Hypofractionated Conformal Radiotherapy with Concurrent Full-Dose Gemcitabine Versus Standard Fractionation Radiotherapy with Concurrent Fluorouracil for Unresectable Pancreatic Cancer: a Multi-Institution Experience.

PURPOSE/OBJECTIVE(S): The purpose of this study was to compare oncologic outcomes and toxicity profile of hypofractionated conformal radiotherapy (RT) with concurrent full-dose gemcitabine versus standard fractionation RT with concurrent 5-fluorouracil (5-FU) in the treatment of unresectable non-metastatic pancreatic cancer. MATERIALS/METHODS: Patients with unresectable non-metastatic adenocarcinoma of the pancreas treated at three institutions were included. All patients were treated with chemoradiotherapy (CRT) consisting of either hypofractionated RT to the gross disease concurrent with a full-dose gemcitabine-based regimen versus standard fractionation RT to the tumor and elective nodes concurrent with 5-FU. End points included rates of gastrointestinal (GI) toxicities, overall survival (OS), and distant metastasis free survival (DMFS). RESULTS: From January 1999 to December 2009, 170 patients were identified (118 RT/gemcitabine, 52 RT/5-FU). There were no differences in demographic or clinical factors. Acute GI toxicities (grades <3 versus ≥3) were 82.2 and 17.8 %, respectively, for patients treated with RT/gemcitabine and 78.9 and 21.2 % for those treated with RT/5-FU (p = 0.67). Late GI toxicities (grades <3 versus ≥3) were 88.1 and 11.9 %, respectively, for RT/gemcitabine and 80.8 and 19.2 % for RT/5-FU (p = 0.23). OS for RT/gemcitabine and RT/5-FU were 52 versus 36 % at 1 year and 14 versus 6 % at 2 years favoring the RT/gemcitabine group (p = 0.02). DMFS at 1 and 2 years for RT/gemcitabine were 41 and 11 % versus 24 and 4 % for RT/5-FU (p = 0.02). CONCLUSIONS: RT/gemcitabine was equivalent in toxicity to RT/5-FU but was associated with superior OS and DMFS. When RT is used in the treatment of unresectable pancreatic cancer, hypofractionated conformal RT with concurrent full-dose gemcitabine may be the preferred approach.

Full-dose gemcitabine with concurrent radiation therapy in patients with nonmetastatic pancreatic cancer: a multicenter phase II trial.

PURPOSE: Gemcitabine is effective in the treatment of pancreatic cancer and is a potent radiosensitizer. This study assessed safety and efficacy of full-dose gemcitabine administered before and during concurrent three-dimensional conformal radiation (3D-CRT) in patients with nonmetastatic pancreatic cancer. PATIENTS AND METHODS: During cycles 1 and 3, patients received gemcitabine at 1,000 mg/m(2) on days 1 and 8 of each 21-day cycle. Cycle 2 included the same dose of gemcitabine on days 1, 8, and 15 of a 28-day cycle with concurrent 3D-CRT at 36 Gy, administered in 15 fractions of 2.4 Gy, over 3 weeks. Resectable patients underwent surgery 4 to 6 weeks after treatment. The primary objective was evaluation of toxicity. Tumor response, CA 19-9, and 1-year survival were also assessed. RESULTS: Forty-one patients enrolled at six institutions between April 2002 and October 2003. Among the 39 treated patients, the most common toxicities were grade 3 neutropenia (12.8%), grade 3 nausea (10.3%), and grade 3 vomiting (10.3%). The response rate was 5.1% and disease control rate was 84.6%. Mean post-treatment CA 19-9 levels (228 +/- 347 U/mL) were significantly (P = .006) reduced compared with pretreatment levels (1,241 +/- 2,124 U/mL). Thirteen (81%) of 16 patients initially judged resectable, three (33%) of nine borderline-resectable patients, and one (7%) of 14 unresectable patients underwent resection after therapy. One-year survival rates were 73% for all patients, 94% for resectable patients, 76% for borderline-resectable patients, and 47% for unresectable patients. CONCLUSION: Full-dose gemcitabine with concurrent radiotherapy was well tolerated and active. Evaluation of this regimen in a larger, randomized trial for patients with resectable or borderline-resectable disease may be warranted.

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 >or=T3 or >or=N1 were treated with capecitabine 1330 mg/m 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 >or=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.

Long-term outcomes after radiotherapy for retroperitoneal and deep truncal sarcoma.

PURPOSE: To determine the long-term outcomes after multimodality treatment of retroperitoneal, pelvic, and deep truncal sarcomas and to identify the factors associated with local control (LC), distant metastasis (DM), and overall survival (OS). METHODS AND MATERIALS: A total of 85 patients with retroperitoneal, pelvic, and deep truncal sarcomas were treated with radiotherapy (RT) between 1987 and 2005. A retrospective analysis of LC, DM, and OS was conducted using log-rank and Cox regression statistical methods. RESULTS: The 2- and 5-year LC, DM, and OS rates were 66% and 51%, 38% and 58%, and 70% and 34%, respectively. Negative surgical margins and a higher radiation dose were associated with greater LC rates on both univariate and multivariate analyses, and female gender was significantly associated with greater LC on multivariate analysis only. None of the analyzed risk factors was significantly associated with DM, although patients with high-grade tumors showed a trend toward an increased risk of DM. Gross residual disease after resection and high tumor grade were associated with worse OS rates on univariate and multivariate analyses, and male gender was significantly associated with worse OS on multivariate analysis only. A time-dependent analysis of LC in relation to DM demonstrated that patients with local failure had a hazard ratio of 19.7 for DM compared with patients without local failure (p < 0.0001). Of the 85 patients, 5 and 8, respectively, had clinically significant acute and late toxicity. CONCLUSION: The results of this study emphasize the importance of LC in patients with retroperitoneal sarcoma. Radiation dose escalation or radiosensitization strategies to enhance LC are warranted.

A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma.

BACKGROUND: We report the results of a multi-institutional phase II trial that used preoperative full-dose gemcitabine and radiotherapy for patients with potentially resectable pancreatic carcinoma. METHODS: Patients were treated before surgery with three cycles of full-dose gemcitabine (1000 mg/m2 intravenously), with radiation during the second cycle (36 Gy in daily 2.4-Gy fractions). Patients underwent surgery 4 to 6 weeks after the last gemcitabine infusion. RESULTS: There were 10 men and 10 women, with a median age of 58 years (range, 50-80 years). Nineteen patients (95%) completed therapy without interruption, and one experienced grade 3 gastrointestinal toxicity. The mean weight loss after therapy was 4.0%. Of 20 patients taken to surgery, 17 (85%) underwent resections (16 pancreaticoduodenectomies and 1 distal pancreatectomy). The complication rate was 24%, with an average length of stay of 13.5 days. There were no operative deaths. Pathologic analysis revealed clear margins in 16 (94%) of 17 and uninvolved lymph nodes in 11 (65%) of 17 specimens. One specimen contained no residual tumor, and three specimens revealed only microscopic foci of residual disease. With a median follow-up of 18 months, 7 (41%) of the 17 patients with resected disease are alive with no recurrence, 3 (18%) are alive with distant metastases, and 7 (41%) have died. CONCLUSIONS: Preoperative gemcitabine/radiotherapy is well tolerated and safe when delivered in a multi-institutional setting. This protocol had a high rate of subsequent resection, with acceptable morbidity. The high rate of negative margins and uninvolved nodes suggests a significant tumor response. Preliminary survival data are encouraging. This regimen should be considered in future neoadjuvant trials for pancreatic cancer.

Capecitabine and radiation therapy preceded and followed by combination chemotherapy in advanced pancreatic cancer.

PURPOSE: The primary objective of this study was to evaluate the tolerance and toxicity of radiation therapy (RT) and capecitabine in patients with advanced, unresectable pancreatic carcinoma. To control micrometastatic disease, combination chemotherapy (gemcitabine and cisplatin) before and after combined modality therapy (CMT) was planned. METHODS AND MATERIALS: Patients with unresectable or metastatic pancreatic cancer were eligible. Gemcitabine 1000 mg/m2 and cisplatin 35 mg/m2 were administered on Days 1 and 8 of a 21-day cycle for two cycles. RT was then given to a dose of 50.4 Gy in 1.8 Gy fractions. Patients were treated with capecitabine 1330 mg/m2 daily during RT. After CMT, two additional cycles of gemcitabine and cisplatin completed the treatment. RESULTS: Twenty-three patients were treated. Eighteen patients completed CMT. One patient was removed from study during CMT for toxicity issues. Treatment delays and dose reductions were common during the final two cycles of gemcitabine and cisplatin as a result of myelosuppression. Median survival was 10.1 months (95% confidence interval [CI] = 7.6, 13.7) for all 23 patients and 12.8 months (95% CI = 8.2, 18.9) for 18 patients without metastasis. CONCLUSION: Combined modality therapy with RT and capecitabine was well tolerated. Chemotherapy after CMT was difficult to complete owing to cumulative myelosuppression. Survival, response, and toxicity were comparable to infusional 5-fluorouracil and RT.

Randomized phase II evaluation of 6 g/m2 of ifosfamide plus doxorubicin and granulocyte colony-stimulating factor (G-CSF) compared with 12 g/m2 of ifosfamide plus doxorubicin and G-CSF in the treatment of poor-prognosis soft tissue sarcoma.

PURPOSE: The relative value of increasing ifosfamide dose in combination chemotherapy for patients with soft tissue sarcoma (STS) is unclear. The purpose of this study was to compare the efficacy and toxicity of doxorubicin with high-dose (HD) ifosfamide or standard-dose (SD) ifosfamide in patients with STS. PATIENTS AND METHODS: Chemotherapy-naive patients with STS were randomly assigned to receive doxorubicin 60 mg/m(2) and either SD ifosfamide (1.5 g/m(2)/d, days 1 through 4) or HD ifosfamide (3.0 g/m(2), days 1 through 4) every 21 days. Patients were stratified by the presence or absence of metastatic disease. End points were overall survival (OS), 1-year disease-free survival (DFS), and toxicity. RESULTS: The study group consisted of 79 patients (52 patients with localized disease and 27 patients with metastases). Both groups were well-balanced with respect to known prognostic factors. There was no significant difference in 1-year DFS comparing SD ifosfamide with HD ifosfamide (55% v 52%; P = .81). For SD ifosfamide, 2- and 3-year OS were 73% and 52% versus 57% and 49% for HD ifosfamide (P = .34). The incidence of grade 3/4 neutropenia, anemia, and thrombocytopenia were 49%, 23%, and 10%, respectively, on the SD ifosfamide arm, compared with 88%, 58%, and 63%, respectively, on the HD ifosfamide arm. There were five early deaths, all on the HD ifosfamide arm. CONCLUSION: When combined with doxorubicin, HD ifosfamide did not improve 1-year DFS and OS. Toxicity was clearly greater with the HD ifosfamide arm, and lack of outcome differences might be explained by toxicities with HD ifosfamide. These results suggest that HD ifosfamide combination regimens should not be used as first-line therapy for patients with STS.

Adjuvant therapy in pancreatic cancer: Phase I trial of radiation dose escalation with concurrent full-dose gemcitabine.

PURPOSE: To determine the maximal tolerated dose of radiation delivered to the primary tumor bed, in combination with full-dose gemcitabine (1000 mg/m(2) weekly x 3), after resection of pancreatic cancer. METHODS AND MATERIALS: Patients with resected pancreatic carcinoma and poor prognostic features, a positive resection margin, or involved lymph nodes were eligible. Radiotherapy (RT) was directed at the preoperative tumor volume with a conformal technique. Regional lymph node basins were not included. The initial starting radiation dose was 24 Gy in 1.6-Gy fractions. Escalation was achieved by increasing the fraction size in 0.2-Gy increments, keeping the duration of RT to 3 weeks. Gemcitabine was given i.v. for 30-40 min at a dose of 1000 mg/m(2) before RT on Days 1, 8, and 15 of a 28-day cycle. After completion of RT and chemotherapy, an additional cycle of gemcitabine was delivered. RESULTS: Between November 1997 and October 2001, 32 patients were entered: 30 after Whipple resection (positive margins in 2, positive nodes in 22, and both in 6), 1 after distal pancreatectomy, and 1 after incomplete resection of a tumor involving the body (both patients with positive margins and nodes). Treatment was well tolerated. Of the 32 patients, 27 completed all protocol therapy and 29 maintained their pretreatment weight within 5%. Five patients experienced dose-limiting toxicity, four with Grade 3 vomiting requiring hospitalization and one fatal toxicity secondary to pneumonia/sepsis. At the final radiation dose level (42 Gy), 2 patients experienced GI dose-limiting toxicity. At the 39-Gy-dose level, 5 of 6 patients were without dose-limiting toxicity. Isolated local or regional progression was documented in 1 patient. Distant progression was documented in 26 of 32 patients (6 with concurrent local or regional progression). The median survival was 16.5 months (95% confidence interval 12.3-19.9) CONCLUSION: The results of our study indicate that the maximal tolerated radiation dose, administered using conformal techniques targeted to the tumor bed, is 39 Gy. In this high-risk population, data on locoregional control suggest that the reduction in radiation dose and field size minimizes toxicity and does not result in excess failures at these sites.

Continuous 28-day iododeoxyuridine infusion and hyperfractionated accelerated radiotherapy for malignant glioma: a phase I clinical study.

PURPOSE: To investigate the maximal tolerated dose of a continuous 28-day iododeoxyuridine (IUdr) infusion combined with hyperfractionated accelerated radiotherapy (HART); to analyze the percentage of IUdr-thymidine replacement in peripheral granulocytes as a surrogate marker for IUdr incorporation into tumor cells; to measure the steady-state serum IUdr levels; and to assess the feasibility of continuous IUdr infusion and HART in the management of malignant glioma. METHODS AND MATERIALS: Patients were required to have biopsy-proven malignant glioma. Patients received 100 (n = 4), 200 (n = 3), 300 (n = 3), 400 (n = 6), 500 (n = 4), 625 (n = 5), or 781 (n = 6) mg/m(2)/d of IUdr by continuous infusion for 28 days. HART was started 7 days after IUdr initiation. The total dose was 70 Gy (1.2 Gy b.i.d. for 25 days with a 10-Gy boost [2.0 Gy for 5 Saturdays]). Weekly assays were performed to determine the percentage of IUdr-DNA replacement in granulocytes and serum IUdr levels using standard high performance liquid chromatography methods. Standard Phase I toxicity methods were used. RESULTS: Between June 1994 and August 1999, 31 patients were enrolled. No patient had Grade 3 or worse HART toxicity. Grade 3 or greater IUdr toxicity predominantly included neutropenia (n = 3), thrombocytopenia (n = 3), and elevated liver function studies (n = 3). The maximal tolerated dose was 625 mg/m(2)/d. Thymidine replacement in the peripheral granulocytes peaked at 3 weeks and increased with the dose (maximal thymidine replacement 4.9%). The steady-state plasma IUdr level increased with the dose (maximum, 1.5 microM). CONCLUSION: In our study, continuous long-term IUdr i.v. infusion had a maximal tolerated dose of 625 mg/m(2)/d. Granulocyte incorporation data verified the concept that prolonged IUdr infusion results in IUdr-DNA replacement that corresponds to a high degree of cell labeling. IUdr steady-state plasma levels increased with increasing dose and attained levels needed for clinical radiosensitization. Continuous IUdr infusion and HART were both feasible and well tolerated.

Phase I trial using a time-to-event continual reassessment strategy for dose escalation of cisplatin combined with gemcitabine and radiation therapy in pancreatic cancer.

PURPOSE: The primary objective of this study was to determine the maximum-tolerated dose of cisplatin that could be added to full-dose gemcitabine and radiation therapy (RT) in patients with pancreatic cancer. PATIENTS AND METHODS: Nineteen patients were treated. Gemcitabine 1,000 mg/m(2) was administered over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Cisplatin followed gemcitabine on days 1 and 15. The initial dose level of cisplatin was 30 mg/m(2), escalated to a targeted dose of 50 mg/m(2) using Time-to-Event Continual Reassessment Method. RT was initiated on cycle 1, day 1, in 2.4 Gy fractions to a total dose of 36 Gy. A second cycle of chemotherapy was planned following a 1-week rest. RESULTS: Four of eight patients experienced acute dose limiting toxicity at the 50 mg/m(2) cisplatin dose level. Patients treated at 30 and 40 mg/m(2) cisplatin dose level tolerated therapy without dose-limiting toxicity. Median survival was 10.7 months (95% CI, 5.4 to 18.2) for all patients, and 12.9 months (95% CI, 7.4 to 21.2) for those without metastasis. CONCLUSION: Cisplatin at doses up to 40 mg/m(2) may be safely added to full-dose gemcitabine and conformal RT. The Time-to-Event Continual Reassessment Method trial design allowed rapid completion of the study and confidence in the conclusion about the maximum tolerated dose, but accrued more patients to a dose level above the maximum tolerated dose than the typical phase I design. Local and systemic disease control and survival in this study cohort supports further investigation of gemcitabine-based RT and combination chemotherapy in this disease.

Radiotherapy potentiates the therapeutic efficacy of intratumoral dendritic cell administration.

We examined whether radiotherapy (RT) could enhance the efficacy of dendritic cell (DC)-based immunotherapy of cancer. Mice bearing s.c. D5 melanoma or MCA 205 sarcoma tumors were treated with intratumoral (i.t.) injections of bone marrow-derived unpulsed DCs in combination with local fractionated tumor irradiation. DC administration alone slightly inhibited D5 tumor growth and had no effect on MCA 205. RT alone caused a modest inhibition of both tumors. DC administration combined with RT inhibited D5 and MCA 205 tumor growth in an additive and synergistic manner, respectively. In both tumor models, RT intensified the antitumor efficacy of DC administration independent of apoptosis or necrosis within the tumor mass. Combination treatment of i.t. DCs plus RT was superior to s.c. injections of tumor lysate-pulsed DCs plus interleukin 2 in inhibiting D5 tumor growth and prolonging survival of mice. Splenocytes from mice treated with i.t. DCs plus RT contained significantly more tumor-specific, IFN-gamma-secreting T cells compared with control groups. Moreover, adoptive transfer of these splenocytes mediated significant tumor regression in mice bearing established pulmonary metastases. Combined treatment followed by resection of residual s.c. tumor conferred protective immunity against a subsequent i.v. tumor challenge. Furthermore, i.t. DC plus RT treatment of s.c. tumor in mice bearing concomitant pulmonary metastases resulted in a significant reduction of lung tumors. i.t. DC administration combined with RT induces a potent local and systemic antitumor response in tumor-bearing mice. This novel regimen may be beneficial in the treatment of human cancers.

Conformal chemoradiation for primary and metastatic liver malignancies.

Historically, radiation therapy has played a minor role in the management of patients with unresectable primary hepatobiliary malignancies and liver metastases from colorectal cancer. This can be attributed chiefly to the low tolerance of the whole liver to radiation. Three-dimensional radiation planning techniques have allowed much higher doses of radiation to be delivered to focal liver tumors, while sparing the majority of the normal liver. When combined with fluorodeoxyuridine (FUdR), high-dose focal liver radiation is associated with excellent response rates, local control, and survival in patients with large unresectable tumors. There appears to be a radiation dose response for intrahepatic malignancies. Advancements in tumor imaging, radiation techniques that can safely deliver higher doses of radiation, novel tumor radiation sensitizers, and normal-tissue radioprotectors should substantially improve the outcome of patients with unresectable intrahepatic malignancies treated with chemoradiation.

Cutaneous angiosarcoma of the scalp: a multidisciplinary approach.

BACKGROUND: Angiosarcoma is a malignant tumor of vascular endothelial cells that arises in the head and neck. It is a rare, difficult to treat, and lethal tumor. METHODS: Clinical data from patients who were diagnosed with angiosarcoma of the scalp between 1975 and 2002 at the University of Michigan were reviewed. Analysis was performed to assess for factors impacting time to recurrence and survival. RESULTS: The study was comprised of 29 patients with a median age of 71.0 years. Most patients presented after a delay in diagnosis with either a bruise-like macule (48.3%) or a nonbruise-like nodule (51.7%). Seventy-five percent of patients had pathologic Stage T2 disease, and 76% of patients had high-grade tumors. Virtually all patients underwent surgical excision (96.6%); however, negative surgical margins were achieved in only 21.4% of patients. Multiple lesions on presentation were associated with a shorter time to recurrence (P = 0.02). The median actuarial survival was 28.4 months. Younger patients and patients with Stage T1 disease had improved survival (P = 0.024 and P = 0.013, respectively). Radiation therapy was associated significantly with a decreased chance of death (hazard ratio, 0.16; P = 0.006). CONCLUSIONS: Although surgery remains the first option for the treatment of patients with angiosarcoma of the scalp, achieving negative margins often is impossible. Patients who are younger and who have less extensive disease fare better. Postoperative radiation therapy should be employed routinely, as it may lead to improved survival.

Surgical resection following radiation therapy with concurrent gemcitabine in patients with previously unresectable adenocarcinoma of the pancreas.

The combination of gemcitabine with concurrent radiation therapy (Gem/RT) is a promising new approach that is being investigated in patients with unresectable pancreatic cancer. However, substantial toxicity with this combination has also been observed. This review was conducted to determine whether Gem/RT could be safely delivered in the neoadjuvant setting, based on our experience with this combined therapy in a cohort of patients with previously unresectable pancreatic cancer, who subsequently underwent surgical resection. Between July 1996 and June 2001, a total of 67 patients with locally unresectable pancreatic cancer, without distant metastatic disease, received Gem/RT at our institution. Seventeen patients (25%) underwent exploratory surgery following Gem/RT, and nine underwent standard Whipple resection. Thus 9 (52%) of 17 patients who had exploratory operations or 9 (13%) of 67 patients, underwent surgical resection. Thirty-day mortality after resection was 0%, and there were no major surgical complications. Median length of hospital stay was 14 days (range 11 to 19 days). With a median follow-up of 32 months, median survival for the resected patients was 17.6 months (95% confidence interval 12.6 to 37.3 months). Median survival for the remaining 58 patients was 11.9 months (95% confidence interval 9.6 to 14.7 months, P=0.013). We conclude that surgical resection may be safely performed after Gem/RT in a select group of patients initially considered to have unresectable pancreatic cancer. The use of Gem/RT in a neoadjuvant setting is currently being investigated in a multi-institutional phase II trial.

Radiation therapy with once-weekly gemcitabine in pancreatic cancer: current status of clinical trials.

Clinical trials investigating a variety of gemcitabine-based chemoradiation therapy regimens were initiated several years ago and remain under active investigation for the treatment of patients with pancreatic cancer. These trials are based, in part, on the activity of gemcitabine as a single agent in pancreatic cancer, preclinical studies that demonstrated radiosensitization, and the need for approaches with greater efficacy than that provided by 5-fluorouracil (5-FU)-based chemoradiation therapy. In this review, we describe and compare several Phase I clinical trials investigating dose escalation of once-weekly gemcitabine with concurrent radiation therapy. We also describe a relatively novel approach successfully investigating radiation dose escalation with a standard weekly dose of gemcitabine. Toxicity data from this trial, and the prior trials of gemcitabine dose escalation with more conventional radiation therapy, suggest that the volume of normal tissue radiated in gemcitabine-based chemotherapy regimens may be the most critical consideration for future trial designs. Finally, we highlight the need to fully consider the design of future trials in the context of both local and distant disease control, given the radiosensitizing potential and systemic activity of gemcitabine.

On the development of gemcitabine-based chemoradiotherapy regimens in pancreatic cancer.

The use of chemotherapy with concurrent radiation therapy remains a standard treatment option for patients with unresectable or resected adenocarcinoma of the pancreas. This treatment strategy is based in large part on data from serial Gastrointestinal Tumor Study Group trials that have included 5-fluorouracil. Unfortunately, the majority of patients continue to succumb to the disease process. Recently, there has been a resurgence in clinical trials utilizing gemcitabine as a single agent, in combination chemotherapy regimens, and with concurrent radiation therapy. Use with concurrent radiation therapy is based in part on laboratory studies investigating mechanisms of radiosensitization and strategies that might increase the therapeutic index. In the current review, the authors summarize the preclinical data that support the use of gemcitabine as a radiosensitizing agent and the clinical trials that have been conducted to date. Issues regarding the use of gemcitabine in concurrent radiotherapy regimens need to be viewed in the context of both local and distant disease control, given the radiosensitizing and systemic activity of this agent.

Analysis of radiation-induced liver disease using the Lyman NTCP model.

PURPOSE: To describe the dose-volume tolerance for radiation-induced liver disease (RILD) using the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model. METHODS AND MATERIALS: A total of 203 patients treated with conformal liver radiotherapy and concurrent hepatic arterial chemotherapy were prospectively followed for RILD. Normal liver dose-volume histograms and RILD status for these patients were used as input data for determination of LKB model parameters. A complication was defined as Radiation Therapy Oncology Group Grade 3 or higher RILD < o r =4 months after completion of radiotherapy. A maximal likelihood analysis yielded best estimates for the LKB NTCP model parameters for the liver for the entire patient population. A multivariate analysis of the potential factors associated with RILD was also completed, and refined LKB model parameters were obtained for patient subgroups with different risks of RILD. RESULTS: Of 203 patients treated with focal liver irradiation, 19 developed RILD. The LKB NTCP model fit the complication data for the entire group. The "n" parameter was larger than previously described, suggesting a strong volume effect for RILD and a correlation of NTCP with the mean liver dose. No cases of RILD were observed when the mean liver dose was <31 Gy. Multivariate analysis demonstrated that in addition to NTCP and the mean liver dose, a primary hepatobiliary cancer diagnosis (vs. liver metastases), bromodeoxyuridine hepatic artery chemotherapy (vs. fluorodeoxyuridine chemotherapy), and male gender were associated with RILD. For 169 patients treated with fluorodeoxyuridine, the refined LKB model parameters were n = 0.97, m = 0.12, tolerance dose for 50% complication risk for whole organ irradiated uniformly [TD50(1)] = 45.8 Gy for patients with liver metastases, and TD50(1) = 39.8 Gy for patients with primary hepatobiliary cancer. CONCLUSION: These data demonstrate that the liver exhibits a large volume effect for RILD, suggesting that the mean liver dose may be useful in ranking radiation plans. The inclusion of clinical factors, especially the diagnosis of primary hepatobiliary cancer vs. liver metastases, improves the estimation of NTCP over that obtained solely by the use of dose-volume data. These findings should facilitate the application of focal liver irradiation in future clinical trials.

Concurrent chemoradiotherapy with gemcitabine and cisplatin for pancreatic cancer: from the laboratory to the clinic.

PURPOSE: We have reported that gemcitabine and concurrent radiation is a promising therapy for patients with pancreatic cancer. We investigated whether the addition of cisplatin, which may increase the systemic efficacy of gemcitabine, would be synergistic with gemcitabine and/or radiation in human pancreatic cancer cell lines. METHODS AND MATERIALS: BxPc3 and Panc-1 human pancreatic cancer cells were treated with three different schedules before radiation: (A) a sequential incubation of gemcitabine for 2 h followed by cisplatin for 2 h, (B) gemcitabine for 2 h, followed by washout of drug, replenishment of media for a 24-h incubation, followed by cisplatin for 2 h, and (C) gemcitabine for 24 h with a concurrent incubation of cisplatin for the last 2 h. Cells were assessed for clonogenic survival using a standard assay. Synergism was evaluated by the median effect analysis. RESULTS: The schedule shown to be maximally synergistic for both cell lines was the consecutive 2-h gemcitabine, 2-h cisplatin exposure, particularly at surviving fractions of <0.5. Cisplatin did not produce radiosensitization nor did it affect gemcitabine-mediated radiosensitization. CONCLUSION: Cisplatin produces synergistic cytotoxicity with gemcitabine without compromising gemcitabine-mediated radiosensitization. On the basis of these laboratory and previous clinical observations, we have initiated a Phase I trial of cisplatin plus gemcitabine and radiotherapy in patients with unresectable pancreatic cancer.

Daily targeting of intrahepatic tumors for radiotherapy.

INTRODUCTION: A system has been developed for daily targeting of intrahepatic tumors using a combination of ventilatory immobilization, in-room diagnostic imaging, and on-line setup adjustment. By reducing geometric position uncertainty, as well as organ movement, this system permits reduction of margins and thus potentially higher treatment doses. This paper reports our initial experience treating 8 patients with focal liver tumors using this system. METHODS AND MATERIALS: The system includes diagnostic X-ray tubes mounted on the wall and ceiling of a treatment room, an active matrix flat panel imager, in-room control for image acquisition and setup adjustment, and a ventilatory immobilization system via active breathing control (ABC). Eight patients participated in the study, two using an early prototype ABC unit, and the remaining six with a commercial ABC system and improved setup measurement tools. Treatment margins were reduced, and dose consequently increased because of increased confidence in target position under this protocol. After daily setup via skin marks, orthogonal radiographs were acquired at suspended ventilation. The images were aligned to the CT model using the diaphragm for inferior-superior (IS) alignment, and the skeleton for left-right (LR) and anterior-posterior (AP) alignment. Adjustments were made for positioning errors greater than a threshold (3 or 5 mm). After treatment, retrospective analysis determined the final setup accuracy, as well as the error in initial setup measurement performed before setup adjustment. RESULTS: Two hundred sixty-two treatment fractions were delivered on eight patients, with 171 treatments requiring repositioning. Typical treatment times were 25-30 min. Patients were able to tolerate ABC throughout the course of treatment. Breath holds up to 35 s long were used for treatment. The use of on-line imaging and setup adjustment reduced setup errors (sigma) from 4.0 mm (LR), 6.7 mm (IS), and 3.8 mm (AP) to 2.1 mm (LR), 3.5 mm (IS), and 2.3 mm (AP). Prescribed doses were increased using this system by an average of 5 Gy. CONCLUSIONS: Daily targeting of intrahepatic targets has been demonstrated to be feasible. The potential for reduction in treatment margin and consequential safe dose escalation has been demonstrated, while maintaining reasonable treatment delivery times.