Mahesh Kudrimoti

Fluorouracil vs Gemcitabine Chemotherapy Before and After Fluorouracil-Based Chemoradiation Following Resection of Pancreatic Adenocarcinoma: A Randomized Controlled Trial

CONTEXT Among patients with locally advanced metastatic pancreatic adenocarcinoma, gemcitabine has been shown to improve outcomes compared with fluorouracil. OBJECTIVE To determine if the addition of gemcitabine to adjuvant fluorouracil chemoradiation (chemotherapy plus radiation) improves survival for patients with resected pancreatic adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled phase 3 trial of patients with complete gross total resection of pancreatic adenocarcinoma and no prior radiation or chemotherapy enrolled between July 1998 and July 2002 with follow-up through August 18, 2006, at 164 US and Canadian institutions. INTERVENTION Chemotherapy with either fluorouracil (continuous infusion of 250 mg/m2 per day; n = 230) or gemcitabine (30-minute infusion of 1000 mg/m2 once per week; n = 221) for 3 weeks prior to chemoradiation therapy and for 12 weeks after chemoradiation therapy. Chemoradiation with a continuous infusion of fluorouracil (250 mg/m2 per day) was the same for all patients (50.4 Gy). MAIN OUTCOME MEASURES Survival for all patients and survival for patients with pancreatic head tumors were the primary end points. Secondary end points included toxicity. RESULTS A total of 451 patients were randomized, eligible, and analyzable. Patients with pancreatic head tumors (n = 388) had a median survival of 20.5 months and a 3-year survival of 31% in the gemcitabine group vs a median survival of 16.9 months and a 3-year survival of 22% in the fluorouracil group (hazard ratio, 0.82 [95% confidence interval, 0.65-1.03]; P = .09). The treatment effect was strengthened on multivariate analysis (hazard ratio, 0.80 [95% confidence interval, 0.63-1.00]; P = .05). Grade 4 hematologic toxicity was 1% in the fluorouracil group and 14% in the gemcitabine group (P < .001) without a difference in febrile neutropenia or infection. There were no differences in the ability to complete chemotherapy or radiation therapy (>85%). CONCLUSIONS The addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected pancreatic cancer, although this improvement was not statistically significant. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00003216.

Elevated sphingomyelinase activity and ceramide concentration in serum of patients undergoing high dose spatially fractionated radiation treatment: implications for endothelial apoptosis.

Spatially Fractionated high dose (Grid) Radiation Treatment (SFGRT) involves irradiation of bulky tumors with one high, grid-delivered, dose of 15 Gy followed by multiple consecutive doses of 2 Gy each. The goal of this study is to determine the effect of this treatment on serum ceramide content and to investigate possible involvement of ceramide in tumor regression after SFGRT. Serum ceramide and Secretory SMase (SSMase) were quantified in 11 patients before and at 24, 48 and 72 h after the dose of 15 Gy. Furthermore, LDL particles were isolated from the serum and their apoptotic ability was tested in human endothelial cells by TUNEL assay. Sixty seven per cent (6/8) of the patients with partial (PR) or complete (CR) response showed statistically significant increase in serum ceramide levels. Of the non-responders in the study, none showed an elevation in ceramide. S-SMase activity underwent similar changes. LDL particles from serum of patients collected 72 hours after SFGRT sensitized the endothelial cells to undergo apoptosis in response to 5 Gy radiation that by itself had only modest effect on cell death. Independent elevation of ceramide content of endothelial cells that were otherwise resistant to radiation-induced cell death also was sufficient to sensitize these cells to apoptosis. Serum S-SMase activity and ceramide content increase following SFGRT and correlate with the clinical response. Apparently, these changes are in the LDL-associated ceramide and may contribute to better tumor reduction after SFGRT, due to the ability of LDL–derived ceramide to sensitize endothelial cells for apoptosis.

Accuracy of self-reported tobacco assessments in a head and neck cancer treatment population.

Prospective analysis was performed of self-reported and biochemically confirmed tobacco use in 50 head and neck cancer patients during treatment. With 93.5% compliance to complete weekly self-report and biochemical confirmatory tests, 29.4% of smokers required biochemical assessment for identification. Accuracy increased by 14.9% with weekly vs. baseline self-reported assessments. Data confirm that head and neck cancer patients misrepresent true tobacco use during treatment.

The Impact of TNF-α Induction on Therapeutic Efficacy following High Dose Spatially Fractionated (GRID) Radiation

A variety of cytokines especially TNF-α and TGF-β are known to be released in response to high dose radiation of tumors. However, these are not normally measurable in systemic circulation unless high levels of these cytokines are produced by tumor cells. This study was undertaken to see if circulating levels of these cytokines could be measured in the serum of patients treated with high dose spatially fractionated (GRID) radiation and to correlate the finding of these cytokines with clinical response to treatment. Thirty-four patients (31 patients had single treatment site and 3 patients had 2 treatment sites) treated with spatially fractionated (GRID) radiation were entered in this study. Serum samples were collected before treatment and at 24, 48 and 72 hours after GRID radiation. Sandwich enzyme linked immunosorbent assay (ELISA) was performed to estimate the levels of TNF-α and activated TGF-β1 proteins. Seven of 37 patients studied had no TNF-α protein before treatment but showed induction of TNF-α after GRID radiation. Three patients showed faint basal level of TNF-α protein before treatment and these levels were induced after treatment. Three patients showed a basal level of TNF-α protein before treatment and these levels decreased after treatment. In 21 cases no TNF-α protein was detected before or after treatment at the time points measured. In the case of TGF-β1 protein, 2 patients showed no TGF-β1 protein before GRID radiation and an induction of TGF-β1 protein was observed after treatment. Seven patients showed basal level of TGF-β1 protein prior to treatment and these levels were induced after treatment. Seventeen patients showed a basal level of TGF-β1 protein before treatment and these levels decreased after treatment. In 8 cases no TGF-β1 protein was detected before or after treatment. Complete clinical response (CR) to GRID therapy was seen in 12/37 (32%) treatment sites and partial response (PR) in 18/37 (49%) treatment sites. A strong correlation was observed between clinical CR rate and TNF-α induction. The rate of CR was 6/10 (60%) in patients where TNF-α was induced as compared to 6/27 (23%) treatment sites in patients where TNF-α induction was not seen (p = 0.029). No significant correlation with CR rate and TGF-β1 induction (44% vs. 28%, p = 0.36) was observed. High dose spatially fractionated (GRID) radiation results in significant induction of TNF-α that can be measured in serum of some patients 24 – 72 hours after radiation. Complete tumor response strongly correlated with the induction of TNF-α levels in the serum.

Nicotinic modulation of therapeutic response in vitro and in vivo

Tobacco use significantly increases the risk of developing cancer. Moreover, there is growing evidence that tobacco use decreases survival in cancer patients. Nicotine, a systemically available component of tobacco, is associated with tumor promotion and decreased apoptosis in cell culture; however, the role of nicotine on response to radiotherapy (RT) or chemoradiotherapy (CRT) in vivo has not been evaluated. Our study evaluated the effects of nicotine administration on cancer cell survival in cell culture and mouse models. Nicotine increased survival in two cell lines following RT in vitro. Nicotine administration in mice during fractionated RT or CRT increased xenograft regrowth as compared to RT or CRT alone. Nicotine increased hypoxia‐inducible factor 1‐alpha (HIF‐1α) expression in tumor xenografts without altering expression of carbonic‐anhydrase, a clinical marker of tumor hypoxia. The effects of nicotine on HIF‐1α expression were transient, returning to baseline levels within 2‐3 days after nicotine removal. Further mechanistic studies indicated that inhibition of phosphoinositide‐3‐kinase (PI3K) prevented nicotine‐mediated increases in HIF‐1α expression as well as the prosurvival effects of nicotine on RT. These findings imply that during tobacco use, nicotine may function as a systemic agent through acute and reversible regulation of HIF‐1α expression and a decreased therapeutic response.

Spatially Fractionated GRID Radiation Treatment of Advanced Neck Disease Associated with Head and Neck Cancer

Advanced nodal disease associated with head and neck cancer warrants aggressive, often multi-modality therapy to maximize local-regional control. The expansion of a novel treatment paradigm developed by our institution includes the addition of a single-fraction of high dose spatially-fractionated radiation (GRID) to a conventional course of treatment. Between 1995 and 2002 a series of 27 patients (median age 65) with bulky N2-3 disease were treated. Median nodal tumor size was 7 cm. Two groups of patients were evaluated. Group 1 (N=14) patients received a median neck dose 69 Gy (range 54–79 Gy) plus GRID treatment. Group 2 (N=13) patients received a median neck dose of 59 Gy (range 54–72 Gy) plus GRID treatment followed by planned neck dissection. Patients were evaluated for local-regional control, pathological response, survival, and morbidity. Median time to follow-up for Group 1 was 10 months (range 3–44 months). Neck control was 93%. Disease specific survival was 50%. Morbidity was limited to soft-tissue related damage and was mild. Median time to follow-up for Group 2 was 38 months (range 5–116 months). Pathologic complete response rate was 85%. Overall neck control rate was 92%. Disease specific survival was 85%. Surgical morbidity was limited to three wound healing complications. GRID treatment may be safely added to conventional treatment management of locally advanced neck disease related to cancer with acceptable morbidity. It may improve pathologic complete response rates in those patients who undergo planned neck dissection, possibly leading to improved survival. In patients with inoperable bulky disease, addition of GRID enhances local-regional control.

Noninvasive diffuse optical monitoring of head and neck tumor blood flow and oxygenation during radiation delivery

This study explored using a novel diffuse correlation spectroscopy (DCS) flow-oximeter to noninvasively monitor blood flow and oxygenation changes in head and neck tumors during radiation delivery. A fiber-optic probe connected to the DCS flow-oximeter was placed on the surface of the radiologically/clinically involved cervical lymph node. The DCS flow-oximeter in the treatment room was remotely operated by a computer in the control room. From the early measurements, abnormal signals were observed when the optical device was placed in close proximity to the radiation beams. Through phantom tests, the artifacts were shown to be caused by scattered x rays and consequentially avoided by moving the optical device away from the x-ray beams. Eleven patients with head and neck tumors were continually measured once a week over a treatment period of seven weeks, although there were some missing data due to the patient related events. Large inter-patient variations in tumor hemodynamic responses were observed during radiation delivery. A significant increase in tumor blood flow was observed at the first week of treatment, which may be a physiologic response to hypoxia created by radiation oxygen consumption. Only small and insignificant changes were found in tumor blood oxygenation, suggesting that oxygen utilizations in tumors during the short period of fractional radiation deliveries were either minimal or balanced by other effects such as blood flow regulation. Further investigations in a large patient population are needed to correlate the individual hemodynamic responses with the clinical outcomes for determining the prognostic value of optical measurements.

Concurrent infusional gemcitabine and radiation in the treatment of advanced unresectable GI malignancy: A phase I study

PURPOSEPreclinical studies have demonstrated significant synergistic tumor cell death when gemcitabine is combined with radiation therapy. The optimal mode for concomitant delivery of drug and radiation therapy remains to be determined. A phase I/II study was undertaken to establish the maximum tolerated dose of infusional gemcitabine when combined with radiation therapy in advanced gastrointestinal malignancies and to assess the response to treatment. MATERIALS AND METHODSTwenty-five patients with advanced or recurrent gastrointestinal malignancy were entered in this dose-escalation study. The initial dose of gemcitabine was 50 mg/m2 as a 24-hour continuous intravenous infusion given weekly × 3 with concurrent radiation therapy. The patients were given a week off chemotherapy after the third injection. The radiation therapy was continued during that week. Gemcitabine was thereafter resumed weekly for another 3 weeks or until the patient completed the radiation therapy (whichever was earlier). Five patients were treated at each dose level. The dose of the drug was escalated in increments of 50 mg/m2 if the toxicity was acceptable at the previous level until the maximum tolerated dose was established. Thirteen patients with advanced unresectable colorectal cancer and 12 patients with advanced unresectable pancreaticobiliary cancers were enrolled on the study. Radiation was delivered at 180 cGy/fraction to a total dose of 4000 cGy ± boost. Because toxicity was severe at the 150 mg/m2 dose level, three additional patients were entered at this dose level. The dose was then dropped to 125 mg/m2, and five more patients were entered at this dose level. Two additional patients were then added in orderto assess toxicity. Patient follow-up ranged from 4 to 22 months, and the median was 8 months. RESULTSAll patients were evaluable for toxicity. The doses of 50 and 100 mg/m2 were well tolerated, but at 150 mg/m2, six of eight patients experienced grade 3 or greater toxicity. The dose was de-escalated to 125 mg/m2, and three of seven patients showed grade 3 diarrhea and weight loss. Clinical tumor response was evaluable in 20 patients. Ten patients had a complete clinical response (50%), five patients had a partial response (25%), three patients had no response, and two patients had progression of disease. No patients experienced late toxicities related to either gemcitabine administration or radiation therapy. Twelve patients are currently alive. CONCLUSIONBased on these results, it appears that the maximum tolerated dose for weekly 24-hour infusion of gemcitabine combined with radiation therapy is 100 mg/m2. Gemcitabine appears to be a potent radiation sensitizer, and when combined with radiation therapy, it has shown encouraging tumor responses. In this study, we found an overall response rate of 75% in patients with locally advanced stage of disease. Further evaluation of gemcitabine at 100 mg/m2 is being undertaken in preparation for a confirmatory multi-institutional phase II study.

Increased expression of PSA mRNA during brachytherapy in peripheral blood of patients with prostate cancer

OBJECTIVES To determine the extent of iatrogenic tumor cell dissemination during brachytherapy by assessing prostate-specific antigen (PSA) mRNA expression in circulating prostate tumor cells using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. The instrumentation used in the radioisotope seed placement of the prostate causes trauma to blood vessels and provides a vascular access for tumor cells that can lead to potential iatrogenic dissemination and systemic failure. METHODS Twenty-five patients treated for brachytherapy were recruited in the study. Controls included 4 normal men and 1 woman; case controls included 4 patients who underwent prostate biopsy for prostate cancer diagnosis. Peripheral blood (10 mL) was collected before, during, and after the brachytherapy procedure. Total RNA was isolated from mononuclear cells and phosphorus-32 RT-PCR was performed to analyze the mRNA expression of PSA and G6PDH genes. RESULTS Of 25 patients, 23 were negative for PSA mRNA expression and 2 were positive for PSA mRNA expression before brachytherapy. Of the 23 patients who were negative for PSA mRNA expression before treatment, 15 patients (65%) turned positive during or after brachytherapy and the remaining 8 patients remained negative throughout the treatment. Eight of the 25 patients developed rising serum PSA levels. Of these 8 patients, 1 (12.5%) did not have PSA mRNA expression in the peripheral blood before, during, or after brachytherapy; the remaining 7 patients who developed rising serum PSA levels had PSA mRNA expression after brachytherapy (P = 0.03). CONCLUSIONS These findings strongly suggest that iatrogenic shedding of prostate cells occurs as a result of brachytherapy and raises the concern that these cells liberated at the time of brachytherapy increase the risk of metastatic deposits and results in systemic failure, as measured by serum PSA levels.

Dosimetric evaluation of parallel opposed spatially fractionated radiation therapy of deep‐seated bulky tumors

Application of a single fraction of parallel opposed GRID beams as a means of increasing the efficiency of radiation delivery to deep-seated tumors has been investigated. This evaluation was performed by measurement of dosimetric characteristics of the GRID radiation field in parallel opposed and single beam geometry. The limitations of the parallel opposed technique in terms of field size and tumor thickness have been evaluated for the conditions of acceptable spatial modulation. The results of this investigation have demonstrated an increase in therapeutic advantage for the parallel opposed technique over the single beam method when treating a deep seated tumor.