# Radiation Oncology/Head & Neck/Hypoxia

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Head & Neck Cancers: Hypoxia

## Overview

* Anemia is associated with significantly worse locoregional control and survival, as shown in secondary analysis of RTOG 85-27
* However, both a European randomized trial and randomized RTOG 99-03 showed worse outcomes in patients given erythropoietin support
* Hypoxic cell sensitizers (misonidazole and etanidazole) did not show a clinical benefit
* Carbogen breathing was also not shown to have any benefit

## 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. Hemoglobin men <13.5 g/DL and women <12.5 g/dL. RT +/- erythropoietin 40K units weeily. If Stage III-IV, concurrent chemo-RT and/or accelerated RT.
** 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
*** Hemoglobin: at 4 weeks control -0.2 g/dL vs. Epo +1.7 g/dL
*** 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

## Transfusion

* DAHANCA 5 (1986-1990) See also discussion at Nimorazole
** Randomized. 414 pts w/ pharynx or supraglottic larynx ca. RT median 66 Gy. Randomized: 1) +/- Nimorazole. Pts stratified by low vs normal hgb level (low: males < 9 mmol/L = 14.5 g/dL; females < 8 mmol/L = 12.9 g/dL). Pts with low hgb level underwent 2nd randomization: 2) +/- transfusion (to achieve and sustain normal level, re-checked q2weeks).
** 1998 PMID 9510041 -- "A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85." (Overgaard J, Radiother Oncol. 1998 Feb;46(2):135-46.) -- Median f/u 9 yrs.
*** 41% of pts had low hgb. 5-yr LRC 46% (high hgb) vs 37% (low). 82 pts randomized to receive transfusion. Only 29/82 transfused pts maintained the goal hgb level. Transfusion did not result in improved LRC (39% transfused vs 35% not transfused).
*** Conclusion: a definite conclusion regarding the effect of transfusion could not be reached and awaits further data from DAHANCA 7.

## Etanidazole

* 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
** 1998 PMID 9869231 -- "Anemia is associated with decreased survival and increased locoregional failure in patients with locally advanced head and neck carcinoma: a secondary analysis of RTOG 85-27." (Lee WR, Int J Radiat Oncol Biol Phys. 1998 Dec 1;42(5):1069-75.)
*** Subset of 451 patients. 46% normal Hgb (men >14.5, women >13), 64% anemic
*** Outcome: 5-year OS normal Hgb 36% vs. anemic 22% (SS); LRFR 52% vs. 68% (SS)
*** Toxicity: Grade 3+ normal Hgb 20% vs. 13% (NS)
*** Conclusion: Low Hgb levels result in worse survival and LR failure

## Misonidazole

* 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

## Nimorazole

Nimorazole is a hypoxic cell radiosensitizer. Compared with misonidazole, nimorazole is better tolerated, with its major toxicity being nausea/vomiting (vs misonidazole which can lead to neuropathy).
* DAHANCA 5 (1986-1990) See also discussion at Transfusion
** Randomized. 414 pts w/ pharynx or supraglottic larynx ca. RT median 66 Gy. Randomized: 1) +/- Nimorazole. Pts with low hgb level underwent 2nd randomization: 2) +/- transfusion.
** Outcome; 1998 PMID 9510041 -- "A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85." (Overgaard J, Radiother Oncol. 1998 Feb;46(2):135-46.) -- Median f/u 9 yrs.
*** 5-yr LRC 49% (NIM) vs 33% (placebo), cause-specific survival 52% vs 41%, but non-sig. difference in OS. Benefit was seen in all subgroups. NIM sensitizes patients with both high and low hgb.
*** Conclusion: improved tumor control with nimorazole
** HPV Response; 2009 PMID 19289615 -- "Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck." (Lassen P, J Clin Oncol. 2009 Apr 20;27(12):1992-8. Epub 2009 Mar 16.)
*** Subset analysis. p16/HPV+ in 22%
*** Outcome: 5-year LRC p16+ 58% vs p16- 28% (SS), DSS 72% vs 34% (SS), OS 62% vs 26% (SS). p16 remained strong predictor on MVA
*** Conclusion: Expression of p16 has a major impact on treatment response and survival
** HPV & Hypoxia; 2010 PMID 19910068 -- "HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer." (Lassen P, Radiother Oncol. 2010 Jan;94(1):30-5. Epub 2009 Nov 10.)
*** Subset analysis. 331 patients with pretreatment tumor blocks, stained for p16. p16+ in 25% (oropharynx 37%, SGL 21%, others 10%)
*** Outcome: Nimorazole improved LRC overall (HR 0.7, SS). p16- improved LRC overall (HR 0.4, SS). If p16-, nimorazole improved LRC (HR 0.7, SS), but if p16+, nimorazole did not improved LRC (HR 0.9, NS)
*** Conclusion: Hypoxic modification improved outcome in HPV/p16 negative patients, but had no impact in HPV/p16 positive patients

## Transfusion

* DAHANCA 5 (1986-1990) See also discussion at Nimorazole
** Randomized. 414 pts w/ pharynx or supraglottic larynx ca. RT median 66 Gy. Randomized: 1) +/- Nimorazole. Pts stratified by low vs normal hgb level (low: males < 9 mmol/L = 14.5 g/dL; females < 8 mmol/L = 12.9 g/dL). Pts with low hgb level underwent 2nd randomization: 2) +/- transfusion (to achieve and sustain normal level, re-checked q2weeks).
** 1998 PMID 9510041 -- "A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85." (Overgaard J, Radiother Oncol. 1998 Feb;46(2):135-46.) -- Median f/u 9 yrs.
*** Outcome: 41% of pts had low hgb. 5-yr LRC 46% (high hgb) vs 37% (low). 82 pts randomized to receive transfusion. Only 29/82 transfused pts maintained the goal hgb level. Transfusion did not result in improved LRC (39% transfused vs 35% not transfused).
*** Conclusion: a definite conclusion regarding the effect of transfusion could not be reached and awaits further data from DAHANCA 7.

## Carbogen (95% oxygen + 5% CO2)

* 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