# Radiation Oncology/Head & Neck/Post-op

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Postoperative RT

## Surgical Technique

* No universally accepted definition of "resectable" vs "unresectable" tumor
* Lymph node dissection classification (PMID 12117328)

### Classification of Neck Dissection

** Radical neck dissection: all ipsilateral cervical LN groups from inferior border of mandible superiorly to clavicle inferiorly and from lateral border of sternohyoid muscle/hyoid bone/contralateral anterior belly of digastric muscle anteriorly to anterior border of trapezius posteriorly. All lymph nodes from Level I - V. Spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscles are removed. No removal of suboccipital, periparotid, buccal, retropharyngeal, and paratracheal lymph nodes
** Modified radical neck dissection: excision of all lymph nodes routinely removed by radical neck dissection with preservation of one or more nonlymphatic structures, ie, spinal accessory nerve, internal jugular vein, and/or sternocleidomastoid muscle.
** Selective neck dissection (SND): cervical lymphadenectomy with preservation of 1 or more of the lymph node groups that are routinely removed in the radical neck dissection. The lymph node groups removed are based on the patterns of metastases, which are predictable relative to the primary site of disease
*** Supraomohyoid neck dissection: SND I-III. Oral cavity cancers. In case of oral tongue, some recommend SND I-IV. For cancers involving midline, bilateral SND I-III
*** Lateral neck dissection: SND II-IV. Oropharyngeal, hypopharyngeal, and laryngeal cancers. If retropharyngeal LNs, they can be dissected as well
*** Posterolateral neck dissection: SND II-V. Cutaneous melanoma
*** Anterior neck dissection: SND VI. Thyroid, larynx, hypopharynx
** Extended neck dissection: removal of 1 or more additional lymph node groups or nonlymphatic structures, or both, not encompassed by the radical neck dissection. Examples of lymph node groups include the parapharyngeal (retropharyngeal), superior mediastinal, perifacial (buccinator), and paratracheal lymph nodes. Examples of nonlymphatic structures include the carotid artery, hypoglossal nerve, vagus nerve, and paraspinal muscles.

### Selective neck dissection

* Goettingen, Germany, 2001 (1986-1997) PMID 11226954 -- "Efficacy of selective neck dissection: a review of 503 cases of elective and therapeutic treatment of the neck in squamous cell carcinoma of the upper aerodigestive tract." (Ambrosch P, Otolaryngol Head Neck Surg. 2001 Feb;124(2):180-7.)
** Retrospective. 503 patients, selective neck dissection. pN0 49% vs pN+ 51%. Postop RT pN0 14% vs. pN+ 62%. Median F/U 3.4 years
** Outcome: 3-year RR pN0 5% vs. pN1 5% vs. pN2 12%. RT marginal benefit for pN1 and significant benefit for pN2 or ECE
** Conclusion: Results achieved with selective neck dissection compare favorably with reported modified radical neck dissection

### Cricopharyngeal myotomy

* 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 myotomy

## Surgery + Post-op RT vs Primary RT

* RTOG; 1993 (1985-1990) PMID 8262821 — "Is a surgical resection leaving positive margins of benefit to the patient with locally advanced squamous cell carcinoma of the head and neck: a comparative study using the intergroup study 0034 and the Radiation Therapy Oncology Group head and neck database." Laramore GE et al. Int J Radiat Oncol Biol Phys. 1993 Dec 1;27(5):1011-6.
** Compared pts treated on a prospective Intergroup study (surgical group) with pts from a historical database who received RT alone, matched for similar characteristics. 109 pts in the surgical group had positive margins and most received post-op RT.
** 4-yr LRC 44% (positive margins) vs 24% (RT). No difference in MS or 4-yr OS.
** Conclusion: incomplete surgery (+adjuvant RT) affords improved local control compared to 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

* Historically, pre-op RT was favored since it facilitated regression of tumor, and improved LRC over surgery alone
* However, morbidity of this approach lead to greater emphasis on post-op RT in 1960's and 1970's (see Fletcher PMID 13403033 (1957), PMID 4190460(1970))
* Randomized trial RTOG 73-03 demonstrated significantly better LRC for post-op RT
* Please see discussion tab for more trials
* 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 — "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
** 10-years; 1999 PMID 1993628 — "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
* Univ. Florida; 1989 (1964-84) - PMID 2912947 — "Postoperative irradiation for squamous cell carcinoma of the head and neck: an analysis of treatment results and complications." (Amdur RJ, Int J Radiat Oncol Biol Phys. 1989 Jan;16(1):25-36.)
** Retrospective. 134 patients, 96% Stage III-IV.
** Outcome: 5-year OS 33%. SM- 37% vs. SM+ 17% (SS); LRC SM- 81% vs. SM+ 53% (SS)

## Induction Chemotherapy
### Resectable Cancers of Head and Neck

* 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
* Chinese Trial; Zhong et al. 2013 PMID: 23129742-- "Induction chemo+/-RT vs. standard surgery + RT"
*** Population: Single centre, RCT, Stage III-IVA resectable oral squamous cell cancers; 256 pts randomised
*** Intervention group: Induction Chemotherapy with TCF (Docetaxel, Cisplatin and 5FU)followed by surgery and post-op RT
*** Control Group: Upfront Surgery with Post-operative radiotherapy. In both arms, Post-op RT was 54 to 60 Gy EBRT, those with high risk features (defined as positive margins, ECE and vascular invasion) were given 66 Gy of EBRT(no chemoradiation was given)
*** Conclusion: Similar outcome.Response rate: 80.6% ; pCR rate:?;Toxicity:None with Grade III or IV;Post-op Complications: Similar; Recurrence Rate: Similar; Survival: DFS and OS are similar.

## Surgery alone vs Postop RT

* For patients with locally advanced disease, surgery + postop RT has been widely practiced since Maccomb and Fletcher publication in 1957
* Two small randomized trials suggested improvement in LRC for postop RT over surgery alone. Similarly, several single institution retrospective series showed benefit for improved LRC
* SEER analysis suggests that postop RT in patients with LN+ results in 5-year CSS/OS increase by 10%. Surgery alone cures a third of patients, adjuvant RT adds 10% survival benefit, although this varies dramatically by site and nodal stage
* Current indications include pT3-T4, pN2-N3 disease, nodal disease in Levels IV-V, PNI+, or LVI+
* Mt. Sinai/SEER analysis (1988-2001)
** Overall; 2008 PMID 18076014 -- "Adjuvant radiotherapy improves overall survival for patients with lymph node-positive head and neck squamous cell carcinoma." (Lavaf A, Cancer. 2008 Feb 1;112(3):535-43.)
*** Population based SEER analysis. 8795 patients, HNSCC, treated with surgery, pN+. excluded nasopharynx. Use of chemo not tracked, but trials showing benefit not published until 2004. Median F/U 4.7 years
*** Outcome: Adjuvant RT used in 84% (preop 7%, postop 89%). 5-year OS surgery alone 33% vs. surgery + RT 43% (SS); 5-year CSS 42% vs. 51% (SS)
*** Conclusion: Adjuvant RT improved 5-year CSS and OS by 10%
** By site; 2008 PMID 18164833 -- "Adjuvant radiotherapy and survival for patients with node-positive head and neck cancer: an analysis by primary site and nodal stage." (Kao J, Int J Radiat Oncol Biol Phys. 2008 Jun 1;71(2):362-70. Epub 2007 Dec 31.)
*** Population based SEER analysis. 5297 patients, HNSCC, treated with surgery, pN+
*** Outcome: Adjuvant RT 81%. 5-year OS surgery 35% vs. surgery + RT 46% (SS)
**** By nodal stage: 5-year OS N1 44% vs. 52% (SS); N2a 28% vs. 44% (SS); N2b 18% vs. 42% (SS); N2c-N3 22% vs. 34% (SS)
**** By primary site: 5-year OS oral cavity 30% vs. 34% (NS); oropharynx 53% vs. 62% (SS); larynx 31% vs. 43% (SS); hypopharynx 24% vs. 39% (SS)
*** Multivariate predictors: adjuvant RT, age, primary site, nodal stage, tumor stage, marital status
*** Conclusion: Adjuvant RT significantly improves overall survival; all stages including N1 appear to benefit
* Mayo Clinic; 1998 (1974-1990) PMID 9486600 -- "Combined neck dissection and postoperative radiation therapy in the management of the high-risk neck: a matched-pair analysis." (Lundahl RE, Int J Radiat Oncol Biol Phys. 1998 Feb 1;40(3):529-34.)
** Retrospective, matched pair. 95 patients with pN+ who underwent postop RT (N1 17%, N2 80%, N3 3%). Median RT dose 55 Gy. Compared with previously published 284 patients treated with neck dissection alone, as matched pairs. Median F/U 5.3 years
** Outcome: Relative risk for dissected neck recurrence 5.8, any neck recurrence 4.7, cancer related death 2.2, and any death 1.7.
** Conclusion: Postop RT for high-risk neck can reduce negative outcomes
* Orissa, India -- surgery +/- postop RT
** 1996 PMID 8903493 -- "Post-operative radiotherapy in carcinoma of buccal mucosa, a prospective randomized trial." (Mishra RC, Eur J Surg Oncol. 1996 Oct;22(5):502-4.)
** Randomized. Locally advanced SCC of buccal mucosa. Arm 1) surgery only vs. Arm 2) postoperative RT
*** Outcome: DFS surgery alone 38% vs. postop RT 68% (SS)
*** Conclusion: Postop RT improves DFS in SCC of buccal mucosa
* City of Hope (1981-1984) -- surgery +/- postop RT
** Randomized. Stopped early due to lack of benefit at interim analysis. 51 patients, stage III-IV SCC of oral cavity, pharynx, or larynx. Arm 1) surgery alone vs. Arm 2) surgery + postop RT
** 1988 PMID 3288812 -- "Postoperative radiation as adjuvant treatment for carcinoma of the oral cavity, larynx, and pharynx: preliminary report of a prospective randomized trial." (Kokal WA, J Surg Oncol. 1988 Jun;38(2):71-6.) Median F/U 2.5 years
*** Outcome: Recurrence rate surgery alone 56% vs. postop RT 37% (NS); trend due to higher recurrence rate in contralateral nonoperated neck (5% vs. 15%). No difference in DFS or OS
*** Conclusion: Adjuvant postop RT doesn't improve DFS or OS; trend toward better control
*** Comment: Lack of benefit ascribed to low dose of RT prescribed (see PMID 9486600 for discussion)
* MD Anderson; 1957 PMID 13403033 -- "Planned combination of surgery and radiation in treatment of advanced primary head and neck cancers." (Maccomb WS, Am J Roentgenol Radium Ther Nucl Med. 1957 Mar;77(3):397-414.)

## Post-op Chemotherapy + Radiation

* Historically, resectable locally advanced HNSCC were treated with surgery + adjuvant RT. Unfortunately, recurrence rates were ~30%, DM rates ~25%, and 5-year OS was ~30%. Majority of recurrences were loco-regional. Patients with SM+ did particularly poorly
* RTOG 85-03(1992,IJROBP)evaluated sequential post-op cisplatin/5-FU followed by RT. There was no benefit in loco-regional control or overall survival
* Meanwhile, early randomized data from Yale (1993,IJROBP) showed an LRC and DFS benefit for concurrent mitomycin C. The LRC and DFS benefit, though without impact on OS, was confirmed in a study from Slovenia evaluating adjuvant mitomycin C and bleomycin
* An early randomized French trial (Bachaud, 1996, IJROBP) demonstrated a survival benefit with concurrent cisplatin
* Concurrent cisplatin with RT was subsequently evaluated in two large randomized trials in US (RTOG 95-01) and Europe (EORTC 22931). The EORTC trial showed significantly better LRC, DFS and OS; the RTOG trial showed significantly better LRC and DFS without impact on OS. Patients had "high-risk" features, which variously included SM+, LN+, ECE, PNI+, LVI+, and T3-4 disease. Joint analysis showed significant benefit for ECE+ or SM+ disease
* Current NCCN recommendations (v2.2008) specify ECE+ or SM+ for concurrent chemo-RT; patients with pT3-T4, pN2-N3, nodal disease in levels IV-V, PNI+ or LVI+ may be treated with RT alone or considered individually for chemo-RT
* However, concurrent cisplatin may be reasonably toxic and a concurrent carboplatin was evaluated. Two trials were closed early due to slow accrual; analysis of the smaller data sets revealed no impact on DFS or OS
* to be continued ...

### 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. R2 excision not allowed. 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 — "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
* RTOG 81-16 -- cisplatin/5-FU
** Phase I/II. Sequential chemotherapy. Two studies (A&B): A) Induction cisplatin/5-FU + surgery + RT (42 patients); B) surgery + sequential cisplatin/5-FU x3 cycles + RT (29 patients)
** 1989 PMID 2499175 — "Chemotherapy following surgery for head and neck cancer. A Radiation Therapy Oncology Group Study." (Jacobs JR, Am J Clin Oncol. 1989 Jun;12(3):185-9.)
*** Conclusion: Sequential post-op chemo-RT is feasible
** 1991 PMID 1998567 -- "5-year results of cisplatin and fluorouracil infusion in head and neck cancer." (Jacobs JR, Arch Otolaryngol Head Neck Surg. 1991 Mar;117(3):288-91.)
*** Outcome: median OS induction group 1.7 years, adjuvant group 2.6 years. 65% of induction chemo group didn't undergo surgery as planned. 5-year OS no difference 27% vs. 23%
* 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

### Post-op Concurrent Chemo-RT

* RTOG H-0024 (2001-3) - early chemo followed by chemo/RT
** Phase II. 70 pts. Taxol (80 mg/m2) weekly x 3, beginning postop day 7-14. RT begins the following week (i.e. during week 5-6). Dose: 60 Gy (range 58-66 Gy), 2Gy/fx. During last 3 weeks, cisplatin (20 mg/m2) + taxol (30 mg/m2) weekly.
** 2009 PMID 19720915 -- "Early postoperative paclitaxel followed by concurrent paclitaxel and cisplatin with radiation therapy for patients with resected high-risk head and neck squamous cell carcinoma: report of the phase II trial RTOG 0024." (Rosenthal DI, J Clin Oncol. 2009 Oct 1;27(28):4727-32.)
*** Median f/u 3.3 yrs. Compared with historical control of RTOG 95-01, LRC, DFS, and OS are improved.
*** Early post-operative chemo and chemo/RT is feasible and tolerable.
* Slovenia (1997-2001) -- mitomycin C and 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)
** 2-years; 2003 PMID 12829141 -- "Postoperative concomitant irradiation and chemotherapy with mitomycin C and bleomycin for advanced head-and-neck carcinoma." (Smid L, Int J Radiat Oncol Biol Phys. 2003 Jul 15;56(4):1055-62.) Median F/U 2.7 years
*** Outcome: 2-year LRC chemo-RT 86% vs. RT alone 69% (SS); DFS 76% vs. 60% (NS); OS 74% vs. 64% (SS). Benefit in high risk patients
*** Conclusion: Concomitant chemo-RT with mitomycin C and bleomycin improves LRC and OS
** 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
* Multi-Institutional -- Carboplatin
** Randomized. (Pittsburgh, Michigan, Cinncinati). Closed early due to slow accrual. 72 patients. Macroscopically resected, Stage III/IV SCCHN, high risk features (SM+, >= 3 LN+, ECE, PNI, LVI). Arm 1) post-op RT alone vs. Arm 2) post-op RT + concurrent carboplatin 100 mg/m2 QW. RT 59.4/33. Median F/U 5.3years
** 2007 PMID 18091334 -- "Long-Term Results of a Phase III Randomized Trial of Postoperative Radiotherapy With or Without Carboplatin in Patients With High-Risk Head and Neck Cancer." (Argiris A, Laryngoscope. 2007 Dec 12 [Epub ahead of print])
*** Outcome: 5-year DFS RT alone 53% vs. RT + carboplatin 41% (NS); OS 47% vs. 41% (NS)
*** Toxicity: Infrequent in both arms
*** Conclusion: No benefit with addition of carboplatin, possibly due to small sample size. Well tolerated.
* ARO 96-3 (Germany)(1997-2004) -- cisplatin + 5-FU
** Randomized. 440 patients with high-risk SCCA (3+ LN, ECE, SM+). Arm 1) RT alone vs. Arm 2) RT with concurrent cisplatin/5-FU. RT 66/33. Chemo cisplatin 20 mg/m2 and 5-FU 600 mg/m2 both day 1-5 and 29-33
** 5-years; 2006 ASCO Abstract -- "Postoperative concurrent radiochemotherapy versus radiotherapy in high-risk SCCA of the head and neck: Results of the German phase III trial ARO 96-3." (Fietkau R, Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 5507)
*** Outcome: 5-year LRC RT 72% vs. chemo-RT 89% (SS); PFS 50% vs. 62% (SS); OS 49% vs. 58% (NS)
*** Toxicity: Grade 3+ mucositis RT 13% vs. 21% (SS)
*** Conclusion: Post-op concurrent chemo-RT improves LRC and PFS
* RTOG 95-01 / Intergroup (1995-2000) -- cisplatin
** 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; 2002 Abstract #903, ASCO 2002 - Cooper et al. Video webcast Video webcast: Discussion Median F/U 2.2 years
*** Outcome: 2-year LRC chemo-RT 79% vs. RT 74% (NS); DFS 63% vs. 442% (SS), OS 63% vs. 57% (NS)
*** Toxicity: 2% treatment-related deaths from chemo/RT.
** 2-years; 2004 PMID 15128893 — "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
** Comment: Higher percentage of patients with oropharynx primaries than EORTC trial, which may explain why radiation alone arm did better compared to EORTC.
** Also see below for combined EORTC/RTOG analysis
* EORTC 22931 (1994-2000) -- cisplatin
** 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: minor differences
*** Conclusion: Post-op concurrent cisplatin with RT is more efficacious in locally advanced H&N, without significantly more complications
** Comment: Patients selected on basis of both pathologic factors (surgical margin, extracapsular extension) and clinical factors (T-stage and N-stage). Very high risk patients (T3-T4 with SM+) were excluded.
** Also see below for combined EORTC/RTOG analysis
* France (1994-2002) -- carboplatin
** Randomized. Stopped early after publication of a French trial (Bachaud). 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
* RTOG 88-24 (1989-1990) -- cisplatin
** Phase II. 51 patients. Resectable, Stage III-IV HNSCC (oral cavity, oropharynx, hypopharynx, larynx). Stage IV 84%, SM+ 53%. RT 60/30 with concurrent cisplatin 100 mg/m2 q3weeks.
** Compared results with historic data of sequential chemo/RT (INT 0034). No significant difference in survival compared with INT 0034.
** 1997 PMID 9128951 -- "Postoperative radiotherapy with concurrent cisplatin appears to improve locoregional control of advanced, resectable head and neck cancers: RTOG 88-24." (Al-Sarraf M, Int J Radiat Oncol Biol Phys. 1997 Mar 1;37(4):777-82.)
*** Outcome: 3-year OS 48%, LRC 81%, DM-free 57%
*** Toxicity: Grade 3 20%, Grade 4 12%
*** Conclusion: Post-op concurrent cisplatin with RT may improve LRC
* France (1984-88) -- cisplatin
** 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 — "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

### Pending

* RTOG 02-34 (ongoing) - A phase II randomized trial of surgery followed by chemoradiotherapy plus C225 (cetuximab) for advanced squamous cell carcinoma of the head and neck.
* RTOG 09-20 (ongoing) - A phase III randomized trial of surgery followed by radiotherapy (IMRT) +/- cetuximab for intermediate risk HN SCCA

## Pathologic N1 Disease

* Louvain, Belgium; 2009 (1990-2002) PMID 18648835 -- "Results of selective neck dissection in the primary management of head and neck squamous cell carcinoma." (Schmitz S, Eur Arch Otorhinolaryngol. 2009 Mar;266(3):437-43. Epub 2008 Jul 22.)
** Retrospective. 146 patients, unilateral/bilateral selective neck dissection in 249 necks. Median F/U 3.1 years
** Outcome: 25% cN0 patients were pN+. Regional recurrence 3% overall, dissected 2% and undissected 1%. pN0 failure rate 1%. pN1 failure rate without PORT 9% vs with PORT 5%. ECE in 16%, almost all treated with PORT, but failure rate still 22%
** Conclusion: Selective node dissection reliable to stage cN0 neck, and as definitive operation for pN0, most pN1 and pN2b necks. PORT not justified for pN1 but justified for pN2b and ECE
* Gottingen, Germany; 2008 (1986-2002) PMID 18302275 -- "Value of postoperative radiotherapy in patients with pathologic N1 neck disease." (Jackel MC, Head Neck. 2008 Jul;30(7):875-82.)
** Retrospective. 118 patients, H&N cancer, curative surgery, pN1 disease without ECE. Majority had selective neck dissection (Level II-III 63%, Level I-III 19%, Level II-IV 15%). Postop RT in 20%, postop chemo-RT 19%; less postop therapy since 1995.
** Outcome: Regional control: Isolated nodal failure 7% (surgery 10% vs. postop RT 2%), all nodal failures 16% (21% vs. 9%). 3-year neck reccurence rate surgery alone 11% vs. postop RT 3% (NS)
** Conclusion: Data suggest a trend to improved regional control for pN1 with postop RT

## Radiation technique
### High-risk groups

Recommendations for postoperative RT or chemo/RT:
* NCCN v2011.2
** Lip:
*** Postoperative RT: multiple positive nodes, PNI or LVI. (Optional RT if 1 LN+.)
*** Postoperative chemoRT: ECE, positive margin
** Oral cavity:
*** Postoperative RT: pT3 or pT4, N2 or N3, nodal disease in levels IV or V, PNI or LVI. (Optional RT if 1 LN+.)
*** Postoperative chemoRT: ECE, positive margin
** Oropharynx:
*** Postoperative RT: positive margin, pT3 or pT4, N2 or N3, nodal disease in levels IV or V, PNI or LVI. (Optional RT if 1 LN+.)
*** Postoperative chemoRT: ECE (any); or positive margin (only if T3-T4 or N2-3)
** Hypopharynx:
*** Postoperative RT: pT3 or pT4, N2 or N3, PNI or LVI.
*** Postoperative chemoRT: ECE, positive margin
** Larynx, glottic:
*** Postoperative RT: pT4, N2 or N3, PNI or LVI.
*** Postoperative chemoRT: ECE, positive margin
** Supraglottic larynx:
*** Postoperative RT: positive margin, pT4, N2 or N3, PNI or LVI. (Optional RT if 1 LN+, Optional RT for T3N0-1)
*** Postoperative chemoRT: ECE, positive margin
* Historical risk factors: Primary disease site (PMID 5014916), surgical margins (PMID 755803), perineural invasion (PMID 476992), number and location of positive nodes (PMID 1015542), extracapsular extension (PMID 7316852)
* Peters: Risk factors included oral cavity, close or positive margins, nerve invasion, 2 or more positive nodes, largest node > 3 cm, extracapsular extension, Zubrod score 2 or more, delay in starting radiotherapy of more than 6 weeks.
** Intermediate risk - 1 risk factor, excluding ECE
** High risk - 2 or more factors, or ECE
* Joint RTOG 85-03 and 88-24 analysis:
** Intermediate risk - extracapsular extension or 2+ involved lymph nodes
** High risk - positive surgical margin
* Joint EORTC/RTOG analysis:
** High risk - Extracapsular extension or positive surgical margin
* Treatment recommendations:
** NCCN v1.2010
*** Postoperative RT: pT4, N2-N3, nodal disease in Levels IV or V, perineural invasion, lymphovascular invasion
*** Postoperative chemo-RT (cisplatin 100 mg/m2 Q3W): extracapsular extension, positive surgical margins, also consider based on clinical data for patients as above for postop RT
** NCCN v2.2008
*** Postoperative RT: pT3-pT4, N2-N3, nodal disease in Levels IV or V, perineural invasion, lymphovascular invasion
*** Postoperative chemo-RT (cisplatin 100 mg/m2 Q3W): extracapsular extension, positive surgical margins, also consider based on clinical data for patients as above for postop RT
** Perez & Brady (5th ed):
*** Postoperative RT: close/positive margins, >1cm subglottic extension, cartilage invasion, perineural invasion, lymphovascular invasion, extension of primary into soft tissues of the neck, multiple positive nodes, extracapsular extension, control of subclinical disease in opposite neck
** UpToDate (2010):
*** Postoperative RT: Advanced T stage (T3/T4), positive or close margins (no consensus on definition, but at least included true positive margin and CIS at the margin, with consideration for tumor <5mm, and premalignant change at margin), lymph node involvement, extracapsular nodal extension, involvement of bone, perineural involvement, lymphovascular invasion, cartilage invasion
* Intermediate Risk Group:
** RTOG 0920 - Eligibility: T1N1-2, T2-3N0-2 (site: OC, OP, Larynx)
*** Have at least 1 intermediate risk factor: PNI, LVI, ≥2 positive LNs, single lymph node > 3 cm, close surgical margins (<5 mm), T3 or T4a (microscopic) primary, T2 oral cavity tumor with >5 mm depth of invasion. Cannot have: positive margins, ECE, or gross residual disease.
*** This subgroup of pts with intermediate risk is predicted to have a LRF rate of 15-35% with post-op RT only.
*** Phase III. RT (60-66 Gy) +/- cetuximab (concurrent, plus 4 weeks post-RT)
* EORTC / RTOG Joint Analysis; 2005 PMID 16161069 — "Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501)." (Bernier J, Head Neck. 2005 Oct;27(10):843-50.)
** Retrospective subgroup analysis of combined data from postop chemo-RT trials EORTC 229131 and RTOG 9501. Both trials concomitant cisplatin 100 mg/m2 Q3W and RT 60-66 Gy. Difference in "high-risk": EORTC SM+ , ECE, clinical involvement of Level IV-V from oral cavity/oropharynx primary, perineural disease, or vascular embolism vs. RTOG SM+, ECE, 2+ LN. Difference in endpoints: EORTC PFS vs RTOG LRC. Difference in dose: EORTC 66 Gy in 91% vs RTOG 66 Gy in 13%.
** Risk factors: ECE or SM+ had negative impact on OS. No other factors (2+ lymph nodes, PNI+, LVI+, Stage III-IV disease) showed difference
*** LRC: Pooled risk reduction 42% (SS). If SM+/ECE+, risk reduction 48%. If other factors, reduction not significant (EORTC 58%, p=0.1; RTOG 18%, p=0.5)
*** DFS: Pooled risk reduction 23% (SS). If SM+/ECE+, risk reduction 30%. If other factors, reduction not significant (EORTC 25%, p=0.3; RTOG 8%, p=0.7)
*** OS: Pooled risk reduction 28% (SS). If SM+/ECE+, risk reduction 30% (SS). If other factors, reduction not significant (EORTC 25%, p=0.06; RTOG 6%, p=.07)
** Conclusion: Significant benefit for chemo-RT over RT in patients with extracapsular extension or SM+, but benefit not significant for 2+ lymph nodes, PNI+, LVI+ or Stage III-IV disease
* RTOG 8503/8824 Joint Analysis - PMID 9744457 — "Precisely defining high-risk operable head and neck tumors based on RTOG #85-03 and #88-24: targets for postoperative radiochemotherapy?" (Cooper JS, Head Neck. 1998 Oct;20(7):588-94.)
** Retrospective. Data collected from RTOG 85-03 (INT 0034) and RTOG 88-24, which were sequential and concurrent chemo-radiotherapy trials for post-op H&N cancers
** New risk factors grouping: Group 1: no risk features; Group 2: 2+ lymph nodes or ECE; Groups 3: SM+
** Outcome: 5-year LRR 17% vs. 27% vs 61%; Median OS 5.6 years vs. 2.6 years vs. 1.5 years
** Conclusion: Suggested benefit for concurrent chemo-radiotherapy with a 50% decrease in local-regional recurrence, but only a small increase in survival (18% reduction in death rate).

### Radiotherapy dose

* Fletcher: 60 Gy
* Peters, 1993: 63 Gy for ECE+, otherwise 57.6 Gy
* RTOG 9501: 60 Gy +/- 6 Gy boost (given in 13%)
* EORTC 22931: 66 Gy to high risk region, 54 Gy to large field
* Recommendations (NCCN v2.2008):
** Primary: >= 60 Gy in 2 Gy/fx
** Involved nodal stations: >= 60 Gy in 2 Gy/fx
** Uninvolved nodal stations: >= 50 Gy in 2 Gy/fx
* Fletcher recommended 50 Gy in 25 fractions to control microscopic disease in an undissected neck. But Fletcher recommended 60 Gy in 30 fractions for a post-operative neck because of hypoxia due to disturbed vascular supply (in the Textbook of Radiotherapy, 2nd edition).
Randomized:
* Peters (M.D. Anderson), 1993 (1983-91) -- 57.6 Gy vs 63 Gy vs 68.4 Gy
** Purpose: 1) define groups with high and low risk for recurrence, 2) determine the optimal radiotherapy dose, 3) study the dose-response relationship for normal tissue injury
** Randomized. 302 pts. (report based on 240 pts). Eligible pts: oral cavity, oropharynx, hypopharynx, larynx, or unknown primary. Used a points system to assign pts to low or high risk. Low-risk pts randomized between 57.6 Gy and 63 Gy. (originally randomized to 52.2-54 Gy as well, but this arm was dropped.) High-risk pts randomized between 63 Gy and 68.4 Gy. All gross tumor had to be removed but + margins allowed. 54 Gy was given to surgically undisturbed sites with subclinical disease (i.e. contralateral neck) or putative sites of unknown primary. 57.6 Gy to dissected but pathologically negative neck. The randomized dose was given to the pathologically involved neck and primary — separate randomized doses to neck and primary, but when the primary site was randomized to a higher dose, it took precedence; if neck was to receive higher dose than the primary, then neck boosted with electrons to the higher dose.
** 1993 PMID 8482629 — "Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial." Peters LJ et al. Int J Radiat Oncol Biol Phys. 1993 Apr 30;26(1):3-11.
*** Disease control by dose: 2-year loco-regional recurrence rate of 26%. Disease-specific survival continued to decline up to about 5 years due to metastatic disease or second primary tumor. Low risk pts receiving <= 54 Gy had a higher primary failure rate than those with >= 57.6 Gy; no increase in control with doses above 57.6 Gy. Also, the point system they used did not accurately predict for recurrence since high and low risk pts receiving the same dose had the same LF rate.
*** Analysis of prognostic factors: analyzed a subset of 199 pts who received at least 57.6 Gy. Only independent risk factor was extracapsular extension; more than 1 positive LN was of borderline significance. Also a cluster of 2 or more risk factors was associated with worse prognosis. Crude recurrence rate was 20-30% if ECE+ but only 5-13% if ECE- and fewer than 4 other risk factors. With 4 or risk factors other than ECE, did just as bad as with ECE.
*** Dose response for high risk group: for pts with ECE, 2-yr control rate was 52% for 57.6 Gy vs 74% for 63 Gy. No added benefit for 68.4 Gy.
*** Conclusions: 57.6 Gy is adequate dose for post-op RT without extracapsular extension; 63 Gy for pts with ECE.
*** See list of risk factors used in this paper (separate section above).
** Update (2017) PMID 28721881 -- "Final Report of a Prospective Randomized Trial to Evaluate the Dose-Response Relationship for Postoperative Radiation Therapy and Pathologic Risk Groups in Patients With Head and Neck Cancer." (Rosenthal DI, Int J Radiat Oncol Biol Phys. 2017 Aug 1;98(5):1002-1011.)
*** 5-yr and 10-yr OS: 32% and 20%. 5-yr and 10-yr CSS: 48% and 46%. LRF in 28%. 5-yr LRC 67% (no events beyond 5 yrs). DM in 31%; 5-yr and 1-yr FDM 64% and 60%. 5-yr and 10-yr RFS 47% and 44%. Second primary cancer in 27%.
*** Tumor prognostic factors: "high risk" factors of SM and ECE were the only independent tumor-related risk factors predicting LRC and OS.
*** Treatment-related factors: no difference in LC between dose levels 57.6 Gy and above (older dose of 54 Gy known to be suboptimal).
*** Conclusion: This long-term report of PORT delivered at 1.8 Gy/d to total doses of 57.6 to 68.4 Gy without chemotherapy for head and neck squamous cell carcinoma demonstrated that increasing dose did not significantly improve tumor control. On multivariate analysis, the only significant treatment variable was TPT (treatment package time). The results confirm that positive surgical margins and/or nodal ECE remains the most significant predictive pathologic factors.

### Alternative Fractionation

* Evidence for intensifying RT through accelerated fractionation/hyperfractionation after surgery is not strong
* Some benefit might be seen in patients who delay start of RT >7 weeks, but this is on subset analysis
* Balanced against this is the fact that toxicity typically tends to be significantly higher
* 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 — "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

### Overall treatment time

* Based, in part, on the fact that overall treatment time for intact head & neck cancers influences outcome and the theory of accelerated repopulation. (Withers' data - Radiobiology).
* Overall treatment time should be less than 100 days.
* RT should begin within 6 weeks of surgery
* University of Pennsylvania; 2002 (1992-97) - PMID 11891941 — "Importance of the treatment package time in surgery and postoperative radiation therapy for squamous carcinoma of the head and neck." Rosenthal DI et al. Head Neck. 2002 Feb;24(2):115-26.
** Retrospective. 208 pts.
** Overall package time (>= vs < 100 days) was significant on multivariate analysis.
* Rouen, France; 2001(1981-92) - PMID 11163507 — "Influence of the delay of adjuvant postoperative radiation therapy on relapse and survival in oropharyngeal and hypopharyngeal cancers." Bastit L et al. Int J Radiat Oncol Biol Phys. 2001 Jan 1;49(1):139-46.
** Retospective. 420 pts.
** Surgery to radiotherapy interval was not a significant predictor for failure.
* Florida; 1997 (1964-94) - PMID 9300748 — "An analysis of factors influencing the outcome of postoperative irradiation for squamous cell carcinoma of the oral cavity." Parsons JT et al. Int J Radiat Oncol Biol Phys. 1997 Aug 1;39(1):137-48.
** Oral cavity.
** Improved local control for the unfavorable group if overall "package time" (i.e. from surgery to end of radiotherapy) was within 100 days. For surgery to XRT interval (cutoff: 45-50 days), there was a nonsignificant trend. Also a trend for shorter duration of RT.
* Memorial Sloan Kettering; 1990 (1975-80) - PMID 2325418 — "Impact of the time interval between surgery and postoperative radiation therapy on locoregional control in advanced head and neck cancer." Schiff PB et al. J Surg Oncol. 1990 Apr;43(4):203-8.
** Retrospective. 111 pts. Examined time from surgery to start of RT (S-R interval).
** Of 50 pts with S-R interval of 6 weeks or more, 11 (22%) had a local recurrence. 8 of these 11 had RT dose < 56 Gy. Of 17 pts with a delay of 6 weeks who had at least 60 Gy, only 2 (12%) had LR. For those who started RT within 6 weeks and had at least 60 Gy, 3/20 (15%) had a LR. The effect of delay was significant only in those who had < 60 Gy.
** Conclusion: prolonged delay in starting RT does not by itself have a negative impact if doses of 60 Gy or more are given.

## Reviews

* 2003 PMID 12560449 - "Does delay in starting treatment affect the outcomes of radiotherapy? A systematic review." Huang J et al. J Clin Oncol. 2003 Feb 1;21(3):555-63.
** Increased LRR for starting RT > 6 wks after surgery (OR = 2.89).
* 1998 PMID 9676534 Full text (PDF), 1998 — "Adjuvant therapy in head and neck cancer." Vikram B et al. CA Cancer J Clin. 1998 Jul-Aug;48(4):199-209.