DE-HyART: Dose Escalation Using Hypoxia-adjusted Radiotherapy
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm 3 - DE-HyART 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
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.
Other Names:
Drug: Cisplatin injection
Concurrent chemotherapy, weekly Inj Cisplatin 40mg/m2. This will be given if clinically indicated
|
| Active Comparator: Arm 2 - Hypoxic Comparator 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. |
Radiation: 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.
Other Names:
Drug: Cisplatin injection
Concurrent chemotherapy, weekly Inj Cisplatin 40mg/m2. This will be given if clinically indicated
|
| Placebo Comparator: Arm 1 - Non-hypoxic arm 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
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
|
Outcome Measures
Primary Outcome Measures
- Locoregional Control (LRC) [Disease recurrence locally or analysis cut-off point. The analysis cut off pint is 24 months]
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.
Secondary Outcome Measures
- Overall Survival (OS) [Death during following up or analysis cut-off point. The analysis cut off pint is 24 months]
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.
Other Outcome Measures
- Acute toxicity [Till 6 months of finishing radiotherapy]
The acute toxicity will be measured by Common Terminology Criteria for Adverse Events (CTCAE) v5.0
- Late toxicity assessment [At 1 year and 2 year follow-up]
Measuring scale: (RTOG/European Organisation for the Research and Treatment of Cancer late toxicity criteria)
- Patient-reported outcome [During treatment, at 3 month and 6 month interval of completion of radiotherapy]
EORTC QLQ-C30 and QLQ-H and N35
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age: 18 - 70 years
-
Willingness to sign informed consent (written/video documentation)
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Performance status: ECOG 0 - 2
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Histology proved - squamous cell carcinoma
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Any grade, gender
-
Tumour sites: Oral Cavity, Oropharynx, Hypopharynx and Larynx
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Sufficient bone marrow reserve within the last 14 days.
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Hb: > 10g/dl (corrected)
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TLC: > 4,000 per cumm
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Platelet: >1.5Lakh per cumm
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Liver functions and kidney functions within normal limits
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Nutritional and dental assessment before inclusion into the study
Exclusion Criteria:
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HPV (p16) positive tumours
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Prior surgery and/or radiation therapy given for any HNC
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T1/T2 Glottis
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Metastatic disease or disease not amenable for definitive locoregional treatment.
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Medical co-morbidity hampering the administration of radiation and/or chemotherapy (cisplatin)
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Pregnancy or lactation
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Rajiv Gandhi Cancer Institute and Research Centre | Delhi | India | 110085 |
Sponsors and Collaborators
- Rajiv Gandhi Cancer Institute & Research Center, India
- Varian, a Siemens Healthineers Company
Investigators
- Principal Investigator: Munish Gairola, MD,DNB Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre
Study Documents (Full-Text)
None provided.More Information
Publications
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Res/SCM/58/2023/33