Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas
The authors report on the local control and toxicity of
stereotactic body radiotherapy (SBRT) for patients with unresectable
Phase I study of stereotactic
radiosurgery in patients with locally advanced pancreatic cancer.
Gemcitabine Chemotherapy and Single-Fraction Stereotactic Body Radiotherapy for Locally Advanced Pancreatic Cancer.
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA.
PURPOSE: Fractionated radiotherapy and chemotherapy for locally advanced pancreatic cancer achieves only modest local control. This prospective trial evaluated the efficacy of a single fraction of 25 Gy stereotactic body radiotherapy (SBRT) delivered between Cycle 1 and 2 of gemcitabine chemotherapy. METHODS AND MATERIALS: A total of 16 patients with locally advanced, nonmetastatic, pancreatic adenocarcinoma received gemcitabine with SBRT delivered 2 weeks after completion of the first cycle. Gemcitabine was resumed 2 weeks after SBRT and was continued until progression or dose-limiting toxicity. The gross tumor volume, with a 2-3-mm margin, was treated in a single 25-Gy fraction by Cyberknife. Patients were evaluated at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. RESULTS: All 16 patients completed SBRT. A median of four cycles (range one to nine) of chemotherapy was delivered. Three patients (19%) developed local disease progression at 14, 16, and 21 months after SBRT. The median survival was 11.4 months, with 50% of patients alive at 1 year. Patients with normal carbohydrate antigen (CA)19-9 levels either at diagnosis or after Cyberknife SBRT had longer survival (p <0.01). Acute gastrointestinal toxicity was mild, with 2 cases of Grade 2 (13%) and 1 of Grade 3 (6%) toxicity. Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4). A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13). CONCLUSION: SBRT with gemcitabine resulted in comparable survival to conventional chemoradiotherapy and good local control. However, the rate of duodenal ulcer development was significant.
tissue dosimetry and toxicity in cyberknife radiosurgical treatment of the pancreas
Treatment of unresectable pancreas cancer by conventional chemoradiotherapy has yielded disappointing results. Many deaths are due to local failure, offering the hope that dose escalation may provide better control. This has been difficult to achieve with conventional external beam radiotherapy, due to increased complication probabilities in nearby normal tissues. We have treated patients on a Phase I dose-escalation protocol, using Cyberknife radiosurgery in a single fraction to deliver highly conformal doses to unresectable pancreas tumors with minimal dose to surrounding normal tissues. We studied the relationship between dose to various tissues and incidence of GI toxicity. Eighteen patients were treated at three dose levels: 15, 20 or 25 Gy prescribed to the tumor in a single fraction. All patients had unresectable adenocarcinoma of the pancreas with maximum tumor size 7.5 cm. Study entry criteria also included ECOG PS of 2 or better, and no chemotherapy within the prior two months. One of the 18 patients had had prior external beam radiotherapy. The average time for which patients were followed and monitored for toxicity was 9 months (time from treatment to death or to this analysis). Three patients were treated at the 15-Gy dose; of these, one had Grade II GI toxicity (by RTOG criteria). Zero of 6 patients treated at 20 Gy and four of 9 patients treated at 25 Gy had either Grade I or Grade II toxicity, for a total of 5 patients in the toxicity group and 13 in the no-toxicity group. To analyze the relationship between organ dose and toxicity, dose-volume histograms were generated for each patient. Contours were drawn on the thin-cut planning CT scan for the tumor as well as for the remaining normal pancreas, duodenum, other bowel, stomach, liver, kidneys, spleen, aorta, inferior vena cava and spinal cord. A body imaging radiologist guided us in localizing the duodenum and other difficult structures. Dose-volume histograms were generated, and doses to duodenum, stomach and other bowel (organs relevant for GI toxicity) were studied using differential area under the curve (integrated area under the dose-volume curve for the portion of the organ receiving a dose greater than 100 cGy) as a parameter.
No patients experienced GI toxicity exceeding Grade II. To evaluate whether the likelihood of toxicity was related to prescribed tumor dose within the studied range (1525 Gy), we calculated the proportion of patients receiving the high dose of 25 Gy in the toxicity group (4/5 = 0.8) and in the no-toxicity group (5/13 = 0.385). When these proportions were compared using the Z statistic, the result was nonsignificant (p > 0.05). To evaluate effects of dose to individual organs, the average differential area under the curve was calculated for each relevant organ in the toxicity and no-toxicity groups. When the results were compared between groups using the t test, we found that the difference was significant (p < 0.05) for the duodenum, but not for the stomach or other bowel. The lack of Grade III or higher toxicities indicates that our maximum dose (25 Gy) is a safe single-fraction dose. We found that patients who had Grade I-II toxicity were not significantly more likely to have been treated at the maximum dose than those who had no toxicity, indicating that the likelihood of toxicity may be related more to the proximity of the tumor to certain normal tissues than to the prescribed tumor dose. In our analysis of dose-volume data for organs relating to GI toxicity, we found that the likelihood of toxicity was significantly related to the duodenal dose, although not to the stomach or remaining bowel doses. From this we conclude that duodenal dose may be the most important determinant for Grade I-II toxicities, and that it may be possible to establish a simple DVH-related parameter to guide radiosurgical treatment planning in avoidance of acute and subacute GI toxicity. Analysis is ongoing for a Phase II study involving a combination of external beam RT followed by radiosurgery, and we hope to be able to draw further conclusions concerning both more severe and late toxicities