Advertisement

Evaluation of risk-tailored individualized selection of radiation therapy target volume for head and neck carcinoma of unknown primary

      Highlights

      • Accurate prediction of hidden disease site is critical to allow RT volume de-escalation for HNCUP.
      • Risk-stratified RT volume de-escalation resulted in favorable outcomes.
      • Concurrent chemotherapy was associated with better DFS and OS in cN2-3 HNCUP.

      Abstract

      Purpose

      Intensity-modulated radiation therapy (IMRT) has enabled risk-tailored approach to elective mucosal and nodal clinical target volumes (CTVs) in treatment of head and neck carcinoma of unknown primary (HNCUP). This study report outcomes following such approach.

      Methods

      HNCUP patients treated with definitive IMRT between 2005 and 2018 were reviewed. Local failure (LF), regional failure (RF), distant metastasis (DM), overall survival (OS) and grade ≥3 late toxicity (LT) were analyzed. Multivariable analysis (MVA) was used to identify OS predictors for entire cohort and cN2-3 subgroup.

      Results

      A total of 203 patients were eligible: cN1 (7%), cN2a (14%), cN2b (46%), cN2c (14%) and cN3 (19%). Among 118 patients with known HPV status (by p16 staining), 81 (68%) were positive. IMRT target volume spared contralateral tonsil (55%), bilateral or contralateral sides of hypopharynx (72%), nasopharynx (72%), larynx (87%) and contralateral uninvolved neck (21%). Median follow-up was 5 years. Five-year LF, RF, DM, OS, and LT were 3%, 14%, 10%, 79%, and 7% respectively. Four patients developed mucosal recurrence: 3 within and 1 at the margin of the elective mucosal CTV. None of ipsilateral neck irradiation patients failed in the contralateral uninvolved neck. MVA identified cN2c-N3, HPV-negative status and older age as predictors for inferior OS. Within cN2-3 subgroup (n = 189): cN2c-N3, HPV-negative status and older age predicted lower OS, while concurrent chemotherapy was associated with better OS.

      Conclusion

      Definitive IMRT with risk-adaptive radiation volume de-escalation for HNCUP resulted in high probability of tumor control with acceptable rate of late toxicity.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Radiotherapy and Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Amsbaugh M.J.
        • Yusuf M.
        • Gaskins J.
        • Silverman C.
        • Potts K.
        • Bumpous J.
        • et al.
        Neck dissection for unknown cancer of the head and neck in the era of chemoradiation.
        Am J Otolaryngol. 2017; 38: 588-592
        • Jereczek-Fossa B.A.
        • Jassem J.
        • Orecchia R.
        Cervical lymph node metastases of squamous cell carcinoma from an unknown primary.
        Cancer Treat Rev. 2004; 30: 153-164
        • Maghami E.
        • Ismaila N.
        • Alvarez A.
        • Chernock R.
        • Duvvuri U.
        • Geiger J.
        • et al.
        Diagnosis and management of squamous cell carcinoma of unknown primary in the head and neck: ASCO guideline.
        J Clin Oncol. 2020; 38: 2570-2596
        • Cabrera Rodríguez J.
        • Cacicedo J.
        • Giralt J.
        • García Miragall E.
        • Lloret M.
        • Arias F.
        • et al.
        GEORCC recommendations on target volumes in radiotherapy for Head Neck Cancer of Unkown Primary.
        Crit Rev Oncol Hematol. 2018; 130: 51-59
        • Carlson L.S.
        • Fletcher G.H.
        • Oswald M.J.
        Guidelines for radiotherapeutic techniques for cervical metastases from an unknown primary.
        Int J Radiat Oncol Biol Phys. 1986; 12: 2101-2110
        • Fletcher G.H.
        Controversial issues in the management of cervical metastases.
        Int J Radiat Oncol Biol Phys. 1990; 19: 1101-1102
        • Grau C.
        • Johansen L.V.
        • Jakobsen J.
        • Geertsen P.
        • Andersen E.
        • Jensen B.B.
        Cervical lymph node metastases from unknown primary tumours. Results from a national survey by the Danish Society for Head and Neck Oncology.
        Radiother Oncol. 2000; 55: 121-129
        • Reddy S.P.
        • Marks J.E.
        Metastatic carcinoma in the cervical lymph nodes from an unknown primary site: results of bilateral neck plus mucosal irradiation vs. ipsilateral neck irradiation.
        Int J Radiat Oncol Biol Phys. 1997; 37: 797-802
        • Fakhrian K.
        • Thamm R.
        • Knapp S.
        • Molls M.
        • Pigorsch S.
        • Haller B.
        • et al.
        Radio(chemo)therapy in the management of squamous cell carcinoma of cervical lymph nodes from an unknown primary siteRadio(chemo)therapie von Patienten mit zervikalen Lymphknotenmetastasen eines Plattenepithelkarzinoms bei unbekanntem Primärtumor: Eine retrospektive Analyse. A retrospective analysis.
        Strahlenther Onkol. 2012; 188: 56-61
        • Ligey A.
        • Gentil J.
        • Créhange G.
        • Montbarbon X.
        • Pommier P.
        • Peignaux K.
        • et al.
        Impact of target volumes and radiation technique on loco-regional control and survival for patients with unilateral cervical lymph node metastases from an unknown primary.
        Radiother Oncol. 2009; 93: 483-487
        • Nieder C.
        • Gregoire V.
        • Ang K.K.
        Cervical lymph node metastases from occult squamous cell carcinoma: cut down a tree to get an apple?.
        Int J Radiat Oncol Biol Phys. 2001; 50: 727-733
        • Hu K.S.
        • Mourad W.F.
        • Gamez M.E.
        • Lin W.
        • Jacobson A.S.
        • Persky M.S.
        • et al.
        Five-year outcomes of an oropharynx-directed treatment approach for unknown primary of the head and neck.
        Oral Oncol. 2017; 70: 14-22
        • Strojan P.
        • Ferlito A.
        • Langendijk J.A.
        • Corry J.
        • Woolgar J.A.
        • Rinaldo A.
        • et al.
        Contemporary management of lymph node metastases from an unknown primary to the neck: II. A review of therapeutic options.
        Head Neck. 2013; 35: 286-293
        • Ren J.
        • Yang W.
        • Su J.
        • Ren X.
        • Fazelzad R.
        • Albert T.
        • et al.
        Human papillomavirus and p16 immunostaining, prevalence and prognosis of squamous carcinoma of unknown primary in the head and neck region.
        Int J Cancer. 2019; 145: 1465-1474
        • Jemal A.
        • Bray F.
        • Center M.M.
        • Ferlay J.
        • Ward E.
        • Forman D.
        Global cancer statistics.
        CA Cancer J Clin. 2011; 61: 69-90
        • Feinmesser R.
        • Miyazaki I.
        • Cheung R.
        • Freeman J.L.
        • Noyek A.M.
        • Dosch H.-M.
        Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration.
        N Engl J Med. 1992; 326: 17-21
        • Macdonald M.R.
        • Freeman J.L.
        • Hui M.F.
        • Cheung R.K.
        • Warde P.
        • McLvor N.P.
        • et al.
        Role of Epstein-Barr virus in fine-needle aspirates of metastatic neck nodes in the diagnosis of nasopharyngeal carcinoma.
        Head Neck. 1995; 17: 487-493
        • Bussu F.
        • Sali M.
        • Gallus R.
        • et al.
        HPV and EBV infections in neck metastases from occult primary squamous cell carcinoma: another virus-related neoplastic disease in the head and neck region.
        Ann Surg Oncol. 2015; 22: 979-984
        • Billfalk-Kelly A.
        • Yu E.
        • Su J.
        • O'Sullivan B.
        • Waldron J.
        • Ringash J.
        • et al.
        Radiologic extranodal extension portends worse outcome in cN+ TNM-8 stage I human papillomavirus-mediated oropharyngeal cancer.
        Int J Radiat Oncol Biol Phys. 2019; 104: 1017-1027
        • Frank S.J.
        • Rosenthal D.I.
        • Petsuksiri J.
        • Ang K.K.
        • Morrison W.H.
        • Weber R.S.
        • et al.
        Intensity-modulated radiotherapy for cervical node squamous cell carcinoma metastases from unknown head-and-neck primary site: M. D. Anderson Cancer Center outcomes and patterns of failure.
        Int J Radiat Oncol Biol Phys. 2010; 78: 1005-1010
        • Wong K.
        • Huang S.H.
        • O’Sullivan B.
        • Lockwood G.
        • Dale D.
        • Michaelson T.
        • et al.
        Point-of-care outcome assessment in the cancer clinic: audit of data quality.
        Radiother Oncol. 2010; 95: 339-343
        • Weir L.
        • Keane T.
        • Cummings B.
        • Goodman P.
        • O'Sullivan B.
        • Payne D.
        • et al.
        Radiation treatment of cervical lymph node metastases from an unknown primary: an analysis of outcome by treatment volume and other prognostic factors.
        Radiother Oncol. 1995; 35: 206-211
        • Fitzpatrick P.J.
        • Kotalik J.F.
        Cervical metastases from an unknown primary tumor.
        Radiology. 1974; 110: 659-663
        • Hosni A.
        • Dixon P.R.
        • Rishi A.
        • Au M.
        • Xu W.
        • Song Y.
        • et al.
        Radiotherapy characteristics and outcomes for head and neck carcinoma of unknown primary vs T1 base-of-tongue carcinoma.
        JAMA Otolaryngol Head Neck Surg. 2016; 142: 1208
        • Shoushtari A.
        • Saylor D.
        • Kerr K.-L.
        • Sheng K.e.
        • Thomas C.
        • Jameson M.
        • et al.
        Outcomes of patients with head-and-neck cancer of unknown primary origin treated with intensity-modulated radiotherapy.
        Int J Radiat Oncol Biol Phys. 2011; 81: e83-e91
        • Klem M.L.
        • Mechalakos J.G.
        • Wolden S.L.
        • Zelefsky M.J.
        • Singh B.
        • Kraus D.
        • et al.
        Intensity-modulated radiotherapy for head and neck cancer of unknown primary: toxicity and preliminary efficacy.
        Int J Radiat Oncol Biol Phys. 2008; 70: 1100-1107
        • Barker C.A.
        • Morris C.G.
        • Mendenhall W.M.
        Larynx-sparing radiotherapy for squamous cell carcinoma from an unknown head and neck primary site.
        Am J Clin Oncol. 2005; 28: 445-448
        • Lu H.
        • Yao M.
        • Tan H.
        Unknown primary head and neck cancer treated with intensity-modulated radiation therapy: to what extent the volume should be irradiated.
        Oral Oncol. 2009; 45: 474-479
        • Wallace A.
        • Richards G.M.
        • Harari P.M.
        • Kirwan J.M.
        • Morris C.G.
        • Katakam H.
        • et al.
        Head and neck squamous cell carcinoma from an unknown primary site.
        Am J Otolaryngol. 2011; 32: 286-290
        • Mehanna H.
        • Beech T.
        • Nicholson T.
        • El-Hariry I.
        • McConkey C.
        • Paleri V.
        • et al.
        Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer: systematic review and meta-analysis of trends by time and region.
        Head Neck. 2013; 35: 747-755
        • Chaturvedi A.K.
        • Engels E.A.
        • Pfeiffer R.M.
        • Hernandez B.Y.
        • Xiao W.
        • Kim E.
        • et al.
        Human papillomavirus and rising oropharyngeal cancer incidence in the United States.
        J Clin Oncol. 2011; 29: 4294-4301
        • Zengel P.
        • Assmann G.
        • Mollenhauer M.
        • Jung A.
        • Sotlar K.
        • Kirchner T.
        • et al.
        Cancer of unknown primary originating from oropharyngeal carcinomas are strongly correlated to HPV positivity.
        Virchows Arch. 2012; 461: 283-290
        • Motz K.
        • Qualliotine J.R.
        • Rettig E.
        • Richmon J.D.
        • Eisele D.W.
        • Fakhry C.
        Changes in unknown primary squamous cell carcinoma of the head and neck at initial presentation in the era of human papillomavirus.
        JAMA Otolaryngol Head Neck Surg. 2016; 142: 223
        • Mourad W.F.
        • Hu K.S.
        • Shasha D.
        • et al.
        Initial experience with oropharynx-targeted radiation therapy for metastatic squamous cell carcinoma of unknown primary of the head and neck.
        Anticancer Res. 2014; 34: 243-248
        • Sinnathamby K.
        • Peters L.J.
        • Laidlaw C.
        • et al.
        The occult head and neck primary: to treat or not to treat?.
        Clin Oncol (R Coll Radiol). 1997; 9: 322-329
        • Marcial-Vela V.A.
        • Cardenes H.
        • Perez C.A.
        • Devineni V.R.
        • Simpson J.R.
        • Fredrickson J.M.
        • et al.
        Cervical metastases from unknown primaries: radiotherapeutic management and appearance of subsequent primaries.
        Int J Radiat Oncol Biol Phys. 1990; 19: 919-928