Multi-institutional phase I study of low-dose ultra-fractionated radiotherapy as a chemosensitizer for gemcitabine and erlotinib in patients with locally advanced or limited metastatic pancreatic cancer

doi:10.1016/j.radonc.2014.08.014

Radiotherapy and Oncology

Volume 113, Issue 1, October 2014, Pages 35-40

https://doi.org/10.1016/j.radonc.2014.08.014 Get rights and content

Abstract

Purpose

Gemcitabine (G) has been shown to sensitize pancreatic cancer to radiotherapy but requires lower doses of G and thus delays aggressive systemic treatment, potentially leading to distant failure. We initiated a phase I trial combining ultra-fractionated low-dose radiotherapy with full dose G and erlotinib in the treatment of patients with advanced pancreatic cancer.

Methods

Patients with locally advanced or metastatic pancreatic cancer confined to the abdomen and an ECOG performance status (PS) of 0–1 who had received 0–1 prior regimens (without G or E) and no prior radiotherapy were eligible. Patients were treated in 21 day cycles with G IV days 1 & 8, E once PO QD, and twice daily RT fractions separated by at least 4 h on days 1, 2, 8, and 9. Whole abdominal RT fields were used. Primary endpoint was to define dose limiting toxicity (DLT) and the maximum tolerated dose (MTD).

Results

27 patients (median age 64 years and 15 male) were enrolled between 11/24/08 and 4/12/12. 1 patient withdrew consent prior to receiving any protocol therapy. 17 patients had a PS of 1. The majority of patients were stage IV. One DLT was noted out of 7 patients at dose level (DL) 1. Subsequently no DLTs were noted in 3 patients each enrolled at DL2-4 or 11 patients in the expansion cohort. The majority of grade 3 toxicities were hematologic with 1 grade 5 bowel perforation in dose level 1 in cycle 4. Best response in 24 evaluable patients: PR (8), stable (15), PD 1. Median survival for the entire group was 9.1 months.

Conclusion

This phase I study combining low-dose ultra-fractionated RT as a sensitizer to full dose G plus E was well tolerated with encouraging efficacy. This represents a novel strategy worthy of further investigation in advanced pancreatic cancer patients.

Section snippets

Eligibility

Patients ⩾18 years of age able to provide written informed consent with locally advanced or minimally metastatic adenocarcinoma of the pancreas with ECOG performance status of 0–1 were eligible for this study. Minimally metastatic was defined as having limited metastatic disease in the upper abdomen or liver that could be included in the upper abdominal radiation port. Patients with prior chemotherapy for metastatic pancreatic cancer were initially ineligible but the study was subsequently

Results

A total of 27 patients were enrolled in the study. One patient withdrew consent before treatment shortly after enrollment leaving 26 analyzable patients. The median follow-up from study enrollment was 8.4 (range: 2.3–47.9) months. The median follow-up from the end of treatment was 4.1 (range: 0–41.2) months. Table 1 summarizes patient characteristics. Patients were relatively evenly split between locally advanced and metastatic disease. Of those patients with metastatic disease, the most common

Discussion

This phase I study combining standard dose chemotherapy with a novel delivery of radiotherapy (low dose per fraction radiotherapy or ultra-fractionation) utilized as a chemosensitizer was found to be relatively well tolerated and safe in patients with locally advanced and metastatic pancreatic cancer. Our efficacy results also compare favorably with other studies utilizing chemotherapy alone for locally advanced and metastatic pancreatic cancer.

Until recently, the standard treatment for

Conflict of interest

Steven J. Cohen has received grant and consulting fees from Genentech.

Dr. Philip Philip has had grant and consulting fees from Genentech outside of work for the study.

Funding

Genentech United States.

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Phase I trialMulti-institutional phase I study of low-dose ultra-fractionated radiotherapy as a chemosensitizer for gemcitabine and erlotinib in patients with locally advanced or limited metastatic pancreatic cancer

Abstract

Purpose

Methods

Results

Conclusion

Section snippets

Eligibility

Results

Discussion

Conflict of interest

Funding

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Cancer Cell

Int J Radiat Oncol Biol Phys

Int J Radiat BIol Phys

Radiother Oncol

Radiother Oncol

Radiother Oncol

The response of Chinese hamster V79 cells to low radiation doses: evidence of enhanced sensitivity of the whole cell population

Radiat Res

Low-dose hyper-radiosensitivity: a consequence of ineffective cell cycle arrest of radiation-damaged G2-phase cells

Radiat Res

Role of apoptosis in low-dose hyper-radiosensitivity

Radiat Res

Effects of exposure to low-dose-rate (60)co gamma rays on human tumor cells in vitro

Radiat Res

Effect of subsequent acute-dose irradiation on cell survival in vitro following low dose-rate exposures

Int J Radiat Biol

Effective palliation without normal tissue toxicity using low-dose ultrafractionated re-irradiation for tumor recurrence after radical or adjuvant radiotherapy

Acta Oncol

Ultrafractionation in A7 human malignant glioma in nude mice

Int J Radiat Biol

Phase I trial
Multi-institutional phase I study of low-dose ultra-fractionated radiotherapy as a chemosensitizer for gemcitabine and erlotinib in patients with locally advanced or limited metastatic pancreatic cancer