Thromboembolic Events Associated with Thalidomide and Multimodality Therapy for Soft Tissue Sarcomas: Results of RTOG 0330.

Introduction. RTOG 0330 was developed to address the toxicity of RTOG 9514 and to add thalidomide (THAL) to MAID chemoradiation for intermediate/high grade soft tissue sarcomas (STSs) and to preoperative radiation (XRT) for low-grade STS. Methods. Primary/locally recurrent extremity/trunk STS: ≥8 cm, intermediate/high grade (cohort A): >5 cm, low grade (cohort B). Cohort A: 3 cycles of neoadjuvant MAID, 2 cycles of interdigitated THAL (200 mg/day)/concurrent 22 Gy XRT, resection, 12 months of adjuvant THAL. Cohort B: neoadjuvant THAL/concurrent 50 Gy XRT, resection, 6 months of adjuvant THAL. Planned accrual 44 patients. Results. 22 primary STS patients (cohort A/B 15/7). Cohort A/B: median age of 49/47 years; median tumor size 12.8/10 cm. 100% preoperative THAL/XRT and surgical resection. Three cycles of MAID were delivered in 93% cohort A. Positive margins: 27% cohort A/29% cohort B. Adjuvant THAL: 60% cohort A/57% cohort B. Grade 3/4 venous thromboembolic (VTE) events: 40% cohort A (1 catheter thrombus and 5 DVT or PE) versus 0% cohort B. RTOG 0330 closed early due to cohort A VTE risk and cohort B poor accrual. Conclusion. Neoadjuvant MAID with THAL/XRT was associated with increased VTE events not seen with THAL/XRT alone or in RTOG 9514 with neoadjuvant MAID/XRT.

Behavioural improvements with thalamic stimulation after severe traumatic brain injury.

Widespread loss of cerebral connectivity is assumed to underlie the failure of brain mechanisms that support communication and goal-directed behaviour following severe traumatic brain injury. Disorders of consciousness that persist for longer than 12 months after severe traumatic brain injury are generally considered to be immutable; no treatment has been shown to accelerate recovery or improve functional outcome in such cases. Recent studies have shown unexpected preservation of large-scale cerebral networks in patients in the minimally conscious state (MCS), a condition that is characterized by intermittent evidence of awareness of self or the environment. These findings indicate that there might be residual functional capacity in some patients that could be supported by therapeutic interventions. We hypothesize that further recovery in some patients in the MCS is limited by chronic underactivation of potentially recruitable large-scale networks. Here, in a 6-month double-blind alternating crossover study, we show that bilateral deep brain electrical stimulation (DBS) of the central thalamus modulates behavioural responsiveness in a patient who remained in MCS for 6 yr following traumatic brain injury before the intervention. The frequency of specific cognitively mediated behaviours (primary outcome measures) and functional limb control and oral feeding (secondary outcome measures) increased during periods in which DBS was on as compared with periods in which it was off. Logistic regression modelling shows a statistical linkage between the observed functional improvements and recent stimulation history. We interpret the DBS effects as compensating for a loss of arousal regulation that is normally controlled by the frontal lobe in the intact brain. These findings provide evidence that DBS can promote significant late functional recovery from severe traumatic brain injury. Our observations, years after the injury occurred, challenge the existing practice of early treatment discontinuation for patients with only inconsistent interactive behaviours and motivate further research to develop therapeutic interventions.

Brain SPECT: a controlled, blinded assessment of intra-reader and inter-reader agreement.

A detailed assessment of intra- and inter-reader variation in the interpretation of brain SPECT scans has been performed. A random sample was selected from scans performed at a community/teaching hospital in Seattle. Scans were interpreted independently by three experienced readers who were blinded to all patient information. Forty-eight scans were interpreted twice by each reader, for a total of 288 readings. Readers recorded detailed assessments of individual lesions and overall impressions using a standardized reporting form. Intra-observer agreement as reflected in per cent agreement for severity scores ranged from 65% to 100%. Intra-observer agreement on the 'overall impression' was very good for Alzheimer's pattern (kappa=0.73-1.00), and fair to good for the 'heterogeneous pattern' (kappa=0.30-0.63). Inter-observer agreement, as reflected in per cent agreement, ranged from 29% to 100%. Inter-observer agreement about the 'overall impression' was fair to moderate for Alzheimer's pattern (kappa=0.24-0.54) and was poor for the descriptors 'heterogeneous' and 'normal'. It is concluded that brain SPECT has great potential value in many important conditions. This study demonstrates a need for further work in the areas of pattern definition and reduction of observer variation.

Local recurrence of breast cancer in the stereotactic core needle biopsy site: case reports and review of the literature.

Early mammographic detection of nonpalpable breast lesions has led to the increasing use of stereotactic core biopsies for tissue diagnosis. Tumor seeding the needle tract is a theorectical concern; the incidence and clinical significance of this potential complication are unknown. We report three cases of subcutaneous breast cancer recurrence at the stereotactic biopsy site after definitive treatment of the primary breast tumor. Two cases were clinically evident and relevant; the third was detected in the preclinical, microscopic state. All three patients underwent multiple passes during stereotactic large-core biopsies (14 gauge needle) followed by modified radical mastectomy. Two patients developed a subcutaneous recurrence at the site of the previous biopsy 12 and 17 months later; one had excision of the skin and dermis at the time of mastectomy revealing tumor cells locally. In summary, clinically relevant recurrence from tumor cells seeding the needle tract is reported in two patients after definitive surgical therapy (without adjuvant radiation therapy). Often, the biopsy site is outside the boundaries of surgical resection. Since the core needle biopsy exit site represents a potential area of malignant seeding and subsequent tumor recurrence, we recommend excising the stereotactic core biopsy tract at the time of definitive surgical resection of the primary tumor.

Lobular carcinoma in situ increases the risk of local recurrence in selected patients with stages I and II breast carcinoma treated with conservative surgery and radiation.

BACKGROUND: Lobular carcinoma in situ (LCIS) is a known risk factor for the development of invasive breast carcinoma. However, little is known regarding the impact of LCIS in association with an invasive carcinoma on the risk of an ipsilateral breast tumor recurrence (IBTR) in patients who are treated with conservative surgery (CS) and radiation therapy (RT). The purpose of this study was to examine the influence of LCIS on the local recurrence rate in patients with early stage breast carcinoma after breast-conserving therapy. METHODS: Between 1979 and 1995, 1274 patients with Stage I or Stage II invasive breast carcinoma were treated with CS and RT. The median follow-up time was 6.3 years. RESULTS: LCIS was present in 65 of 1274 patients (5%) in the study population. LCIS was more likely to be associated with an invasive lobular carcinoma (30 of 59 patients; 51%) than with invasive ductal carcinoma (26 of 1125 patients; 2%). Ipsilateral breast tumor recurrence (IBTR) occurred in 57 of 1209 patients (5%) without LCIS compared with 10 of 65 patients (15%) with LCIS (P = 0.001). The 10-year cumulative incidence rate of IBTR was 6% in women without LCIS compared with 29% in women with LCIS (P = 0.0003). In both groups, the majority of recurrences were invasive. The 10-year cumulative incidence rate of IBTR in patients who received tamoxifen was 8% when LCIS was present compared with 6% when LCIS was absent (P = 0.46). Subsets of patients in which the presence of LCIS was associated with an increased risk of breast recurrence included tumor size < 2 cm (T1), age < 50 years, invasive ductal carcinoma, negative lymph node status, and the absence of any adjuvant systemic treatment (chemotherapy or hormonal therapy) (P < 0.001). LCIS margin status, invasive lobular carcinoma histology, T2 tumor size, and positive axillary lymph nodes were not associated with an increased risk of breast recurrence in these women. CONCLUSIONS: The authors conclude that the presence of LCIS significantly increases the risk of an ipsilateral breast tumor recurrence in certain subsets of patients who are treated with breast-conserving therapy. The risk of local recurrence appears to be modified by the use of tamoxifen. Further studies are needed to address this issue.

Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas.

We examined the effect of preoperative chemoradiotherapy on the ability to obtain pathologically negative resection margins in patients undergoing pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas. Between 1987 and 2000, 100 patients underwent Whipple resection with curative intent for primary adenocarcinoma of the head of the pancreas. Pathologic assessment of six margins (proximal and distal superior mesenteric artery, proximal and distal superior mesenteric vein, pancreas, retroperitoneum, common bile duct, and hepatic artery) was undertaken by either frozen section (pancreas and common duct) or permanent section. A margin was considered positive if tumor was present less than 1 mm from the inked specimen. Margins noted to be positive on frozen section were resected whenever possible. Of the 100 patients treated, 47 (47%) underwent postoperative radiation and chemotherapy (group I) and 53 (53%) received preoperative chemoradiotherapy (group II) with either 5-fluorouracil (32 patients) or gemcitabine (21 patients). Patient demographics and operative parameters were similar in the two groups, with the exception of preoperative tumor size (CT scan), which was greater in group II (P < 0.001), and number of previous operations, which was greater in group II (P < 0.0001). Statistical analysis of the number of negative surgical margins clear of tumor was performed using Fisher's exact test. All patients (100%) had six margins assessed for microscopic involvement with tumor. In the preoperative therapy group, 5 (7.5%) of 53 patients had more than one positive margin, whereas 21 (44.7%) of 47 patients without preoperative therapy had more than one margin with disease extension (P < 0.001). Additionally, only 11 (25.6%) of the 47 patients without preoperative therapy had six negative margins vs. 27 (50.9%) of 53 in the group receiving preoperative therapy (P = 0.013). Survival analysis reveals a significant increase in survival in margin-negative patients (P = 0.02). Similarly, a strong trend toward improved disease-free and overall survival is seen in patients with a single positive margin vs. multiple margins. Overall, we find a negative impact on survival with an increasing number of positive margins (P = 0.025, hazard ratio 1.3). When stratified for individual margin status, survival was decreased in patients with positive superior mesenteric artery (P = 0.06) and vein (P = 0.04) margins. However, this has not yet resulted in a significant increase in disease-free or overall survival for patients receiving preoperative therapy (P = 0.07).

Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade.

INTRODUCTION: Vascular endothelial growth factor (VEGF), an endothelial-specific mitogen overexpressed in various epithelial malignancies is thought to be a potent regulator of angiogenesis. We hypothesized that some soft tissue sarcomas, due to their high propensity for hematogenous metastases (1) would overexpress VEGF, (2) that the degree of expression may represent a significant biologic predictor for disease-specific survival, and (3) that recurrent tumor would express as high or higher VEGF compared with the primary tumor. METHODS: Selected paraffin-embedded tissue of surgical specimens from 79 patients with soft tissue sarcomas, treated between 1989 and 1995 were stained with a rabbit polyclonal anti-VEGF antibody at a concentration of 2 microg/ml. Slides were assessed for VEGF expression as high or low by two investigators blinded to the clinicopathologic data. Twelve patients had VEGF expression of their primary tumors, and their recurrent tumors were compared. The Fishers' exact test assessed for differences in VEGF expression; survival analyses were performed according to the methods of Kaplan and Meier. RESULTS: Seventy-eight percent (29 of 37) of patients who died of disease had high VEGF expression. However, VEGF expression was not an independent predictor of either overall or disease-free survival. Tumor grade correlated with VEGF expression significantly. For the low-grade tumors, 7 of 13 expressed low VEGF, whereas for high-grade tumors, 53 of 66 expressed high VEGF (P = .016). Seven of the 12 paired tumor samples expressed identical VEGF immunostaining. CONCLUSIONS: The majority of high-grade soft tissue sarcomas in this study have high intensity VEGF expression. This finding may provide useful information on individual soft tissue sarcomas and offer the basis for therapeutic and biologic targeting in high-risk patients using anti-angiogenesis strategies. However, in our analysis, after accounting for tumor grade, VEGF does not seem to be an independent predictor of clinical outcome.

Trimodality therapy for advanced gallbladder cancer.

We conducted a retrospective review of all patients who underwent surgical extirpation for stage III, stage IV, or recurrent carcinoma of the gallbladder. Between 1991 and 1999 ten patients underwent surgical resection for advanced gallbladder cancer. All patients received adjuvant therapy either pre- or postoperatively. Radiotherapy was used in all patients and chemotherapy in 90 per cent of patients. Two patients subsequently underwent resection for locally recurrent disease. An additional patient with stage II disease initially was also treated surgically for a local recurrence. Surgical management involved cholecystectomy and resection of various amounts of liver surrounding the gallbladder bed and regional lymphadenectomy. Contiguously involved structures were resected en bloc. Resection of recurrent disease included excision of all gross tumor. The median overall survival excluding the one 30-day mortality was 53.6 months (range 8-73 months). Four patients have survived 4 or more years, and currently four patients are alive and disease free at 73, 49, 33, and 8 months. Median disease-free interval after each resection of recurrent disease was 13.8 months (range 4-28 months). We conclude that trimodality therapy in selected patients with stage III, IV, or recurrent carcinoma of the gallbladder is possible and may result in prolonged survival.

Gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are mesenchymal gut tumors that differ dramatically from other histologically similar neoplasms, such as leimomyomas, leiomyosarcomas (LMS), and neural tumors. Complete surgical removal remains the best current therapy for GISTs, but even major resections are associated with recurrence in approximately 90% of cases. GISTs are remarkably resistant to irradiation and standard chemotherapy; there is no role for treatment with those modalities. Treatment of advanced GIST patients with STI571, a novel selective tyrosine kinase inhibitor, results in remission rates that approach 60% and overall tumor control rates of 85%. Selected groups of patients, as based on tumor mutational status, have response rates as high as 80%. To date, STI571 therapy remains the only systemic treatment for GISTs to have meaningful clinical activity. Though other molecularly targeted therapies exist in oncology (eg, trastuzumab), STI571 is one of the first that applies a drug specifically designed to inhibit the product of a constitutively-activating mutation that drives pathogenesis of a solid tumor. Its use can serve as a paradigm for designing molecularly targeted therapies for other malignancies.

Binding and selectivity in L-type calcium channels: a mean spherical approximation.

L-type calcium channels are Ca(2+) binding proteins of great biological importance. They generate an essential intracellular signal of living cells by allowing Ca(2+) ions to move across the lipid membrane into the cell, thereby selecting an ion that is in low extracellular abundance. Their mechanism of selection involves four carboxylate groups, containing eight oxygen ions, that belong to the side chains of the "EEEE" locus of the channel protein, a setting similar to that found in many Ca(2+)-chelating molecules. This study examines the hypothesis that selectivity in this locus is determined by mutual electrostatic screening and volume exclusion between ions and carboxylate oxygens of finite diameters. In this model, the eight half-charged oxygens of the tethered carboxylate groups of the protein are confined to a subvolume of the pore (the "filter"), but interact spontaneously with their mobile counterions as ions interact in concentrated bulk solutions. The mean spherical approximation (MSA) is used to predict ion-specific excess chemical potentials in the filter and baths. The theory is calibrated using a single experimental observation, concerning the apparent dissociation constant of Ca(2+) in the presence of a physiological concentration of NaCl. When ions are assigned their independently known crystal diameters and the carboxylate oxygens are constrained, e.g., to a volume of 0.375 nm(3) in an environment with an effective dielectric coefficient of 63.5, the hypothesized selectivity filter produces the shape of the calcium binding curves observed in experiment, and it predicts Ba(2+)/Ca(2+) and Na(+)/Li(+) competition, and Cl(-) exclusion as observed. The selectivities for Na(+), Ca(2+), Ba(2+), other alkali metal ions, and Cl(-) thus can be predicted by volume exclusion and electrostatic screening alone. Spontaneous coordination of ions and carboxylates can produce a wide range of Ca(2+) selectivities, depending on the volume density of carboxylate groups and the permittivity in the locus. A specific three-dimensional structure of atoms at the binding site is not needed to explain Ca(2+) selectivity.

Pancreatic carcinoma deemed unresectable at exploration may be resected for cure: an institutional experience.

Only a minority of patients with a diagnosis of pancreatic adenocarcinoma (PA) have disease amenable to curative resection. Between April 1987 and March 1999, 40 patients with pancreatic adenocarcinoma deemed unresectable at exploration at other institutions were considered for neoadjuvant treatments and then re-evaluated for possible re-exploration. We retrospectively compared the clinical outcomes, including overall survival (OS), among three groups: Group A, 22 previously unresectable patients who were subsequently successfully resected, 20 after induction therapy; Group B, 31 patients who received preoperative chemoradiotherapy before their only operation; and Group C, 33 patients who were primarily resected, 27 of whom were then treated with adjuvant therapy. Of those resectable from Group A, 5 required portal venorrhaphy and 3 had hepatic artery reconstruction. Eighteen of the 40 patients were unresectable because of progression of disease with a mean OS of 8 months; 12 were assessed at second laparotomy; 6 were excluded from second operation on the basis of preoperative imaging studies. Kaplan-Meier curves showed no differences in OS among the three groups: OS in Group A was 34 months; Group B, 21; and Group C, 13 (P = 0.15). Margin status was comparable in all three groups (P = 0.52). As expected, nodal positivity was greatest in Group C (P = 0.001). There were no operative mortalities in Group A, and the morbidity rate was comparable with that of Groups B and C. Upon re-evaluation, many tumors (54%) previously deemed "unresectable" were surgically extirpated for cure with a median survival comparable with that of patients who did not undergo previous exploration.

Minimum 5-year results of degenerative spondylolisthesis treated with decompression and instrumented posterior fusion.

STUDY DESIGN: An analysis of consecutive cases of degenerative spondylolisthesis treated by one of two surgeons at a university hospital. OBJECTIVES: To assess at a minimum 5-year follow-up the complication rate, reoperation rate, radiographic results, and patient satisfaction with surgical treatment of lumbar degenerative spondylolisthesis by means of segmental posterior instrumented fusion with decompression. SUMMARY OF BACKGROUND DATA: No reports of minimum 5-year follow-up for surgical treatment of degenerative spondylolisthesis were found in the literature. METHODS: The potential study population consisted of 49 consecutive patients who had undergone no prior surgery for degenerative spondylolisthesis (average age, 66.7 years; range, 52.2-78.7 years) with mean follow-up of 6.5 years (range, 5-10.75 years) who were treated with decompression, autogenous iliac crest bone grafting, intertransverse process fusion, and segmental (pedicle screw) instrumentation. Eight patients had died; the remaining 41 were included in the study sample. Thirty-six (88%) of the 41 patients returned an outcome questionnaire and had current radiographs. RESULTS: There was one case of instrument failure (one broken screw with late fusion), and one superficial infection. There were no neurologic deficits, no pseudarthroses, no recurrent stenosis at the fused segment, and no progression of deformity at the fused level. Five patients had symptomatic adjacent level transition syndromes. There were seven additional currently asymptomatic radiographic transition syndromes. Segmental sagittal Cobb angles were maintained at the fused level (17.7 +/- 8-18.8 +/- 7 degrees). Eighty-three percent reported satisfaction with the procedure, 86% thought their back and leg pain was still significantly better than before surgery, and 77% would have the procedure again if needed. Poor satisfaction (n = 4) was associated with more than four medical comorbidities (P < 0.03). A significant number (12 of 49, 24%) of patients had died or were ill more than 5 years after surgery. CONCLUSIONS: Radiographic transition syndromes were common. Major complications (2%), implant failures (2%), and symptomatic pseudarthroses (0%) were low.

Local excision and chemoradiation for low rectal T1 and T2 cancers is an effective treatment.

Lesions located in the distal third of the rectum are usually treated with abdominoperineal resection or a low anterior resection with a coloanal anastomosis. However, in a select group of patients with favorable histology and a low probability of lymphatic spread, sphincter-sparing procedures will afford long-term disease-free survival and cure without the need for extensive, complicated surgery. We performed a 10-year retrospective review, including pathologic examination of specimens by a single pathologist, in an attempt to identify factors associated with a decreased disease-free survival. Thirty-five patients (median age, 71 years; range, 48-88) with low rectal carcinomas were treated with full-thickness disc excision (with or without chemoradiation), with curative intent. Median follow-up was 46 months (range, 8-120). There were 15 T1, 16 T2, and 4 T3 lesions. Tumors with poor histologic factors or greater than T1 received adjuvant radiation (with or without 5-fluorouracil). Four patients developed a local failure at a median of 21.5 months (range, 9-30) and were salvaged with abdominoperineal resection. The 5-year cancer-specific survival was 91 per cent. Negative margins approached statistical significance (P < 0.07) in influencing local control. We conclude that, when combined with chemoradiation for lesions deeper than submucosa or with adverse histologic factors, local resection of rectal cancer is an effective treatment in selected patients.

Selectivity and permeation in calcium release channel of cardiac muscle: alkali metal ions.

Current was measured from single open channels of the calcium release channel (CRC) of cardiac sarcoplasmic reticulum (over the range +/-180 mV) in pure and mixed solutions (e.g., biionic conditions) of the alkali metal ions Li+, K+, Na+, Rb+, Cs+, ranging in concentration from 25 mM to 2 M. The current-voltage (I-V) relations were analyzed by an extension of the Poisson-Nernst-Planck (PNP) formulation of electrodiffusion, which includes local chemical interaction described by an offset in chemical potential, which likely reflects the difference in dehydration/solvation/rehydration energies in the entry/exit steps of permeation. The theory fits all of the data with few adjustable parameters: the diffusion coefficient of each ion species, the average effective charge distribution on the wall of the pore, and an offset in chemical potential for lithium and sodium ions. In particular, the theory explains the discrepancy between "selectivities" defined by conductance sequence and "selectivities" determined by the permeability ratios (i.e., reversal potentials) in biionic conditions. The extended PNP formulation seems to offer a successful combined treatment of selectivity and permeation. Conductance selectivity in this channel arises mostly from friction: different species of ions have different diffusion coefficients in the channel. Permeability selectivity of an ion is determined by its electrochemical potential gradient and local chemical interaction with the channel. Neither selectivity (in CRC) seems to involve different electrostatic interaction of different ions with the channel protein, even though the ions have widely varying diameters.

Brain SPECT imaging and neuropsychological testing in coronary artery bypass patients: single photon emission computed tomography.

BACKGROUND: Cognitive deficits appear frequently after cardiac operation. While the etiology remains unclear, alterations in cerebral perfusion during cardiopulmonary bypass may be causative. Single photon emission computed tomography (SPECT) scanning utilizes a radiopharmaceutical to provide images of cerebral perfusion. We proposed to study the cerebral circulation of patients during coronary artery bypass operation employing cardiopulmonary bypass. METHODS: Thirty-five neurologically normal patients underwent preoperative SPECT brain scanning and neuropsychological testing. A second SPECT brain perfusion scan was obtained by administering the radioisotope during cardiopulmonary bypass, with subsequent scanning upon completion of the procedure. Postoperative neuropsychological testing was performed prior to discharge. RESULTS: Fourteen (40%) of patients demonstrated significant neuropsychological decline. Patients who suffered cognitive impairment were no different in demographic, general health, or surgical variables. Patients who demonstrated neuropsychological decline had significantly poorer cerebral perfusion both at baseline and during operation. CONCLUSIONS: Impaired cerebral perfusion at baseline may identify patients at risk for cognitive injury after cardiac operation. Alterations in cerebral perfusion during cardiopulmonary bypass is common, and may be a factor in neuropsychological deficits seen after cardiac operation.

Biliary CA 19-9 values correlate with the risk of hepatic metastases in patients with adenocarcinoma of the pancreas.

Serum values of the tumor-associated antigen CA 19-9 are useful as an independent predictor of survival in patients with adenocarcinoma of the pancreas. However, the utility of biliary CA 19-9 values is unknown. This study was undertaken to determine whether biliary CA 19-9 levels are predictive of hepatic metastases. Between 1991 and 1996, thirty-eight patients treated for adenocarcinoma of the pancreas were evaluated using a biliary CA 19-9 assay. Bile was obtained from percutaneous stents placed during the perioperative period. Five of the 38 patients had low serum levels of CA 19-9 (<2 U/ml) and were excluded from the study. Twenty-seven (80%) of the 33 patients developed distant metastases: five pulmonary, five peritoneal, and 17 hepatic. Liver metastases were discovered initially in 10 and after resection of the primary tumor in seven (median interval 10 months). Biliary CA 19-9 values were significantly higher in patients with hepatic metastases (median 267, 400 U/ml; range 34,379 to 5,000,000 U/ml) compared to patients without metastatic disease (median 34,103 U/ml; range 6,620 to 239, 880 U/ml; P <0.006). Patients with hepatic, peritoneal, and pulmonary metastases had median survivals of 8,14, and 35 months, respectively (P <0.0041). All patients without metastatic disease are alive (median follow-up 13 months). Biliary CA 19-9 values are associated with a stepwise increase in the risk of developing metastatic disease. Patients with biliary CA 19-9 levels greater than 149,490 U/ml have an increased risk of developing recurrent disease in the liver and may warrant further hepatic evaluation or therapy.

Phase I dose escalating trial of hyperfractionated pre-operative chemoradiation for locally advanced rectal cancer.

PURPOSE: To determine the acute toxicity, post-operative complications, pathologic response and extent of downstaging to high dose pre-operative radiation using a hyperfractionated radiation boost and concurrent chemotherapy in a prospective Phase I trial. MATERIALS & METHODS: To be eligible for this study, patients had to have adenocarcinoma of the rectum less than 12 cm from the anal verge with either Stage T4 or T3 but greater than 4 cm or greater than 40% of the bowel circumference. All patients received 45 Gy pelvic radiation (1.8 Gy per fraction). Subsequent radiation was given to the region of the gross tumor with a 2 cm margin. This "boost" treatment was given at 1.2 Gy twice daily to a total dose of 54.6 Gy for Level I, 57 Gy for Level II, and 61.8 Gy for Level III. 5-FU was given at 1g/m2 over 24 hours for a four day infusion during the first and sixth weeks of radiation, with the second course concurrent with the hyperfractionated radiation. Surgical resection was carried out 4-6 weeks following completion of chemoradiation (in curative cases) and additional adjuvant chemotherapy consisting of 5-FU and Leucovorin was given for an additional 4 monthly cycles Days 1 through 5 beginning four weeks post surgery. RESULTS: Twenty-seven patients, age 40-82 (median 61), completed the initial course of chemoradiation and are included in the analysis of toxicity. The median follow-up is 27 months (range 8-68). Eleven patients were treated to a dose of 54.6 Gy, nine patients to 57 Gy, and seven patients to 61.8 Gy. Twenty-one patients had T3 tumors, and six patients T4 tumors. Grade III acute toxicity from chemoradiation included proctitis (5 patients), dermatitis (9), diarrhea (five), leukopenia (1), cardiac (1). Grade IV toxicities included one patient with diarrhea (on dose Level I) and one patient (on dose Level III) with cardiac toxicity (unrelated to radiation). Surgical resection consisted of abdominal perineal resection in 16 and low anterior resection in 7. Four patients did not undergo a curative resection; three initially presented with metastases and one developed metastasis during the pre-operative regimen. Post-operative complications included pelvic or perineal abscess in two (on dose Levels I & II), and delayed wound healing in two (one of whom, on dose Level III, developed perineal wound dehiscence requiring surgical reconstruction). Of the 23 patients who had a curative resection, four manifested pathologic complete responses (17.4%). Thirteen of 23 patients (57%) had evidence of pathologic downstaging and only 1/23 patients (on dose Level I) had a positive resection margin. Of these 23 patients (with a minimum follow-up of 8 months), the patient with positive margins was the only one who developed a local failure (Fisher's Exact p=.04). The 3-year actuarial OS, DFS and LC rates are 82%, 72% and 96%, respectively. Twelve of 13 patients (92% at 3 years) > or = 61 years vs. 5/10 patients (45% at 3 years) < 61 years remained disease-free (log-rank p=0.017). CONCLUSION: This regimen of high dose pre-operative chemoradiation employing a hyperfractionated radiation boost is feasible and tolerable and results in significant downstaging in locally advanced rectal cancer. The vast majority of patients (96%) achieved negative margins, which appears to be a prerequisite for local control (p= 0.04). Older age (> or =61 years) was a significant predictor for improved DFS. This regimen (at dose Level III, 61.8 Gy) is currently being tested in a Phase II setting.