# Radiation Oncology/Head & Neck/Concurrent Chemo-RT

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Head & Neck Cancer: Concurrent Chemotherapy and Radiation Therapy

## Standard Fractionation +/- Concurrent Chemotherapy

4 randomized trials showed the superiority of RT with concurrent chemotherapy over RT alone: 1) Intergroup Nasopharynx trial, 2) RTOG 91-11, 3) Head & Neck Intergroup trial, 4) GORTEC trial
* RTOG 91-11
** See details in the Larynx chapter
* RTOG 97-03 (1997-99) Protocol
** Purpose: tolerability of these regimens
** Phase II. 241 pts. Advanced Stage III-IV (T3-4,N1-3,M0) of OC, OP, or HP. Randomized to 1) 70 Gy / 7 weeks with daily cisplatin and 5-FU during the last 10 days of RT (XCF); 2) 70 Gy / 13 weeks every other week with concurrent daily hydroxyurea and 5-FU (FHX); 3) 70 Gy / 7 weeks with weekly cisplatin and paclitaxel (XCT). Arm 1 is intended to give the maximum intensity of treatment during the period of accelerated repopulation.
** ASCO 2001 Abstract — "Preliminary Results of RTOG 9703 - a Phase II Randomized Trial of Concurrent Radiation (RT) and Chemotherapy for Advanced Squamous Cell Carcinomas (SCC) of the Head and Neck." Garden AS et al. Abstract #891. Proc Am Soc Clin Oncol 2001;20:223a.
*** Median f/u 1.6 yrs. 1-yr and 2-yr OS 72% and 60% (XCF), 87% and 65% (FHX), and 80% and 67% (XCT). Compared to historic controls from RTOG database treated with RT alone or with RT + cisplatin on RTOG 8117, large reductions in death rates for pts treated on all 3 arms.
** PMID 15254053, 2004 — "Preliminary results of Radiation Therapy Oncology Group 97-03: a randomized phase II trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck." Garden AS et al. J Clin Oncol. 2004 Jul 15;22(14):2856-64.
*** 2-yr DFS and OS 38.2% and 57.4% for XCF, 48.6% and 69.4% for FHX, and 51.3% and 66.6% for XCT.
** Long-term results, 2007: No PMID. Abstract — "Results of Radiation Therapy Oncology Group 97-03 - A randomized phase II trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck: long-term results and late toxicities." Garden AS et al. Int J Radiat Oncol Biol Phys 2007;69(2):S140 (Abstract #10)
*** No significant difference in OS, LRF, or toxicities. 10% of patients had grade 4 late toxicity; 20% required long-term feeding tube.
** Conclusion: All arms were tolerable with acceptable toxicity.
* Hellenic COG (Greece)(1995-1999) -- concurrent cisplatin or concurrent carboplatin
** Randomized, 3 arms. 124 patients, locally advanced HNC (no NPC). Arm 1) RT alone 70/35 vs. Arm 2) RT with concurrent cisplatin 100 mg/m2 vs. Arm 3) RT with concurrent carboplatin 7 AUC.
** 3-years; 2004 PMID 15299181 -- "Concomitant radiochemotherapy vs radiotherapy alone in patients with head and neck cancer: a Hellenic Cooperative Oncology Group Phase III Study." (Fountzilas G, Med Oncol. 2004;21(2):95-107.)
*** Outcome: Median time-to-progression RT 6 months vs. RT + cisplatin 45 months vs. RT + carboplatin 18 months (SS); median OS 1 year vs. 4 years vs. 2 years (SS); 3-year OS 17% vs. 52% vs. 42% (SS)
*** Toxicity: more severe N/V in RT + cisplatin
*** Conclusion: Platinum-based concurrent chemo-RT improves survival compared to RT alone; cisplatin better than carboplatin
* GORTEC, France (1994-1997) -- RT alone vs RT + concurrent 5-FU/carboplatin
** 1999 PMID 10601378 — "Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma." (Calais G, J Natl Cancer Inst. 1999 Dec 15;91(24):2081-6.)
** Randomized. 222 patients, Stage III-IV oropharynx. Arm 1) RT 70/35 vs Arm 2) Same RT with concurrent 5-FU 600 mg/m2 and carboplatin 70 mg/m2 x3 cycles
*** Outcome: 3-year LRC 42% vs 66% (SS); 3-year OS RT 31% vs chemo-RT 51% (SS)
*** Toxicity: Grade 3-4 mucositis RT 39% vs chemo-RT 71% (SS), skin toxicity comparable
*** Conclusion: Significant improvement in locoregional control and overall survival with concurrent chemotherapy
** ASTRO 2002: 5-yr OS 23% vs 16% (p=0.05), 5-yr LRC 48% vs 25% (SS), no diff in DM.
* 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 — "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
* Slovenia (1991-1993) -- concurrent mitomycin C and bleomycin
** Randomized. Closed prematurely due to superior result of concurrent treatment. 64 patients (oropharynx 41), inoperable H&N. Arm 1) RT alone 66-70 Gy in 2 Gy/fx vs. Arm 2) Same RT with concurrent mitomycin C and bleomycin (and nicotinamide, chlorpromazine, dicoumarol)
** 1998 PMID 9719123 -- "Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report." (Zakotnik B, Int J Radiat Oncol Biol Phys. 1998 Jul 15;41(5):1121-7.). Median F/U 3.5 years
*** Outcome: DFS RT 8% vs. chemo-RT 37% (SS); OS 7% vs. 26% (p=0.08). Oropharynx subgroup OS 10% vs. 38% (SS)
*** Conclusion: Concurrent chemo significantly improves CR, DFS and OS in inoperable oropharyngeal cancer
** 5-years; 2005 PMID 15800716 -- "Inoperable oropharyngeal carcinoma treated with concomitant irradiation, mitomycin C and bleomycin - long term results." (Budihna M, Neoplasma. 2005;52(2):165-74.) Median F/U 7.1 years
*** Oropharyngeal subset. 95 patients. RT 60-73 Gy, concurrent mitomycin C + bleomycin
*** Outcome: 5-year LRC 55%, DFS 51%, OS 32%. Probability of new malignancy 23%. Gamma-value of dose-response curve 2.86
*** Conclusion: Outcome directly proportional to intensity of RT and chemo. MiC increased radioresponsiveness by effect on hypoxic fraction
* UK HAN1 (1990-2000) -- RT vs concurrent chemo vs adjuvant chemo vs concurrent+adjuvant chemo
** Randomized, primary and post-op strata. 966 patients, either definitive or postop. Chemo was non-platin (MTX or MTX + vincristine + bleomycin + 5-FU)
*** Definitive: Arm 1) RT alone vs Arm 2) concurrent chemo vs Arm 3) adjuvant chemo vs Arm 4) concurrent + adjuvant chemo.
*** Post-op: Arm 1) RT vs. Arm 2) RT + concurrent chemo
** 10-years; 2009 PMID 19875337 -- "Chemoradiotherapy for locally advanced head and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial." (Tobias JS, Lancet Oncol. 2009 Oct 27. [Epub ahead of print])
*** Outcome:
**** Definitive: Median OS RT 2.6 years vs. concurrent 4.7 years vs adjuvant 2.3 years vs concurrent + adjuvant 2.7 year; median EFS 1.0 vs 2.2 vs 1.0 vs 1.0 years
**** Post-op: Median OS RT 5.0 years vs. concurrent 4.6 years (NS); median EFS 3.7 vs 3.0 years (NS)
*** Toxicity: RT 11% vs. concurrent 28% vs. adjuvant 12% vs concurrent + adjuvant 36%. In postop: RT 9% vs. concurrent 20%
*** Conclusion: Concurrent non-platinum chemo-RT improves outcomes; chemo after RT is ineffective. Post-op patients do not benefit from non-platinum chemo
* Head & Neck Intergroup / RTOG 84-06 (ECOG 1982-1987, RTOG 1984-1987) -- concurrent cisplatin 20 mg/m2
** Randomized. 319 patients. All sites, 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
* RTOG 81-17 (1981-1984)
** Phase I/II. 124 patients, locally advanced inoperable H&N cancer (oropharynx 39%, nasopharynx 22%, oral cavity 18%, hypopharynx 7%, larynx 7%, sinuses 7%). Stage III 18%, Stage IV 82%. Concurrent RT 66-73.8 Gy with cisplatin 100 mg/m2 q3 weeks. 60% completed planned treatment
** 1987 PMID 3802013 -- "Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study." (Al-Sarraf M, Cancer. 1987 Jan 15;59(2):259-65.)
*** Severe toxicity: stomatitis 31%, leukopenia 11%, anemia 8%, N/V 6%
*** Outcome: 1-year DFS 51%, OS 66%. Nasopharynx CR 82%, OP/larynx/sinuses 75%, oral cavity 56%, hypopharynx 37%
*** Conclusion: Concurrent cisplatin effective and safe in advanced H&N
** 1990 PMID 2224782 — "Concomitant cisplatin chemotherapy and radiotherapy in advanced mucosal squamous cell carcinoma of the head and neck. Long-term results of the Radiation Therapy Oncology Group study 81-17." (Marcial VA et al. Cancer. 1990 Nov 1;66(9):1861-8.)
*** Outcome: 4-year LRC 43%, OS 34%. LRC and OS better in non-keratinizing SCC. High CR rate in nasopharynx.
*** Toxicity: renal 1 Grade 5 and 2 Grade 4
*** Conclusion: Results justify a randomized trial of chemo-RT vs. RT alone
* Wisconsin (1961-1973)
** 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

## Altered Fractionation +/- Chemotherapy

* Please see the Altered Fractionation page

## Cetuximab (Erbitux)
### Cetuximab + RT

* Phase III (1999-2002)
** Randomized. 424 pts. Stage III-IV, scca of oropharynx, hypopharynx, or larynx. 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.
** 2004 ASCO Abstract 5507 — "Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab." Bonner JA et al. Proc Am Soc Clin Oncol 23:488, 2004 (abstr 5507)
** 2005 ASCO Abstract 5533 — "Improved Preservation of Larynx with the Addition of Cetuximab to Radiation for Cancers of the Larynx and Hypopharynx" Bonner JA et al.
*** Subset analysis, including 171 pts with tumors of the hypopharynx or larynx. Hazard ratio for larynx preservation was 0.62 (confidence interval included 1). Underpowered study for this endpoint.
** 3-years, 2006 PMID 16467544, 2006 — "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.
** 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
** 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
** 5-years; 2010 PMID 19897418 -- "Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival." (Bonner JA, Lancet Oncol. 2010 Jan;11(1):21-8. Epub 2009 Nov 10.)
*** Outcome: Primary endpoint (LRC) not reported. Median OS RT+cetuximab 4.1 years vs RT alone 2.4 years (HR 0.7, SS). 5-year OS 46% vs 36% (SS). Survival significantly better if at least Grade 2 cetuximab rash median OS 5.7 years vs 2.1 years (HR 0.5, SS). On subgroup analysis, benefit for cetuximab confined to BID or concomitant boost arms only
*** Toxicity: Cetuximab rash typically within 35 days; Grade 2 in 61%.
*** Conclusion: Cetuximab + RT significantly improves 5-year survival; patients with cetuximab G2 rash have better survival
* Phase I PMID 11432891, 2001 (1997-98) — "Phase I study of anti--epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer." Robert F et al. J Clin Oncol. 2001 Jul 1;19(13):3234-43.
** 16 pts. Dose finding study. RT to 70 Gy, 3 pts with hyperfractionated RT to 76.8 Gy. Cetuximab given with loading dose of 400-500 mg/m2 then weekly infusions of 100-250 mg/m2.
Cetuximab + RT Toxicity
* Dusseldorf, 2007 PMID 17671265 -- "Severe cutaneous reaction during radiation therapy with concurrent cetuximab." (Budach W, N Engl J Med. 2007 Aug 2;357(5):514-5.)
** 2 cases reported. Grade 4 toxicity. Images.

### Cetuximab + Chemo/RT

* RTOG 0522 (2005-2009) -- AFX plus concurrent cisplatin +/- cetuximab
** See details at Altered Fractionation (RT Alone vs Concurrent Chemo-AFX RT)

## Intraarterial Chemotherapy

* 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
* RTOG 96-15 - RADPLAT
** PMID 15735120, 2005 — "Supradose intra-arterial cisplatin and concurrent radiation therapy for the treatment of stage IV head and neck squamous cell carcinoma is feasible and efficacious in a multi-institutional setting: results of Radiation Therapy Oncology Group Trial 9615." Robbins KT et al. J Clin Oncol. 2005 Mar 1;23(7):1447-54.

## Induction Chemotherapy with Concurrent Chemo-RT

    See also: Neoadjuvant Chemotherapy (without concurrent chemo-RT)
* Spain (2002-2007) -- Induction chemo + chemo-RT vs chemo-RT alone
** Randomized. 439 patients, locally advanced unresectable H&N (oropharynx/oral cavity 63%, T4 75%, N2-N3 61%). Arm 1) Induction PF x3 cycles followed by chemo-RT cisplatin 100 mg/m2 Q3W + RT 70 Gy vs. Arm 2) Induction TPF x3 cycles followed by chemo-RT vs. Arm 3) Chemo-RT alone
** 2009 ASCO Abstract -- "Final results of a randomized phase III trial comparing induction chemotherapy with cisplatin/5-FU or docetaxel/cisplatin/5-FU follow by chemoradiotherapy (CRT) versus CRT alone as first-line treatment of unresectable locally advanced head and neck cancer (LAHNC). (Hitt R, J Clin Oncol 27:15s, 2009 (suppl; abstr 6009))
*** Outcome: Time-to-progression induction 12 months vs chemo-RT 4.9 months (HR 0.5, SS). LRC induction 61% vs. chemo-RT 44% (OR 0.5, SS)
*** Toxicity: G3+ mucositis induction 83% vs chemo-RT 69%
*** Conclusion: Combination of induction chemo followed by chemo-RT increases loco-regional control and prolongs time-to-progression compared with chemo-RT alone
* Spain -- Induction chemo (CF vs PCF) then chemo-RT.
** Randomized. 382 pts.
** 2005 PMID 16275937 -- "Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer." (Hitt R, J Clin Oncol. 2005 Dec 1;23(34):8636-45.)
*** Conclusion: "Induction chemotherapy with PCF was better tolerated and resulted in a higher CR rate than CF. However, new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment."

## Chemo benefit RT equivalent

* Birmingham, UK; 2010 PMID 19880297 -- "Radiobiological modelling of the therapeutic ratio for the addition of synchronous chemotherapy to radiotherapy in locally advanced squamous cell carcinoma of the head and neck." (Hartley A, Clin Oncol (R Coll Radiol). 2010 Mar;22(2):125-30. Epub 2009 Oct 31.)
** Modeling. Alpha = 0.3Gy(-1)
** Outcome: Chemo contribution to local control 9.3 Gy(10)
** Toxicity: Chemo contribution to Grade 3 mucositis 6.4 Gy(10). For equivalent RT dose escalation, mucosal sparing with chemo was 5.2 Gy(10) or equivalent 2 Gy/fx dose of 4.3 Gy EQD2
** Conclusion: Small therapeutic gain for concurrent chemo over dose escalation due to less mucositis
* Duke; 2007 PMID 17674979 -- "How much radiation is the chemotherapy worth in advanced head and neck cancer?" (Kasibhatla M, Int J Radiat Oncol Biol Phys. 2007 Aug 1;68(5):1491-5.)
** Modeling. Data from RTOG 90-03.
** Outcome: 1% increase in BED yields 1.1% in LRC. Mean BED for standard fractionated RT 60.2 Gy, for altered fractionated RT 66 Gy, for standard fractionated chemo-RT 71 Gy, and for altered fractionated chemo-RT 76 Gy
** Conclusion: Chemo increases BED by ~10 Gy, equivalent to 12 Gy in 2 Gy/fx
** Comment (Fowler JF, PMID 18474309): correction of several elementary radiobiologic errors. Average gain is 8.8 Gy(10) not 10.6 Gy (10). Concomitant chemotherapy is equivalent to additional 3.6 fractions of 2 Gy/fx