James A. Knol

Clinical practice guidelines in oncology

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

Phase II Trial of High-Dose Conformal Radiation Therapy With Concurrent Hepatic Artery Floxuridine for Unresectable Intrahepatic Malignancies

PURPOSE A phase II trial was conducted to determine if high-dose radiation with concurrent hepatic arterial floxuridine would improve survival in patients with unresectable intrahepatic malignancies. PATIENTS AND METHODS Three-dimensional conformal high-dose radiation therapy was delivered concurrently with hepatic arterial floxuridine in 128 patients. The radiation dose was based on a normal-tissue complication probability model and subjected the patient to an estimated maximum risk of radiation-induced liver disease of 10% to 15%. The study design provided more than 80% power to detect a two-fold increase in median survival compared with historical controls at a 5% significance level. RESULTS The median radiation dose delivered was 60.75 Gy (1.5-Gy fractions bid). At a median follow-up time of 16 months (26 months in patients who were alive) the median survival was 15.8 months (95% CI, 12.6 to 18.3 months), significantly longer than in the historical control. The actuarial 3-year survival was 17%. The total dose was the only significant predictor of survival. Primary hepatobiliary tumors had a significantly greater tendency to remain confined to the liver than did colorectal cancer metastases. Overall toxicity was acceptable, with 27 patients (21%) and 11 patients (9%) developing grade 3 and 4 toxicity, respectively, and one treatment-related death. CONCLUSION The results suggest that, compared with historical controls, high-dose focal liver irradiation with hepatic artery floxuridine prolongs survival in patients with unresectable chemotherapy-refractory metastatic colorectal cancer and primary hepatobiliary tumors. This provides a rationale for intensification of local therapy for unresectable hepatobiliary cancers and integration of this regimen with newer systemic therapy for patients with colorectal cancer.

Dual-phase helical CT of nonfunctioning islet cell tumors

PURPOSE The aim of this study was to evaluate the utility of dual-phase imaging in the assessment of nonfunctioning islet cell tumors (NFITs). METHOD Six patients with histologically and biochemically proven NFIT were evaluated by arterial and portal venous dual-phase helical CT. Scan delay was 20 s for the arterial phase and 70 s for the portal phase. Each phase was assessed by consensus reading and specifically evaluated for tumor conspicuity, hepatic metastases, vascular encasement by tumor, and presence of lymphadenopathy. RESULTS Overall, tumor conspicuity was greater in the arterial phase (5/6) than in the portal venous phase (1/6) with a mean tumor/normal pancreas attenuation difference of 31.8 HU in the arterial phase compared with 19.2 HU in the portal venous phase. The arterial phase detected a total of 17 liver metastases compared with 9 seen in the portal phase. Lymph node enlargement was noted in three patients, which, although visible in both phases, was more easily discernible in the arterial phase. Venous encasement by tumor was better evaluated on the delayed portal venous phase than the arterial phase. CONCLUSION Dual-phase helical CT scanning leads to improvement in the detection and staging of NFITs.

Comparisons of dynamic infusion and delayed computed tomography, intraoperative ultrasound, and palpation in the diagnosis of liver metastases*

The purpose of this study was to determine whether delayed computed tomography (DCT) of the liver would more accurately detect hepatic malignancy when compared with bolus contrast-enhanced dynamic computed tomography (BCDCT). Fifty-one patients who required operation for intra-abdominal malignancy (92% with colorectal cancers) underwent preoperative BCDCT followed by DCT. At operation, palpation and intraoperative ultrasound (IOUS) examination of the liver were performed for localization and biopsy of tumor nodules. The standard for diagnosis was defined for this study as the combined results of IOUS, palpation, and biopsy. The sensitivities of BCDCT and DCT for hepatic metastases were 50% and 54%, respectively, with a corresponding specificity of 72% for each. DCT demonstrated no significant improvement over BCDCT in the detection of individual hepatic lesions. The sensitivity of palpation for the detection of metastases was 82%, equal to that of IOUS. Both palpation and IOUS were significantly superior to BCDCT or DCT in excluding false-positive and false-negative results (p < 0.001). IOUS failed to identify surface lesions less than 1.0 cm in diameter (sensitivity: 40%). Conversely, palpation was limited in the detection of subsurface tumors less than 1.0 cm in diameter (sensitivity: 33%). Combined IOUS and palpation were significantly more accurate in the detection of hepatic metastases than any single modality that was evaluated (p < 0.001).

Management of spontaneous umbilical hernia disruption in the cirrhotic patient

Umbilical hernia is a common finding in cirrhotic patients with ascites. Spontaneous disruption of the hernia and attendant discharge of ascitic fluid is an unusual and rarely reported complication in these patients and is associated with an overall mortality rate of nearly 30%. During the 5-year period 1977–1982, nine patients with hepatic cirrhosis and ascites were treated for spontaneous rupture of an umbilical hernia. Ascites was attributed to alcoholic cirrhosis in all cases and was present for an average of 21 months prior to rupture. In two cases, failed peritoneovenous shunts resulted in reaccumulation of massive ascites. Initial management included sterile occlusive dressings, fluid repletion, and intravenous antibiotic administration. Hernia repair was performed an average of 4.2 days after rupture. General anesthesia was used in eight cases and local anesthesia in one case. In one instance, the hernia became incarcerated and required urgent repair. Postoperative complications, including wound infection and colonic dilatation, occurred separately in two patients (22%). One patient died of hepatic failure 28 days after operation, for an overall mortality rate of 11%. Surviving patients have been followed for an average of 8 months, and most have done well. Spontaneous rupture of umbilical hernia in patients with ascites occurs uncommonly. Operative management is indicated uniformly and can be conducted safely when the patients condition has stabilized. The prognosis is favorable for patients with good hepatic reserve.

Completion gastrectomy for postsurgical gastroparesis syndrome. Preliminary results with 15 patients.

Postsurgical gastroparesis syndrome (PGS) is a complex disorder characterized by postprandial nausea, vomiting, and gastric atony without evidence of mechanical gastric outlet obstruction. These symptoms can be disabling and are frequently unresponsive to drug therapy. Fifteen patients with documented PGS, including 13 women and two men, were recently treated by completion gastrectomy (CG) over a 5-year period. Gastric emptying study (GES) was markedly prolonged in 12 of the patients studied, and improved partially in only one patient (8%) with the administration of metoclopramide alone or combined with other gastrokinetic drugs. Patients were evaluated both before and after surgery, using a modified Visick rating system and a severity of symptoms (SS) score based on seven gastrointestinal (G.I.) and five systemic variables. All 15 patients underwent CG and reconstruction with a 50 cm Roux-en-Y limb. There were no operative deaths or complications related to the esophagojejunal anastomosis. Mean postoperative follow-up was 13.9 months, with a range of 2–65 months. After CG, the Visick rating and overall SS score improved significantly. The improvement in SS score was primarily due to a significant decrease in G.I. symptoms with little or no change in systemic symptoms. Overall, 86% of patients reported a satisfactory clinical result. CG, while seemingly radical, can be performed with low risk, and for properly selected patients with PGS, may be the treatment of choice.

Low molecular weight dextran in experimental pancreatitis: Effects on pancreatic microcirculation

UNLABELLED Although low molecular weight (LMW) dextran has been said to decrease the lethality of experimental acute pancreatitis (AP) by reversing stasis in the pancreatic microcirculation, the actual mechanism(s) of action is unknown. This investigation was designed to measure the effects of low molecular weight dextran on pancreatic capillary flow (QCAP) and arteriovenous shunt flow (QAVS), and on pancreatic oxygen consumption (O2CP) following bile-trypsin-induced AP in dogs. Total pancreatic blood flow (QT) was measured with an electromagnetic flow probe on the superior pancreaticoduodenal artery (SPDA). QAVS was measured by liver trapping of 99mTc-albumin microspheres after SPDA injection. QCAP was calculated as QT minus QAVS. Seventeen dogs were treated with lactated Ringers (LR) solution at 6.5 ml/kg/hr; 10 dogs were treated with LMW dextran 10% in normal saline at 1.5 ml/kg/hr plus LR at 5.0 ml/kg/hr. Mean arterial and central venous pressures remained constant throughout the 4-hr experiment. In the dogs receiving LR only, QT decreased from 42.7 to 24.4 ml/min (P less than 0.001); QAVS remained constant at 1.35 +/- 0.04 ml/min. During the first 30 min O2CP decreased from 1.17 to 0.76 ml O2/min (P less than 0.05) and remained constant thereafter. LMW dextran treatment altered none of these hemodynamic or metabolic parameters significantly. CONCLUSIONS bile trypsin AP in the dog causes significant decreases in QT and QCAP without altering QAVS. The decrease in O2CP in association with a constant QAVS suggests a metabolic block to oxygen uptake at the cellular level. Continuous infusion of LMW dextran at a dose of 1.5 ml/kg/hr in the dog does not reverse these abnormalities.

A phase II study of preoperative capecitabine and radiation therapy in patients with rectal cancer

Objectives:The purpose of this study was to evaluate the safety and efficacy of preoperative capecitabine and radiation therapy (RT) in patients with locally advanced rectal cancer (LARC). Methods:Patients with adenocarcinoma of the rectum stage ≥T3 or ≥N1 were treated with capecitabine 1330 mg/m2 per day in 2 divided doses days 1 to 42 and 50.4 Gy of RT in 28 1.8-Gy fractions. Patients with metastatic disease were eligible provided that operative intervention on primary site was anticipated. Surgery resection occurred 4 to 6 weeks after completion of preoperative therapy. Results:Thirty eligible patients were enrolled at two institutions. Median age and performance status were 62 years and 90%, respectively. Twenty-eight patients (93%) completed combined modality therapy and 27 underwent resection, including 17 abdominal-perineal and 9 low anterior resections. Three of 27 (11%) had pathologic complete response (pCR) with an additional 7 (26%) having minimal residual disease. Two patients who were felt to require abdominal perineal resection prior to combined modality therapy (CMT) were able to have sphincter-sparing surgery. No patients had progression during CMT which precluded surgical resection. Treatment was well tolerated with ≥grade 3 toxicities limited to diarrhea (5 patients), hand-foot syndrome (1 patient), dermatitis (1 patient). Twenty-four patients are living, 18 with no evidence of disease. Conclusions:The combination of preoperative capecitabine and RT in patients with LARC has significant antitumor activity, efficacy, and a low toxicity profile.

Surgery for primary and metastatic colorectal cancer.

Carcinoma of the colon and rectum currently ranks as the second leading cause of death from cancer in the United States. Surgery remains the cornerstone of treatment for colorectal cancer but has inherent limitations imposed by the biology and stage of the tumor and its location. Ultimately, 50% of patients who undergo curative resection develop local, regional, or widespread recurrence. These statistics have remained relatively constant over several decades despite improved methods of early diagnosis and surgical treatment but may change as new multimodality treatment regimens are developed and clinically evaluated. This article summarizes the surgical management of colorectal cancer and discusses issues pertaining to postoperative surveillance and the diagnosis and management of local or widespread cancer recurrence.

A phase I clinical and pharmacology study using amifostine as a radioprotector in dose-escalated whole liver radiation therapy.

PURPOSE Diffuse intrahepatic tumors are difficult to control. Whole-liver radiotherapy has been limited by toxicity, most notably radiation-induced liver disease. Amifostine is a prodrug free-radical scavenger that selectively protects normal tissues and, in a preclinical model of intrahepatic cancer, systemic amifostine reduced normal liver radiation damage without compromising tumor effect. We hypothesized that amifostine would permit escalation of whole-liver radiation dose to potentially control microscopic disease. We also aimed to characterize the pharmacokinetics of amifostine and its active metabolite WR-1065 to optimize timing of radiotherapy. METHODS AND MATERIALS We conducted a radiation dose-escalation trial for patients with diffuse, intrahepatic cancer treated with whole-liver radiation and intravenous amifostine. Radiation dose was assigned using the time-to-event continual reassessment method. A companion pharmacokinetic study was performed. RESULTS Twenty-three patients were treated, with a maximum dose of 40 Gy. Using a logistical regression model, compared with our previously treated patients, amifostine increased liver tolerance by 3.3 ± 1.1 Gy (p = 0.007) (approximately 10%) with similar response rates. Peak concentrations of WR-1065 were 25 μM with an elimination half-life of 1.5 h; these levels are consistent with radioprotective effects of amifostine in patients. CONCLUSION These findings demonstrate for the first time that amifostine is a normal liver radioprotector. They further suggest that it may be useful to combine amifostine with fractionated or stereotactic body radiation therapy for patients with focal intrahepatic cancer.