# Radiation Oncology/Head & Neck/Altered Fractionation

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Head & Neck Cancer: Altered Fractionation

## RT Alone

* IAEA-ACC (1999-2004) -- 5 fractions vs 6 fractions per week
** Multicenter randomized trial from nine centers in developing countries (Asia, Europe, the Middle East, Africa, and South America). SCCHN, stage I-IV larynx, pharynx, and oral cavity were randomly assigned to 6F/wk (n=458) or 5F/wk (n=450). RT dose 66-70Gy/33-35F. Overall treatment time 40 days (6F/wk) and 47 days (5F/wk).
** 2010 PMID 20382075 -- "Five versus six fractions of radiotherapy per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): a randomised, multicentre trial." (Lancet Oncol. 2010 Jun;11(6):553-60. Epub 2010 Apr 8.)
*** Results : 5yrs LRC and DSS were 42% (6F) vs 30% (5F) (p=0.004) and 50% vs 40%(p=0.03). OS was trend to favor 6F/Wk but not statistical significant 35% vs 28%(p=0.07). No significant differences in late radiation side-effects.
* Chandigarh, India (1998-2004) -- Standard QD vs. Concomitant Boost
** Randomized. SCCHN, Stage III-IV oropharynx, hypopharynx, larynx. Arm 1) 66/33 vs. Arm 2) concomitant boost 45/25 + 22.5/15 over 5 weeks, >6 hours apart. Compliance >95%
** 2008 PMID 18343310 -- "Concomitant Boost Radiotherapy Compared with Conventional Radiotherapy in Squamous Cell Carcinoma of the Head and Neck - a Phase III Trial from a Single Institution in India." (Ghoshal S, Clin Oncol (R Coll Radiol). 2008 Apr;20(3):212-20.)
*** Outcome: 2-year DFS standard 52% vs. concomitant 72% (SS), LRC 55% vs. 74% (SS).
*** Toxicity: Grade 3 mucositis standard 19% vs. concomitant 35% (SS). No difference in days missed
*** Conclusion: Concomitant boost superior in advanced H&N cancers
* DAHANCA 6 and 7 (1992-1999) -- 5 fractions per week vs 6 fractions per week
** Randomized. 1485 pts. Randomized to RT with 5 fractions per week (overall treatment time: 46 days) vs 6 fractions per week (39 days), but with the same total dose and same number of fractions (66-68 Gy in 33-34 fx). The 6th fraction was given either on a weekend or during the week as a 2nd daily fraction (>6 hrs interval). Pts recd hypoxic radiosensitizer nimorazole (except those with glottic ca).
** DAHANCA 6 & 7 are subprotocols. DAHANCA 6 was for glottic tumors only. Nimorazole was not given. DAHANCA 7 included SGL, pharynx, and OC, and nimorazole was given. All other aspects of the trials were the same.
** 2003 PMID 14511925 Full text -- "Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial." (Overgaard J, Lancet. 2003 Sep 20;362(9388):933-40.)
*** 5-yr LRC 70% (6/wk) vs 60% (5/wk). Benefit was seen for primary tumor control but not nodes. Improved larynx preservation 80% vs 68%. Improved DSS 73% vs 66%, but no difference in OS. Increased acute morbidity for the 6/wk treatment.
* RTOG 90-03 (1991-1997) -- SF vs HF vs Split course AFX vs AFX-CB
** Randomized, 4 arms. 1073 patients. Stage III-IV (oral cavity, oropharynx, or supraglottic larynx) or Stage II-IV (base of tongue, hypopharynx). Arm 1) SF standard fractionation 70/35 @ 2 Gy/fx vs. Arm 2) HF hyperfractionated 81.6/68 @ 1.2 Gy BID vs. Arm 3) AFX-S split course accelerated fractionation 67.2/42 @ 1.6 Gy BID with 2 week break after 38.4 Gy vs. Arm 4) AFX-CB concomitant boost 72 Gy given 54/30 @ 1.8 Gy + 18/12 @ 1.5 Gy concurrent BID boost
** 2-years; 2000 PMID 10924966 -- "A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003." (Fu KK, Int J Radiat Oncol Biol Phys. 2000 Aug 1;48(1):7-16.). Median F/U 2 years, 3.4 for alive patients
*** Outcome: 2-year LRC SF 46% vs. HF 54% (SS) vs. AFX-S 47% (NS) vs. AFX-CB 54% (SS); DFS 32% vs. 38% (NS) vs. 33% (NS) vs. 39% (NS); OS 46% vs. 54% (NS) vs. 46% (NS) vs. 51% (NS)
*** Sites of failure: LF 44% vs. 38% vs. 43% vs. 375; RF 32% vs. 27% vs. 31% vs. 33%
*** Toxicity: Increased acute effects but no increase in late effects
*** Conclusion: HF or CB improve LRC compared to SF, no impact on DFS and OS. Split course comparable to SF
** 5-years; 2005 ASTRO abstract 2005 -- "Long Term Outcomes of RTOG 90–03: A Comparison of Hyperfractionation and Two Variants of Accelerated Fractionation to Standard Fractionation Radiotherapy for Head and Neck Squamous Cell Carcinoma." (Trotti A, Int J Radiat Oncol Biol Phys. 2005 Oct 1;63:S70-71.). Median F/U 1.8 years, 5.3 for alive patients
*** Outcome: 5-year LRC SF 40.9% vs. HF 48.8% (SS) vs. AFX-S 42.2% (NS) vs. AFX-CB 48.3% (SS); DFS 21.2% vs. 30.7% (SS) vs. 26.6% (NS) vs. 28.9% (SS); OS 29.5% vs. 37.1% (NS, but trend with p=0.063) vs. 30.8% (NS) vs. 33.5% (NS)
*** Toxicity: Increased acute effects with all 3 altered fractionation variants, trend for increase in grade 3+ late effects with AFX-CB (p=0.066)
*** Conclusion: HF or CB improve LRC and DFS compared to SF, trend for better OS with HF. AFX-CB may lead to more grade 3+ late effects.
** Education; 2003 PMID 14508838 -- "Effect of education level on outcome of patients treated on Radiation Therapy Oncology Group Protocol 90-03." (Konski A, Cancer. 2003 Oct 1;98(7):1497-503.)
*** Post hoc analysis. More patients in SF had higher education level
*** Outcome: patients attending college significantly better LRC and OS; significant predictor of outcome on multivariate analysis
*** Conclusion: Better education predicts for better outcome
** Nutrition; 2006 PMID 16287132 -- "Impact of nutrition support on treatment outcome in patients with locally advanced head and neck squamous cell cancer treated with definitive radiotherapy: a secondary analysis of RTOG trial 90-03." (Rabinovitch R, Head Neck. 2006 Apr;28(4):287-96.)
*** Post hoc analysis. Prospective data on nutritional support (NS) before treatment (BNS), during treatment (TNS), or after treatment (NoNS). BNS patients had higher Stage, poorer KPS
*** Outcome: Patients with BNS had significantly less weight loss and Grade 3+ mucositis. However, they had worse 5-year LRC: BNS 29% vs. TNS 55% vs. NoNS 57% (SS), and OS 16% vs. 36% vs. 49% (SS). On multivariate analysis, BNS independent prognostic factor for LRF and OS
*** Conclusion: Nutritional support before RT associated with inferior treatment outcome
** Emotional; 2007 PMID 17955501 -- "Emotional well-being does not predict survival in head and neck cancer patients: a Radiation Therapy Oncology Group study." (Coyne JC, Cancer. 2007 Dec 1;110(11):2568-75.)
*** Post-hoc analysis. RTOG 9003 and RTOG 9111. Prospective analysis of FACT-G questionnaire
*** Outcome: No impact of well-being on any outcomes
*** Conclusion: Emotional functioning not independent predictor of survival
** TWiST Analysis; 2008 PMID 19107946 -- "Quality-adjusted survival analysis of Radiation Therapy Oncology Group (RTOG) 90-03: Phase III randomized study comparing altered fractionation to standard fractionation radiotherapy for locally advanced head and neck squamous cell carcinoma." (Konski AA, Head Neck. 2008 Dec 23. [Epub ahead of print])
*** Quality-adjusted survival analysis using Q-TWiST methodology (quality-adjusted time without toxicity or relapse); utilities obtained by threshold analysis
*** Outcome: Quality-adjusted survival (relapse utility = 0.5, toxicity utility = 0.8): SFX 13 mo vs. HFX 14.3 mo (0.06) vs. split-AFX 13.5 (NS) vs. AFX-CB 13.6 (NS)
*** Conclusion: Quality adjusted survival better only for hyperfractionated fractionation, not for accelerated. Q-TWiST analysis can identify patient groups that would benefit from more aggressive therapy based on their utilities
* MRC CHART Trial (1990-1995) -- CHART 54/36 over 12 days vs RT 66/33
** Randomized. 918 patients, suitable for radical RT (excluding T1N0). Arm 1) CHART (54/36 @ 1.5 Gy/fx TID over 12 consecutive days vs Arm 2) 66/22 over 6.5 weeks. No chemotherapy
** EGRF Status; 2005 PMID 16110017 -- "Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial." (Bentzen SM, J Clin Oncol. 2005 Aug 20;23(24):5560-7.)
*** Subgroup analysis. 304 patients with available pretreatment biopsy material, stained for EGFR status. EGFR expression in 84%, EGFR index >25% in 63% of samples. Higher EGFR index in more differentiated tumors
*** Outcome: 3-year LRC in high EGFR better with CHART (HR 1.8, SS), no difference in low EGFR (HR 1.04, NS). No impact on DF or OS
*** Conclusion: Key role for EGFR receptor in determining response to fractionated RT
** 10-years; 2010 PMID 20394851 -- "Mature results of a randomized trial of accelerated hyperfractionated versus conventional radiotherapy in head-and-neck cancer." (Saunders MI, Int J Radiat Oncol Biol Phys. 2010 May 1;77(1):3-8.)
*** Outcome: 10 year LRC CHART 43% vs conventional 50% (NS); DSS 56% vs 58% (NS), OS 26% vs 29% (NS)
*** Toxicity: Lower skin toxicity, severe xerostomia, laryngeal edema, and mucosal necrosis with CHART (SS)
*** Conclusion: Control with CHART similar to conventional RT; a treatment option for patients unable to undergo concurrent chemo-RT
* RTOG 88-09 (1989-90) -- Split course AFX vs. AFX-CB
** Phase I/II, randomized. 70 patients, Stage III-IV HNSCC. Arm 1) split-course accelerated hyperfractionation AFX-S 1.6 Gy/fx BID to 67.2 Gy/6 weeks, 2-week break after 38.4 Gy vs. Arm 2)concomitant boost AFX-C 1.8 Gy/fx QD to 54 Gy and 1.5 Gy/fx to a boost field during the last 11 treatment days for a total dose of 70.5 Gy/6 weeks.
** 1995 PMID 7790243 — "Randomized phase I/II trial of two variants of accelerated fractionated radiotherapy regimens for advanced head and neck cancer: results of RTOG 88-09." (Fu KK et al. Int J Radiat Oncol Biol Phys. 1995 Jun 15;32(3):589-97.) Median F/U 2 years
*** Outcome: No difference in LRC, DFS, or OS
*** Toxicity: Acute mucositis increased in both arms, no difference in late toxicity (Grade 4 6% vs. 17%)
*** Conclusion: Regimens can be given; no difference between the two schemes. Resulted in RTOG 90-03
* M.D.Anderson (1985-88) -- CB
** PMID 2262355 — "Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx." Ang KK et al. Int J Radiat Oncol Biol Phys. 1990 Dec;19(6):1339-45.
** 79 pts, mostly oropharynx. Treated with 1 of 3 regimens of concomitant boost. 69-72 Gy in 6 weeks with the boost consisting of 10-12 fractions.
** Trend toward better primary tumor control (p=0.11) if boost given during last the last 10-12 fractions versus the first 10-12 fractions or twice a week throughout the treatment.
* RTOG 83-13 (1983-1987) -- HF Dose Escalation
** Phase I/II, randomized. 451 patients. Advanced H&N cancer. Dose escalation with hyperfractionation. 1.2 Gy BID, 4 hrs apart, to 67.2 (n=59) -> 72.0 (n=119) -> 76.8 (n=98) -> 81.6 Gy (n=123). Daily interfraction interval >4 hours in 32%, 50%, 43%, and 71%
** 2-years; 1990 PMID 2180866 -- "Dose-response for local control with hyperfractionated radiation therapy in advanced carcinomas of the upper aerodigestive tracts: preliminary report of radiation therapy oncology group protocol 83-13." (Cox JD, Int J Radiat Oncol Biol Phys. 1990 Mar;18(3):515-21.)
*** Outcome: 2-year LC 25% vs. 37% vs. 42% (p=0.08) No survival difference.
*** Toxicity: 2-year Grade 4 necrosis 10% vs. 5% vs. 14%, no info yet for 81.6 Gy group
*** Conclusion: Trend to improved LC with higher doses
** Late effects; 1995 PMID 7790242 -- "Late effects of hyperfractionated radiotherapy for advanced head and neck cancer: long-term follow-up results of RTOG 83-13." (Fu KK, Int J Radiat Oncol Biol Phys. 1995 Jun 15;32(3):577-88.) Median F/U 1.7 year, if alive 6.1 years
*** Late toxicity: No difference between groups. Grade 4 7% vs. 3% vs. 7% vs. 5%; Grade 3 17% vs. 14% vs. 20% vs. 13%
*** Interfraction interval: Constant 2% if >4.5 hours; if <4.5 hours then increasing 2-years 6.3%, 3-years 7.5%, 4 years 8.0%, 5-years 8.6%
*** Conclusion: No apparent dose-response relationship for lat effects; daily interfraction interval needs to be >4.5 hours
* EORTC 22811, 1986 - multiple fractions per day +/- misonidazole vs standard RT
** 523 pts. TID regimen: 1.6 Gy TID x 10 days (48 Gy), 3 week rest, then boost to 67.2 Gy (4 more days). Total 6 weeks. Standard: 1.7-2 Gy/fx to 70 Gy in 7 weeks.
** Early results (1986): PMID 3516953
*** No difference in survival or local control.
* EORTC 22791 (1980-87)
** PMID 1480768 — "Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy." Horiot JC et al. Radiother Oncol. 1992 Dec;25(4):231-41.
** 356 pts. T2-3 N0-1 oropharynx excluding base of tongue, size < 3 cm. Randomized to 70 Gy in 7-8 weeks vs 80.5 Gy pure hyperfractionation in 70 fx in 7 weeks (1.15 Gy BID)
** 59% (HF) local disease-free vs 40% (CF). Superiority of HF over CF in T3 tumors but not T2 tumors. Trend in improvement in overall survival (p=0.08). No difference in late effects.
* RTOG 79-13 (1979-83) - 1.2 Gy BID vs. 1.8-2 Gy daily
** Randomized. 187 patients. Stage III-IV, or T2N0 base of tongue, nasopharynx, and maxillary sinus. Conventional RT (66-73.8 Gy in 1.8-2 Gy/fx QD) vs hyperfractionated (60 Gy in 1.2 Gy BID, 3-6 hrs apart)
** 1987 PMID 3542916 — "Hyperfractionated photon radiation therapy in the treatment of advanced squamous cell carcinoma of the oral cavity, pharynx, larynx, and sinuses, using radiation therapy as the only planned modality: (preliminary report) by the Radiation Therapy Oncology Group (RTOG)." Marcial VA et al. Int J Radiat Oncol Biol Phys. 1987 Jan;13(1):41-7.
*** Outcome: 2-year LRC conventional 29% vs. hyperfractionated 30% (NS)
*** Toxicity: Worse acute toxicity but similar rate of late reactions. More severe acute reactions if interfraction interval <4.5 hours
*** Conclusion: No outcome difference, worse acute toxicity
* U.Florida; 1993 (1978-89) - PMID 8440619 — "Twice-a-day radiotherapy for squamous cell carcinoma of the head and neck: the University of Florida experience." Parsons JT et al. Head Neck. 1993 Mar-Apr;15(2):87-96.
** 419 patients, locally advanced. 1.2 Gy BID to 74.4-79.2 Gy.
** LC was improved or the same as historical controls (with qd RT) for each stage, T2-T4.
* RTOG 77-03; 1978 - No PMID. "Hyperfractionation where we stand - a preliminary RTOG report." (Marks R, In J Radiat Oncol Biol Phys 1978 2:139-140.
** Hyperfractionation pilot study.
** Outcome: 1.25 Gy BID to 66 Gy gave adequate tumor control, with acceptable acute and late toxicity. But 1.5 Gy BID was too toxic, and required treatement break
** Results led to RTOG 79-13

## AFX RT Alone vs Concurrent Chemo-AFX RT

* RTOG 0522 (2005-2009) -- AFX plus concurrent cisplatin +/- cetuximab
** Phase III. 895 pts. Stage III-IV (OP, L, HP). Cisplatin (100 mg/m2) days 1 and 22. Cetuximab given weekly.
** RT options: 1) 72 Gy in 42 fx over 6 weeks, using concomitant boost (54/1.8 qd, 2nd fraction of 1.5 Gy for last 12 treatments) or 2) 70 Gy in 35 fx (IMRT) over 6 weeks, which requires 6 fx/week for 5 of 6 weeks, either giving a Saturday treatment or 2nd daily fraction.
** 2011; 2.4 years ASCO Abstract 5500 -- "A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC)." (Ang KK, J Clin Oncol 29: 2011 (suppl; abstr 5500))
*** 90% of pts completed cisplatin and 74% completed cetuximab (in Arm A). 2-yr PFS 63% (CDDP+cetux) vs 64% (CDDP alone), NS; OS 83% vs 80%. Grade 3-5 adverse events 92% vs 90%, NS. Higher rates of gr 3-4 mucositis (45% vs 35%) and skin reactions (40% vs 17%); no difference in gr 3-4 dysphagia (62% vs 66%).
*** The addition of cetuximab to RT+cisplatin (accelerated RT) did not improve PFS or OS.
* RTOG 0129 (2002-2005) -- Concurrent SFX vs. concurrent AFX with cisplatin
** Randomized. 723 patients, selected Stage III-IV (T2N2-3M0, T3-4 Any N M0, no T1-2N1 or T1N2-3) oral cavity, oropharynx, hypopharynx, or larynx. Arm 1) Conventional chemo-RT 70/35 in 7 weeks vs Arm 2) Concomitant boost chemo-RT 72/42 in 6 weeks. Cisplatin 100 mg/m2 Q3W
** 2007 ASTRO Abstract - "A phase III trial to compare standard versus accelerated fractionation in combination with concurrent cisplatin for head and neck carcinomas (RTOG 0129): report of compliance and toxicity." (Ang K,Int J Radiat Oncol Biol Phys 69 (3 Suppl): A-21, S12-13, 2007) Median F/U 2.0 years, living 2.4 years
*** Outcome: Feeding tube before therapy SFX 25% vs. 22%, EOT 68% vs. 67%, 1-year 30% vs. 27%. No difference in any toxicity endpoint
*** Conclusion: Compliance high, no higher acute toxicity in C-AFX compared with C-SFX arm
** 2009 ASTRO Abstract - "A Phase III Trial to Test Accelerated Versus Standard Fractionation in Combination with Concurrent Cisplatin for Head and Neck Carcinomas (RTOG 0129): Report of Efficacy and Toxicity." (Ang K, IJROBP 2010; 77(1):1-2).
*** Outcome: OS AFX 59% versus SFX 56% (NS), LRF 31% versus 28% (NS). Worst grade 3-4 toxicity 26% versus 21%.
*** Conclusion: AFX-C did not improve outcome or increase late toxicity in patients with LA-HNC.
* Spanish trial, 1990 — "Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer." Sanchiz F et al. IJROBP 1990; 19(6):1347-50.
* Brizel (Duke), 1998 - PMID 9632446 — "Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer." Brizel DM et al. N Engl J Med. 1998 Jun 18;338(25):1798-804.
** Improved LRC 26% and OS 21%, absolute at 3 yrs.
* Jeremic, 2000 - PMID 10735893 — "Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial." Jeremic B et al. J Clin Oncol. 2000 Apr;18(7):1458-64.
* German trial, 2001 - PMID 11483325 — "Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer." Staar S et al. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1161-71.
** Difference in LRC and OS (increase of 6% and 9%) N.S.
* Swiss trial, 2004 (1994-2000) - PMID 15534360 — "Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy." Huguenin P et al. J Clin Oncol. 2004 Dec 1;22(23):4665-73.
** Randomized to HF-RT (1.2 Gy BID to 74.4 Gy) +/- concomitant cisplatin (2 cycles of 20 mg/m2 on days 1-5 of weeks 1 and 5)
** Improved LRC and distant DFS but no difference in OS.
* RTOG 99-14 (2000)
** Phase II. 84 pts. Enrolled Stage III-IV OC, OP, HP, and larynx. Concomitant boost 72 Gy in 6 weeks. Large field 32.4 Gy (1.8 Gy/fx). Boost field 1.5 Gy/fx x 12 fx = 18 Gy, >6 hrs after first daily fraction with additional 21.6 Gy (1.8 Gy/fx) to large field. Total dose to large field is 54 Gy. Offcord at 45 Gy. Cisplatin 100 mg/m2 on days 1 and 22.
** 2005 PMID 15860857 — "Concomitant boost radiation plus concurrent cisplatin for advanced head and neck carcinomas: radiation therapy oncology group phase II trial 99-14." (Ang KK et al. J Clin Oncol. 2005 May 1;23(13):3008-15.)
** 2008 PMID 18640496 — "Long-term results of concomitant boost radiation plus concurrent cisplatin for advanced head and neck carcinomas: a phase II trial of the radiation therapy oncology group (RTOG 99-14)." (Garden AS, Int J Radiat Oncol Biol Phys. 2008 Aug 1;71(5):1351-5.) -- Median f/u 4.3 yrs
*** LR failure 33% (2 yr) and 36% (4 yr). OS 70% (2 yr) and 54% (4 yr). Toxicity: Late grade 3-4 42%. Gastrostomy tube: 83% (any time), 41% (12 mo), 17% (48 mo).
** Conclusion: Feasible to combine AFX-Concomitant Boost with cisplatin. LRC and OS compare favorably with historical results from AFX-C alone or chemo/RT. Relatively high late toxicity + dysphagia.

## Accelerated ChemoRT vs. Conventional ChemoRT vs. Very Accelerated RT

* GORTEC 99-02 (2000-2007) -- conventional chemoradiotherapy (70 Gy in 7 weeks plus three cycles of 4 days’ concomitant carboplatin-fluorouracil), accelerated radiotherapy-chemotherapy (70 Gy in 6 weeks plus two cycles of 5 days’ concomitant carboplatin-fluorouracil), or very accelerated radiotherapy alone (64.8 Gy [1.8 Gy twice daily] in 3.5 weeks)
** Phase III. 840 pts. Stage II-IV (OC, OP, L, HP). When given, chemotherapy was three cycles of 4 days of carboplatin 70 mg/m2 per day plus fluorouracil 600 mg/m2 per day for days 1-4 (conventional) or days 1-5 (accelerated)
*** RT options: 1) 70 Gy in 7 weeks (five fractions of 2 Gy per week) with spinal cord exclusion at 40 Gy and chemotherapy of three cycles; 2) 70 Gy in 6 weeks: five fractions of 2 Gy per week until 40 Gy (with spinal cord exclusion at 40 Gy) and then 1.5 Gy per fraction twice daily for 5 days per week for the remaining 30 Gy and concomitant chemotherapy of two cycles; 3) 64.8 Gy in 3.5 weeks without chemotherapy (1.8 Gy twice daily for five days per week), with spinal cord exclusion at 34.2 Gy.
*** RT Methods: 3D conformal; IMRT not allowed; Cervical posterior nodes were treated with electron beams (8–12 MeV) or with oblique posterior photon beams. The prophylactic nodal irradiation dose was 45 Gy in the uninvolved neck in the very accelerated radiotherapy group and 50 Gy for the two other groups.
** 2012 PMID 22261362 — "Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial." Bourhis et. al. Lancet Oncol 2012; 13: 145–53.
*** Methods: Median follow-up was 5·2 years; rates of chemotherapy and radiotherapy compliance were good in all groups. Treatment as above.
*** Results: Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional chemoradiotherapy (HR 1.02, 95% CI 0.84–1.23; p=0·88) or very accelerated radiotherapy (0.83, 0.69–1.01; p=0.060); conventional chemoradiotherapy improved PFS compared with very accelerated radiotherapy (0.82, 0.67–0.99; p=0.041). 3-year PFS was 37.6% (95% CI 32.1–43.4) after conventional chemoradiotherapy, 34.1% (28.7–39.8) after accelerated radiotherapy- chemotherapy, and 32.2% (27.0–37.9) after very accelerated radiotherapy.
*** Authors' Conclusions: Chemotherapy has substantial treatment effect given concomitantly with RT and accelerated RT cannot compensate for the absence of chemotherapy. Best Outcomes were in conventional chemoradiotherapy arm, suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules.
** Editorial: Contrary to the main hypothesis to the trial, there was no benefit for accelerated RT with respect to PFS ([HR] 1.02, 95% CI 0.84–1.23; p=0.88), overall survival (1.05, 0.86–1.29; p=0.60), locoregional failures (0.97, 0.74–1.26; p=0.81), or distant metastases (1.26, 0.90–1.75; p=0.18). This corroborates results from RTOG 0129, which failed to demonstrate a survival advantage of accelerated-fractionation RT compared with standard-fractionation combined with concurrent carboplatin. In this trial, very accelerated RT (without chemotherapy) resulted in more frequent acute grade 3–4 mucosal toxic effects, a higher proportion of PEG-dependency, and inferior PFS and OS than did conventional chemoradiotherapy. From these results, it seems safe to conclude that with 2D/3D fields, the addition of chemotherapy to conventional RT compensates for a potential benefit from acceleration of radiotherapy.
** Strengths: With 840 patients randomly allocated during more than 7 years, GORTEC 99-02 was the largest randomized study to assess the potential benefit of combination of different intensification strategies to date.
** Caveats: 1) No IMRT allowed; 2) Conventional ChemoRT group received 17% more chemo than accelerated group by trial design; 3) Archaic chemo regimen utilized (5-FU); 4) No information/stratification by HPV status.

## Meta-analysis

* MARCH Trial (Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck)
** 2017 PMID 28757375 -- "Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis." (Lacas B, Lancet Oncol. 2017 Jul 27.[Epub ahead of print])
*** Comparison 1: conventional fraction RT vs altered fractionation.
**** For altered fractionation, improved OS (HR 0.94), 5 yr difference of 3.1% and 10 yr difference of 1.2%.
**** For hyperfractionated RT (HR 0.83), 5 yr difference of 8.1%, 10 yr difference of 3.9%.
*** Comparison 2: conventional fraction RT+chemo vs altered fractionation RT alone.
**** OS worse for altered fractionation RT alone compared with std chemo-RT (HR 1.22), 5 yr diff of 5.8%, 10 yr diff of 5.1%.
*** Conclusion: This update confirms ... that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested.