. Thus, the use of ad libitum feedings after pyloromyotomy for HPS appears indicated.