Stereotactic body radiation therapy with concurrent full-dose gemcitabine for locally advanced pancreatic cancer: a pilot trial demonstrating safety
- Marie K Gurka†1,
- Sean P Collins†1,
- Rebecca Slack2, 3,
- Gary Tse1,
- Aline Charabaty4,
- Lisa Ley2,
- Liam Berzcel2,
- Siyuan Lei1,
- Simeng Suy1,
- Nadim Haddad4,
- Reena Jha5,
- Colin D Johnson6,
- Patrick Jackson7,
- John L Marshall2 and
- Michael J Pishvaian2Email author
© Gurka et al.; licensee BioMed Central Ltd. 2013
Received: 4 December 2012
Accepted: 25 February 2013
Published: 1 March 2013
Concurrent chemoradiation is a standard option for locally advanced pancreatic cancer (LAPC). Concurrent conventional radiation with full-dose gemcitabine has significant toxicity. Stereotactic body radiation therapy (SBRT) may provide the opportunity to administer radiation in a shorter time frame with similar efficacy and reduced toxicity. This Pilot study assessed the safety of concurrent full-dose gemcitabine with SBRT for LAPC.
Patients received gemcitabine, 1000 mg/m2 for 6 cycles. During week 4 of cycle 1, patients received SBRT (25 Gy delivered in five consecutive daily fractions of 5 Gy prescribed to the 75-83% isodose line). Acute and late toxicities were assessed using NIH CTCAE v3. Tumor response was assessed by RECIST. Patients underwent an esophagogastroduodenoscopy at baseline, 2, and 6 months to assess the duodenal mucosa. Quality of life (QoL) data was collected before and after treatment using the QLQ-C30 and QLQ-PAN26 questionnaires.
Between September 2009 and February 2011, 11 patients enrolled with one withdrawal during radiation therapy. Patients had grade 1 to 2 gastrointestinal toxicity from the start of SBRT to 2 weeks after treatment. There were no grade 3 or greater radiation-related toxicities or delays for cycle 2 of gemcitabine. On endoscopy, there were no grade 2 or higher mucosal toxicities. Two patients had a partial response. The median progression free and overall survival were 6.8 and 12.2 months, respectively. Global QoL did not change between baseline and immediately after radiation treatment.
SBRT with concurrent full dose gemcitabine is safe when administered to patients with LAPC. There is no delay in administration of radiation or chemotherapy, and radiation is completed with minimal toxicity.
KeywordsPancreatic cancer Gemcitabine Radiation Stereotactic body radiation therapy SBRT CyberKnife Quality of life QLQ-C30 QLQ-PAN26 Upper endoscopy
Quality of life (QoL) is of paramount importance when cure is not achievable, as is currently the case with locally advanced pancreatic cancer (LAPC). In the United States, concurrent chemoradiation therapy is commonly considered the standard of care for LAPC patients, but outcomes are still poor. Randomized clinical trials of chemoradiation vs. chemotherapy alone have shown mixed results, with some trials showing a survival benefit with chemoradiation [1–4] and others demonstrating that is has a negative impact on overall survival [5, 6]. Furthermore, in trials in which there was a survival advantage, toxicity was often higher in the chemoradiation arm [1, 3, 4]. Therefore, clinicians and patients must weigh the small potential gain in overall survival versus the potential adverse effects with chemoradiation.
Traditionally, chemoradiation trials include the use of conventional external beam radiation. This technique uses large radiation fields that deliver a high percentage of the prescription dose to surrounding critical structures possibly leading to significant toxicity and decreased quality of life. When irradiating abdominal tumors with conventional external beam radiation, strict adherence to normal structure dose constraints may limit the delivery of the intended radiation dose to the tumor and potentially result in premature local failure and death. Conversely, delivering high doses of radiation to adjacent critical structures without strict dose constraints increases the risk of late radiation induced complications. Intensity-modulated radiation therapy (IMRT) has made advances over 3D conformal treatment in protecting critical structures and reducing toxicity [7, 8]; however grade 3 and 4 toxicities are still reported and treatment breaks are required that may reduce the treatment’s effectiveness. Tumor motion due to respiration  and unpredictable gastrointestinal distention , require large IMRT planning target volume expansions that limit the maximum prescription dose. Furthermore, daily IMRT treatments for approximately six weeks can be taxing to these ill patients and their families and society . SBRT may prevent local progression of disease while sparing nearby critical structures, thus providing an improved durable QoL. Furthermore, SBRT is an appealing option for LAPC since it allows reduced treatment times. Previous studies have investigated SBRT (25 Gy in one fraction) as a boost to IMRT with concurrent 5-FU, and SBRT monotherapy (25 Gy in one fraction) with gemcitabine [12, 13]. In both of these trials, local control was excellent; however, late duodenal toxicity was significant, and was related to the amount of duodenum irradiated . Median overall survival was comparable to modern expected outcomes [4, 15, 16]. In an effort to decrease late duodenal toxicity, we and others [17–20], have examined the use of fractionated SBRT with full dose gemcitabine. Here, we report the results of our feasibility trial.
Patients with biopsy-proven, non-metastatic, unresectable pancreatic adenocarcinoma who had an adequate performance status and normal hepatic and renal function were eligible for enrollment on this study. Unresectable disease was defined as any greater than 180° encasement of the celiac, superior mesenteric, hepatic, or gastroduodenal arteries, or greater than 2 cm involvement of the portal or splenic veins, or any venous tumor thrombus. Patients with duodenal mucosal involvement (at time of initial endoscopy) were excluded. The Georgetown University institutional review board approved this study and all patients provided informed written consent.
SBRT treatment was delivered with the CyberKnife (Accuray Incorporated, Sunnyvale, CA) which uses real time tumor tracking and requires 3 visible, non-collinear fiducials on the orthogonal x-ray images . Three to five gold fiducials were placed endoscopically in the pancreatic mass as previously described . Seven days after fiducial placement, fine-cut (1.25 mm) treatment planning CT’s with oral and IV contrast were obtained during a full inhalation breath hold.
Radiation treatment parameters
Other Bowel (V25Gy)
Toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0. Due to the lack of a systematic endoscopic grading system for radiation induced mucosal injury, a previously developed descriptive based scoring system  was used to evaluate for extent of telangiectasia, congested mucosa, ulceration, stricture and necrosis.
Quality of life assessment
All patients were asked to complete two quality of life questionnaires: the EORTC QLQ-C30 version 3 and EORTC QLQ-PAN26, on the first day of each chemotherapy cycle. The QLQ-C30 measures generic health status. QLQ-PAN26 is a pancreatic cancer treatment specific instrument that assesses patient function and bother .
Baseline characteristics and adverse events were tabulated. Adverse events were described for each symptom according to Wachter, et al. and the NCI CTCAE version 3.0. Each symptom was counted once per patient at the highest grade it occurred. Progression-Free Survival (PFS) was calculated as the date gemcitabine was started to the date of progression or death, whichever came first. Overall survival (OS) was calculated from the start date of gemcitabine to date of death. Since patients were followed until death, no censoring occurred for PFS or OS. OS and PFS were calculated using the Kaplan-Meier method . Median OS and PFS times were reported with 95% confidence intervals (CI). Local control was determined by continued growth of the primary on serial radiologic imaging. Wilcoxon rank sum test was used to assess QoL score changes.
Results and discussion
Patient and tumor characteristics
Head & Body
Withdrew before completing radiation
Screening failure due to metastatic disease
Screening failure due to elevated liver function.
Screening failure due to inability to place fiducials.
All patients completed SBRT as prescribed. The mean PTV was large with a mean volume of 360 cc (range, 154 cc – 548 cc) and the mean GTV was 175 cc (range, 103 – 336 cc) (Table 1). Radiation was delivered to a mean prescription isodose line of 78% (range, 75% - 83%) in 5 treatments (Table 1). The mean percent target coverage was 95.42%. Treatment plans were conformal with a mean new conformity index (the target volume multiplied by the prescription isodose volume divided by the target volume covered by prescription isodose volume squared ) of 1.39. Plans were inhomogeneous by design (mean homogeneity index of 1.28) to minimize dose to adjacent critical structures. There were no major protocol variations; one minor protocol variation occurred when 1.0 cc of duodenum received 25 Gy (Table 1).
From the start of SBRT and for 1–2 weeks thereafter, patients generally exhibited grade 1–2 nausea and abdominal cramping, but there were no grade 3 radiation-related acute toxicities, and cycle 2 of gemcitabine was not delayed. Serial endoscopy showed 60% of patients had asymptomatic, small mucosal ulcerations (Grade 1) at 2 months. Of the five patients who completed endoscopy at six months one patient had residual grade one mucosal congestion. There were no grade 2 or higher mucosal toxicities.
Overall, 8 of 10 patients completed 6 cycles of gemcitabine, although all patients required dose reductions or schedule modifications, mostly due to myelosuppression from the chemotherapy. Of the two patients who did not complete all six cycles, one patient became critically ill during cycle three, was admitted for sepsis and taken off study. The other patient progressed with distant metastases after chemotherapy cycle five and was changed to an alternative chemotherapy regimen.
Individual clinical outcomes
Best response (RECIST)
Time to progression (days)
First site of progression
Time to death (days)
Local + distant
Capecitabine (maintenance); Radiation
Erlotinib with gemcitabine
Progressed on gemcitabine, switched to lapatinib + capecitabine
Quality of life
In pancreatic cancer, improved methods of controlling the primary cancer are needed as local progression adversely affects the length and quality of life. Dose escalation with standard external beam radiation therapy has been attempted . However, the inability to limit normal tissue doses led to severe life-threatening toxicity. On the other hand, standard radiation treatment for 5–6 weeks prolongs treatment time and delays administration of systemic therapy. Recent data suggest that large radiation fraction sizes are radio-biologically favorable over lower fraction sizes in slow growing tumors such as pancreatic cancer [34, 35]. This is supported by trials that achieved improved pancreatic cancer local control rates by utilizing large fraction sizes with intraoperative radiation therapy or brachytherapy [36–42]. Analysis of these data suggested that radiobiologic dose escalation to the tumor volume could improve local control in pancreatic cancer.
Gemcitabine is a potent pancreatic cancer radiosensitizer . As previously shown, by the Eastern Cooperative Oncology Group, in patients with LAPC, concurrent gemcitabine at a reduced dose (600 mg/m2) and radiation (50.4 Gy in 28 fractions) provided survival benefit over gemcitabine (1000 mg/m2) alone (4). Furthermore, full dose gemcitabine (1000 mg/m2/week) with concurrent radiation therapy has been shown to be feasible and safe with the omission of elective nodal irradiation and radiation dose reductions . The combination of full dose gemcitabine with radiation therapy should enhance local and systemic tumor control.
In our study, patients received full dose gemcitabine (1000 mg/m2) and concurrent SBRT with an included elective nodal volume The radiation dose given was 25 Gy in five consecutive fractions, which is an equivalent dose in 2 Gy fractions of approximately 40 Gy. We felt that this would be a safe but effective dose drawing from the University of Michigan’s IMRT dose escalation trial. In their trial the MTD was determined to be 36 Gray given in 2.4 Gray fractions, which is equivalent to 41.4 Gray in 1.8 Gray fractions . Furthermore, the inhomogenity is much greater with SBRT than IMRT and consequently the central tumor dose is significantly higher than the prescription dose to the periphery.
Hypofractionated stereotactic body radiation therapy was completed in one week in all patients. Critical organs including the bowel, liver, spinal cord, and kidneys were spared. There were no grade 3 or 4 acute toxicities secondary to radiation and the initiation of the second cycle of chemotherapy was not delayed. Our protocol had strict duodenal dose restrictions and additionally monitoring for late toxicity by endoscopy was performed. With our dose limitations no late toxicity was observed. Chemotherapy toxicity from full dose gemcitabine was as expected with the majority secondary to adverse hematologic effects. However, our local control was lower than that achieved with a single fraction of 25 Gy. This is despite the fact that our patients received concurrent full dose (1000 mg/m2) gemcitabine rather than sequential chemotherapy. This may be due to the relatively low biological effective dose used in this trial.
Despite the lower local control, our median progression free survival and overall survival of 6.8 and 12.2 months are comparable to contemporary chemoradiation trials. Quality of life scores were difficult to interpret due to the small number of patients that completed all the questionnaires. This could have biased the results since patients who progressed were taken off study and did not complete the questionnaires and patients too ill to complete the questionnaires would most likely report lower QOL scores.
Our results from this pilot study demonstrate the feasibility and tolerability of delivering SBRT with concurrent full dose gemcitabine. Unfortunately, local and distant progression remains the predominant patterns of failure for these patients. Nonetheless, SBRT remains a useful tool to optimize available treatment for patients with tumors in close proximity to critical structures while maintaining QOL. Additional studies combining SBRT with regimens that have been proven to improve the control of systemic disease, such as FOLFIRINOX, are also being evaluated .
We are planning to conduct a Phase II trial to confirm the efficacy of this treatment. While outcomes were comparable to contemporary trials, this study only included ten patients. Furthermore, the SBRT dose used in this trial is currently lower than what our institution is safely using at this time. With the low toxicity profile experienced by patients on this trial we will increase the SBRT dose and our future trial will most likely treat patients in five consecutive fractions of 6 Gy per fraction. This will hopefully provide improved local control. While there is still an issue with controlling distant disease, local tumor progression leads to significant morbidity.
This trial was funded by the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers and supported by NIH Grant P30CA051008.
Quality of life
Locally advances pancreatic cancer
Stereotactice body radiation therapy
Intensity-modulated radiation therapy
Gross target volume
Planning target volume
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