The Impact of Novel Radiation Treatment Techniques on Toxicity and Clinical Outcomes in Rectal Cancer
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Purpose of Review
Three-dimensional conformal radiation therapy (3DCRT) has been the standard technique in the treatment of rectal cancer. The use of new radiation treatment technologies such as intensity-modulated radiation therapy (IMRT), proton therapy (PT), stereotactic body radiation therapy (SBRT), and brachytherapy (BT) has been increasing over the past 10 years. This review will highlight the advantages and drawbacks of these techniques.
IMRT, PT, SBRT, and BT achieve a higher target coverage conformity and a higher organ at risk sparing and enable dose escalation compared to 3DCRT. Some studies suggest a reduction in gastrointestinal and hematologic toxicities and an increase in the complete pathologic response rate; however, the clinical benefit of these techniques remains controversial.
The results of these new techniques seem encouraging despite conclusive data. Further trials are required to establish their role in rectal cancer.
KeywordsNovel technologies IMRT Proton therapy SBRT Rectal cancer
This work was supported by the following grants: NIH R01 CA198128 (TW). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Compliance with Ethical Standards
Conflict of Interest
Lara Hathout and Salma K. Jabbour declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 2.Surveillance E, End Results (SEER). 18 registries National Cancer Institute. 2015.Google Scholar
- 4.Havenga K, Enker WE, Norstein J, Moriya Y, Heald RJ, van Houwelingen HC, et al. Improved survival and local control after total mesorectal excision or D3 lymphadenectomy in the treatment of primary rectal cancer: an international analysis of 1411 patients. Eur J Surg Oncol. 1999;25(4):368–74.CrossRefPubMedGoogle Scholar
- 6.Battersby NJ, How P, Moran B, Stelzner S, West NP, Branagan G, et al. Prospective validation of a low rectal cancer magnetic resonance imaging staging system and development of a local recurrence risk stratification model: the MERCURY II study. Ann Surg. 2016;263(4):751–60.CrossRefPubMedGoogle Scholar
- 7.Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med. 1997;336(14):980-7.Google Scholar
- 26.• Samuelian JM, Callister MD, Ashman JB, Young-Fadok TM, Borad MJ, Gunderson LL. Reduced acute bowel toxicity in patients treated with intensity-modulated radiotherapy for rectal cancer. Int J Radiat Oncol Biol Phys. 2012;82(5):1981–7. Retrospective analysis of 92 patients of whom 66% were treated with 3DCRT and 34% with IMRT. IMRT was associated with a lower rate of GI toxicity.CrossRefPubMedGoogle Scholar
- 28.• Jabbour SK, Patel S, Herman JM, Wild A, Nagda SN, Altoos T, et al. Intensity-modulated radiation therapy for rectal carcinoma can reduce treatment breaks and emergency department visits. Int J Surg Oncol. 2012;2012:891067. A retrospective review of 86 patients treated with IMRT (n=30) and 3DCRT (n=56). They were fewer hospitalizations, treatment breaks and grade ≥ 3 toxicities in the IMRT arm.PubMedPubMedCentralGoogle Scholar
- 29.•• Hong TS, Moughan J, Garofalo MC, Bendell J, Berger AC, Oldenburg NB, et al. NRG Oncology Radiation Therapy Oncology Group 0822: a phase 2 study of preoperative chemoradiation therapy using intensity modulated radiation therapy in combination with capecitabine and oxaliplatin for patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2015;93(1):29–36. Largest prospective trial evaluating the rate of GI toxicity of neoadjuvant chemoradiation with capecitabine, oxaliplatin, and IMRT in patients with locally advanced rectal cancer. Acute grade 2 to 5 GI toxicity was the primary outcome. IMRT failed to reduce acute GI toxicity.CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Wong SJ, Winter K, Meropol NJ, Anne PR, Kachnic L, Rashid A, et al. Radiation Therapy Oncology Group 0247: a randomized phase II study of neoadjuvant capecitabine and irinotecan or capecitabine and oxaliplatin with concurrent radiotherapy for patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2012;82(4):1367–75.CrossRefPubMedGoogle Scholar
- 33.Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011;29(20):2773–80.CrossRefPubMedGoogle Scholar
- 34.Gerard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne PL, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol. 2010;28(10):1638–44.CrossRefPubMedGoogle Scholar
- 35.O’Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2014;32(18):1927–34.CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015;16(8):979–89.CrossRefPubMedGoogle Scholar
- 39.Mell LK, Schomas DA, Salama JK, Devisetty K, Aydogan B, Miller RC, et al. Association between bone marrow dosimetric parameters and acute hematologic toxicity in anal cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2008;70(5):1431–7.CrossRefPubMedGoogle Scholar
- 42.Bazan JG, Luxton G, Kozak MM, Anderson EM, Hancock SL, Kapp DS, et al. Impact of chemotherapy on normal tissue complication probability models of acute hematologic toxicity in patients receiving pelvic intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2013;87(5):983–91.CrossRefPubMedGoogle Scholar
- 43.• Newman NB, Sidhu MK, Baby R, Moss RA, Nissenblatt MJ, Chen T, et al. Long-term bone marrow suppression during postoperative chemotherapy in rectal cancer patients after preoperative chemoradiation therapy. Int J Radiat Oncol Biol Phys. 2016;94(5):1052–60. Retrospective analysis of 35 patients treated with preoperative chemoradiation followed by adjuvant chemotherapy for locally advanced rectal cancer. The primary endpoint was to quantify bone marrow suppression during postoperative chemotherapy resulting from preoperative chemoradiation. Sparing of the bone marrow during preoperative radiation therapy can reduce hematologic toxicity and aid tolerance of adjuvant chemotherapy.CrossRefPubMedGoogle Scholar
- 44.Hong YS, Nam BH, Kim KP, Kim JE, Park SJ, Park YS, et al. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2014;15(11):1245–53.CrossRefPubMedGoogle Scholar
- 47.Freedman GM, Meropol NJ, Sigurdson ER, Hoffman J, Callahan E, Price R, et al. Phase I trial of preoperative hypofractionated intensity-modulated radiotherapy with incorporated boost and oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2007;67(5):1389–93.CrossRefPubMedGoogle Scholar
- 48.• Li JL, Ji JF, Cai Y, Li XF, Li YH, Wu H, et al. Preoperative concomitant boost intensity-modulated radiotherapy with oral capecitabine in locally advanced mid-low rectal cancer: a phase II trial. Radiother Oncol. 2012;102(1):4–9. A phase II study of 63 patients treated with IMRT with simultaneous integrated boost with concurrent capecitabine evaluating the toxicity, postoperative complications, and pathological complete response (pCR). IMRT with concurrent boost can achieve a high pCR rate and a low toxicity profile.CrossRefPubMedGoogle Scholar
- 49.• Zhu J, Gu W, Lian P, Sheng W, Cai G, Shi D, et al. A phase II trial of neoadjuvant IMRT-based chemoradiotherapy followed by one cycle of capecitabine for stage II/III rectal adenocarcinoma. Radiat Oncol. 2013;8:130. A phase II trial of 42 patients treated with IMRT and concurrent oxaliplatin and capecitabine revealed good treatment outcomes with mild toxicities and acceptable surgical complications.CrossRefPubMedPubMedCentralGoogle Scholar
- 50.•• Appelt AL, Ploen J, Harling H, Jensen FS, Jensen LH, Jorgensen JC, et al. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol. 2015;16(8):919–27. Prospective observational study examining the efficacy of high-dose chemoradiotherapy and brachytherapy boost in patients with distal rectal cancer followed by watchful waiting in clinical complete responders.CrossRefPubMedGoogle Scholar
- 54.• Blanco Kiely JP, White BM. Robust proton pencil beam scanning treatment planning for rectal cancer radiation therapy. Int J Radiat Oncol Biol Phys. 2016;95(1):208–15. Proton Pencil Beam Scanning was compared to VMAT to evaluate the potential to offer advantages relative to interfraction uncertainties and dose volume histograms. It was found to be as robust as VMAT.CrossRefPubMedGoogle Scholar
- 55.Vuong T, Devic S. High-dose-rate pre-operative endorectal brachytherapy for patients with rectal cancer. J Contemp Brachytherapy. 2015;7(2):183–188.Google Scholar
- 76.Plastaras JP, Berman AT, Freedman GM. Special cases for proton beam radiotherapy: re-irradiation, lymphoma, and breast cancer. J Seminoncol. 2014. doi: 10.1053/j.seminoncol.2014.10.001.
- 77.•• Appelt AL, Vogelius IR, Ploen J, Rafaelsen SR, Lindebjerg J, Havelund BM, et al. Long-term results of a randomized trial in locally advanced rectal cancer: no benefit from adding a brachytherapy boost. Int J Radiat Oncol Biol Phys. 2014;90(1):110–8. Largest study evaluating the benefit from a brachytherapy boost addition to long-course neoadjuvant chemoradiation. Despite an increased rate of pathologic tumor response after surgery, the addition of a brachytherapy boost did not impact late outcome.CrossRefPubMedPubMedCentralGoogle Scholar
- 82.Harrison LB, Minsky BD, Enker WE, Mychalczak B, Guillem J, Paty PB, et al. High dose rate intraoperative radiation therapy (HDR-IORT) as part of the management strategy for locally advanced primary and recurrent rectal cancer. Int J Radiat Oncol Biol Phys. 1998;42(2):325–30.CrossRefPubMedGoogle Scholar
- 83.Diaz-Gonzalez JA, Calvo FA, Cortes J, Garcia-Sabrido JL, Gomez-Espi M, Del Valle E, et al. Prognostic factors for disease-free survival in patients with T3-4 or N+ rectal cancer treated with preoperative chemoradiation therapy, surgery, and intraoperative irradiation. Int J Radiat Oncol Biol Phys. 2006;64(4):1122–8.CrossRefPubMedGoogle Scholar
- 85.Krempien R, Roeder F, Oertel S, Roebel M, Weitz J, Hensley FW, et al. Long-term results of intraoperative presacral electron boost radiotherapy (IOERT) in combination with total mesorectal excision (TME) and chemoradiation in patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2006;66(4):1143–51.CrossRefPubMedGoogle Scholar
- 88.•• Goodman KA, Patton CE, Fisher GA, Hoffe SE, Haddock MG, Parikh PJ, et al. Appropriate customization of radiation therapy for stage II and III rectal cancer: executive summary of an ASTRO clinical practice statement using the RAND/UCLA appropriateness method. Pract Radiat Oncol. 2016;6(3):166–75. An ASTRO practice clinical statement has been recently published addressing the appropriate customization of radiation therapy in different clinical scenarios.CrossRefPubMedGoogle Scholar