Dose Escalation Using Hypoxia-adjusted Radiotherapy

Head and Neck Squamous Cell Carcinoma Clinical Trial

— DE-HyART  

Official title:

A Phase II Randomised Controlled Study Assessing the Role of Dose Escalation Using [18F] FMISO PET CT in Head and Neck Cancer: The DE-HyART (Dose Escalation Using Hypoxia-adjusted Radiotherapy) Protocol

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06087614
• Other study ID #: Res/SCM/58/2023/33
• Status: Recruiting
• Phase: Phase 2
• Start date: April 8, 2024
• Est. completion date: April 2028

Study information

• Verified date: April 2024
• Source: Rajiv Gandhi Cancer Institute & Research Center, India
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

DE-HyART is a randomized, non-blinded study that assesses the effects of combining IMRT (using SIB-Sequential planning) with dose-escalation to hypoxic sub-volume delineated using [18-F] FMISO. The treatment protocol will also include concurrent chemotherapy with cisplatin at standard uniform dosing.

Patients with HNSCC whose cancer is determined to originate from the oral cavity, oropharynx, larynx, and hypopharynx will be selected. The included patients will be subjected to [18F] FMISO scan, labeled as baseline FMISO. Depending upon the result of the baseline FMISO, the patient will be either hypoxic or anoxic. Patients exhibiting no hypoxia in their tumor will be labeled as Arm 1 and act as an external cohort. Patients with hypoxia will be randomized (1:1) into two arms - Arms 2 and 3. Both arms will be subjected to chemoradiation by IMRT and concurrent chemotherapy with cisplatin at 40mg/m2. In Arm 3, the trial arm will receive an additional 10 Gy @ 2 Gy per fraction in phase II (total 80 Gy) to the HSV + 5mm isotropic margin.

One twenty-four patients will recruited in a 1:1 fashion between Arm 3 and Arm 2. The primary endpoint will be locoregional control and its possible increase in control.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 124
• Est. completion date: April 2028
• Est. primary completion date: April 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• 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

• Nutritional and dental assessment before inclusion into the study

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Head and Neck Squamous Cell Carcinoma
• Hypoxia
• Squamous Cell Carcinoma of Head and Neck

Intervention

Radiation:
• DE-HyART
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.
• Standard Arm
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.

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

Radiation:
• Standard fractionation (Radiation Oncology preference)
Standard institutional practice is detailed before starting the patient. Doses 66-70 Gy over 6-7 weeks

Locations

Country	Name	City	State
India	Rajiv Gandhi Cancer Institute and Research Centre	Delhi

Sponsors (2)

Lead Sponsor	Collaborator
Rajiv Gandhi Cancer Institute & Research Center, India	Varian, a Siemens Healthineers Company

Country where clinical trial is conducted

India, 

References & Publications (17)

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. — View Citation

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. — View Citation

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. — View Citation

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 nec — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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? — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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 — View Citation

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. — View Citation

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. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Acute toxicity	The acute toxicity will be measured by Common Terminology Criteria for Adverse Events (CTCAE) v5.0	Till 6 months of finishing radiotherapy
Other	Late toxicity assessment	Measuring scale: (RTOG/European Organisation for the Research and Treatment of Cancer late toxicity criteria)	At 1 year and 2 year follow-up
Other	Patient-reported outcome	EORTC QLQ-C30 and QLQ-H and N35	During treatment, at 3 month and 6 month interval of completion of radiotherapy
Primary	Locoregional Control (LRC)	The duration of LRC was defined from the date of randomisation to the first histopathologically proven relapse of locoregional disease. If there is no proven recurrence, the LRC duration will be cut-off at the analysis point.	Disease recurrence locally or analysis cut-off point. The analysis cut off pint is 24 months
Secondary	Overall Survival (OS)	The duration of OS was defined from the date of surgery to death from any cause. Therefore, if there is no death (for any reason), the OS duration will be cut-off at the analysis.	Death during following up or analysis cut-off point. The analysis cut off pint is 24 months