Daily targeting of intrahepatic tumors for radiotherapy Balter, James M; Brock, Kristy K; Litzenberg, Dale W ...
International journal of radiation oncology, biology, physics,
2002, 2002-Jan-01, 2002-1-00, 20020101, Letnik:
52, Številka:
1
Journal Article
Recenzirano
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 (σ) 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.
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.
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.
Radiosensitizing Nucleosides McGinn, Cornelius J.; Shewach, Donna S.; Lawrence, Theodore S.
JNCI : Journal of the National Cancer Institute,
09/1996, Letnik:
88, Številka:
17
Journal Article
Recenzirano
Odprti dostop
Chemotherapeutic drugs that perturb nucleotide metabolism have the potential to produce substantial sensitization of tumor cells to radiation treatment. The process is called radiosensitization, and ...the agents that induce it are called radiosensitizers. The clinical effectiveness of fluoropyrimidines as radiosensitizers has been proven in multiple randomized trials. Thymidine analogues and hydroxyurea also appear to produce clinically relevant increases in radiation sensitivity. Recent laboratory investigations have identified difluorodeoxycytidine (gemcitabine) and fludarabine as promising agents to use in combination with radiation. Until recently, little was known about how the biochemical changes caused by these drugs produced radiosensitization. However, advances in related fields, such as cell cycle checkpoint control, have permitted the development of a hypothesis that may explain the relative tumor selectivity of fluoropyrimidine-mediated radiosensitization. In addition, recent findings suggest that the rational manipulation of drug administration schedules and the use of combinations of radiosensitizers have the potential to improve the efficacy of the currently used agents and to establish the benefit of new ones. J Natl Cancer Inst 1996;88:1193–1203
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 × 3), after resection of pancreatic cancer.
...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.
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)
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
The combination of preoperative capecitabine and RT in patients with LARC has significant antitumor activity, efficacy, and a low toxicity profile.
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