Dose Escalation Using Hypoxia-adjusted Radiotherapy

NCT06087614 | Recruiting Phase 2 DMC

• 1 other identifier: Res/SCM/58/2023/33
• Study Type: interventional
• Target: 124
• Locations: 1 country
• Sites: 1

Brief Summary

DE-HyART is a phase II clinical trial aimed at understanding the effects of escalating radiation doses to hypoxic sub-volumes inherent to squamous cell head and neck cancer. The study is aimed at assessing locoregional control, feasibility, and acceptable toxicity with such a strategy.

Conditions

Head and Neck Squamous Cell Carcinoma

Outcome Measures

Primary Outcomes (1)

• Locoregional Control (LRC)

  LRC is defined as the absence of tumor recurrence or progression within the primary tumor site and the regional lymph nodes, as determined by clinical evaluation, imaging studies, and/or biopsy confirmation. LRC will be assessed at predefined time points, with the primary time point being 2 years post-treatment

  Disease recurrence locally or analysis cut-off point. The analysis cut off pint is 24 months

Secondary Outcomes (2)

• Overall Survival (OS)

  Death during following up or analysis cut-off point. The analysis cut off pint is 24 months

• Locoregional Relapse Free Survival (LRFS)

  Disease/Death during following up or analysis cut-off point. The analysis cut off pint is 24 months

Other Outcomes (4)

• Acute toxicity

  Till 6 months of finishing radiotherapy

• Late toxicity assessment

  At 1 year and 2 year follow-up

• Patient-reported outcome questionnaire

  During treatment, at 3 month and 6 month interval of completion of radiotherapy

Study Arms (3)

Arm 3 - DE-HyART

EXPERIMENTAL

The radiation dose will be similar to 'arm 2'. In addition, the HSV identified on baseline FMISO scans will be contoured, and an isotropic margin of 5 mm will be given. This volume will be boosted in phase II to a total dose of 80 Gy. (Addition of 30 Gy in 3 Gy daily fraction added in phase II as a simultaneous integrated boost - SIB).

Radiation: DE-HyART; Drug: Cisplatin injection

Arm 2 - Hypoxic Comparator Arm

ACTIVE COMPARATOR

The prescribed radiotherapy dose will be 70 Gy in 2 Gy per fraction daily. The elective volume will be treated with 50 Gy in 2 Gy per fraction daily till the first 5 weeks. The entire treatment will be delivered in a phased mannered using sequential planning.

Radiation: Standard Arm; Drug: Cisplatin injection

Arm 1 - Non-hypoxic arm

PLACEBO COMPARATOR

The patients will be treated with a standard of care where the treatment will not be controlled, and these patients will act as external control representing clinical practice. However, these patients will be discussed in the head and neck multispeciality clinic and follow the institutional approach. They will be subjected to treatment similar to 'arm 2' but are allowed protocol deviation as per treating radiation oncology discretion.

Drug: Cisplatin injection; Radiation: Standard fractionation (Radiation Oncology preference)

Interventions

DE-HyART RADIATION

The HSV delineation will be done for patients in arm 3 using baseline FMISO. The HSV will be contoured and adjusted according to the second FMISO scan done between the 4th - the 5th week of radiation treatment. A planning CT will also be repeated at the time for adjusting the HSV to account for temporal changes. The Biological Target Volume thus generated after adequate margins will be prescribed 30 Gy in 10 fractions over and above the standard fractination.

Also known as: Dose escalated radiotherapy, Hypoxic sub volume, FMISO

Arm 3 - DE-HyART

Standard Arm RADIATION

The prescribed radiotherapy dose will be 70 Gy in 2 Gy per fraction daily. The elective volume will be treated with 50 Gy in 2 Gy per fraction daily till the first 5 weeks. The entire treatment will be delivered in a phased mannered using sequential planning.

Also known as: Standard Sequential fractionation without dose escalation

Arm 2 - Hypoxic Comparator Arm

Cisplatin injection DRUG

Concurrent chemotherapy, weekly Inj Cisplatin 40mg/m2. This will be given if clinically indicated

Arm 1 - Non-hypoxic arm; Arm 2 - Hypoxic Comparator Arm; Arm 3 - DE-HyART

Standard fractionation (Radiation Oncology preference) RADIATION

Standard institutional practice is detailed before starting the patient. Doses 66-70 Gy over 6-7 weeks

Arm 1 - Non-hypoxic arm

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age: 18 - 70 years
• Willingness to sign informed consent (written/video documentation)
• Performance status: ECOG 0 - 2
• Histology proved - squamous cell carcinoma
• Any grade, gender
• Tumour sites: Oral Cavity, Oropharynx, Hypopharynx and Larynx
• Sufficient bone marrow reserve within the last 14 days.
• Hb: \> 10g/dl (corrected)
• TLC: \> 4,000 per cumm
• Platelet: \>1.5Lakh per cumm
• Liver functions and kidney functions within normal limits

You may not qualify if:

• HPV (p16) positive tumours
• Prior surgery and/or radiation therapy given for any HNC
• T1/T2 Glottis
• Metastatic disease or disease not amenable for definitive locoregional treatment.
• Medical co-morbidity hampering the administration of radiation and/or chemotherapy (cisplatin)
• Pregnancy or lactation

Sponsors & Collaborators

• Rajiv Gandhi Cancer Institute & Research Center, India: lead
• Varian, a Siemens Healthineers Company: collaborator

Study Sites (1)

Rajiv Gandhi Cancer Institute and Research Centre

Delhi, 110085, India

RECRUITING

Related Publications (18)

• Mortensen LS, Johansen J, Kallehauge J, Primdahl H, Busk M, Lassen P, Alsner J, Sorensen BS, Toustrup K, Jakobsen S, Petersen J, Petersen H, Theil J, Nordsmark M, Overgaard J. FAZA PET/CT hypoxia imaging in patients with squamous cell carcinoma of the head and neck treated with radiotherapy: results from the DAHANCA 24 trial. Radiother Oncol. 2012 Oct;105(1):14-20. doi: 10.1016/j.radonc.2012.09.015. Epub 2012 Oct 16.

  PMID: 23083497 BACKGROUND

• Lock S, Perrin R, Seidlitz A, Bandurska-Luque A, Zschaeck S, Zophel K, Krause M, Steinbach J, Kotzerke J, Zips D, Troost EGC, Baumann M. Residual tumour hypoxia in head-and-neck cancer patients undergoing primary radiochemotherapy, final results of a prospective trial on repeat FMISO-PET imaging. Radiother Oncol. 2017 Sep;124(3):533-540. doi: 10.1016/j.radonc.2017.08.010. Epub 2017 Aug 23.

  PMID: 28843726 BACKGROUND

• Kikuchi M, Yamane T, Shinohara S, Fujiwara K, Hori SY, Tona Y, Yamazaki H, Naito Y, Senda M. 18F-fluoromisonidazole positron emission tomography before treatment is a predictor of radiotherapy outcome and survival prognosis in patients with head and neck squamous cell carcinoma. Ann Nucl Med. 2011 Nov;25(9):625-33. doi: 10.1007/s12149-011-0508-9. Epub 2011 Jul 1.

  PMID: 21720778 BACKGROUND

• Rischin D, Fisher R, Peters L, Corry J, Hicks R. Hypoxia in head and neck cancer: studies with hypoxic positron emission tomography imaging and hypoxic cytotoxins. Int J Radiat Oncol Biol Phys. 2007;69(2 Suppl):S61-3. doi: 10.1016/j.ijrobp.2007.05.043. No abstract available.

  PMID: 17848298 BACKGROUND

• Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol. 1996 Oct;41(1):31-9. doi: 10.1016/s0167-8140(96)91811-3.

  PMID: 8961365 BACKGROUND

• Tandon S, Gairola M, Ahlawat P, Karimi AM, Tiwari S, Muttagi V, Sachdeva N, Sharief MI, Dobriyal K. Failure patterns of head and neck squamous cell carcinoma treated with radical radiotherapy by intensity modulated radiotherapy technique using focal volume and dosimetric method. Head Neck. 2019 Jun;41(6):1632-1637. doi: 10.1002/hed.25586. Epub 2018 Dec 23.

  PMID: 30582238 BACKGROUND

• Bourhis J, Le Maitre A, Baujat B, Audry H, Pignon JP; Meta-Analysis of Chemotherapy in Head, Neck Cancer Collaborative Group; Meta-Analysis of Radiotherapy in Carcinoma of Head, Neck Collaborative Group; Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma Collaborative Group. Individual patients' data meta-analyses in head and neck cancer. Curr Opin Oncol. 2007 May;19(3):188-94. doi: 10.1097/CCO.0b013e3280f01010.

  PMID: 17414635 BACKGROUND

• Brockstein B, Haraf DJ, Rademaker AW, Kies MS, Stenson KM, Rosen F, Mittal BB, Pelzer H, Fung BB, Witt ME, Wenig B, Portugal L, Weichselbaum RW, Vokes EE. Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience. Ann Oncol. 2004 Aug;15(8):1179-86. doi: 10.1093/annonc/mdh308.

  PMID: 15277256 BACKGROUND

• Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, Tjulandin S, Shin DM, Cullen K, Ervin TJ, Murphy BA, Raez LE, Cohen RB, Spaulding M, Tishler RB, Roth B, Viroglio Rdel C, Venkatesan V, Romanov I, Agarwala S, Harter KW, Dugan M, Cmelak A, Markoe AM, Read PW, Steinbrenner L, Colevas AD, Norris CM Jr, Haddad RI; TAX 324 Study Group. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007 Oct 25;357(17):1705-15. doi: 10.1056/NEJMoa070956.

  PMID: 17960013 BACKGROUND

• Pignon JP, le Maitre A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009 Jul;92(1):4-14. doi: 10.1016/j.radonc.2009.04.014. Epub 2009 May 14.

  PMID: 19446902 BACKGROUND

• Zegers CM, Hoebers FJ, van Elmpt W, Bons JA, Ollers MC, Troost EG, Eekers D, Balmaekers L, Arts-Pechtold M, Mottaghy FM, Lambin P. Evaluation of tumour hypoxia during radiotherapy using [18F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer. Eur J Nucl Med Mol Imaging. 2016 Nov;43(12):2139-2146. doi: 10.1007/s00259-016-3429-y. Epub 2016 Jun 1.

  PMID: 27251643 BACKGROUND

• Zschaeck S, Lock S, Hofheinz F, Zips D, Sakso Mortensen L, Zophel K, Troost EGC, Boeke S, Sakso M, Monnich D, Seidlitz A, Johansen J, Skripcak T, Gregoire V, Overgaard J, Baumann M, Krause M. Individual patient data meta-analysis of FMISO and FAZA hypoxia PET scans from head and neck cancer patients undergoing definitive radio-chemotherapy. Radiother Oncol. 2020 Aug;149:189-196. doi: 10.1016/j.radonc.2020.05.022. Epub 2020 May 15.

  PMID: 32417350 BACKGROUND

• Welz S, Paulsen F, Pfannenberg C, Reimold M, Reischl G, Nikolaou K, La Fougere C, Alber M, Belka C, Zips D, Thorwarth D. Dose escalation to hypoxic subvolumes in head and neck cancer: A randomized phase II study using dynamic [18F]FMISO PET/CT. Radiother Oncol. 2022 Jun;171:30-36. doi: 10.1016/j.radonc.2022.03.021. Epub 2022 Apr 5.

  PMID: 35395276 RESULT

• Pigorsch SU, Wilkens JJ, Kampfer S, Kehl V, Hapfelmeier A, Schlager C, Bier H, Schwaiger M, Combs SE. Do selective radiation dose escalation and tumour hypoxia status impact the loco-regional tumour control after radio-chemotherapy of head & neck tumours? The ESCALOX protocol. Radiat Oncol. 2017 Mar 1;12(1):45. doi: 10.1186/s13014-017-0776-1.

  PMID: 28249612 RESULT

• Rajendran JG, Hendrickson KR, Spence AM, Muzi M, Krohn KA, Mankoff DA. Hypoxia imaging-directed radiation treatment planning. Eur J Nucl Med Mol Imaging. 2006 Jul;33 Suppl 1:44-53. doi: 10.1007/s00259-006-0135-1.

  PMID: 16763816 RESULT

• Thorwarth D, Eschmann SM, Paulsen F, Alber M. Hypoxia dose painting by numbers: a planning study. Int J Radiat Oncol Biol Phys. 2007 May 1;68(1):291-300. doi: 10.1016/j.ijrobp.2006.11.061.

  PMID: 17448882 RESULT

• Lee NY, Mechalakos JG, Nehmeh S, Lin Z, Squire OD, Cai S, Chan K, Zanzonico PB, Greco C, Ling CC, Humm JL, Schoder H. Fluorine-18-labeled fluoromisonidazole positron emission and computed tomography-guided intensity-modulated radiotherapy for head and neck cancer: a feasibility study. Int J Radiat Oncol Biol Phys. 2008 Jan 1;70(1):2-13. doi: 10.1016/j.ijrobp.2007.06.039. Epub 2007 Sep 14.

  PMID: 17869020 RESULT

• Tandon S, Gupta M, Ahlawat P, Verma M, Nayak A, Bellige A, Chufal KS, Sethi JS, Pahuja A, Rai S, Singh A, Arora V, Yadav V, Simson DK, Ahmad I, Singh S, Vashisht D, Ansari A, Bansal R, Bhadri A, Vyas H, Mishra M, Saha R, Agarwal M, Chowdhary PS, Dewan AK, Gairola M. DEHyART trial: Study protocol for phase 2 randomised controlled study assessing the role of dose escalation using [18F] fluoromisonidazole positron emission tomography/computed tomography in head and neck cancers. Ecancermedicalscience. 2025 Jul 2;19:1937. doi: 10.3332/ecancer.2025.1937. eCollection 2025.

  PMID: 40949474 DERIVED

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck

Interventions

fluoromisonidazole; Cisplatin

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Study Officials

• Munish Gairola, MD,DNB Radiation Oncology

  Rajiv Gandhi Cancer Institute and Research Centre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sarthak Tandon, DNB

CONTACT

+911147022009; tandon.sarthak@rgcirc.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr

Study Record Dates

• First Submitted: September 18, 2023
• First Posted: October 18, 2023
• Study Start: April 8, 2024
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2028
• Last Updated: January 17, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)