The safety and efficacy of gemcitabine and concurrent radiation to the upper abdomen followed by weekly gemcitabine in patients with resected pancreatic cancer was determined. Patients with resected adenocarcinoma of the pancreas were treated with intravenous gemcitabine administered twice-weekly (40 mg m −2 ) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy in 5½ weeks). At the completion of the chemoradiation, patients without disease progression were given gemcitabine (1000 mg m −2 ) weekly for two cycles. Each cycle consisted of 3 weeks of treatment followed by 1 week without treatment. Forty-seven patients were entered, 46 of whom are included in this analysis. Characteristics: median age 61 years (range 35–79); 24 females (58%); 73% stage T3/T4; and 70% lymph node positive. Grade III/IV gastrointestinal or haematologic toxicities were infrequent. The median survival was 18.3 months, while the median time to disease recurrence was 10.3 months. Twenty-four percent of patients were alive at 3 years. Only six of 34 patients with progression experienced local regional relapse as a component of the first site of failure. These results confirm the feasibility of delivering adjuvant concurrent gemcitabine and radiation to the upper abdomen. This strategy produced good local regional tumour control.

PURPOSEWe hypothesized that tumor uptake and elimination of 2',2'-difluoro-2'-deoxycytidine/2',2'-difluoro-2'-deoxycytidine 5'-triphosphate (dFdCyd/dFdCTP) would be altered after dCK gene transfer and that this change would result in an enhanced cytotoxic effect. To test this hypothesis, we examined dFdCyd/dFdCTP uptake and clearance in HT-29 human colon carcinoma xenografts in nude mice by high-performance liquid chromatography (HPLC) and fluorine-19 magnetic resonance spectroscopy (F-19 MRS).EXPERIMENTAL DESIGNHT-29 tumors were grown from cells infected with either the retroviral vector alone (LNPO-LacZ) or vector containing the dCK gene (LNPO-dCK). HPLC and F-19 MRS analyses were performed after a single 160 mg/kg i.p. injection of dFdCyd. Tumor response was determined in animals receiving a similar dosing schedule of dFdCyd.RESULTSHPLC experiments revealed an increased tumor accumulation of dFdCTP in xenografts overexpressing dCK compared with wild-type controls (P < or = 0.05). dFdCTP in the dCK-infected tumors was easily identified at 24 h postinjection. Conversely, no dFdCTP could be detected in the control xenografts 14 h postinjection. Subsequent F-19 MRS experiments confirmed an altered uptake, revealing a 2.5-fold greater accumulation of dFdCyd/dFdCTP in the dCK xenografts. Whereas a modest tumor growth delay was observed in the wild-type tumors receiving dFdCyd, dCK xenografts demonstrated a marked tumor growth delay following treatment (P < or = 0.05).CONCLUSIONSThese data support the hypothesis that increased expression of dCK cDNA in HT-29 xenografts results in an enhanced dFdCTP accumulation and prolonged elimination kinetics, and ultimately a potentiated in vivo tumor response to dFdCyd. Related to these effects, changes in the overall tumor metabolism of dFdCyd/dFdCTP was detectable by noninvasive F-19 MRS. These data are relevant to future preclinical and clinical studies evaluating dCK gene transfer and dFdCyd therapy.

OBJECTIVES:To measure the efficacy and toxic effects of our chemoradiotherapy regimen by means of response and survival in patients with advanced squamous cell carcinoma of the head and neck (HNSCC) for organ preservation in resectable disease or palliation in unresectable disease.DESIGN:All patients underwent evaluation by the multidisciplinary head and neck cancer team, with pathological diagnosis and staging. All patients underwent assessment for response to therapy using results of physical examination and radiologic imaging. Patients were followed up at 3-month intervals for a planned period of 5 years.SETTING:Academic center.PATIENTS:Thirty-eight previously untreated patients with newly diagnosed HNSCC were treated from June 1, 1996, through December 31, 1998, of whom 20 had resectable and 18 had unresectable tumors.INTERVENTION:Patients received intravenous cisplatin, 100 mg/m(2) for 1 hour on days 1 and 29; a 24-hour continuous infusion of fluorouracil, 1000 mg/m(2) on days 1 through 4 and 29 through 32; and radiation therapy, 150 rad twice daily for 12 days. The patients were given a 7- to 10-day break, and radiation therapy was restarted on day 29 for 12 additional days (total dose, 7200 rad).MAIN OUTCOME MEASURES:Complete, partial, and total response rates; disease-free survival; overall survival; and toxic effects.RESULTS:Toxic effects of treatment were moderately severe, including grades III to IV mucositis (89%), neutropenia (71%), and renal toxic effects (8%). In the 18 patients in the unresectable group, complete response in the 17 primary tumors and 15 cervical nodal metastases was achieved in 12 (71%) and 9 (60%), respectively; in the 20 patients undergoing organ preservation, complete response rates were 100% in the 23 primary tumors and 15 cervical nodal metastases. Complete response for all 38 patients was achieved in 31 (82%). In the unresectable group, the Kaplan-Meier relapse-free survival estimate is 56%, with follow-up from 29 to 45 months. In the organ preservation group, 75% of patients are alive without disease, and 8 have been followed up for 36 to 48 months. Of the 5 patients who have died, only 2 died of disease, with recurrences at 13.0 and 16.5 months.CONCLUSIONS:Chemoradiotherapy consisting of cisplatin, fluorouracil, and twice-daily external beam radiation is highly effective in achieving durable complete responses in patients with resectable HNSCC undergoing organ preservation and patients with unresectable HNSCC undergoing palliation. Toxic effects of this regimen were moderate to severe.

PURPOSE:To determine the maximum-tolerated dose, dose-limiting toxicities, and potential antitumor activity of twice-weekly gemcitabine and concurrent radiation in patients with locally advanced pancreatic cancer.PATIENTS AND METHODS:Nineteen patients with histologically confirmed adenocarcinoma of the pancreas were studied at the Wake Forest University Baptist Medical Center and the University of North Carolina at Chapel Hill. The initial dose of gemcitabine was 20 mg/m(2) by 30-minute intravenous infusion each Monday and Thursday for 5 weeks concurrent with 50.4 Gy of radiation to the pancreas. Gemcitabine doses were escalated in 20-mg/m(2) increments in successive cohorts of three to six additional patients until dose-limiting toxicity was observed.RESULTS:The dose-limiting toxicities at 60 mg/m(2) given twice-weekly were nausea/vomiting, neutropenia, and thrombocytopenia. Twice-weekly gemcitabine at a 40-mg/m(2) dose was well tolerated. Of the eight patients eligible for a minimum follow-up of 12 months, three remain alive, one of whom has no evidence of disease progression.CONCLUSION:A dose of twice-weekly gemcitabine at 40 mg/m(2) produced mild thrombocytopenia, neutropenia, nausea, and vomiting when delivered with concurrent radiation to the upper abdomen in patients with advanced pancreatic cancer. These data suggest this regimen is well tolerated and may possess significant activity. These data and other observations have resulted in a phase II Cancer and Leukemia Group B study to ascertain the efficacy of this treatment regimen in patients with locally advanced pancreatic cancer.

A electronic text-based medical record system used in a radiation oncology department since 1990 is described. The database is composed of a group of subfiles linked with a powerful relational database. The clinically relevant subfile structures are described and the hardware and software requirements for the system are itemized. Data entry is accomplished primarily by transcriptionists with some additional input by physicians at the time a dictation is reviewed. The database has been the exclusive source of radiation oncology notes since 1990. The flow of information from the dictaphone to the printed copy is described. Compared with a standard transcription service, addition clinical information is collected at the time of the patient encounter, and this information can be abstracted in reports. While not entirely replacing the paper record, the easy and rapid access to text-based digital information from any computer within the department has been invaluable.

The fluoropyrimidines (fluorodeoxyuridine [FdUrd] and fluorouracil [5-FU] are potent radiation sensitizers. This article summarizes recent data concerning potential mechanisms of fluoropyrimidine-radiation interactions at the cellular and tumoral level. Evidence now suggests cells can be radiosensitized when exposed to the fluoropyrimidines either before or after radiation but by different mechanisms. Sensitization is not explained by redistribution of cells into a sensitive phase of the cell cycle. Rather, cells that are exposed to FdUrd before radiation progress in S phase in the presence of fluoropyrimidines and are radiosensitized. Radiation can also increase the anabolism of 5-FU into the toxic metabolite and decrease drug clearance from the tumor. These laboratory data may aid in the design of clinical trials combining radiation and fluoropyrimidines.

Historically, patients with retroperitoneal sarcomas have had a poor prognosis. Surgical resection continues to be the standard treatment for these tumors. However, their anatomic location and large size at presentation often make complete surgical resection infeasible. Even with complete gross removal of tumor, most patients will experience local failure. Adjuvant radiation therapy has been used to improve local control rates. In the postoperative setting, radiation doses to the tumor bed are limited by radiation tolerances of surrounding normal tissues. Extrapolation of data from soft-tissue sarcomas at other sites suggests that delivery of higher radiation doses, in combination with surgery, may favorably affect local control. Preoperative radiation therapy, in combination with brachytherapy or intraoperative radiation therapy at the time of surgical resection, allows for the safe delivery of higher doses of radiation than is possible in the postoperative setting. These approaches make it possible to maximize the likelihood of local control and cure while minimizing normal tissue toxicity.

In an attempt to improve the grave prognosis associated with the diagnosis of pancreatic cancer, researchers have explored a number of novel therapies. These include hormonal therapy, immunotherapy, radiopharmaceuticals, and novel chemotherapeutic agents. Unfortunately, most of these efforts have led at best to modest improvements in median survival, and have provided little opportunity for cure. Recent advances at the molecular level may provide an alternative approach to the management of pancreatic cancer. The majority of pancreatic cancers possess K-ras mutations. K-ras proteins are small (21-kd) proteins that normally serve as guanosine triphosphate (GTP)-regulated switches to control a diverse array of cellular signals that modulate highly regulated programs of proliferation, differentiation, and death. Newer therapies aimed at modifying the ras signal transduction pathways may provide avenues for future clinical investigation.

Purpose: To develop a portable software tool for fast computation of digitally reconstructed radiographs (DRR) with a friendly user interface and versatile image format and display options. To provide a means for interfacing with commercial and custom three-dimensional (3D) treatment planning systems. To make the tool freely available to the Radiation Oncology community.Methods and Materials: A computer program for computing DRRs was enhanced with new features and rewritten to increase computational efficiency. A graphical user interface was added to improve ease of data input and DRR display. Installer, programmer, and user manuals were written, and installation test data sets were developed. The code conforms to the specifications of the Cooperative Working Group (CWG) of the National Cancer Institute (NCI) Contract on Radiotherapy Treatment Planning Tools.Results: The interface allows the user to select DRR input data and image formats primarily by point-and-click mouse operations. Digitally reconstructed radiograph formats are predefined by configuration files that specify 19 calculation parameters, Enhancements include improved contrast resolution for visualizing surgical clips, an extended source model to simulate the penumbra region in a computed port film, and the ability to easily modify the CT numbers of objects contoured on the planning computed tomography (CT) scans.Conclusions: The DRR tool can be used with 3D planning systems that lack this functionality, or perhaps improve the quality and functionality of existing DRR software. The tool can be interfaced to 3D planning systems that run on most modern graphics workstations, and tan also function as a stand-alone program.

One hundred thirty-three patients with Stage B2, B3, and C colonic carcinoma had resection for curative intent followed by adjuvant postoperative radiotherapy to the tumor bed. The 5-year actuarial local control and disease-free survival rates for these 133 patients were 82% and 61%, respectively. Stage for stage, the development of local regional failure was reduced for patients receiving postoperative radiotherapy compared with a historic control series. Local recurrence occurred in 8%, 21%, and 31% of patients with Stage B3, C2, and C3 tumors who had radiation therapy, respectively, whereas the local failure rates were 31%, 36%, and 53% in patients treated with surgery alone. There was a 13% and 12% improvement in the 5-year disease-free survival rate in the patients with Stage B3 and C3 lesions who had radiotherapy compared with the historic controls. For patients with Stage C disease, local control and disease-free survival rates decreased progressively with increasing nodal involvement; however, local control and disease-free survival rates were higher in the patients who had radiotherapy than in those who had surgery alone. Failure patterns in the patients who had radiotherapy did not show any notable changes compared with those for patients who had surgery alone. Postoperative radiation therapy for Stage B3, C2, and C3 colonic carcinoma is a promising treatment approach that deserves further investigation.

The transfer of medical records from a paper system to a computer-based system is inevitable. However, the widespread acceptance of electronic medical records has been delayed by problems such as high cost, inefficiency, data entry errors and poor physician acceptance. We have developed a database system that has overcome these difficulties and now serves as an electronic medical record. Our system has been in use for a year and a half, and currently contains information on over two thousand patients. The database provides an electronic radiation oncology chart containing patients' demographic information, technical treatment data and dictated reports. All dictated notes are captured, including consultation notes, treatment summaries, on-treatment visits, letters and follow up reports. The system provides data validation upon entry, required few additional software or hardware purchases, and allows for efficient retrieval of data. Unlike other database systems which require the hiring of data entry clerks to input the data, ours combines transcription and data entry. The database runs on a local area network of computers and uses a commercially available relational database package. It makes extensive use of mouse interface features such as pull-down menus, pop-up lists, buttons, multi-page forms, and scrolling fields, making the system easy to use with minimal training. Many custom features are built in, such as help screens, control functions, audit trails, and a system that keeps track of each patient's referring and other relevant physicians. For research purposes, the system has the capability to perform survival analyses on arbitrary user-defined subsets of patients. Data may also be exported transparently to statistical packages for other types of analyses.

Radiation treatment planning is currently in a state of rapid change. Dissatisfaction with past planning technology stems from the growing realization that: (1) Increases in the local regional tumor control rate will increase the cure rate in many malignancies. (2) Even at the best treatment centers geometric tumor misses are commonplace. (3) Traditional constraints on treatment techniques, originally imposed for simplicity and reproducibility, are no longer necessary, and can result in suboptimal treatment. (4) Treatment plans judged "optimal" in two dimensions may be far from optimal when viewed over the entire treatment volume. (5) Lack of treatment reproducibility is also commonplace, and can be demonstrated to adversely affect treatment outcome. On the positive side, recent developments in computer graphics, image processing, radiation physics, and radiation biology are now making it possible to define, design, and deliver sophisticated 3D radiation treatments. However, because many of these technologies are being developed for other disciplines, their applicability to radiation therapy treatment planning is not widely appreciated. We outline the current status and new developments in radiation therapy treatment planning.

Whole abdominal radiation therapy (WART) has come into increased use for gynecologic malignancies, and is intended to deliver a therapeutic dose to the entire peritoneal surface for tumors that spread by exfoliation or irmaperitoneal metastasis, namely ovarian and endometrial carcinomas.The standard treatment technique involves anteroposterior (AP)-postemanterior (PA) beams with PA blocks over the kidneys, the dose limiting organ.Kidney shielding is necessary so that tolerance is not exceeded, but this results in the underdosage of the peritoneal surfaces.To evaluate this problem, various techniques were investigated to compare dose distribution to the target volume and the kidney using CT based data and 3dimensional treatment planning.We have developed a 3-dimensional(3-D) treatment planning tool which is used to calculate the 3-D dose distributions from various treatment plans.The dose calculation utilizes a differential SAR method which is a 3-D extension of Cunningham's CBEAM code.The method correctly compensates for 3-D patient and arbitrary beam shapes.The ideal model for WART would involve delivering a homogenous tumoricidal dose to the peritoneal surfaces, while minimizing kidney dose.For beam planning, we consider the peritoneum to be composed of fixed parietal components lining the anterior abdominal wall and anterior surfaces of the kidneys, and mobile visceral components overlying bowel and omentum.We assume that the dose to the renal parietal peritoneum approximates that to the kidney because of their intimate spatial relationship.We also assume that small bowel and omentum are primarily mobile, so we cannot accurately estimate dosimetry to their mesentary.Thus, in evaluating different WART techniques, our attention is focused on the dosages to the kidneys and the anterior abdominal wall parietal peritoneum.We also consider the differences in the area of anterior parietal and the volume of visceral peritoneum treated as different beams and blocks are used.We have evaluated these parameters in the consideration of whole abdominal AP-PA treatment utilizing isocentric technique with the dose prescribed to mid-plane for both 6MV and 20 MV linear accelerator data using AP or PA kidney blocks for a typical patient.The following table show that dose delivered to the kidneys increases witb the "se of anterior kidney blocks, and that the dose delivered to the anterior abdominal wall parietal peritoneum increases with the use of posterior kidney blocks.The difference is less pronounced with the 20 MV as compared to the 6 MV linear accelerator (Table 1).We see that anterior kidney blocks minimize the area of anterior parietal peritoneum shielded (Table 2).Since the volume of visceral peritoneum under the anterior or posterior blocks is proportional to the arca of the kidney block, and since a posterior kidney block is always huger than an anterior kidney block, the anterior kidney block shields less of the visceral peritoneum.In conclusion, posterior kidney blocks have the advantage of lower kidney and higher anterior parietal peritoneal doses, but they underdose a larger area of anterior parietal and volume of visceral peritoneum.The anterior kidney blocks have the advantage of underdosing a smaller area and volume of peritoneum, at the expense of a higher kidney dose.At our institution, we utilize posterior kidney blocks throughout treatment, and supplement the underdosed anterior parietal peritoneum with electron beam therapy.

To identify patterns of failure following curative resection of gastric carcinoma, the records of 130 patients undergoing resection with curative intent at the Massachusetts General Hospital were reviewed. The total local-regional failure rate was 38% (49/130 patients), with 21 patients having local-regional failure alone and 28 patients having local-regional failure and distant metastases. The incidence of local failure rose with the more advanced stages of disease. Tumors staged B2, B3, C2, and C3 had local-regional failure rates in excess of 35%. This group of patients might benefit from adjuvant radiation therapy to the tumor bed and regional lymphatics. Local-regional failure rate was highest in the anastomosis or stump 33/130 (25%), followed by the stomach bed 27/130 (21%). The overall incidence of distant metastases was 52% (67/130 patients) and rose in the more advanced disease stages. Tumors staged B2, B3, C2, and C3 had rates of distant metastases greater than 50%. Sixty-one patients (77%) had failure in the abdomen (liver, peritoneal surface, adrenal, kidney, and spleen, but excluding tumor bed, anastomosis, or regional nodes). Patients with Stage B2, B3, C2, and C3 tumors had total abdominal failure rates greater than 40%. The highest failure rates in the liver were in Stages B3 and C3, in which the subsequent development of liver metastasis was 40% and 47%, respectively. Peritoneal seeding occurred in 30/130 (23%) of patients and was highest in Stages C2 and C3, with rates of 27% and 41%, respectively.

Good radiation treatment planning requires that the target volume be treated with a high and uniform dose of radiation while irradiating normal tissue as little as possible. Even if the merits of a given treatment plan are judged only on the appearance of isodose lines in one or a few planes it can sometimes be difficult for the experienced radiation oncologist to select the best of several alternative plans. If consideration is given to the entire spatial distribution of dose, however, the problem becomes far more difficult because of the enormous amount of data that must be evaluated. We believe that the lack of suitable methods to display these data has greatly contributed to the slow incorporation of 3D considerations into routine radiation treatment planning. In the past few years there have been great advances in both the theory of how to produce effective 3D displays and in the display hardware itself. In this paper we survey some of the methods used at the University of North Carolina, and show specific examples of how these displays can be used in radiation therapy treatment planning.