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 Head & Neck Randomized Evidence 

Surgical Technique

 * RTOG 85-30 (1989-1994)
 * Randomized. 125 patients. Arm 1) standard surgery vs. Arm 2) surgery + cricopharyngeal myotomy
 * 1999 PMID 10488976 -- "Failure of cricopharyngeal myotomy to improve dysphagia following head and neck cancer surgery." (Jacobs JR, Arch Otolaryngol Head Neck Surg. 1999 Sep;125(9):942-6.)
 * Outcome: No difference in oropharyngeal swallowing efficiency at 6 months
 * Conclusion: No benefit for cricopharyngeal myotomoy

Surgery + RT vs Primary RT

 * Scottland (1991-1993) -- Surgery + post-op RT vs radical RT
 * Randomized. Trial closed prematurely after significant survival benefit for combined arm. 35 of expected 350 patients, 4 institutions, oral cavity/oropharynx, excluded T1N0. Arm 1) Surgery + postop RT 60/30 vs Arm 2) radical RT 66/33 alone. Only 50% and 41% of patients respectively received XRT as planned, mainly due to machine breakdown
 * 1998 PMID 9704176 -- "Early closure of a randomized trial: surgery and postoperative radiotherapy versus radiotherapy in the management of intra-oral tumours." (Robertson AG, Clin Oncol (R Coll Radiol). 1998;10(3):155-60.) Median F/U 1.9 years
 * Outcome: OS combined arm 53% vs. RT 11% (HR 0.24, SS); DSS 65% vs 33% (SS). Residual local disease 0% vs. 53% (SS)
 * Conclusion: Surgery with postop RT superior to radical RT alone

Surgery + RT vs. Primary Chemo-RT

 * Singapore (1996-2000)
 * Randomized. Stopped early due to slow accrual. 199 patients, resectable Stage III/IV SCHNC excluding NPC and salivary glands (larynx 32% (supraglottis 23%), oral cavity 27%, oropharynx 21%, hypopharynx 12%). T4 56%. Arm 1) surgery + adjuvant RT 60/30 vs. Arm 2) RT 66/33 + concurrent cisplatin 20 mg/m2 + 5-FU 1000 mg/m2 x2 cycles. 90% received at least 1 cycle of chemo
 * 2005 PMID 16012523 -- "Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison." (Soo KC, Br J Cancer. 2005 Aug 8;93(3):279-86.) Median F/U 6 years
 * Outcome: 3-year DFS: S+RT 50% vs. chemo-RT 40% (NS). Organ preservation (larynx/hypopharynx 68%, oropharynx 55%, oral cavity 21%, paranasal sinus 0%). Chemo-RT group had poor surgical salvage of 47%, with no long-term survivors
 * Conclusion: Chemo-RT not superior to surgery+RT, but can be attempted for organ preservation in larynx, hypopharynx, and oropharynx

Pre-op RT vs. Post-op RT

 * RTOG 73-03 (1973-1979)
 * Randomized. 320 patients. Operable stage T2-T4 any N (but not fixed); oral cavity, oropharynx, supraglottic larynx, hypopharynx, or maxillary sinus. Arm 1) Pre-op RT 50 Gy vs. Arm 2) Post-op RT 60 Gy. In addition, OC and OP lesions may be randomized Arm 3) definitive RT 65-70 Gy, with surgery reserved for salvage (n=43).
 * 5-years; 1987 PMID 3449477 &mdash; "Combined radiation therapy and surgery in the management of advanced head and neck cancer: final report of study 73-03 of the Radiation Therapy Oncology Group." (Kramer S et al. Head Neck Surg. 1987 Sep-Oct;10(1):19-30.) Median F/U 5 years
 * Outcome: LRC post-op 65% vs pre-op 48% (SS). Higher rate of persistent disease and recurrence in pre-op. Trend toward improved survival, 38% vs 33% (p=0.1).
 * Toxicity: Complication rate similar.
 * Definitive RT arm: For OC and OP lesions (three-arm randomization), 4-yr OS pre-op 30% vs post-op 36% vs definitive 33% (NS), and LRC 43% vs 52% vs 38% (NS); however total number of patients was small
 * Conclusion: Post-op RT superior to pre-op RT; insufficient info on definitive RT comparison
 * 10-years; 1999 PMID 1993628 &mdash; "Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03." (Tupchong L et al. Int J Radiat Oncol Biol Phys. 1991 Jan;20(1):21-8.)
 * Only pre-op vs. post-op subset (n=277). Oral cavity (14%), oropharynx (17%), hypopharynx (43%), supraglottic larynx (26%)
 * Outcome: LRC pre-op 58% vs. post-op 70% (SS), <2 years no difference (failures 59% vs. 58%), but marked >2 years (failures 27% vs 8%); OS no difference due to late (>2 years) deaths from DM and from second primaries
 * Supraglottic larynx: LRC pre-op 53% vs. post-op 77% (SS); 78% failures <2 years
 * Toxicity: no difference
 * Conclusion: Post-op RT better for LRC (especially in SGL), but no impact on OS due to distant failure and second primaries
 * Comment: some argument for definitive chemoRT instead of surgery and post-op RT since after 2 yrs, distant mets are primary cause of failure resulting in similar 10 OS in this trial. LRC still better for post-op vs definitive RT alone. Also, different doses used, at the time believed equivalent given the setting

Induction Chemotherapy vs. Surgery + Post-op RT

 * SWOG 8006 (1980-1985) -- Induction chemo vs. standard surgery + RT
 * Randomized. 158 patients. Stage III-IV, resectable HNSCC (oral cavity, oropharynx, hypopharynx, larynx). Arm 1) Surgery + post-op RT vs. Arm 2) Induction cisplatin 50 mg/m2 + MTX + vincristine + bleomycin
 * 1988 PMID 3054373 -- "Preoperative chemotherapy in advanced resectable head and neck cancer: final report of the Southwest Oncology Group." (Schuller DE, Laryngoscope. 1988 Nov;98(11):1205-11.) Median F/U 5 years
 * Outcome: median OS induction chemo 1.5 years vs. control 2.5 years (NS)
 * Conclusion: No benefit for induction chemo

Post-op RT vs. Post-op concurrent chemo-RT

 * RTOG 95-01 / Intergroup (1995-2000) -- cisplatin 100 mg/m2 Q3W
 * Randomized. 416 patients. Oral cavity, oropharynx, larynx, hypopharynx. Macroscopically complete resection. High risk (2 or more positive lymph nodes, or ECE, or SM+). Arm 1) RT alone vs RT with concurrent cisplatin (100 mg/m2 Q3W x 3 cycles). RT 60/30 plus optional boost to 66/33 high-risk areas. High risk groups: 81% with 2+ LN or ECE+; 19% with positive margins. Primary endpoint LRC.
 * 2-years; 2004 PMID 15128893 &mdash; "Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck." (Cooper JS et al. N Engl J Med. 2004 May 6;350(19):1937-44.). Median F/U 3.7 years
 * Outcome: 2 year LRC chemo-RT 82% vs. RT 72% (SS), DFS significantly increased with a HR of 0.78 (2-year estimates not reported), but OS not significantly different.
 * Toxicity: acute Grade 3+ chemo-RT 77% vs. RT 34% (SS); late effects 21% vs. 17% (NS); 2% treatment-related death, all in chemo-RT group
 * Conclusion: In high risk patients, postop concurrent chemo-RT improves LRC and DFS. Toxicity is substantially higher


 * France (1994-2002) -- carboplatin
 * Randomized. Stopped early after publication of French trial (Bachaud 1996). 144 patients, oropharynx (49%), hypopharynx (29%), larynx (22%), T1-4N0-3, macroscopic resection. Surgery + neck dissection. Arm 1) RT vs. Arm 2) RT + concurrent carboplatin 50mg/m2 BIW. RT 54 Gy if R0, 72 Gy if R1, bilateral neck 54 Gy, ECE boost 9 Gy.
 * 2008 PMID 18222010 -- "Randomized clinical trial of post-operative radiotherapy versus concomitant carboplatin and radiotherapy for head and neck cancers with lymph node involvement." (Racadot S, Radiother Oncol. 2008 Jan 24 [Epub ahead of print]). Median F/U 8.8 years
 * Outcome: 2-year LRC RT alone 68% vs. chemo-RT 73% (NS), worse for oropharynx vs. larynx; OS 55% vs. 58% (NS)
 * Conclusion: Concurrent carboplatin BIW showed no benefit


 * EORTC 22931 (1994-2000) -- cisplatin 100 mg/m2 Q3W
 * Randomized. 334 patients. Oral cavity, oropharynx, hypopharynx, or larynx. T3-4 any N with negative margins (except T3N0 of larynx); T1-2 N2-3; T1-2 N0-1 with high-risk features (ECE, SM+, PNI, LVI); or oral cavity/oropharynx with LN+ at levels IV or V. Arm 1) RT alone vs. Arm 2) RT + concurrent cisplatin 100 mg/m2 Q3W. RT dose 54/27 + boost to 66 Gy high risk areas. High risk groups: 56% with 2+ LN; 26% with positive margins; 53% with extracapsular extension. Primary end-point PFS.
 * 5-years; 2004 PMID 15128894 - "Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer." (Bernier J, N Engl J Med. 2004 May 6;350(19):1945-52.) Median F/U 5 years
 * Outcome: 5-year PFS chemo-RT 47% vs RT 36% (SS); OS 53% vs 40% (SS); LRC 82% vs 69% (SS). No difference in DM rate (21% vs. 25%, NS).
 * Toxicity: No difference between groups
 * Conclusion: Post-op concurrent cisplatin with RT is more efficacious in locally advanced H&N, without significantly more complications


 * France (1984-88) -- cisplatin 50 mg/m2 QW
 * Randomized. Closed early due to slow accrual due to increasing use of neoadjuvant chemotherapy. 83 patients. Stage III-IV oral cavity, oropharynx, hypopharynx, larynx, or unknown primary, LN+ with ECE. Arm 1) RT alone vs. Arm 2) RT + cisplatin 50 mg/m2 QW. RT 65-70 Gy (1.7 Gy/fx), neck 54 Gy
 * 1996 PMID 8985019 &mdash; "Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial." (Bachaud JM et al. Int J Radiat Oncol Biol Phys. 1996 Dec 1;36(5):999-1004.)
 * Outcome: LRF RT alone 41% vs. chemo-RT 23% (p=0.08), similar DM rate, 2-year OS 46% vs. 72% (SS), 5-year OS 13% vs. 36% (SS)
 * Severe late toxicity: RT alone 15% vs. chemo-RT 20%
 * Conclusion: Improved survival with concurrent cisplatin


 * Yale (1980-92) -- Mitomycin C
 * Randomized. 2 consecutive randomized trials. 113 patients, treated with surgery. Arm 1) RT vs. Arm 2) RT with concurrent Mitomycin C 15 mg/m2 x 1-2 doses. Second trial: Arm 1) RT vs. Arm 2) RT + Mitomycin C with dicoumarol.
 * 5-years; 1993 PMID 7691784 -- "Mitomycin C as an adjunct to postoperative radiation therapy in squamous cell carcinoma of the head and neck: results from two randomized clinical trials." (Haffty BG, Int J Radiat Oncol Biol Phys. 1993 Sep 30;27(2):241-50.) Median F/U 7.7 years
 * Outcome: LRC mitomycin C 87% vs. control 67% (SS), DFS 67% vs. 44%, OS 56% vs. 41% (NS). No local failures in Mitomycin C arm vs. 12 in RT alone
 * Conclusion: Concurrent Mitomycin C with RT results in improved DFS, and LRC benefit

Post-op RT vs. Post-op sequential chemo-RT

 * RTOG 85-03 / Intergroup 0034 (1984-1989) - cisplatin/5-FU
 * Randomized. 442 patients. Completely resected tumors of oral cavity, oropharynx, hypopharynx, or larynx. Arm 1) Post-op RT alone vs Arm 2) Post-op chemotherapy (cisplatin/5-FU x 3 courses q3wk) followed by RT. RT dose 50-54 Gy; boost to 60 Gy for close margins (<5mm) or ECE.
 * 1992 PMID 1618662 &mdash; "Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: report on Intergroup Study 0034." (Laramore GE, Int J Radiat Oncol Biol Phys. 1992;23(4):705-13.) Median F/U 3.8 years
 * Outcome: 4-year OS RT 44% vs. chemo-RT 48% (NS); DFS 38% vs. 46% (NS); LRC 70% vs. 74% (NS); reduced first failure in neck 10% vs. 5% (SS), DM 23% vs. 15% (SS)
 * Subgroup analysis of high-risk group (margins < 5mm, CIS at margin, ECE) showed a trend to improvement in LC with chemo. So it may be important to select high-risk group to see a benefit from chemo.
 * Conclusion: No benefit for adjuvant sequential chemo-RT over RT alone


 * Loma Linda (1979-1983) -- induction/sequential adjuvant MTX
 * Randomized. 55 patients. Potentially resectable SCCHN. Arm 1) Surgery + RT vs. Arm 2) Induction MTX x4 doses then surgery then MTX x4 doses then RT then MTX x8 doses. RT 60 Gy or 65 Gy with close SM
 * 1987 PMID 3806169 -- "Adjuvant methotrexate escalated to toxicity for resectable stage III and IV squamous head and neck carcinomas--a prospective, randomized study." (Rentschler RE, J Clin Oncol. 1987 Feb;5(2):278-85.)
 * Outcome: No difference in DFS or OS (numbers not given); no difference in sites of recurrence
 * Conclusion: No benefit for sequential MTX

Postop Alternative Fractionation

 * Sklodowska-Curie Cancer Center, Poland (2001-2004) -- conventional RT 5-days/week vs. accelerated RT 7-days/week
 * Randomized. 279 patients, high-risk SCC larynx (57%) vs. oral cavity/oropharynx (43%). High risk determined by score using tumor site, SM status, SM width, LVI, grade, number of LN+, ECE, and LN grade. Surgery + lymph node dissection. Arm 1) Conventional RT 63/35 over 7 weeks vs. Arm 2) Accelerated RT 63/35 over 5 weeks
 * 2008 PMID 18342964 -- "Randomized clinical trial on 7-days-a-week postoperative radiotherapy for high-risk squamous cell head and neck cancer." (Suwinski R, Radiother Oncol. 2008 May;87(2):155-63. Epub 2008 Mar 14.)
 * Outcome: 3-year LRC CF 64% vs. CAIR 70% (NS). Planned subset analysis oropharynx/oral cavity 53% vs. 74% (SS), larynx 72% vs. 67% (NS). LC 73% vs. 81% (NS); neck control 81% vs. 83% (NS). 3-year OS 52% vs. 55% (NS)
 * Toxicity: Confluent mucositis CF 33% vs. CAIR 60%, but considered acceptable. Late toxicity Grade 3-4 CF 6% vs. 13%
 * Conclusion: Improvement in LRC restricted to patients with oropharynx/oral cavity; no benefit in patients with larynx


 * Italy Multi-Institutional (1994-2001) -- conventional 60/30 vs. accelerated concomitant boost 64/35
 * Randomized. 226 patients, locally advanced oral cavity, oropharynx, larynx, or hypopharynx, with high-risk features (pT4, SM+, N2-3, PNI+, LVI+, ECE+, subglottic extension) after surgery. Arm 1) conventional RT 60/30 vs. Arm 2) accelerated RT "biphasic concomitant boost" during first/last week to deliver 64 Gy over 5 weeks. Primary endpoint LRC
 * 2005 PMID 15708255 -- "Accelerated versus conventional fractionated postoperative radiotherapy for advanced head and neck cancer: results of a multicenter Phase III study." (Sanguineti G, Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):762-71.) Median F/U 2.5 years
 * Outcome: 2-year LRC CF 80% vs. AF 78% (NS), trend to benefit for patients with RT delay >7 weeks. 2-year OS 67% vs. 64% (NS)
 * Toxicity: Confluent mucositis CF 27% vs. AF 50% (SS), duration same. Late toxicity 18% vs. 27% (NS), though data preliminary
 * Conclusion: Accelerated fractionation not beneficial overall, might be option for patients who delay starting RT


 * MDACC/Mayo/Moffitt (1991-1995) -- risk adapted; conventional 63/35 in 7 weeks vs. accelerated 63/35 in 5 weeks
 * Risk adapted, part randomized. 213 patients, oral cavity, oropharynx, larynx, hypopharynx. Risk factors ECE, >1 nodal group, >=2 LN+, >3-cm LN, oral cavity, SM+, PNI+ (Peters 1993)
 * Low risk (no risk factors): no RT
 * Intermediate risk (1 risk factor, excluding ECE): conventional RT 57.6/32
 * High risk (ECE or 2+ risk factors): randomized Arm 1) conventional RT 63/35 in 7 weeks vs. accelerated RT 63/35 in 5 weeks concomitant boost. Undissected neck received 54 Gy and dissected but negative neck 57.6 Gy.
 * 2001 PMID 11597795 &mdash; "Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer." (Ang KK, Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):571-8.) Median F/U 4.9 years
 * Outcome: 5-year LRC low risk patients 90% vs. intermediate risk patients 94% vs. high risk patients 68% (SS). High risk CF ~60% vs. AF ~75% (NS). 5-year OS low risk 83% vs. intermediate risk 66% vs. high risk 42%, CF ~35% vs. AF ~50% (NS)
 * Treatment time: 5-year LRC <11 weeks 76% vs. >11 weeks 62% vs >13 weeks 38% (SS); 5-year OS 48% vs. 27% v. 25% (SS). Surgery-RT interval >6 weeks detrimental
 * Conclusion: Risk stratification appropriate. Accelerated fractionation better for patients with delay >6 weeks of starting RT, combined treatment time should be <11 weeks


 * Cairo, Egypt -- conventional RT 60/30 vs. accelerated RT 46.2/33 TID in 2 weeks
 * Randomized. 70 patients, T2N1-2 or T3-4 any N, s/p radical surgery. Arm 1) conventional RT 60/30 vs. Arm 2) accelerated RT 46.2/33 TID over 2 weeks
 * 2002 PMID 11870530 -- "Accelerated hyperfractionation (AHF) compared to conventional fractionation (CF) in the postoperative radiotherapy of locally advanced head and neck cancer: influence of proliferation." (Awwad HK, Br J Cancer. 2002 Feb 12;86(4):517-23.)
 * Outcome: 3-year LRC AHF 88% vs. CF 57% (SS), 3-year OS 60% vs. 46% (NS). No benefit for T(pot) evaluation on multivariate analysis, though rapid tumors higher risk of DM. Surgery-RT gap shouldn't exceed 6 weeks
 * Toxicity: acute mucositis more severe in AHF, fibrosis and late edema also worse in AHF
 * Conclusion: Accelerated hyperfractionation improved local control, but without survival impact


 * Cairo, Egypt -- conventional RT 50/25 vs. accelerated RT 42/30 TID in 11 days
 * Randomized. 56 patients, locally advanced HNSCC, s/p radical surgery. Arm 1) conventional RT 50/25 vs. Arm 2) accelerated RT 42/30 TID over 11 days
 * 1992 PMID 1480771 -- "Accelerated versus conventional fractionation in the postoperative irradiation of locally advanced head and neck cancer: influence of tumour proliferation." (Awwad HK, Radiother Oncol. 1992 Dec;25(4):261-6.)
 * Outcome: 3-year DFS 46%, no difference between arms. AHF better survival in fast growing tumors (thymidine labeling index >10.4%)
 * Toxicity: Acute toxicity higher in AF arm, but 3-year late toxicity CF 87% vs. AF 64% (SS)
 * Conclusion: No survival benefit for AF overall, but benefit in faster growing tumors

Primary RT vs. Concurrent Chemo-RT

 * Slovenia (1997-2001) -- RT vs. RT + mitomycin C + bleomycin
 * Randomized. 114 patients, Stage III-IV SCCHN (oral cavity, oropharynx, hypopharynx, larynx). Primary curative surgery. Arm 1) Post-op RT (56 Gy if R0, 66-70 Gy if R1-2) vs. Arm 2) Same RT + concurrent mitomycin C and bleomycin. Stratified in regular risk and high risk (ECE, PNI, LVI, R1-2)
 * 5-years; 2007 PMID 17197122 -- "Patterns of failure in patients with locally advanced head and neck cancer treated postoperatively with irradiation or concomitant irradiation with Mitomycin C and Bleomycin." (Zakotnik B, Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):685-90. Epub 2006 Dec 29.)
 * Outcome: 5-year LRC chemo-RT 88% vs. RT alone 65% (SS), DFS 53% vs. 33% (SS), OS 55% vs. 37% (NS). No difference in DM rate (20% vs. 22%, NS). Second malignancy chemo-RT 8% vs. RT 34% (SS)
 * Toxicity: Grade 3+ chemo-RT 26% vs. RT 19% (NS), thyroid dysfunction 56% vs. 36% (NS)
 * Conclusion: Concomitant chemo-RT improves LRC and DFS; second primaries less frequent


 * Head and Neck Intergroup (1992-1999) -- RT vs. chemo-RT vs. split-course chemo-RT
 * Randomized, 3 arms. Stopped prematurely for poor accrual. 295/462 patients with strictly unresectable HNSCC, excluding nasopharynx, paranasal sinus, salivary glands, or unknown primary. Arm 1) RT alone 70/35 vs. Arm 2) RT 70/35 + concurrent cisplatin 100 mg/m2 Q3W (based on RTOG 81-17) vs. Arm 3) Split course RT 30/15 + concurrent cisplatin 75 mg/m2 and 5-FU 1000 mg/m2, followed by surgery (if resectable, 16%), otherwise additional RT 30-40 Gy
 * 2003 PMID 12506176 &mdash; "An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer." (Adelstein DJ, J Clin Oncol. 2003 Jan 1;21(1):92-8.) Median F/U 3.4 years
 * Outcome: 3-year OS RT 23% vs. chemo-RT 37% (SS) vs. Split-course chemo-RT 27% (NS); 3-year DSS 33% vs. 51% (SS) vs. 41% (NS). No difference in site of failure, DM rate ~20%
 * Toxicity: Grade 3+ RT 52% vs. chemo-RT 89% vs. split-course chemo-RT 77%
 * Conclusion: Addition of concurrent high dose cisplatin to conventional radiation improves surival


 * RTOG 84-06 (1984-1987) -- low dose (20 mg/m2) cisplatin
 * Randomized. 371 patients. Stage III-IV unresectable. Arm 1) RT alone conventional 68-78 Gy vs. Arm 2) same RT + low dose cisplatin 20 mg/m2/week
 * 1990 No PMID - "Radiation alone vs. radiation with weekly low dose cisplatinum in unresectable cancer of the head and neck" (Haselow RE, in Head and Neck Cancer Vol II. Fee WE (ed), Toronto: B. C. Decker: 1990:279-281)
 * Outcome: No difference in LRC or OS
 * Conclusion: No benefit for concurrent low-dose weekly cisplatin


 * Wisconsin (1961-1973) -- 5-FU
 * Randomized. Subset report of 136 patients oral cavity, oropharynx. Advanced SCCHN. Arm 1) RT alone vs. Arm 2) RT + concurrent 5-FU 5 mg/kg. RT 50-60 Gy using orthovoltage/Cobolt/4MV sources
 * 1976 PMID 175693 -- "Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: a randomized study." (Lo TC, AJR Am J Roentgenol. 1976 Feb;126(2):229-35.)
 * Outcome: LC and OS better in chemo-RT, but only oral cavity significant (2-year LC 18% vs. 55%)
 * Toxicity: Both acute and late complications more severe in concurrent group
 * Conclusion: Concurrent 5-FU appears effective, but complications

Primary RT +/- Cetuximab

 * Cetuximab Trial (1999-2002) -- RT +/- cetuximab
 * Randomized. 424 pts. Stage III-IV, scca of oropharynx, hypopharynx, or layrnx. 56-63% had tumors of the oropharynx. Randomized to RT +/- cetuximab. Given as 400 mg/m2 loading dose IV one week before RT, followed by weekly infusions of 250 mg/m2 during RT.
 * One of three radiotherapy regimens (70 Gy at 2 Gy/fx qd, 72-76.8 Gy at 1.2 Gy BID, or 72 Gy in 42 fractions concomitant boost 1.8+1.5 Gy). 56% used concomitant boost, 26% once daily, and 18% twice daily.
 * 3-years, 2006 PMID 16467544, 2006 &mdash; "Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck." Bonner JA et al. N Engl J Med 2006; 354: 567-78. Median F/U 4.5 years.
 * Locoregional control: Median duration Cetuximab + RT 24.4 months vs RT alone 14.9 mo (SS); 3-year LRC: 47% vs. 34%. Cetuximab 32% reduction in LR progression
 * Progression-free survival: Median 17.1 months vs. 12.4 months; 3-year PFS 42% vs. 31%; Risk of DM similar
 * Survival: Median 4.1 years vs 2.4 years (SS); 3-yr OS 55% vs 45%. Cetuximab 26% reduction in the risk of death.
 * Toxicity: Comparable, except 9 patients rash. Second primary cancer in 8% vs 5%.
 * Conclusion: improved survival (10% absolute at 3-yrs) and locoregional control.
 * QoL, 2007 PMID 17538164 -- "Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab." (Curran D, J Clin Oncol. 2007 Jun 1;25(16):2191-7.)
 * Quality of Life assessment (QLQ-C30) at baseline, week 4, month 4, month 8, one year.
 * Outcome: No significant differences
 * Conclusion: Cetuximab improves locoregional control and survival without adversely impacting QoL
 * Editorial PMID 16467552: RT alone in the control arm is suboptimal therapy; current standard of care is RT + cisplatin, which has shown greater benefit than cetuximab. Also, cetuximab appeared only effective in the hyperfractionated arms. No survival benefit for hypopharynx and larynx subgroups. Standard of care should still be RT + cisplatin, but if not tolerated, then cetuximab a good option

Primary RT vs. Induction Chemo + RT

 * RTOG 68-01
 * Randomized. 638 patients, Stage III-IV oral cavity (23%), oropharynx (55%), supraglottic larynx (12%), hypopharynx (10%). Arm 1) RT alone vs. Arm 2) IV MTX 25 mg q3d x5 followed by RT. RT 55-80 Gy
 * 1980 PMID 7410127 -- "Adjuvant intravenous methotrexate or definitive radiotherapy alone for advanced squamous cancers of the oral cavity, oropharynx, supraglottic larynx or hypopharynx." (Fazekas JT, Int J Radiat Oncol Biol Phys. 1980 May;6(5):533-41.)
 * Outcome: median OS RT vs. MTX-RT: oral cavity 11.8 mo vs. 12.4 mo, oropharynx 13.6 mo vs. 13.1 mo, SGL 17.2 mo vs. 19.2 mo, hypopharynx 9.7 mo vs. 13.4 mo
 * Conclusion: Minimal gain, induction methotrexate should not be used

RT with concurrent IV cisplatin vs IA cisplatin

 * Netherlands Cancer Institute (2000-2004) -- Concurrent RT and intra-arterial cisplatin vs intravenous cisplatin
 * Randomized. 239 patients, unresectable H&N. Arm 1) intravenous cisplatin 100 mg/m2 Q3W vs Arm 2) intra-arterial cisplatin 150 mg/m2 QW x4 weeks + sodium thiosulfate rescue. RT 70/35
 * 2010 PMID 20187094 -- "Intra-arterial versus intravenous chemoradiation for advanced head and neck cancer: Results of a randomized phase 3 trial." (Rasch CR, Cancer. 2010 Feb 24. [Epub ahead of print]) Median F/U 2.7 years
 * Outcome: 3-year LC IV 70% vs IA 76% (NS); LRC 65% vs 63% (NS); DFS 47% vs 44% (NS); OS 47% vs 51% (NS)
 * Toxicity: renal Grade 3+ IV 9% vs IA 1% (SS)
 * Conclusion: Intra-arterial cisplatin chemo-RT not superior to intravenous chemo-RT

Altered fractionation

 * 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


 * 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 &mdash; "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

Neutrons

 * NTCWG 85-22 (1986-1991) -- neutrons vs photons
 * Randomized. 5 institutions in US and UK. 169 patients, Stage III-IV (T1N3, T2N+, or T3-4) SCC of H&N. Arm 1) neutrons 20.4/12 over 4 weeks vs. Arm 2) photons 70/35
 * 1995 PMID 7790244 -- "Fast-neutron therapy in advanced head and neck cancer: a collaborative international randomized trial." (Maor MH, Int J Radiat Oncol Biol Phys. 1995 Jun 15;32(3):599-604.)
 * 3-year outcome: CR neutrons 70% vs. photons 52% (SS); LRF 63% vs. 68% (NS); OS 27% both arms (NS)
 * Toxicity: acute comparable, late Grade 3-5 neutrons 40% vs. photons 18% (SS)
 * Conclusion: Long term outcomes comparable, but toxicity worse with neutrons


 * RTOG-MRC Neutron Trial -- neutrons vs. photons/electrons
 * Randomized. Stopped early due to neutron advantage. 32 patients, inoperable or recurrent major or minor salivary gland tumors. Arm 1) Neutrons (17-22 nGy) vs. Arm 2) photon/electrons (55 Gy/4 weeks or 70 Gy/7.5 weeks)
 * Final; 1993 PMID 8407397 -- "Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial." (Laramore G, Int J Radiat Oncol Biol Phys. 1993 Sep 30;27(2):235-40)
 * Outcome: 10-year LRC neutrons 56% vs. photons/electrons 17% (SS); OS 25% vs. 15% (NS). Median OS 3 years vs. 1.2 years
 * Toxicity: Severe toxicity worse in neutron arm, but no difference in "life-threatening" complications
 * Conclusion: Fast neutron RT appears to be the treatment of choice for patients with inoperable/recurrent salivary gland tumors


 * US Neutron Cooperative (1977-1982) -- neutrons/photons vs. photons/electrons
 * Randomized. 327 patients, inoperable SCC of H&N (oral cavity, oropharynx, supraglottic larynx, hypopharynx), T2-4 any N. Arm 1) neutron/photon beams (photons 40-44 Gy + neutrons 7.5-10 Gy) vs. 2) photon/electron beams 66-74 Gy
 * 1989 PMID 2681103 -- "Mixed neutron/photon irradiation of unresectable squamous cell carcinomas of the head and neck: the final report of a randomized cooperative trial." (Griffin TW, Int J Radiat Oncol Biol Phys. 1989 Nov;17(5):959-65.). Minimum F/U 6 years
 * Outcome: no difference in LRC or OS; LRC subgroup N+ mixed 30% vs. photons 18% (p=0.05), N0 mixed 33% vs. photons 64% (SS); control of disease in LN 45% vs. 26% (SS)
 * Conclusion: No difference between neutron/photon vs. photon/electron beam

Hypoxia
Erythropoietin:
 * RTOG 99-03 (2000-2003) - study closed early
 * Randomized. Closed early due to other data suggesting worse locoregional control. 141 patients (40% of goal) with SCCHN, Stage I-IV. RT +/- erythropoietin 40K units/week. If Stage III-IV, concurrent chemo-RT and/or accelerated RT. Pre-RT hemoglobin men <13.5 and women <12.5.
 * 2007 PMID 17716826 -- "Radiotherapy With or Without Erythropoietin for Anemic Patients With Head and Neck Cancer: A Randomized Trial of the Radiation Therapy Oncology Group (RTOG 99-03)." (Machtay M, Int J Radiat Oncol Biol Phys. 2007 Nov 15;69(4):1008-17. Epub 2007 Aug 23.). Median F/U 2.5 years
 * Outcome: 3-year LRF control 36% vs. Epo 44% (NS). No difference in OS (52% vs. 47%) or toxicity
 * Conclusion: Addition of Epo did not improve outcomes


 * European Multinational (1997-2001)
 * Randomized. 351 patients with oral cavity, oropharynx, hypopharynx, larynx. Hemoglobin <13.0 g/dL men, <12.0 g/dL women. RT 60-70 Gy +/- Epo 300 U/kg 3x weekly
 * 2003 PMID 14575968 -- "Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial" (Henke M, Lancet. 2003 Oct 18;362(9392):1255-60.)
 * Hemoglobin: 82% given Epo reached >14.0 (men) or >15 (women) compared with 15% control
 * Outcome: LR failure placebo 54% vs. Epo 64% (SS), median PFS 2.0 years vs. 1.1 years (SS); OS 48% vs. 39% (same 34% mortality from cancer but worse cardiac/general mortality for Epo)
 * Conclusion: Significantly worse LR control and survival with Epo

Etanidazole - hypoxic cell sensitizer
 * RTOG 85-27 (1988-1991)
 * Randomized. 521 pts. Stage III-IV. Randomized to RT 66-74 Gy alone or RT + etanidazole (ETA) 3x/week.
 * 1995 PMID 7790241 -- "Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas." (Lee DJ, Int J Radiat Oncol Biol Phys. 1995 Jun 15;32(3):567-76.)
 * Outcome: 2-year LRC control 40% vs etanidazole 40% (NS); OS 41% vs 43%. For N0-1 patients, advantage for ETA for LRC 55% vs 37% (SS).
 * Conclusion: No benefit for etanidazole overall, subset benefit in N0-1 disease

Misonidazole - hypoxic cell sensitizer
 * RTOG 79-15 (1979-1983)
 * Randomized. 206 patients, 42% oropharynx, 78% T3-T4, 84% N+. Arm 1) RT + placebo vs. Arm 2) RT + misonidazole 2.0 gm/m2 weekly (on day of misonidazole, RT given BID)
 * 1987 PMID 3301758 -- "Failure of misonidazole-sensitized radiotherapy to impact upon outcome among stage III-IV squamous cancers of the head and neck." (Fazekas J, Int J Radiat Oncol Biol Phys. 1987 Aug;13(8):1155-60.)
 * Outcome: 2-year LR rate placebo 26% vs. misonidazole 22% (NS); 3-year OS 22% in both groups
 * Conclusion: No benefit
 * 1989 PMID 2689395 -- "The role of hemoglobin concentration in the outcome of misonidazole-sensitized radiotherapy of head and neck cancers: based on RTOG trial #79-15." (Fazekas JT, Int J Radiat Oncol Biol Phys. 1989 Dec;17(6):1177-81.)
 * Outcome: No difference
 * RTOG 79-04 (1979-1983)
 * Randomized. 40 patients, unresectable Stage III-IV oral cavity, oropharynx, hypopharynx. Arm 1) RT 44-52 Gy in 4 Gy/fx vs. Arm 2) same RT + misonidazole 1.5 gm/m2 3x per week
 * 1989 PMID 2646255 -- "A phase I/II study of the hypoxic cell sensitizer misonidazole as an adjunct to high fractional dose radiotherapy in patients with unresectable squamous cell carcinoma of the head and neck: a RTOG randomized study (#79-04)." (Lee DJ, Int J Radiat Oncol Biol Phys. 1989 Feb;16(2):465-70.)
 * Outcome: 2-year LRC: RT alone 10% vs. RT + MISO 17% (NS)
 * Toxicity: No difference
 * Conclusion: No benefit for misonidazole; high fractional dose RT tolerable

Carbogen - (95% oxygen, 5% C02)
 * RTOG 70-02 (1972-1976)
 * Randomized. 254 patients. T2-4N0-3, Oral cavity, oropharynx, nasopharynx, hypopharynx, larynx; also esophageal cancers (24%). Arm 1) RT + concurrent carbogen breathing vs. Arm 2) RT + air. RT 60-70 Gy (oral cavity max 80 Gy)
 * 1979 PMID 120869 - "Carbogen breathing during radiation therapy-the Radiation Therapy Oncology Group Study." (Rubin P, Int J Radiat Oncol Biol Phys. 1979 Nov-Dec;5(11-12):1963-70.)
 * Outcome: 2-year LC carbogen 51% vs. air 51% (NS); no SS difference by site. Median OS carbogen 1.5 years vs. air 1.5 years (NS)
 * Toxicity: No significant difference
 * Conclusion: No difference

Hyperbaric Oxygen
 * Yale (1974-1975) -- RT in air vs RT in HBO
 * Randomized. 48 patients, locally advanced unresectable SCCHN. Arm 1) RT in air 25.3/2 vs. Arm 2) RT in HBO-4 23/2. HBO given under general anesthesia, 4 atmospheres
 * 1999 PMID 10606475 -- "Radiation therapy with hyperbaric oxygen at 4 atmospheres pressure in the management of squamous cell carcinoma of the head and neck: results of a randomized clinical trial." (Haffty BG, Cancer J Sci Am. 1999 Nov-Dec;5(6):341-7.)
 * Outcome: CR air 52% vs. HBO 84%, 5-year LC 16% vs. 29%. No difference in OS, DM or second primary tumors
 * Severe toxicity: air 28% vs. HBO 52%
 * Conclusion: Substantial improvement in response rate with HBO. Hypofractionation scheme suboptimal

Second Primary Prevention

 * Italian Head and Neck Chemoprevention Study Group (1992-1996) -- low-dose isotretinoin
 * Randomized. 267 patients. Radically treated Stage III-IV HNSCC. Arm 1) placebo vs. Arm 2) isotretinoin 0.5 mg/kg vs. Arm 3) isotretinoin + Interferon alpha-2a (only 15 patients assigned due to financial problems) x1 year
 * 2004 PMID 15138569 &mdash; "13-cis retinoic acid in head and neck cancer chemoprevention: results of a randomized trial from the Italian Head and Neck Chemoprevention Study Group." (Toma S, Oncol Rep. 2004 Jun;11(6):1297-305.) Mean F/U 3.2 years
 * Outcome: 5-year OS isotretinoin 59% vs. placebo 57% (NS); RFS 49% vs. 56% (NS)
 * Toxicity: Grade III-IV in 4%, Grade I-II 69%
 * Conclusion: Low-dose isotretinoin ineffective at chemoprevention


 * Retinoid Head and Neck Second Primary Trial (INT/RTOG 91-15) (1991-1999) -- low dose isotretinoin
 * Randomized. 1190 patients, treated, with Stage I-II HNSCC (oral cavity, larynx, pharynx), disease-free at least 4 months. Arm 1) low-dose isotretinoin (30 mg/day) vs. Arm 2) placebo x3 years
 * 6-years; 2006 PMID 16595780 -- "Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients." (Khuri FR, J Natl Cancer Inst. 2006 Apr 5;98(7):441-50.) Median F/U 6 years
 * Outcome: Second primary tumors rate 4.6%/year in both arms (NS); no difference in primary tumor–free survival, RFS, smoking-associated DFS, and OS
 * Predictors: second cancers 261 (22%); current smokers (HR 1.64, SS) more risk than former smokers (HR 1.32, SS) compared with non-smokers. Risk of death current smokers 2.51 vs. former smokers 1.60
 * Sites of 2nd tumors: lung (31%), oral cavity (17%), larynx (8%), pharynx (5%)
 * Conclusion: Low-dose isotretinoin not effective at reducing second primary tumors


 * France -- etretinate
 * Randomized. 316 patients, SCHNN T1-2N0-1 <=3 cm. Arm 1) etretinate 25 mg/day vs. Arm 2) placebo x2 years
 * 5-years; 1994 PMID 7917535 -- "Prevention of second primary tumours with etretinate in squamous cell carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomised study." (Bolla M, Eur J Cancer. 1994;30A(6):767-72.) Median F/U 3.4 years
 * Outcome: second primary tumor 18% (NS). No difference on LR or DM rate. 5-year OS and DFS no difference
 * Toxicity: discontinued in etretinate 33% vs. placebo 23% (SS)
 * Conclusion: Etretinate does not preven second primary tumors


 * Queensland (Australia) -- high-dose or low-dose isotretinoin
 * Randomized. Trial stopped early by sponsor after early analysis showed no benefit. 151 patients. T1-4N0-2 HNSCC. Arm 1) high-dose isotretinoin 1 mg/kg x1 year, then low-dose isotretinoin 0.5 mg/kg x2 years vs. Arm 2) low-dose isotretinoin x3 years vs. Arm 3) placebo x3 years. 67% did not complete therapy (~1/3 in high-dose due to side effects)
 * 2005 PMID 15781758 -- "Chemoprevention of head and neck cancer with retinoids: a negative result." (Perry CF, Arch Otolaryngol Head Neck Surg. 2005 Mar;131(3):198-203.)
 * Outcome: Second primary cancer high-dose 9% vs. low-dose 17% vs. placebo 14% (NS); no difference in DFS, RFS, or OS
 * Toxicity: No difference between groups
 * Conclusion: Use of isotretinoin not indicated for prophylaxis


 * MD Anderson -- high-dose isotretinoin
 * Randomized. 103 patients, treated Stage I-IV HNSCC. Arm 1) high dose isotretinoin 50-100 mg/m2 vs Arm 2) placebo x1 year.
 * 5-years; 1994 PMID 8271298 -- "Prevention of second primary tumors with isotretinoin in patients with squamous cell carcinoma of the head and neck: long-term follow-up." (Benner SE, J Natl Cancer Inst. 1994 Jan 19;86(2):140-1.) Median F/U 4.5 years
 * Outcome: second primary tumors isotretinoin 14% vs. placebo 31% (SS); but impact diminishes with time. By 8 years, estimated rates of 19% vs. 44%. No patients developed second primary tumor while on drug
 * Toxicity: 70% required dose reduction, 25% stopped
 * No difference in OS. No impact on behavior of primary tumor.

Altered Fractionation

 * RTOG 71-03 (1971-1979)
 * Randomized. 121 patients. All Stages. Arm 1) split course RT (30/10, 3 week rest, 30/10) vs. Arm 2) 66/33 or 66/30
 * 1980 PMID 6993442 -- "Split-course radiation therapy of carcinoma of the nasopharynx: results of a national collaborative clinical trial of the Radiation Therapy Oncology Group." (Marcial VA, Int J Radiat Oncol Biol Phys. 1980 Apr;6(4):409-14.)
 * 5-year outcome: LC 86% vs. 80% (NS), LRC 86% vs. 78% (NS), DFS 40% vs. 30% (NS)
 * Late toxicity: comparable, except edema worse with continuous RT (42% vs. 24%)
 * Conclusion: No difference between fractionation schedules, less social impact with split course

Concurrent Chemo-RT

 * Hong Kong NPC-9902 (T-disease) (1999-2004)
 * Randomized, 2x2 design. Closed early due to slow accrual. 189 patients, WHO grade II-III, Stage T3-4N0-1 (AJCC-5)(key problem locoregional failure; see companion trial NPC-9901). Arm 1) conventional RT alone vs. Arm 2) accelerated RT vs. Arm 3) conventional RT + concurrent chemo vs. Arm 4) accelerated RT + concurrent chemo. Conventional RT >=66 in 2 Gy/fx, 5 days/week. Accelerated same regimen but 6 days/week. Technique 2D or 3D-CRT or IMRT boost. Concurrent chemo cisplatin 100 mg/m2 q3 weeks, adjuvant chemo cisplatin 80 mg/m2 + 5-FU 1000 mg/m2
 * 3-years; 2006 PMID 16904519 -- "Preliminary results of a randomized study (NPC-9902 Trial) on therapeutic gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal carcinoma." (Lee AW, Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):142-51.). Median F/U 2.9 years
 * Outcome: 3-year FFS RT 70%, AFRT 63%, chemo-RT 74%, chemo-AFRT 94% (SS). On multivariate analysis, concurrent chemo significant, accelerated RT not significant. OS 83%, 73%, 87%, 88% (NS)
 * Toxicity Grade 3-5: Acute: RT 55%, AFRT 70%, chemo-RT 83%, chemo-AFRT 86% (concurrent chemo SS worse). Late: 17%, 21%, 27%, 32% (chemo-AFRT borderline p=0.05 worse). Most late toxicity otologic.
 * Conclusion: Preliminary, concurrent chemo with accelerated fractionation could significantly improve local tumor control


 * Hong Kong NPC-9901 (N-disease) (1999-2004)
 * Randomized. 348 patients, WHO grade II-III, T1-4N2-N3 (AJCC-5)(key problem distant failure; see companion trial NPC-9902). Arm 1) RT alone vs. Arm 2) RT + concurrent cisplatin 100 mg/m2 q3 weeks. RT >= 66 Gy (2D, 3D-CRT or IMRT)
 * 3-years; 2005 PMID 16192584 -- "Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group." (Lee AW, J Clin Oncol. 2005 Oct 1;23(28):6966-75.) Median F/U 2.3 years
 * Outcome: DFS chemo-RT 72% vs. RT alone 62% (SS), LRC 92% vs. 82% (SS), DM 76% vs. 73% (NS), OS 78% vs. 78% (NS)
 * Toxicity: acute chemo-RT 84% vs. RT alone 53% (SS); late 28% vs. 13% (SS), most late toxicity otologic
 * Conclusion: Preliminary, significant benefit for tumor control at the cost of higher toxicity. No early OS benefit


 * Singapore SQNP01 (1997-2003)
 * Randomized. 221 patients, WHO II-III, T3-4 or N2-3 (AJCC-5). Arm 1) RT alone vs. Arm 2) RT + concurrent cisplatin 100 mg/m2 q3 weeks + adjuvant cisplatin 80 mg/m2 + 5-FU 1000 mg/m2 x3 cycles. RT technique 70 Gy primary, 60 Gy neck + 10 Gy electron boost to lymph nodes. 71% patients received all 3 cycles of concurrent chemo
 * 3-years; 2005 PMID 16170180 -- "Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety." (Wee J, J Clin Oncol. 2005 Sep 20;23(27):6730-8.) Median F/U 3.2 years
 * Outcome: 3-year DFS chemo-RT 72% vs. RT 53% (SS); OS 80% vs. 65% (SS); 2-year DM chemo-RT 13% vs. RT alone 30% (SS)
 * Toxicity: Grade 3-5 in 48%, mucositis chemo-RT 48% vs. RT 32% (SS), anorexia 22% vs. 4% (SS), emesis 5% vs. 0% (SS). Also significant hematologic toxicity
 * Conclusion: Confirmation of INT 0099 results; also applicable in endemic NPC


 * Queen Mary Hospital, Hong Kong (1995-2001)
 * Randomized, 2x2 design (concurrent chemo vs. none, adjuvant chemo vs. none). Ho's Stage T3 or N2-3 or LN >=4 cm (AJCC 6th II-IV). Arm 1) RT alone vs. Arm 2) concurrent chemo-RT vs. Arm 3) RT + adjuvant chemo vs. Arm 4) concurrent chemo-RT + adjuvant RT. Concurrent chemo was FU prodrug uracil/tegafur, adjuvant chemo was cisplatin/5-FU and vincristine/bleomycin/MTX x3+3 cycles. RT 1995-1997 62.5/25 split course with 1 week break; 1997-2001 68/34 primary and 66/33 neck. If parapharyngeal extension or residual disease, 10 Gy boost
 * 3-years; 2004 PMID 15226332 -- "Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study." (Kwong DL, J Clin Oncol. 2004 Jul 1;22(13):2643-53.)
 * Outcome: 3-year concurrent CRT vs. RT alone FFS 69% vs. 58% (NS), OS 86% vs. 77% (p=0.06), LRC 80% vs. 72% (NS), DM 15% vs. 29% (SS). 3-year adjuvant chemo vs. none FFS 62% vs. 65% (NS), OS 80% vs. 83% (NS), no difference on LRC or DM.
 * Conclusion: Trend to improvement with concurrent chemo-RT over RT alone (p=0.06), no benefit to adjuvant chemo


 * Prince of Wales Hospital / Queen Elizabeth Hospital, Hong Kong (1994-1999)
 * Randomized. 350 patients, Ho's Stage N2-3 or N1 with LN >=4 cm (AJCC-6 Stage II-IVB). Arm 1) RT with concurrent cisplatin 40 mg/m2 q week vs. Arm 2) RT alone. RT 66 Gy, parapharyngeal boost 10-20 Gy allowed. Primary end point PFS
 * 2-years; 2002 PMID 11956263 -- "Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial." (Chan AT, J Clin Oncol. 2002 Apr 15;20(8):2038-44.) Median F/U 2.7 years
 * Outcome: 2-year PFS chemo-RT 76% vs. RT alone 69% (NS). Subgroup analysis benefit for Ho's T3
 * Conclusion: Concurrent chemo-RT well tolerated, but no benefit
 * 5-years; 2005 PMID 15812080 -- "Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma." (Chan AT, J Natl Cancer Inst. 2005 Apr 6;97(7):536-9.) Median F/U 5.5 years
 * Outcome: 5-year OS chemo-RT 70% vs. RT 59% (p=0.07). Subgroup analysis no benefit for T1-2, but benefit for T3-4 (HR 0.51)
 * Conclusion: Trend for survival benefit; promising treatment strategy


 * Taiwan (1993-1999)
 * Randomized. 284 patients, NPC Stage III-IV M0, histology WHO I (3%), WHO II (73%), WHO III (24%). Arm 1) RT 70-74 Gy alone vs. Arm 2) concurrent cisplatin 20 mg/m2 + 5-FU 400 mg/m2 during week 1 and 5. RT: CTV = GTV+2cm, included entire base of skull, sphenoid sinus, 2cm beyond mastoid process, posterior half of maxillary sinus/nasal cavity. Dose 70-74 Gy primary tumor and LN+, 50-60 Gy N0 neck. Chemo completed by 94% patients
 * 5-years; 2003 PMID 12586799 -- "Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival." (Lin JC, J Clin Oncol. 2003 Feb 15;21(4):631-7.). Median F/U 5.4 years
 * 5-year outcome: PFS RT alone 53% vs. chemo-RT 72% (SS); OS 54% vs. 72% (SS)
 * Toxicity Grade 3-4: mucositis 35% vs. 45%, skin 26% vs. 35%
 * Conclusion: Concurrent chemo-RT superior to RT alone for advanced NPC
 * Re-analysis; 2004 PMID 15337551 -- "Another way to estimate outcome of advanced nasopharyngeal carcinoma--is concurrent chemoradiotherapy adequate?" (Lin JC, Int J Radiat Oncol Biol Phys. 2004 Sep 1;60(1):156-64.)
 * Original (AJCC 1992) stage: Stage III 20%, Stage IV 80%. Restaged (AJCC 1997): Stage II/III 71%, Stage IV 29%. New risk definition: high-risk (LN >6cm or SCV LN or AJCC 1992 T4N2 or multiple LN mets with 1 LN >4cm) 42% vs. low-risk 58%
 * Low-risk group (chemo-RT vs. RT): LC 95% vs. 77% (SS), neck control 100% vs. 96% (NS), DM 90% vs. 78% (SS), PFS 87% vs. 61% (SS), OS 83% vs. 60% (SS). Chemo-RT significantly better
 * High-risk group (chemo-RT vs. RT): LC 75% vs. 68% (NS), neck control 92% vs. 87% (NS), DM 60% vs. 60% (NS), PFS 44% vs. 43% (NS), OS 56% vs. 46% (NS). No difference with concurrent chemo
 * Conclusion: Concurrent chemo-RT superior for low-risk patients, but inadequate for high-risk patients


 * Intergroup 0099 / RTOG 88-17 (1989-1995)
 * Randomized. Trial stopped early due to significant survival benefit. 147 patients. NPC Stage III-IV (Stage IV 91%; but also included few N1 patients, which are IIB today), histology WHO I (25%), WHO II (35%), WHO III (41%). Arm 1) RT 70 Gy alone vs RT 70 Gy with concurrent cisplatin 100 mg/m2 q3 weeks and adjuvant cisplatin + 5-Fu . CT-based treatment planning. Fields: included 2 cm margin on gross disease and included entire base of skull and sphenoid sinus, 2 cm posterior to mastoid process; anteriorly included posterior 1/3 of maxillary sinus and nasal cavity. Dose: 70 Gy to primary. For neck to clavicle, 50 Gy for N0 disease, 66 Gy for nodes <= 2 cm, and 70 Gy for nodes > 2 cm. Cisplatin given every 3 weeks at 100 mg/m2 x 3 cycles. Then adjuvant chemo began 4 weeks after finishing RT: cisplatin 80 mg/m2 and 5-FU 1000 mg/m2/d by 96-hr infusion q4w x 3 cycles. Partial or radical neck dissections for persistent neck disease. Chemo completed by 55%
 * 1998 PMID 9552031 - "Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099." Al-Sarraf et al. J Clin Oncol. 1998 Apr;16(4):1310-7. Median F/U 2.7 years
 * 3-year outcome: PFS chemo-RT 69% vs. RT alone 24% (SS); OS 78% vs 47% (SS). Median OS not reached for chemo-RT vs. 2.5 years for RT alone.
 * Toxicity Grade 3-4: stomatitis 29% vs. 19%, nausea 14% vs. 5%, leukopenia 23% vs. 1%
 * Conclusion: Concurrent chemo-RT superior to RT alone for advanced NPC
 * Comment: First randomized trial to show a survival benefit for the use of concurrent chemo, unexpectedly low RT alone outcome (several retrospective series showed >70% OS with RT alone in endemic patients), RT technique considered less aggressive than that practiced in Asia (particularly lack of parapharyngeal and intracavitary boost), not applicable to non-US patients

Concurrent RT + biologics

 * Beijing Hospital, China (2001-2003) -- RT +/- recombinant adenovirus-p53
 * Randomized. 82 patients with NPC. Arm 1) RT 70/35 alone vs. Arm 2) RT + recombinant adenovirus-p53 (rAd-p53) injected intratumorally QW x8
 * 2008 PMID 19103729 -- "Effect of Recombinant Adenovirus-p53 Combined With Radiotherapy on Long-Term Prognosis of Advanced Nasopharyngeal Carcinoma." (Pan JJ, J Clin Oncol. 2008 Dec 22. [Epub ahead of print]) Median F/U 5.1 years
 * Outcome: p53 mRNA detected in 94% postinjection biopsies, with upregulation of p21 and Bax. 5-year LRF RT 28% vs RT + rAd-p53 3% (SS); 5-year DFS 57% vs. 67% (NS); 5-year OS 59% vs. 67% (NS)
 * Toxicity: Transient fever after rAd-p53 administration
 * Conclusion: rAd-p53 was safe and biologically active, and improves tumor control and survival rate

Induction chemo-RT vs. RT alone

 * Pooled long-term AOCOA/Guangzhou data (1989-1994)
 * Pooled data from 2 similar PIII trials comparing induction chemo-RT vs. RT alone. 784 patients. Induction cisplatin, bleomycin, 5-FU or cisplatin, epirubicin. RT 70 Gy. Median F/U 5.6 years
 * 5-years; 2005 PMID 15657403 -- "Long-term survival after cisplatin-based induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of two phase III trials." (Chua DT, J Clin Oncol. 2005 Feb 20;23(6):1118-24.)
 * Outcome: 5-year DFS induction chemo 63% vs. RT 58% (SS), OS 62% vs. 58% (NS). LRF decreased by 18%, DM decreased by 13%, but no significant difference in failure patterns
 * Conclusion: Induction chemo-RT modest decrease in DFS, but no impact on OS. Concurrent chemo-RT should remain standard of care


 * Guangzhou (1993-1994) - cisplatin, 5-FU, bleomycin
 * Randomized. 456 patients. Chinese stage III-IV M0. Arm 1) RT alone vs. Arm 2) Neoadjuvant cisplatin 100 mg/m2, bleomycin 10 mg/m2, and 5-FU 800 mg/m2 x2-3 cycles, followed by RT within 2 weeks. RT 68-72 Gy primary tumor, involved neck 60-62 Gy, uninvolved neck 60 Gy. If residual tumor after RT, could boost 10-14 Gy EBRT or 20-24 Gy HDR in 4-5 fractions
 * 5-years; 2001 PMID 11230478 -- "Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma." (Ma J, J Clin Oncol. 2001 Mar 1;19(5):1350-7.)
 * Outcome: 5-year OS induction chemo 63% vs. RT alone 56% (NS); RFS 59% vs. 49% (SS); LRC 82% vs. 74% (p=0.05); no difference on DM
 * Conclusion: No survival benefit for induction chemotherapy


 * Hokkaido RTOG (1991-1998) -- cisplatin, 5-FU
 * Randomized. 80 patients. Stage I-IV M0. Arm 1) RT alone vs. Arm 2) Neoadjuvant cisplatin 80 mg/m2, 5-FU 800 mg/m2 q3 weeks x2 cycles. RT 66-68 Gy to primary tumor and LN+, 50 Gy to negative LNs
 * 5-years; 2002 PMID 12001120 -- "A prospective, randomized trial comparing neoadjuvant chemotherapy with radiotherapy alone in patients with advanced nasopharyngeal carcinoma." (Hareyama M, Cancer. 2002 Apr 15;94(8):2217-23.). Median F/U 4.1 years
 * Outcome: 5-year OS induction chemo 60% vs. RT alone 48% (NS); DFS 55% vs. 43% (NS). No difference in LRC; most patients experienced LR failure before DM failure
 * Conclusion: Neoadjuvant chemo didn't improve DFS or OS


 * Asian-Oceanic Clinical Oncology Association (AOCOA) (1989-1993) -- cisplatin, epirubicin
 * Randomized. 286 patients. Ho's staging T3 or N2-N3 disease or LN+ >= 3cm. Arm 1) neoadjuvant cisplatin 60 mg/m2 + epirubicin 110 mg/m2 x2-3 cycles followed by RT vs. Arm 2) RT alone. RT dose 66-74 Gy (median 71 Gy) to primary tumor, 60-76 Gy (median 66 Gy) to neck.
 * 3-years; 1998 PMID 9840526 -- "Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Asian-Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group." (Chua DT, Cancer. 1998 Dec 1;83(11):2270-83.). Median F/U 2.5 years
 * Outcome: 3-year RFS induction chemo 48% vs. RT 42% (NS); OS 78% vs. 71% (NS)
 * Conclusion: No benefit for induction chemo


 * International Nasopharynx Cancer Study Group: VUMCA I (1989-1993) -- cisplatin, epirubicin, bleomycin
 * Randomized. 339 patients. Undifferentiated carcinoma (WHO 2 or 3), any T stage, N2-3, M0. Arm 1) RT 70 Gy alone vs. Arm 2) induction BEC (bleomycin, epirubicin, cisplatinum) q3 weeks x 3 cycles followed by RT.
 * 1996 PMID 8655368 &mdash; "Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival." (No Authors, Int J Radiat Oncol Biol Phys. 1996 Jun 1;35(3):463-9.) Median F/U 4.1 years
 * Toxicity: treatment-related deaths RT alone 1% vs chemo->RT 8%
 * Outcome: 2-year DFS RT alone 40% vs. chemo->RT 60% (per graph), no difference in LRC. No difference in OS.
 * Conclusion: BEC chemotherapy improves DFS, no impact on OS


 * Hong Kong (1988-1991) -- cisplatin, 5-FU
 * Randomized. 82 patients. Ho's classification N3 or LN+ >4 cm. Arm 1) Neoadjuvant cisplatin 100 mg/m2 + 5-FU 1000 mg/m2, 4 weeks later RT 66 Gy with lower neck to 58 Gy, then 4 cycles of adjuvant chemo vs. Arm 2) RT alone. Could boost residual disease after RT to 18-24 Gy in 3 fractions with Ir-192 HDR
 * 2-years; 1995 PMID 7558945 &mdash; "A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma." (Chan AT, Int J Radiat Oncol Biol Phys. 1995 Oct 15;33(3):569-77.) Median F/U 2.4 years
 * Outcome: 2-year DFS chemo-RT 68% vs. RT alone 72% (NS); OS 80% vs. 80% (NS); no difference in LRC, DM, or time-to-relapse
 * Conclusion: No benefit for sequential chemo-RT

Adjuvant chemo after RT

 * Hong Kong (1995-2001)
 * Randomized, 2x2 design (concurrent chemo vs. none, adjuvant chemo vs. none). Ho's Stage T3 or N2-3 or LN >=4 cm (AJCC 6th II-IV). Arm 1) RT alone vs. Arm 2) concurrent chemo-RT vs. Arm 3) RT + adjuvant chemo vs. Arm 4) concurrent chemo-RT + adjuvant RT. Concurrent chemo was FU prodrug uracil/tegafur, adjuvant chemo was cisplatin/5-FU and vincristine/bleomycin/MTX x3+3 cycles. RT 1995-1997 62.5/25 split course with 1 week break; 1997-2001 68/34 primary and 66/33 neck. If parapharyngeal extension or residual disease, 10 Gy boost
 * 3-years; 2004 PMID 15226332 -- "Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study." (Kwong DL, J Clin Oncol. 2004 Jul 1;22(13):2643-53.)
 * Outcome: 3-year concurrent CRT vs. RT alone FFS 69% vs. 58% (NS), OS 86% vs. 77% (p=0.06), LRC 80% vs. 72% (NS), DM 15% vs. 29% (SS). 3-year adjuvant chemo vs. none FFS 62% vs. 65% (NS), OS 80% vs. 83% (NS), no difference on LRC or DM.
 * Conclusion: Trend to improvement with concurrent chemo-RT over RT alone (p=0.06), no benefit to adjuvant chemo


 * Taiwan COG (1994-1999) -- observation vs. cisplatin/5-FU/leucovorin
 * Randomized. 154 patients. Stage IV M0 (AJCC 1992). Arm 1) RT 70-72 Gy vs. Arm 2) weekly cisplatin 20 mg/m2, 5-FU 2200 mg/m2, leucovorin 120 mg/m2 x9 weeks
 * 5-years; 2002 PMID 11955734 -- "A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients." (Chi KH, Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1238-44.) Median F/U 4.1 years
 * Outcome: 5-year OS RT alone 60% vs. adjuvant chemo 50% (NS), RFS 54% vs. 54% (NS)
 * Toxicity: No Grade 3+ mucositis; Grade 3+ leukopenia 2%
 * Conclusion: Adjuvant chemo after RT offers no benefit for OS or RFS


 * Italian NRC (1979-83) -- observation vs. vincristine/cyclophosphamide/adriamycin
 * Randomized. 229 NPC patients, T1N1-T4N3. Complete remission after RT, then Arm 1) observation vs. Arm 2) VCA (vincristine, cyclophosphamide, adriamycin) x 6 monthly cycles. RT 60-70 Gy to primary tumor, base of skull, and involved nodes, negative LN 50 Gy (frequently split course over 8-10 weeks)
 * 4-years; 1988 PMID 3047335 &mdash; "Adjuvant chemotherapy with vincristine, cyclophosphamide, and doxorubicin after radiotherapy in local-regional nasopharyngeal cancer: results of a 4-year multicenter randomized study." (Rossi A et al. J Clin Oncol. 1988 Sep;6(9):1401-10.)
 * Outcome: 4-year RFS observation 56% vs. chemo 58% (NS), no difference in OS; Similar pattern of failure with distant mets in about 50% who failed.
 * Toxicity: mild to moderate in most patients
 * Conclusion: No benefit for adjuvant VCA chemo
 * Comment: more patients at low risk for distant failure; less active chemo combination

Altered Fractionation

 * RTOG 71-02 (1971-1976) -- BOT continuous vs. split-course
 * Randomized. 141 patients, base of tongue. Arm 1) Split course 30/10 + 30/10 vs. Arm 2) Continuous 66/30
 * 1983 PMID 6343309 -- "Split-course radiation therapy of carcinoma of the base of the tongue: results of a prospective national collaborative clinical trial conducted by the Radiation Therapy Oncology Group." (Marcial VA, Int J Radiat Oncol Biol Phys. 1983 Apr;9(4):437-43.)
 * Outcome: LC split course 48% vs. continuous 41% (NS), Neck control 48% vs. 45% (NS), LRC 38% vs. 37% (NS), median OS 1.2 years vs. 1.1 years (NS)
 * Toxicity: Severe toxicity split course 43% vs. continuous 35%; significant hospitalization split course 14% vs. continuous 21%
 * Conclusion: No difference


 * RTOG 71-01 (1971-1976) -- Tonsil continuous vs. split-course
 * 1993 PMID 8213620 -- ""Compensated" split-course versus continuous radiation therapy of carcinoma of the tonsillar fossa. Final results of a prospective randomized clinical trial of the Radiation Therapy Oncology Group." (Marcial VA, Am J Clin Oncol. 1993 Oct;16(5):389-96.)
 * Randomized. 137 patients. All stages, no adenoCA. Arm 1) split course RT 30/10 + 30/10 vs. Arm 2) continuous RT 60/30-66/33
 * Outcome: 5-year LRC split course 25% vs. continuous 28% (NS); 5-year OS 19% vs. 29% (NS)
 * Late toxicity: split course 17% vs. continuous 24% (NS)
 * Conclusion: No difference

Field Size

 * Osaka (Japan)(1982-1992) -- RT 5x5 cm vs. RT 6x6 cm
 * Randomized. 273 patients with T1N0 glottic cancer, treated with RT 4 MV bilateral portals. Arm 1) field size 5x5 cm vs. Arm 2) field size 6x6 cm. Dose 60/30
 * 5-years; 1996 PMID 8721266 -- "Radiation therapy for early glottic carcinoma (T1N0M0). The final results of prospective randomized study concerning radiation field." (Chatani M, Strahlenther Onkol. 1996 Mar;172(3):169-72.)
 * Outcome: 5-year RFS 5x5 88% vs 6x6 88% (NS)
 * Toxicity: acute toxicity same (NS); late toxicity 5x5 17% vs. 6x6 23% (SS)
 * Conclusion: Small field (5x5 cm) is recommended

Fractionation

 * Osaka (Japan)(1993-2001) -- RT 2 Gy/fx vs. RT 2.25 Gy/fx
 * Randomized. 180 patients with glottic T1N0. Arm 1) RT 60/30 (small tumors) or 66/33 (large tumors) @ 2 Gy/fx vs. Arm 2) RT 56.25/25 (small tumors) or 63/28 (large tumors) @ 2.25 Gy/fx. Parallel opposed fields with individualized wedge-filtered technique, majority 5x5 cm
 * 5-years; 2006 PMID 16169681 -- "Radiotherapy for early glottic carcinoma (T1N0M0): results of prospective randomized study of radiation fraction size and overall treatment time." (Yamazaki H, Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):77-82. Epub 2005 Sep 19.)
 * Outcome: 5-year LC 2 Gy/fx 77% vs. 2.25 Gy/fx 92% (SS); CSS 97% vs. 100% (NS)
 * Late Toxicity: no severe late toxicity, no difference in early/minor late toxicity
 * Conclusion: Use of 2.25 Gy/fx with shorter overall treatment time showed superior local control compared to conventional 2 Gy/fx, without worse toxicity

Chemo-RT

 * EORTC 24954 (1996-2004) -- Sequential chemo-RT vs. alternating chemo-RT
 * Randomized. 450 patients. Larynx T2-T4 N0-N2 or Hypopharynx T2-T4 N0-N2, surgical candidates for total laryngectomy not requiring flap closure. Excluded if candidates for partial laryngectomy. Arm 1) Sequential chemo->RT. Induction cisplatin 100 mg/m2 + 5-FU 1000 mg/m2 x4 cycles followed by RT 70 Gy; if stable/progression on chemo, total laryngectomy vs Arm 2) Alternating chemo->RT. Cisplatin 20 mg/m2 + 5-FU 200 mg/m2 x1 week -> RT 20 Gy -> cisplatin/5-FU x1 week -> RT 20 Gy -> cisplatin/5-FU x1 week
 * 2009 PMID 19176454 -- "Phase 3 Randomized Trial on Larynx Preservation Comparing Sequential vs Alternating Chemotherapy and Radiotherapy." (Lefebvre JL, J Natl Cancer Inst. 2009 Jan 27. [Epub ahead of print]) Median F/U 6.5 years
 * Outcome: Larynx preservation sequential 1.6 years vs. 2.3 years (NS); 5-year larynx preservation 30% vs. 36% (NS). Median OS sequential 4.4 years vs. alternating 5.1 years (NS); median PFS 3.0 vs 3.1 years (NS). Salvage surgery sequential 30% vs. alternating 22%. No difference in patterns of relapse
 * Toxicity: Grade 3-4 mucositis sequential 32% vs. alternating 21%; late fibrosis 16% vs. 11%
 * Conclusion: Both strategies valid for larynx preservation
 * Comment: larynx preservation defined as larynx without tumor, tracheotomy or use of feeding tube

Postoperative

 * GETTEC (1986-1989) -- total laryngectomy + postop RT vs induction chemo + RT
 * Randomized. Trial stopped prematurely because patients refused laryngectomy. 68 patients. Larynx, T3N0-N2b. Supraglottic larynx or resectable disease not eligible. Arm 1) Total laryngectomy, if N0 then modified neck dissection, if N+ then radical neck dissection followed by post-op RT. Postop RT 50 Gy if SM- and LN-; else 65-70 Gy vs. Arm 2) Induction chemo cisplatin 100 mg/m2 + 5-FU 1000 mg/m2 Q3W x3 cycles, followed by RT 65-70 Gy (36%). If tumor progression on chemo, received total laryngectomy (55%)
 * 1998 PMID 9692058 -- "Randomized trial of induction chemotherapy in larynx carcinoma." (Richard JM, Oral Oncol. 1998 May;34(3):224-8.) Median F/U 8.3 years
 * Outcome: Induction 55% progressed and required laryngectomy. 2-year OS induction 69% vs. laryngectomy 84% (SS)
 * Conclusion: Larynx preservation cannot be considered a standard treatment at the present time

Hypopharynx

 * France (2001-2005) -- Induction chemo-RT vs. concurrent chemo-RT
 * Randomized. 75 patients, T3 pyriform sinus (N0-N3). 4 centers. Arm 1) concurrent chemo-RT. Chemo cisplatin 100 mg/m2 Q3W, RT 70 Gy vs. Arm 2) induction chemo cisplatin 100 mg/m2 + 5-FU 100 mg/m2 x2 courses. If CR/PR >80%, RT 70 Gy, else total laryngectomy
 * 2009 PMID 19449227 -- "Randomized phase III trial comparing induction chemotherapy followed by radiotherapy to concomitant chemoradiotherapy for laryngeal preservation in T3M0 pyriform sinus carcinoma." (Prades JM, Acta Otolaryngol. 2009 May 15:1-6.) Median F/U 2 years
 * Outcome: 2-year laryngeal preservation concurrent 92% vs induction 68% (SS). Local control 81% vs. 62%. Distant mets 19% vs 38%. EFS 36% vs. 41% (NS). 2-year OS 47% vs. 51% (NS)
 * Toxicity: any toxicity 76% vs 71%
 * Conclusion: Concurrent chemo-RT superior to sequential chemo-RT


 * EORTC 24954 (1996-2004) -- Sequential chemo-RT vs. alternating chemo-RT
 * Randomized. 450 patients. Larynx T2-T4 N0-N2 (21% by AJCC staging) or Hypopharynx T2-T4 N0-N2 (79% by AJCC staging), surgical candidates for total laryngectomy not requiring flap closure. Excluded if candidates for partial laryngectomy. Arm 1) Sequential chemo->RT. Induction cisplatin 100 mg/m2 + 5-FU 1000 mg/m2 x4 cycles followed by RT 70 Gy; if stable/progression on chemo, total laryngectomy vs Arm 2) Alternating chemo->RT. Cisplatin 20 mg/m2 + 5-FU 200 mg/m2 x1 week -> RT 20 Gy -> cisplatin/5-FU x1 week -> RT 20 Gy -> cisplatin/5-FU x1 week (based on prior Italian randomized data)
 * 6-years; 2009 PMID 19176454 -- "Phase 3 Randomized Trial on Larynx Preservation Comparing Sequential vs Alternating Chemotherapy and Radiotherapy." (Lefebvre JL, J Natl Cancer Inst. 2009 Jan 27. [Epub ahead of print]) Median F/U 6.5 years
 * Outcome: Larynx preservation sequential 1.6 years vs. 2.3 years (NS); 5-year larynx preservation 30% vs. 36% (NS). Median OS sequential 4.4 years vs. alternating 5.1 years (NS); median PFS 3.0 vs 3.1 years (NS). DSS ~50%. Salvage surgery sequential 30% vs. alternating 22%. No difference in patterns of relapse
 * Toxicity: Grade 3-4 mucositis sequential 32% vs. alternating 21%; late fibrosis 16% vs. 11%
 * Conclusion: Both strategies valid for larynx preservation
 * Editorial (PMID 19176460): larynx preservation defined as survival with larynx without tumor, tracheotomy or use of feeding tube, which gives these states equal utility as death; other issues with endpoints used for larynx preservation. Need a common standardized endpoint


 * EORTC 24891 (1990-1993) - Surgery + post-op RT vs Induction cisplatin/5-FU + RT
 * Randomized. 194/202 patients. Operable SCC of the pyriform sinus or AE fold, Stage T2-T4 N0-N2b, N3 (N2c initially allowed, stopped in 1992). Arm 1) Immediate surgery + post-op RT 50-70 Gy vs. Arm 2) Induction cisplatin 100 mg/m2 + 5-FU 1000 mg/m2 x2 cycles. If CR, then RT 70 Gy. If PR, then cisplatin/5-FU x another cycle. If CR, then RT 70 Gy. If PR, or PD anytime, then surgery. RT given 50 Gy bilateral neck + 20 Gy boost to tumor/palpable LNs. Surgery was total laryngectomy with partial pharyngectomy to allow primary closure
 * 10-years; 2004 ASCO Abstract -- "Is laryngeal preservation (LP) with induction chemotherapy (ICT) safe in the treatment of hypopharyngeal SCC? Final results of the phase III EORTC 24891 trial." (Lefebvre JL, Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 5531) Median F/U 10 years
 * Outcome: 5-year OS surgery 33% vs. chemo-RT 38%; 10-year OS 14% vs. 13%. 5-year PFS 26% vs. 32%. Larynx preservation 5-years 22% (58% survivors), 10-years 9% (69% survivors)
 * Conclusion: Similar survival curves with larynx preservation as with conventional total laryngectomy, with 2/3 survivors retaining their larynx

Salivary Glands

 * RTOG-MRC Neutron Trial -- neutrons vs. photons/electrons
 * Randomized. Stopped early due to neutron advantage. 32 patients, inoperable or recurrent major or minor salivary gland tumors. Arm 1) Neutrons (17-22 nGy) vs. Arm 2) photon/electrons (55 Gy/4 weeks or 70 Gy/7.5 weeks)
 * Final; 1993 PMID 8407397 -- "Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial." (Laramore G, Int J Radiat Oncol Biol Phys. 1993 Sep 30;27(2):235-40)
 * Outcome: 10-year LRC neutrons 56% vs. photons/electrons 17% (SS); OS 25% vs. 15% (NS). Median OS 3 years vs. 1.2 years
 * Toxicity: Severe toxicity worse in neutron arm, but no difference in "life-threatening" complications
 * Conclusion: Fast neutron RT appears to be the treatment of choice for patients with inoperable/recurrent salivary gland tumors

Surgery + Chemo-RT

 * GETTC/GORTEC (1999-2005) -- salvage surgery +/- reirradiation + chemotherapy
 * Randomized. 130 patients, H&N cancer, either recurrence or second primary in a previously irradiated area, no major sequelae. Treated with R0-R1 surgery. Arm 1) adjuvant salvage chemotherapy + re-irradiation vs. Arm 2) observation. RT given 60 Gy over 11 weeks with concurrent 5-FU and hydroxyurea
 * 2008 PMID 18936479 -- "Randomized Trial of Postoperative Reirradiation Combined With Chemotherapy After Salvage Surgery Compared With Salvage Surgery Alone in Head and Neck Carcinoma." (Janot F, J Clin Oncol. 2008 Oct 20. [Epub ahead of print])
 * Outcome: DFS improved (HR 1.68, SS), OS no difference
 * Late toxicity: 2-years Grade 3-4 RT arm 39% vs. observation arm 10% (p=0.06)
 * Conclusion: Full-dose reirradiation combined with chemo after salvage surgery significantly improved DFS but not OS. Toxicity was higher

Chemo Alone

 * EXTREME (2004-2005) -- Chemotherapy (cisplatin or carbo/5-FU) +/- cetuximab
 * Randomized. 442 patients with recurrent or metastatic SCC of H&N. Arm 1) chemotherapy (cisplatin 100 mg/m2 or carbo AUC 5 + 5F-FU 1000 mg/m2) x6 cycles vs. Arm 2) same chemotherapy + cetuximab 250 mg/m2 x6 cycles. If stable disease, cetuximab until disease progression or toxicity
 * 2008 PMID 18784101 -- "Platinum-based chemotherapy plus cetuximab in head and neck cancer." (Vermorken JB, N Engl J Med. 2008 Sep 11;359(11):1116-27.)
 * Outcome: Median OS chemo 7 months vs. chemo+cetuximab 10 months (SS)
 * Toxicity: Grade 4 comparable except sepsis worse in cetuximab arm
 * Conclusion: Cetuximab + platinum chemotherapy improved overall survival compared with chemotherapy alone

Setup

 * Princess Margaret (2006-2008) -- standard immobilization mask vs skin-sparing immobilization mask
 * Randomized. 762 CBCT scans in 20 patients. Arm 1) standard mask (SM) vs Arm 2) skin-sparing mask (SSM) modified with low neck cutouts
 * 2010 PMID 20056344 -- "Cone-beam CT assessment of interfraction and intrafraction setup error of two head-and-neck cancer thermoplastic masks." (Velec M, Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3):949-55. Epub 2010 Jan 7.)
 * Outcome: Initial interfraction sigma SM 1.6 mm or 1.1 degrees vs SSM 2.0 mm and 0.8 degrees. No difference after CBCT correction. Initial intrafraction sigma <1 mm and <1 degree for both masks.
 * Conclusion: Interfraction and intrafraction setup error not significantly different between masks. Mask cutouts should be considered to reduce skin toxicity


 * Karolinska Hospital (Sweden)(1998-2001) -- head mask vs head-and-neck mask setup
 * Randomized. 241/260 patients. H&N cancers excluding NPC. Arm 1) Head mask vs. Arm 2) Head-and-shoulder mask. Both Posicast thermoplastic masks. Assessed reproducibility (port films and table positions), patient tolerability (fit, pain, movement within, claustrophobia), and skin damage
 * 2005 PMID 15629618 -- "Randomized trial on two types of thermoplastic masks for patient immobilization during radiation therapy for head-and-neck cancer." (Sharp L, Int J Radiat Oncol Biol Phys. 2005 Jan 1;61(1):250-6.)
 * Outcome: No difference in reproducibility of setup
 * Toxicity: Claustrophobia head mask 45% vs. head-and-shoulder maks 58% (SS), otherwise no difference in tolerability. Skin toxicity Grade 3 head mask 21% vs. head-and-shoulder mask 39% (SS)
 * Conclusion: Smaller head maks reduced claustrophobial and skin reactions, without compromising reproducibility of the setup

IMRT
IMRT salivary function
 * Prince of Wales Hospital; 2007 (Hong Kong)(2001-2003) PMID 17971582 -- "Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients." (Kam MK, J Clin Oncol. 2007 Nov 1;25(31):4873-9.)
 * Randomized. 60 patients with T1-2bN0-1 nasopharynx. Arm 1) IMRT 66 Gy (CTV=GTV + 1cm; at-risk anatomic sites; LN Levels IB-II, LN upper Level V, LN retropharyngeal; PTV=CTV+3mm), lower neck LN+ 66 Gy anterior field, LN- 54-60 Gy + intracavitary BT boostvs. Arm 2) 66 Gy 2D + intracavitary BT boost
 * Outcome: observer-rated severe xerostomia IMRT 39% vs. 2D-RT 82% (SS), stimulated parotid flow (SS), unstimulated parotid flow (SS), but no difference in patient-reported feeling of xerostomia
 * Conclusion: IMRT superior in preserving objective parotid function, but no difference in patient-reported benefit
 * Editorial (PMID 17971579): Observer-rated scoring underestimates patient reports and has low agreement among various observers. Suspect sparing of parotid alone not sufficient. Parotid gland produces saliva without mucins (lubricants, bind water, and provide selective permeability barrier). Mucin-secreting glands (e.g. minor salivary glands, submandibular glands) produce <10% saliva but >50% mucins. May need to spare these glands as well for subjective feeling of benefit


 * Queen Mary Hospital; 2006 (Hong Kong)(2000-2004) PMID 17145528 -- "Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial." (Pow EH, Int J Radiat Oncol Biol Phys. 2006 Nov 15;66(4):981-91.)
 * Randomized. 51 patients, Stage II (T2N0-1, AJCC 1997). Arm 1) conventional RT 68 Gy, neck 66 Gy vs. Arm 2) IMRT, GTV dose 68-72 Gy, PTV 66-68 Gy. Stimulated whole (SWS) and parotid (SPS) saliva flow evaluated, QoL SF-36, EORTC Core, EORTC QLQ-H&N35 questionnaires. Minimum F/U 1 years
 * 1-year outcome: 25% whole flow (SWS) IMRT 50% vs. 2D 5% (SS), 25% parotid flow (SPS) 83% vs. 9% (SS). At 2 months, both group had xerostomia, but IMRT group improved significantly better over time. Also improvements in QoL
 * Conclusion: IMRT significantly better than conventional RT for salivary function and QoL

Middle ear ventilation tube

 * Hong Kong; 2002 PMID 12512893 -- "Randomized evaluation of the audiologic outcome of ventilation tube insertion for middle ear effusion in patients with nasopharyngeal carcinoma." (Ho WK, J Otolaryngol. 2002 Oct;31(5):287-93.)
 * Randomized. ? patients. NPC and middle ear effusion. Arm 1) pre-RT ventilation tube insertion vs. Arm 2) observation. Audiologic assessment throughout. F/U 4 years
 * Outcome: No difference in hearing changes up to 4 years
 * Conclusion: Ventilation tube insertion before RT did not offer hearing benefit

Time of radiation

 * NCIC HN3 -- morning RT vs. afternoon RT
 * Randomized, proof of principle. 205/216 patients, receiving primary or postop RT. Arm 1) morning (8-10 AM) RT vs. Arm 2) afternoon (4-6 PM) RT. Primary outcome mucositis
 * 2008 PMID 18805649 -- "Comparison of Toxicity Associated with Early Morning Versus Late Afternoon Radiotherapy in Patients with Head-and-Neck Cancer: A Prospective Randomized Trial of the National Cancer Institute of Canada Clinical Trials Group (HN3)." (Bjarnason GA, Int J Radiat Oncol Biol Phys. 2008 Sep 19. [Epub ahead of print])
 * Outcome: Grade 3+ mucositis AM RT 53% vs. PM RT 62% (p=0.2). In patients with RT dose 66-70 Gy, 45% vs. 67% (SS). Also longer time-to-mucositis >7.9 weeks vs. 5.6 weeks (SS). Significant benefit in patients who continued to smoke 43% vs. 76% (SS)
 * Conclusion: Morning RT associated with significantly less weight loss, and reduction in oral mucositis in patients getting >=66 Gy

Candidiasis

 * Genoa (Italy)
 * Randomized. 270 patients with H&N tumors. Arm 1) fluconazole 100 mg QD vs. Arm 2) placebo. Starting 6th treatment until end of treatment.
 * 2008 PMID 18419630 -- "Effects of fluconazole in the prophylaxis of oropharyngeal candidiasis in patients undergoing radiotherapy for head and neck tumour: results from a double-blind placebo-controlled trial." (Corvo R, Eur J Cancer Care (Engl). 2008 May;17(3):270-7.)
 * Outcome: candidiasis-free survival improved (SS); time-to-outbreak fluconazole 56 days vs. placebo 47 days; mean duration of RT fluconazole 39.9 days vs. placebo 43.5 days (SS)
 * Toxicity: fluconazole 70% vs. placebo 67% (NS)
 * Conclusion: Prophylaxis with fluconazole significantly reduces rate and improves time to development of oral candidiasis

Mucositis
Antiseptic mouth rinse
 * Complutense University, Spain -- antiseptic mouth rinse vs placebo
 * Randomized. 36 patients, RT for HNC. Arm 1) antiseptic mouth rinse vs Arm 2) placebo
 * 2010 PMID 20173709 -- "Mucositis in irradiated cancer patients: effects of an antiseptic mouthrinse." (Lanzos I, Med Oral Patol Oral Cir Bucal. 2010 Feb 21. [Epub ahead of print])
 * Outcome: No difference in degree of mucositis; 2-week mucositis worse in placebo group
 * Conclusion: Mouth rinse may lead to some improvement

Honey
 * Egypt (2005-2006) -- chemo-RT +/- honey
 * Randomized. 40 patients with H&N cancer, treated with chemo-RT with significant area of oral or oropharynx mucosa in treatment field. Arm 1) topical application of pure natural honey vs. Arm 2) no honey. Evaluated weekly, aerobic cultures and candida colonisation assessed
 * 2008 PMID 18485252 -- "Honey as topical prophylaxis against radiochemotherapy-induced mucositis in head and neck cancer." (Rashad UM, J Laryngol Otol. 2008 May 19:1-6. [Epub ahead of print])
 * Outcome: Grade 3-4 mucositis honey 15% vs. no honey 65% (SS); candidiasis 15% vs. 60% (SS); aerobic pathogens 15% vs. 65% (SS)
 * Conclusion: Prophylaxis with pure natural honey effective in reducing mucositis

Caphosol
 * Tufts -- caphosol + fluoride vs. fluoride alone
 * Randomized. 95 patients undergoing stem cell transplant. Arm 1) Caphosol + fluoride vs. Arm 2) fluoride alone
 * 2003 PMID 12692611 -- "A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation." (Papas AS, Bone Marrow Transplant. 2003 Apr;31(8):705-12.)
 * Outcome: Mucositis days Caphosol 3.7 days vs. control 7.2 days (SS); duration of pain 2.9 vs. 7.7 (SS); morphine dose 34 mg vs. 123 mg, days of morphine 1.3 days vs. 4.0 days (SS); and days to onset of ANC 11.1 days vs. 12.6 days
 * Conclusion: Caphosol is superior to fluoride rinse alone for oral mucositis

Iseganan
 * Multi-National (2000-2001) -- iseganan vs. placebo vs supportive care
 * Randomized, 3 arms. 545 patients with RT for H&N cancer. Arm 1) iseganan solution (microbicidal solution) vs. Arm 2) placebo vs. Arm 3) standard oral care
 * 2004 PMID 14967419 -- "A multinational, randomized phase III trial of iseganan HCl oral solution for reducing the severity of oral mucositis in patients receiving radiotherapy for head-and-neck malignancy." (Trotti A, Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):674-81.)
 * Outcome: No ulcerative mucositis iseganan 9% vs. placebo 9% (NS) vs. supportive care 2% (SS). No difference in mouth pain or difficulty swallowing. Some benefit for nausea
 * Toxicity: No significant difference
 * Conclusion: Iseganan oral solution safe but didn't reduce risk of ulcerative mucositis

Accupuncture

 * South Korea
 * Randomized. 12 patients with H&N cancer and radiation-induced xerostomia. Arm 1) real acupuncture vs. Arm 2) sham acupuncture BIW x 6 weeks. Measured whole stimulated and unstimulated salivary flow rate, and questionnaire at 3 and 6 weeks after acupuncture
 * 2008 PMID 18532895 -- "Manual Acupuncture Improved Quality of Life in Cancer Patients with Radiation-Induced Xerostomia." (Cho JH, J Altern Complement Med. 2008 Jun 4. [Epub ahead of print])
 * Outcome: Whole salivary flow rate: no difference. Unstimulated flow rate: acupuncture significantly better. Subjective: acupuncture significantly less xerostomia
 * Conclusion: Significantly improved amelioration of subjective xerostomia

Feeding tube

 * Peter MacCallum Cancer Centre (Australia) -- NGT vs PEG tube
 * Randomized. Closed early due to poor accrual. 33/150 patients, H&N cancer planned for curative RT, 'anticipated to require enteral feeding' (whole oral cavity RT, AHFX, CRT, >10% weight loss). Arm 1) percutaneous endoscopic gastrostomy (PEG) tube vs. Arm 2) nasogastric (NGT) tube. Criteria for insertion: intake <50% of calculated daily nutritional requirement and/or >5kg weight loss from start of treatment
 * 2008 PMID 19032398 -- "Randomized study of percutaneous endoscopic gastrostomy versus nasogastric tubes for enteral feeding in head and neck cancer patients treated with (chemo)radiation." (Corry J, J Med Imaging Radiat Oncol. 2008 Oct;52(5):503-10.)
 * Outcome: No difference in absolute weight, upper arm circumference at 6 weeks post treatment. No difference in weight loss at 6 months. Median duration of use PEG 4.6 months vs. NGT 2.2 months (SS)
 * Toxicity: No difference in G3 dysphagia. PEG site infections 27%, NGT dislodgement 61%. No difference in chest infection. QoL overall no difference, but more pain with PEG (SS), more inconvenience with NGT (SS), more altered body image with NGT (SS) during first week. No difference at removal.
 * Cost: NGT $76 vs. PEG $736
 * Conclusion: No evidence to support routine use of PEG tubes over NGT

Hyperbaric Oxygen

 * Erasmus Medical Center (2006-2007) -- RT +/- HBO
 * Randomized. Trial stopped prematurely due to slow accrual and lack of financial support. 19 of expected 132 patients, oropharynx or nasopharynx. Standard RT, then Arm 1) HBO vs. Arm 2) control. HBO given in 30 sessions @ 2.5 ATA x 90 minutes, started within 2 days after RT completion. Primary outcome toxicity
 * 2009 PMID 19386439 -- "Early hyperbaric oxygen therapy for reducing radiotherapy side effects: early results of a randomized trial in oropharyngeal and nasopharyngeal cancer." (Teguh DN, Int J Radiat Oncol Biol Phys. 2009 Nov 1;75(3):711-6. Epub 2009 Apr 20.)
 * Outcome: Significant improvement in QoL for HBO, particularly swallowing, stickly saliva, xerostomia, and pain in mouth
 * Conclusion: HBO after RT results in better quality of life