Phase I study evaluating the treatment of patients with locally advanced pancreatic cancer with carbon ion radiotherapy: the PHOENIX-01 trial

BackgroundTreatment options for patients with locally advanced pancreatic cancer include surgery, chemotherapy as well as radiotherapy. In many cases, surgical resection is not possible, and therefore treatment alternatives have to be performed. Chemoradiation has been established as a convincing treatment alternative for locally advanced pancreatic cancer. Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 1.16 and 2.46 depending on the pancreatic cancer cell line as well as the endpoint analyzed. Japanese Data on the evaluation of carbon ion radiation therapy showed promising results for patients with pancreatic cancer.Methods and designThe present PHOENIX-01 trial evaluates carbon ion radiotherapy using the active rasterscanning technique in patients with advanced pancreatic cancer in combination with weekly gemcitabine and adjuvant gemcitabine. Primary endpoint is toxicity, secondary endpoints are overall survival, progression-free survival and response.DiscussionThe physical and biological properties of the carbon ion beam promise to improve the therapeutic ratio in patients with pancreatic cancer: Due to the inverted dose profile dose deposition in the entry channel of the beam leads to sparing of normal tissue; the Bragg peak can be directed into the defined target volume, and the sharp dose fall-off thereafter again spares normal tissue behind the target volume. The higher RBE of carbon ions, which has been shown also for pancreatic cancer cell lines in the preclinical setting, is likely to contribute to an increase in local control, and perhaps in OS. Early data from Japanese centers have shown promising results. In conclusion, this is the first trial to evaluate actively delivered carbon ion beams in patients with locally advanced pancreatic cancer within a dose-escalation strategy.Trial registrationNCT01795274

[1]  K. Rückert,et al.  Surgical treatment of pancreatic cancer , 1984, World Journal of Surgery.

[2]  Jeffrey E. Lee,et al.  Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  J. Lee,et al.  Dose Escalation Methods in Phase I Cancer Clinical Trials , 2009, Journal of the National Cancer Institute.

[4]  C. Mcginn,et al.  Surgical resection following radiation therapy with concurrent gemcitabine in patients with previously unresectable adenocarcinoma of the pancreas , 2003, Journal of Gastrointestinal Surgery.

[5]  M. Goitein,et al.  Tolerance of normal tissue to therapeutic irradiation. , 1991, International journal of radiation oncology, biology, physics.

[6]  H. Friess,et al.  Randomized phase II – study evaluating EGFR targeting therapy with Cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer – PARC: study protocol [ISRCTN56652283] , 2005, BMC Cancer.

[7]  M. Hiraoka,et al.  Phase II Study of Radiation Therapy Combined With Weekly Low-Dose Gemcitabine for Locally Advanced, Unresectable Pancreatic Cancer , 2011, American journal of clinical oncology.

[8]  B. Eisenberg,et al.  Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas , 2001, Journal of Gastrointestinal Surgery.

[9]  K. Lillemoe,et al.  Resected adenocarcinoma of the pancreas— 616 patients: Results, outcomes, and prognostic indicators , 2000, Journal of Gastrointestinal Surgery.

[10]  L. Schwartz,et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). , 2009, European journal of cancer.

[11]  D. Stocken,et al.  A Randomized Phase 2 Trial of Neoadjuvant Chemotherapy in Resectable Pancreatic Cancer: Gemcitabine Alone Versus Gemcitabine Combined with Cisplatin , 2007, Annals of Surgical Oncology.

[12]  Leila Mohammadi,et al.  BMC Cancer , 2001 .

[13]  H. Friess,et al.  Surgical Treatment of Pancreatic Cancer , 2008, Annals of the New York Academy of Sciences.

[14]  Hirohiko Tsujii,et al.  Particle radiation therapy using proton and heavier ion beams. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  H. Kocher,et al.  Pancreatic Cancer , 2019, Methods in Molecular Biology.

[16]  J. Barkin,et al.  Therapy of locally unresectable pancreatic carcinoma: A randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5‐fluorouracil), and high dose radiation + 5‐fluorouracil. The gastrointestinal tumor study group , 1981, Cancer.

[17]  J. Vauthey,et al.  Combining gemcitabine with radiation in pancreatic cancer: understanding important variables influencing the therapeutic index. , 2001, Seminars in oncology.

[18]  Tibor Schuster,et al.  Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages , 2010, PLoS medicine.

[19]  A. Lowy.  Neoadjuvant Therapy for Pancreatic Cancer , 2008, Journal of Gastrointestinal Surgery.

[20]  K. Lillemoe,et al.  DNA content and other factors associated with ten‐year survival after resection of pancreatic carcinoma , 1998, Journal of surgical oncology.

[21]  F. Ames,et al.  Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. , 1992, Archives of surgery.

[22]  B. Eisenberg,et al.  A pilot study of preoperative chemoradiation for patients with localized adenocarcinoma of the pancreas. , 1995, American journal of surgery.

[23]  Edgar Ben-Josef,et al.  Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. , 2007, International journal of radiation oncology, biology, physics.

[24]  N. Girard,et al.  Radiochemotherapy in the management of pancreatic cancer--part I: neoadjuvant treatment. , 2005, Seminars in radiation oncology.

[25]  F Lohr,et al.  Extracranial stereotactic radiation therapy: set-up accuracy of patients treated for liver metastases. , 2000, International journal of radiation oncology, biology, physics.

[26]  D. Schulz‐Ertner.  The Clinical Experience With Particle Therapy in Adults , 2009, Cancer journal.

[27]  N. Girard,et al.  Estimating optimal dose of twice-weekly gemcitabine for concurrent chemoradiotherapy in unresectable pancreatic carcinoma: mature results of GEMRT-01 Phase I trial. , 2010, International journal of radiation oncology, biology, physics.

[28]  E. Paulson,et al.  Neoadjuvant Chemoradiation for Localized Adenocarcinoma of the Pancreas , 2001, Annals of Surgical Oncology.

[29]  Yoshifumi Matsui,et al.  Effects of Carbon-Ion Beams on Human Pancreatic Cancer Cell Lines That Differ in Genetic Status , 2004, American journal of clinical oncology.

[30]  R. Hruban,et al.  Pancreatic Cancer Cell DNA Content Correlates With Long‐term Survival After Pancreatoduodenectomy , 1991, Annals of surgery.

[31]  Tadashi Kamada,et al.  A Review of Update Clinical Results of Carbon Ion Radiotherapy , 2012, Japanese journal of clinical oncology.

[32]  Jeffrey E. Lee,et al.  Borderline Resectable Pancreatic Cancer: Definitions, Management, and Role of Preoperative Therapy , 2006, Annals of Surgical Oncology.

[33]  A. Muratore,et al.  Pancreatic Resections after Chemoradiotherapy for Locally Advanced Ductal Adenocarcinoma: Analysis of Perioperative Outcome and Survival , 2006, Annals of Surgical Oncology.

[34]  J. Yu,et al.  A margin-negative R0 resection accomplished with minimal postoperative complications is the surgeon’s contribution to long-term survival in pancreatic cancer , 2006, Journal of Gastrointestinal Surgery.

[35]  Jeffrey E. Lee,et al.  Neoadjuvant Chemoradiotherapy for Adenocarcinoma of the Pancreas: Treatment Variables and Survival Duration , 2001, Annals of Surgical Oncology.

[36]  Jürgen Weitz,et al.  Neoadjuvant chemoradiation with Gemcitabine for locally advanced pancreatic cancer , 2012, Radiation oncology.

[37]  Jeffrey E. Lee,et al.  Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  D. Moore,et al.  Gemcitabine, cisplatin, and radiotherapy for patients with locally advanced pancreatic adenocarcinoma: results of the North Central Cancer Treatment Group Phase II Study N9942. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.