Proton beam therapy for Pancreatic cancer (Bauchspeicheldrüsenkrebs)

Proton beam therapy for Pancreatic cancer (Bauchspeicheldrüsenkrebs)

Proton beam therapy for Pancreatic cancer (Bauchspeicheldrüsenkrebs)

Introduction

Pancreatic cancer is the fourth most common cause for cancer related mortality in the U.S. [40]. Incidence in 2009 was 10.9 /105 for men and 7.5/105 [2] for women and peaks between the seventh and eighth decade of life [6]. Consumption of nicotine and more than 45 grams of alcohol per day [41,42], diabetes and a history of pancreatitis are among the accredited risk factors [43-46]. Neither incidence, nor the mortality rate has changed substantially over the past 20 years [47]. In 2011 approximately 44,030 new patients were diagnosed, while 37,660 people died of pancreatic cancer in the U.S. [40]. Prognosis remains poor and overall 5-year survival rate is below 4% [48]. Only 20% of tumours are small (<3cm) and localized to the pancreas without extra-capsular spread or metastases. Complete surgical resection could yield 5-year survival rates between 18 to 24% for limited disease [49]. As for all other stages chemotherapy and or radiation, as well as palliative operation and best supportive care mark the standards of therapy. It is in the opinion of several panels that patients with any stage of pancreatic cancer should be considered for clinical trials since response to either conventionally used treatment modality is poor [50,51]

Treatment strategy of conventional radiotherapy

Adjuvant therapy strategy for resectable stage I and II tumour is controversial and may consider either chemoradiation with 5-FU and/or gemcitabine [52,53], or gemcitabine alone [54-56]. Locoregional advanced stage III tumours are mostly unresectable due to vascular impingement or infiltration. Neoadjuvant chemoradiation for borderline resectable tumour may improve operability [57-59]. For unresectable tumour chemoradiation [60-63] or intraoperative radiotherapy (IORT) [64,65] can be considered for elected patients. Prescribed dose for percutaneous radiotherapy (EBRT) varies institutionally and ranges depending on treatment intent from 30 to 60 Gy in 1.8 – 3.0 Gy fractions. Commonly prescribed dose for unresectable disease is 45-46 Gy for CTV and 50-54 Gy for gross tumour volume in 1.8-2.0 Gy fractions. IORT is commonly prescribed as single fraction of 15-20 Gy alone, or 10-20 Gy in combination with EBRT [64-68].Planning should be performed based on a contrast enhanced 3D – CT dataset and can be assisted by MRI or PET [51]. GTV encompasses macroscopic tumour. In case of biliary obstruction stent placement before radiotherapy should be considered [69]. PTV dose should follow ICRU-62 guidelines [70]. For adjuvant EBRT the CTV includes tumour bed derived from preoperative imaging or anastomoses/strategically set clips and peripancreatic lymph nodes. CTV margins for PTV consider organ motion/breathing and set-up errors and range from 0.5-2.0 cm. Breath holding/gating techniques in combination with IMRT or stereotactic body radiotherapy (SBRT) may be used to reduce margins and increase dose conformity [71-73]. Recommended dose constraints for liver is Dmean < 30 Gy, bilateral kidney Dmean < 15-18 Gy, only one working kidney V18Gy < 10%, stomach D100 < 45 Gy, small bowel V45Gy < 195cc and spinal cord Dmax < 45-50 Gy [9,51].

Treatment outcome of conventional radiotherapy

Several trials showed that median survival after adjuvant chemoradiation was mostly superior to operation alone for locally advanced stages, ranging 15-22.7 months (mos) vs. 10.9-15 mos [49,52,74,75]. Survival after IORT for locally advanced pancreatic cancer ranged 8 -16.5 mos, being similar to combined IORT and EBRT with 7.3 -16.5 mos. As for resectable tumours IORT yielded a median survival of 5-19 mos (one trial with low patient numbers reported 39 mos [76]) [77].

Therapeutical gap between conventional radiotherapy and ion beam therapy

Results for photon therapy for pancreatic cancer are jeopardized by radiosensitive organs at risk and resistance of tumour against irradiation. Both handicaps might hint to a potential benefit for treatment with protons. Developments in photon beam application like breath holding techniques and IMRT improved therapy related morbidity within the last years [71-73]. However, first results of planning studies reported improvements with PBT. In a preparation for a phase I trial Kozak et al. [78] evaluated a planning study that compared 5 fractions of 5 GyE PBT with conventionally fractionated IMRT (50.4 / 1.8 Gy). They learned that the Dose Volume Histograms showed improvements for organs at risk (kidney, liver, small bowel) in favor of the PBT-plan. Also another similar study demonstrated the superior dose distribution in PBT-plans compared to conventional 3D plans with photons [79]. In January 2011 Massachusetts general hospital reported a phase I study on the feasibility of neoadjuvant hypofractionated proton beam chemoradiation with Capecitabine for resectable adenocarcinoma of the head pancreatic [80]. Fifteen patients were enrolled and grouped into four dose levels with either 10 x 3 GyE (level 1) or 5 x 5 GyE with progressively shortened total treatment time schedules (level 2-4). All patients had the same dose of capecitabine over 10 days and were scheduled for operation within 4 to 6 weeks after chemotherapy. Grade 3 toxicity was seen in 4 patients (pain, stent obstruction, infection). 11 out of 15 patients were operated (3 had metastases, 1 patient remained inoperable). No unexpected 30 day post-operative complications were seen. A phase II study is in progress. The lower integral dose of PBT may offer options like reduced treatment time using hypofractionated protocols as well as the possibility to escalate tumour dose [81]. However, until today there is little experience and further surveys are needed to increase level of evidence.

author: Dr. David Kuczer

 

References

1.         Kamangar F, Dores GM, Anderson WF.Patterns of Cancer Incidence, Mortality, and Prevalence across Five Continents: Defining Priorities to Reduce Cancer Disparities in different Geographic Regions of the World. J Clin Oncol. 2006;24(14):2137-2150.

2.         Statistik Austria ,Statistisches Jahrbuch Österreichs 2011, Kapitel 03 – Gesundheit. Stand Dezember 2009 (Statistik Austria, Austrias statistical yearbook 2011, chapter 3-health. Status December 2009)

3.         Pearson JG, Leroux BT. Malignant tumors of the esophagus. In: Vantaappgen G, Hellman J, eds. Diseases of the esophagus. New York: Springer-Verlag, 1974:447.

4.         Akiyama H, Tsurumaru M Kawamuru T, et al. Principles of surgical treatment for carcinoma of the esophagus: analysis of lymph node involvement. Ann Surg 1981;194:438

5.         Dormans E. Das Oesophaguscarcinoma: Ergebnisse der unter Mitarbeit von 39 Pathologischen Instituten Deutschlands durchgeführten Erhebung  über das Oesophaguscarcinomon (1925-1933). ZKrebsforsch 1939;49:86

6.         Jemal A,Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300

7.         Withers HR, Peters LJ. Basic principles of radiotherapy: basic clinical parameters. In: Fletcher GH, ed. Textbook of radiotherapy 3rd ed. Philadelphia: Lea & Febiger, 1980:180.

8.         National Comprehensive Cancer Network. NCCN Guidelines Version 2.2011 Esophageal and Esophagogastric Junction Cancers; Principles of systemic therapy

9.         Marks LB, Yorke ED, et al. Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S10-9.

10.       Chandra A., et al., Feasibility of using intensity-modulated radiotherapy to improve lung sparing in treatment planning for distal esophageal cancer. Radiother Oncol. 2005 Dec;77(3):247-53. Epub 2005 Nov 17.

11.       Walsh TN, Noonan N, Hollywood D, et al. A comparison of multi-modality therapy and surgery for esophageal adenocarcinoma. N Engl j Med 1996;335:462.

121.     Kelson DP,Ginsberg R, Pajak TF,et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998;339:1979

13.       Urba SG, Orringer M, Iannettoni M, et al. A phase II trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001;19:305.

14.       Bosset JF, Gignoux M, Triboulet JP,et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous cell cancer of the esophagus. N Engl J Med 1997;337:161.

15.       www.aco-asso.at/publikationen/consens/bulletin/bull_k17.html

16.       Isacsson U, Lennernas B, Grusell E, et al. Comparative treatment planning between proton and X-ray therapy in esophageal cancer. Int J Radiat Oncol Biol Phys 1998; 41:441-450

17.       Zhang X, Zhao KL, Guerrero TM, et al. Four-dimensional computed tomography-based treatment planning for intensity-modulated radiation therapy and proton therapy for distal esophageal cancer. Int J Radiat Oncol Biol Phys 2008;72:278-287.

18.       Welsh J, Gomez D,et al. Intensity-modulated proton therapy further reduces normal tissue exposure during definitive therapy for locally advanced distal esophageal tumors: a dosimetric study. Int J Radiat Oncol Biol Phys. 2011 Dec 1;81(5):1336-42. Epub 2011 Apr 4.

19.       Mizumoto M, Sugahara S, etal., Clinical results of proton-beam therapy for locoregionally advanced esophageal cancer. Strahlenther Onkol. 2010 Sep; 186(9):482-8. Epub 2010 Aug 30.

20.       Koyama S, Tsujii H. Proton beam therapy with high-dose irradiation for superficial and advanced esophageal carcinomas. Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3571-7.

21.       National Comprehensive Cancer Network. NCCN Guidelines Version 2.2011 Gastric cancer

22.       Coggon D, Barker DJP, Cole RB, et al. Stomach cancer and food storage. J Natl Cancer Inst 1989; 81:1178.

23.       Howson CP, Hiyama T, Wynder EL. The decline in gastric cancer: Epidemiology of an unplanned triumph. Epidemiol Rev 1986; 8:1

24.       Fuchs CS, Mayer RJ. Gastric carcinoma. N Engl J Med 1995;333:32.

25.       J R Siewert, K Böttcher, H J Stein, and J D Roder, Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg. 1998 October; 228(4): 449–461.

26.       Ajani JA, Mayer RJ, Ota DM, et al. Preoperative and postoperative combination chemotherapy for potentially resectable gastric carcinoma. J Natl Cancer Inst. 1993 Nov 17;85(22):1839-44.

27.       Leichman L, Silberman H, Leichman CG, et al. Preoperative systemic chemotherapy followed by adjuvant postoperative intraperitoneal therapy for gastric cancer: a University of Southern California pilot program. J Clin Oncol. 1992 Dec;10(12):1933-42.

28.       Cunningham D, Allum WH, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20.

29.       Macdonald JS., Role of post-operative chemoradiation in resected gastric cancer. J Surg Oncol. 2005 Jun 1;90(3):166-70.

30.       The concept of locally advanced gastric cancer. Effect of treatment on outcome. The Gastrointestinal Tumor Study Group. Cancer. 1990 Dec 1;66(11):2324-30.

31.       Moertel CG, Childs DS Jr, Reitemeier RJ, et al. Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet. 1969 Oct 25;2(7626):865-7.

32.       National Comprehensive Cancer Network, Gastric Cancer, NCCN Guidelines Version 2.2011

33.       Macdonald JS, Smalley SR, Benedetti J,et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6;345(10):725-30.

34.       Zhang ZX, Gu XZ, Yin WB, et al.Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)–report on 370 patients. Int J Radiat Oncol Biol Phys. 1998 Dec 1;42(5):929-34.

35.       Valentini V, Cellini F, Minsky BD, et al. Survival after radiotherapy in gastric cancer: systematic review and meta-analysis..Radiother Oncol. 2009 Aug;92(2):176-83. Epub 2009 Jul 6.

36.       Milano MT, Garofalo MC, Chmura SJ, et al. Intensity-modulated radiation therapy in the treatment of gastric cancer: early clinical outcome and dosimetric comparison with conventional techniques., Br J Radiol. 2006 Jun;79(942):497-503.

37.       Emami B, Lyman J,et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991 May 15;21(1):109-22.

38.       Moertel CG, Childs DS, O’Fallon JR, et al. Combined 5-fluorouracil and radiation therapy as a surgical adjuvant for poor prognosis gastric carcinoma. J Clin Oncol. 1984 Nov;2(11):1249-54.

39.       Allen A., Pawlicki T, et al An Evaluation of Proton Beam Therapy, Evaluation Subcommittee of ASTRO´s Emerging Technologies Committee, ASTRO 2011

40.       Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011 Jul-Aug;61(4):212-36.

41.       Lynch SM, Vrieling A, Lubin JH, et al. Cigarette smoking and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Am J Epidemiol. 2009 Aug 15;170(4):403-13.

42.       Michaud DS, Vrieling A, Jiao L, et al. Alcohol intake and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan)., Cancer Causes Control. 2010 Aug;21(8):1213-25.

43.       Chari ST, Leibson CL, et al. Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology. 2008 Jan;134(1):95-101.

44.       Chari ST, Leibson CL, Rabe KG, et al. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology. 2005 Aug;129(2):504-11.

45.       Gupta S, Vittinghoff E, Bertenthal D, et al. New-onset diabetes and pancreatic cancer. Clin Gastroenterol Hepatol. 2006 Nov;4(11):1366-72;

46.       Bracci PM, Wang F, Hassan MM, et al. Pancreatitis and pancreatic cancer in two large pooled case-control studies. Cancer Causes Control. 2009 Nov;20(9):1723-1731

47.       StatBite. U.S. pancreatic cancer rates. J Natl Cancer Inst. 2010 Dec 15;102(24):1822. Epub 2010 Dec 7

48.       Greenlee RT, Murray T, Bolden S, et al.: Cancer statistics, 2000. CA Cancer J Clin 50 (1): 7-33, 2000 Jan-Feb.

49.       Yeo CJ, Abrams RA, Grochow LB, et al.: Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 225 (5): 621-33; discussion 633-6, 1997.

50.       Pancreatic Cancer Treatment (PDQ®), General Information about pancreatic cancer, National Cancer Institute 2010-08-13

51.       National Comprehensive Cancer Network , Pancreatic Adenocarcinoma, NCCN Guidelines Version 2.2011

52.       Kalser MH, Ellenberg SS: Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 120 (8): 899-903, 1985.

53.       Regine WF, Winter KA, Abrams RA, et al.: Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA 299 (9): 1019-26, 2008.

54.       Neoptolemos JP, Dunn JA, Stocken DD, et al.: Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 358 (9293): 1576-85, 2001.

55.       Neoptolemos JP, Stocken DD, Friess H, et al.: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350 (12): 1200-10, 2004.

56.       Oettle H, Post S, Neuhaus P, et al.: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 297 (3): 267-77, 2007.

57.       Sharma C, Eltawil KM, et al. Advances in diagnosis, treatment and palliation of pancreatic carcinoma: 1990-2010. World J Gastroenterol. 2011 Feb 21;17(7):867-97.

58.       Brunner TB, Grabenbauer GG, Kastl S, et al.  Preoperative Chemoradiation in Locally Advanced Pancreatic Carcinoma: A Phase II Study. Onkologie. 2000 Oct;23(5):436-442.

59.       Kastl S, Brunner T, Herrmann O, et al. Neoadjuvant radio-chemotherapy in advanced primarilynon-resectable carcinomas of the pancreas. Eur J Surg Oncol. 2000 Sep;26(6):578-82.

60.       A multi-institutional comparative trial of radiation therapy alone and in combination with 5-fluorouracil for locally unresectable pancreatic carcinoma. The Gastrointestinal Tumor Study Group. Ann Surg 189 (2): 205-8, 1979.

61.       Moertel CG, Frytak S, Hahn RG, 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. Cancer 48 (8): 1705-10, 1981.

62.       Cohen SJ, Dobelbower R Jr, Lipsitz S, et al.: A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Int J Radiat Oncol Biol Phys 62 (5): 1345-50, 2005.

63.       Chauffert B, Mornex F, Bonnetain F, et al.: Phase III trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced non metastatic pancreatic cancer: a FFCD-SFRO study. [Abstract] J Clin Oncol 24 (Suppl 18): A-4008, 180s, 2006.

64.       Reni M, Panucci MG, Ferreri AJ, et al.: Effect on local control and survival of electron beam intraoperative irradiation for resectable pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys 50 (3): 651-8, 2001

65.       Tepper JE, Noyes D, Krall JM, et al.: Intraoperative radiation therapy of pancreatic carcinoma: a report of RTOG-8505. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 21 (5): 1145-9, 1991.

66.       Nishimura Y, Hosotani R, et al.  External and intraoperative radiotherapy for resectable and unresectable pancreatic cancer: analysis of survival rates and complications. Int J Radiat Oncol Biol Phys. 1997 Aug 1;39(1):39-49.

67.       Shipley WU, Tepper JE, et al. Intraoperative radiation therapy for patients with pancreatic carcinoma.World J Surg. 1984 Dec;8(6):929-34.

68.       Garton GR, Gunderson LL, et al High-dose preoperative external beam and intraoperative irradiation for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 1993 Dec 1;27(5):1153-7.

69.       van den Bosch RP, van der Schelling GP, Klinkenbijl JH, et al.: Guidelines for the application of surgery and endoprostheses in the palliation of obstructive jaundice in advanced cancer of the pancreas. Ann Surg 219 (1): 18-24, 1994.

70.       Chavaudra J, Bridier A. Definition of volumes in external radiotherapy: ICRU reports 50 and 62. Cancer Radiother. 2001 Oct;5(5):472-8.

71.       Spalding AC, Jee KW, et al Potential for dose-escalation and reduction of risk in pancreatic cancer using IMRT optimization with lexicographic ordering and gEUD-based cost functions.Med Phys. 2007 Feb;34(2):521-9.

72.       Yovino S, Poppe M, et al. Intensity-modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers. Int J Radiat Oncol Biol Phys. 2011 Jan 1;79(1):158-62.

73.       Koong AC, Christofferson E, Le QT, et al. Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(2):320-3.

74.       Foo ML, Gunderson LL, et al. Patterns of failure in grossly resected pancreatic ductal adenocarcinoma treated with adjuvant irradiation +/- 5 fluorouracil. Int J Radiat Oncol Biol Phys. 1993 Jun 15;26(3):483-9.

75.       Gastrointestinal Tumor Study Group .Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer. 1987 Jun 15;59(12):2006-10.

76.       Okamoto A, Tsuruta K, et al. Intraoperative radiation therapy for pancreatic carcinoma. The choice of treatment modality. Int J Pancreatol. 1994 Oct-Dec;16(2-3):157-64.

77.       Perez CA, Brady LW, et al. Principles and practice of radiation oncology chpt. 52, cancer of the pancreas , table 52.6 -52.10. Lippincott Williams & Wilkins 4th ed. 2004

78.       Kozak KR, Kachnic LA, et al. Dosimetric feasibility of hypofractionated proton radiotherapy for neoadjuvant pancreatic cancer treatment. Int J Radiat Oncol Biol Phys. 2007 Aug 1;68(5):1557-66.

79.       Hsiung-Stripp DC, McDonough J, et al.Comparative treatment planning between proton and X-ray therapy in pancreatic cancer. Med Dosim. 2001 Fall;26(3):255-9.

80.       Hong TS, Ryan DP,et al. Phase I study of preoperative short-course chemoradiation with proton beam therapy and capecitabine for resectable pancreatic ductal adenocarcinoma of the head. Int J Radiat Oncol Biol Phys. 2011 Jan 1;79(1):151-7.

81.       Rossi CJ; Proton and Carbon Ion Radiotherapy of Gastrointestinal Malignancies. presented at ESTRO school teaching course:” Radiotherapy with protons and ions” Sept., 2011

82.       Bruix J, Sherman M; Management of hepatocellular carcinoma: an update. American Association for the Study of Liver Diseases.Hepatology. 2011 Mar;53(3):1020-2.

83.       Blumberg BS, Larouzé B, London WT, et al.: The relation of infection with the hepatitis B agent to primary hepatic carcinoma. Am J Pathol 81 (3): 669-82, 1975.

84.      Tsukuma H, Hiyama T, Tanaka S, et al.: Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 328 (25): 1797-801, 1993.

85.      Mor E, Kaspa RT, Sheiner P, et al.: Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation. Ann Intern Med 129 (8): 643-53, 1998.

86.      Fong Y, Sun RL, Jarnagin W, et al.: An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 229 (6): 790-9; discussion 799-800, 1999.

87.      Klintmalm GB: Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome. Ann Surg 228 (4): 479-90, 1998.

88.       Pichlmayr R, Weimann A, Oldhafer KJ, et al.: Appraisal of transplantation for malignant tumours of the liver with special reference to early stage hepatocellular carcinoma. Eur J Surg Oncol 24 (1): 60-7, 1998.

89.       Zhou XD, Tang ZY: Cryotherapy for primary liver cancer. Semin Surg Oncol 14 (2): 171-4, 1998.

90.       Livraghi T, Goldberg SN, Lazzaroni S, et al.: Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 210 (3): 655-61, 1999.

91.       Tanaka K, Nakamura S, Numata K, et al.: The long term efficacy of combined transcatheter arterial embolization and percutaneous ethanol injection in the treatment of patients with large hepatocellular carcinoma and cirrhosis. Cancer 82 (1): 78-85, 1998.

92.      Livraghi T, Benedini V, Lazzaroni S, et al.: Long term results of single session percutaneous ethanol injection in patients with large hepatocellular carcinoma. Cancer 83 (1): 48-57, 1998.

93.       Curley SA, Izzo F, Delrio P, et al.: Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg 230 (1): 1-8, 1999.

94.       Llovet JM, Ricci S, Mazzaferro V, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359 (4): 378-90, 2008.

95.       Cheng SH, Lin YM, Chuang VP, et al. A pilot study of three-dimensional conformal radiotherapy in unresectable hepatocellular carcinoma. J Gastroenterol Hepatol. 1999 Oct;14(10):1025-33.

96.       Cárdenes HR, Price TR, et al. Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma. Clin Transl Oncol. 2010 Mar;12(3):218-25.

97.       Tse RV, Hawkins M, et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2008 Feb 1;26(4):657-64.

98.       Hawkins MA, Dawson LA. Radiation therapy for hepatocellular carcinoma: from palliation to cure. Cancer. 2006 Apr 15;106(8):1653-63. Review.

99.       Guo WJ, Yu EX.Evaluation of combined therapy with chemoembolization and irradiation for large hepatocellular carcinoma. Br J Radiol. 2000 Oct;73(874):1091-7.

100.     Seong J, Keum KC, et al. Combined transcatheter arterial chemoembolization and local radiotherapy of unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 1999 Jan 15;43(2):393-7.

101.     Yasuda S, Ito H, et al. Radiotherapy for large hepatocellular carcinoma combined with transcatheter arterial embolization and percutaneous ethanol injection therapy. Int J Oncol. 1999 Sep;15(3):467-73.

102.     Price TR, Perkins SM, et al. Evaluation of response after stereotactic body radiotherapy for hepatocellular carcinoma. Cancer. 2011 Oct 24. doi: 10.1002/cncr.26404.

103.     Takeda A, Oku Y, et al. Dose volume histogram analysis of focal liver reaction in follow-up multiphasic CT following stereotactic body radiotherapy for small hepatocellular carcinoma. Radiother Oncol. 2012 Jan 14.

104.     Facciuto ME, Singh MK, et al.Stereotactic body radiation therapy in hepatocellular carcinoma and cirrhosis: Evaluation of radiological and pathological response.J Surg Oncol. 2011 Sep 29. doi: 10.1002/jso.22104.

105.     Andolino DL, Johnson CS, et al.Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):e447-53.

106.     Matsuzaki Y, Osuga T, et al. A new, effective, and safe therapeutic option using proton irradiation for hepatocellular carcinoma.Gastroenterology. 1994 Apr;106(4):1032-41.

107.     Hata M, Tokuuye K, et al. Proton beam therapy for hepatocellular carcinoma with portal vein tumor thrombus. Cancer. 2005 Aug 15;104(4):794-801.

108.     Hashimoto T, Tokuuye K,et al.Repeated proton beam therapy for hepatocellular carcinoma.Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):196-202. Epub 2006 Mar 24.

109.     Hata M, Tokuuye K, et al. Proton beam therapy for hepatocellular carcinoma patients with severe cirrhosis. Strahlenther Onkol. 2006 Dec;182(12):713-20.

110.     Komatsu S, Fukumoto T,, et al. Clinical results and risk factors of proton and carbon ion therapy for hepatocellular carcinoma. Cancer. 2011 Nov 1;117(21):4890-904. doi: 10.1002/cncr.26134.

111.     Nakayama H., Sugahara S., et al. Proton beam therapy for hepatocellular carcinoma located adjacent to the alimentary tract. Int J Radiat Oncol Biol Phys, 2011 Jul 15;80(4):992-5.

112.     Sugahara S., Nakayama H., et al. Proton-beam therapy for hepatocellular carcinoma associated with portal vein thrombosis. Strahlenther. Onkol. 2009 Dec;185(12):782-8.

113.     Sugahara S., Oshiro Y., et al. Proton beam therapy for large hepatocellular carcinoma. Int J Radiat Oncol Biol Phys, 2010 Feb 1;76(2):460-6.

114.     Cheng L, Eng C, et al. Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976 to 2005. Am J Clin Oncol. 2011 Dec;34(6):573-80. doi: 10.1097/COC.0b013e3181fe41ed.

115.     Nelson H, Petrelli Net al.; National Cancer Institute Expert Panel.Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst. 2001 Apr 18;93(8):583-96.

116.     Blanke CD, Goldberg RM, et al.KRAS and colorectal cancer: ethical and pragmatic issues in effecting real-time change in oncology clinical trials and practice. Oncologist. 2011;16(8):1061-8. Epub 2011 Jul 7.

117.     Bailey HR, Huval WV, Max E, et al.: Local excision of carcinoma of the rectum for cure. Surgery 111 (5): 555-61, 1992.

118.     Benson R, Wong CS, Cummings BJ, et al.: Local excision and postoperative radiotherapy for distal rectal cancer. Int J Radiat Oncol Biol Phys 50 (5): 1309-16, 2001.

119.     Steele GD Jr, Herndon JE, Bleday R, et al.: Sphincter-sparing treatment for distal rectal adenocarcinoma. Ann Surg Oncol 6 (5): 433-41, 1999 Jul-Aug.

120.     Sitzler PJ, Seow-Choen F, Ho YH, et al.: Lymph node involvement and tumor depth in rectal cancers: an analysis of 805 patients. Dis Colon Rectum 40 (12): 1472-6, 1997.

121.     O’Connell MJ, Martenson JA, Wieand HS, et al.: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331 (8): 502-7, 1994.

122.     Tepper JE, O’Connell M, Niedzwiecki D, et al.: Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control–final report of intergroup 0114. J Clin Oncol 20 (7): 1744-50, 2002.

123.     Smalley SR, Benedetti JK, Williamson SK, et al.: Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 24 (22): 3542-7, 2006.

124.     Sauer R, Becker H, Hohenberger W, et al.: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351 (17): 1731-40, 2004.

125.     Willett CG, Badizadegan K, Ancukiewicz M, et al.: Prognostic factors in stage T3N0 rectal cancer: do all patients require postoperative pelvic irradiation and chemotherapy? Dis Colon Rectum 42 (2): 167-73, 1999.

126.     Gunderson LL, Sargent DJ, Tepper JE, et al.: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 22 (10): 1785-96, 2004.

127.     Guillem JG, Díaz-González JA, Minsky BD, et al.: cT3N0 rectal cancer: potential overtreatment with preoperative chemoradiotherapy is warranted. J Clin Oncol 26 (3): 368-73, 2008.

128.     NCCN Guidelines Version 2.2012 Rectal Cancer, National Comprehensive Cancer Network

129.     Folkesson J, Birgisson H, et al. Swedish Rectal Cancer Trial: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol. 2005 Aug 20;23(24):5644-50.

130.     Wolmark N, Wieand HS, et al.   Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02.J Natl Cancer Inst. 2000 Mar 1;92(5):388-

131.     Collette L, Bosset JF, et al. European Organisation for Research and Treatment of Cancer Radiation Oncology Group. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol. 2007 Oct 1;25(28):4379-86.

132.     van Gijn W, Marijnen CA, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011 Jun;12(6):575-82. Epub 2011 May 17.

133.     Peeters KC, Marijnen CA, et al. The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg. 2007 Nov;246(5):693-701.

134.     Birgisson H, Påhlman L, et al. Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol. 2005 Dec 1;23(34):8697-705.

135.     Birgisson H, Påhlman L, et al. Late adverse effects of radiation therapy for rectal cancer – a systematic overview. Acta Oncol. 2007;46(4):504-16. Review.

136.     Tatsuzaki H, Urie MM, Willett CG. 3-D comparative study of proton vs. x-ray radiation therapy for rectal cancer. Int J Radiat Oncol Biol Phys. 1992;22(2):369-74.

137.     Isacsson U, Montelius A, Jung B, Glimelius B. Comparative treatment planning between proton and X-ray therapy in locally advanced rectal cancer. Radiother Oncol. 1996 Dec;41(3):263-72.

138.     Yamada S, Shinoto M, Shigeo Y, et al. Current status and perspective of heavy ion beam therapy for patients with pelvic recurrence after primarily resected rectal cancer. Gan To Kagaku Ryoho. 2009 Aug;36(8):1263-6.