A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head-and-neck cancer

Matthew G. Fury, Nancy Y. Lee, Eric Sherman, Alan L. Ho, Shyam Rao, Adriana Heguy, Ronglai Shen, Susan Korte, Donna Lisa, Ian Ganly, Snehal Patel, Richard J. Wong, Ashok Shaha, Jatin Shah, Sofia Haque, Nora Katabi, David G. Pfister

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Purpose Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m2 weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. Results Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. Conclusions Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins.

Original languageEnglish (US)
Pages (from-to)479-486
Number of pages8
JournalInternational Journal of Radiation Oncology Biology Physics
Volume87
Issue number3
DOIs
StatePublished - Nov 1 2013
Externally publishedYes

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Head and Neck Neoplasms
Peptide Initiation Factors
Cisplatin
radiation therapy
Radiotherapy
cancer
Maximum Tolerated Dose
protein synthesis
dosage
Neoplasms
margins
Failure to Thrive
Surgical Pathology
Mucositis
Lymphopenia
Oropharynx
Proteins
Nasopharynx
Salivary Glands
Scalp

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head-and-neck cancer. / Fury, Matthew G.; Lee, Nancy Y.; Sherman, Eric; Ho, Alan L.; Rao, Shyam; Heguy, Adriana; Shen, Ronglai; Korte, Susan; Lisa, Donna; Ganly, Ian; Patel, Snehal; Wong, Richard J.; Shaha, Ashok; Shah, Jatin; Haque, Sofia; Katabi, Nora; Pfister, David G.

In: International Journal of Radiation Oncology Biology Physics, Vol. 87, No. 3, 01.11.2013, p. 479-486.

Research output: Contribution to journalArticle

Fury, MG, Lee, NY, Sherman, E, Ho, AL, Rao, S, Heguy, A, Shen, R, Korte, S, Lisa, D, Ganly, I, Patel, S, Wong, RJ, Shaha, A, Shah, J, Haque, S, Katabi, N & Pfister, DG 2013, 'A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head-and-neck cancer', International Journal of Radiation Oncology Biology Physics, vol. 87, no. 3, pp. 479-486. https://doi.org/10.1016/j.ijrobp.2013.06.2043
Fury, Matthew G. ; Lee, Nancy Y. ; Sherman, Eric ; Ho, Alan L. ; Rao, Shyam ; Heguy, Adriana ; Shen, Ronglai ; Korte, Susan ; Lisa, Donna ; Ganly, Ian ; Patel, Snehal ; Wong, Richard J. ; Shaha, Ashok ; Shah, Jatin ; Haque, Sofia ; Katabi, Nora ; Pfister, David G. / A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head-and-neck cancer. In: International Journal of Radiation Oncology Biology Physics. 2013 ; Vol. 87, No. 3. pp. 479-486.
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abstract = "Purpose Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m2 weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. Results Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92{\%}), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. Conclusions Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins.",
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AU - Sherman, Eric

AU - Ho, Alan L.

AU - Rao, Shyam

AU - Heguy, Adriana

AU - Shen, Ronglai

AU - Korte, Susan

AU - Lisa, Donna

AU - Ganly, Ian

AU - Patel, Snehal

AU - Wong, Richard J.

AU - Shaha, Ashok

AU - Shah, Jatin

AU - Haque, Sofia

AU - Katabi, Nora

AU - Pfister, David G.

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N2 - Purpose Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. Methods and Materials This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m2 weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. Results Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. Conclusions Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins.

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