David:

The NCCN guidance was based on the two reports [1,2] of the Phase II MD Anderson trial of capecitabine + concomitant boost radiotherapy (it is the same trial: first reported in abstract form at ASCO 2004 [2], later published for peer-review in JCO in 2006 [1]).

However NCCN guideline on boost radiotherapy in LARC has not been updated in the light of subsequent and more robust findings, and the recommendation now stands as arguable, since we have, I would argue from my own recent internal review, conflicting findings and insufficient robust high-methodological quality prospective trial data to support a clear recommendation for clinical practice. Thus, the prospective Phase II KROG 04-01 trial [3] found that concomitant boost irradiation does not improve clinical outcomes of downstaging rates, tumor regression grades, and tumor volume reduction rates compared with standard-of-care preoperative chemoradiotherapy regimens, and it warns, correctly, of the potential for concomitant small field boost irradiation to induce unplanned sphincter ablation. Furthermore, in the long-term follow-up of this trial [4] (median follow-up time of 69 months) these results were confirmed, with the benefit of concomitant small-field boost irradiation for 5 weeks in rectal cancer patients being non-superior to conventional irradiation for 6 weeks in terms of both tumor response and survival.

In contrast however the just published Rome University study [5] of neoadjuvant chemoradiation with concomitant boost radiotherapy found positive benefit in terms of local outcomes, as did a number of other small trials [6,7,8], all limited however by small sample size and short follow-up. And although the Swedish trial [9] found a significant overall survival benefit with the addition of hypofractionated (25 Gy/5 fractions) preoperative RT, there were methodological flaws and limitations including the low rates of performed TME in the surgery alone group, and note further that absolutely no other trial has ever uncovered an overall survival benefit.

Part of the problem and cause of these divergent findings is the wide variability of the different fractionated RT regimens deployed in various trials. Nonetheless, I would argue that although the evidence for concomitant boost irradiation using conventional RT remains dissonant, other studies using intensity-modulated RT (IMRT) as part of preoperative CRT for LARC patients, are far more consistently positive, finding effective reductions in the irradiated small bowel volume and the bowel toxicity [10,11], likely due in large part to the better coverage of the planning target volume by IMRT compared with conventional RT techniques. Confirming this further is the just published Madrid prospective pilot study [12,13] of complete pathological responses in LARC after preoperative IMRT plus integrated-boost chemoradiation which found that the scheme offered higher rates of ypCR and pT downstaging, with no significant increase in toxicity.

And it must therefore be concluded, against the certitude of the unrevised NCCN recommendation, that the precise role of intensified preoperative radiation treatment as to response (as opposed to just local control) remains unsettled given that we to this day lack compelling data comparing the different fractionated RT regimens in association with concurrent chemotherapy, although we have found in our review:

(1) that the strongest evidence of benefit derives from the IMRT context;

(2) that regardless of RT regimen, it does not appear that overall survival is positively influenced, so that

(3) we need larger more robust prospective trials to help settle the outstanding issues, and finally,

(4) we require meta-analytic studies that will compare and weigh the different influences of different fractionated RT regimens, and until such time, we cannot legitimately compare findings across studies of different RT schemes.

METHODOLOGY OF THE REVIEW

A search of the PUBMED, Cochrane Library / Cochrane Register of Controlled Trials, MEDLINE/MedlinePlus, EMBASE, AMED (Allied and Complimentary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, ISI Web of Science (WoS), BIOSIS, LILACS (Latin American and Caribbean Health Sciences Literature), ASSIA (Applied Social Sciences Index and Abstracts), SCEH (NHS Evidence Specialist Collection for Ethnicity and Health), and scope-qualified Boolean searches submitted to Google Scholar and SLIM, was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations), OpenThesis or Proquest. Sources in languages foreign to this reviewer were translated by language translation software.

REFERENCES

1. Krishnan S, Janjan NA, Skibber JM, et al. Phase II study of capecitabine (Xeloda) and concomitant boost radiotherapy in patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2006 Nov 1;66(3):762-71.

2. Shi GG, Lin E, Eng C, et al. Phase II study of capecitabine and radiotherapy (RT) plus concomitant boost in patients (pts) with locally advanced rectal cancer (LARC). J Clin Oncol 2004. ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2004; 22: No 14S (July 15 Supplement), Abstract 3775.

3. Kim DY, Kim TH, Jung KH, et al. Preoperative chemoradiotherapy with concomitant small field boost irradiation for locally advanced rectal cancer: a multi-institutional phase II study (KROG 04-01). Dis Colon Rectum 2006; 49(11):1684-91.

4. Lee JH, Kim DY, Nam TK, et al. Long-term follow-up of preoperative pelvic radiation therapy and concomitant boost irradiation in locally advanced rectal cancer patients: a multi-institutional phase II study (KROG 04-01). Int J Radiat Oncol Biol Phys 2012 Nov 15; 84(4):955-61.

5. Osti MF, Agolli L, Bracci S, et al. Neoadjuvant chemoradiation with concomitant boost radiotherapy associated to capecitabine in rectal cancer patients. Int J Colorectal Dis 2014 May 14.

6. Vestermark LW, Jacobsen A, Qvortrup C, Hansen F, Bisgaard C, Baatrup G, Rasmussen P, Pfeiffer P (2008) Long-term results of a phase II trial of high-dose radiotherapy (60 Gy) and UFT/l-leucovorin in patients with non-resectable locally advanced rectal cancer (LARC). Acta Oncol 47:428–433.

7. Vestermark LW, Jensen HA, Pfeiffer P (2012) High-dose radiotherapy (60 Gy) with oral UFT/folinic acid and escalating doses of oxaliplatin in patients with non-resectable locally advanced rectal cancer (LARC): a phase I trial. Acta Oncol 51:311–317.

8. Engineer R, Mohandas KM, Shukla PJ, Shrikhande SV, Mahantshetty U, Chopra S, Goel M, Mehta S, Patil P, Ramadwar M, Deodhar K, Arya S, Shrivastava SK (2013) Escalated radiation dose alone vs. concurrent chemoradiation for locally advanced and unresectable rectal cancers: results from phase II randomized study. Int J Color Dis 28:959–966.

9. Anonymous. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Eng J Med 1997; 336:980–987.

10. Kim JY, Kim DY, Kim TH, et al. Intensity-modulated radiotherapy with a belly board for rectal cancer. Int J Colorectal Dis 2007;22:373–379.

11. 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;82:1981–1987.

12. Hernando-Requejo O, López M, Cubillo A, et al. Complete pathological responses in locally advanced rectal cancer after preoperative IMRT and integrated-boost chemoradiation. Strahlenther Onkol 2014 Apr 9.

13. Cubillo A, Hernando-Requejo O, Garcia-Garcia E et al. A prospective pilot study of target-guided personalized chemotherapy with intensity-modulated radiotherapy in patients with early rectal cancer. AM J Clin Oncol 2014; 37:117–121

Dear dr. Kaniklidis,

Thank you very much for this great answer - it is indeed very insightful and of great value to me. Thank you very much from berlin.

Thanks David. Great question!

Constantine