Elsevier

Radiotherapy and Oncology

Volume 85, Issue 1, October 2007, Pages 156-170
Radiotherapy and Oncology

Educational review
Evidence-based radiation oncology in head and neck squamous cell carcinoma

https://doi.org/10.1016/j.radonc.2007.04.002Get rights and content

Abstract

Background and purpose

Historically, radiation therapy (RT) has been an available treatment option for patients with early resectable head and neck squamous cell carcinoma (HNSCC) and the sole therapy for those with unresectable or inoperable disease. Recently, four noteworthy strategies have emerged for the improvement of therapeutic outcome in the curative treatment of HNSCC: they include the development of altered fractionation radiotherapy, integration of chemotherapy with radiotherapy, incorporation of intensity-modulated radiotherapy and the introduction of targeted biological therapy. These strategies are briefly reviewed in an effort to help interpret evidence-based data and to facilitate clinical-decision making in a clinical context.

Materials and methods

For patients with early stage HNSCC no level 1 study exists in which radiation therapy is compared with conservative surgery for the evaluation of local control or survival. Only evidence from prospective and retrospective cohort studies is available to evaluate the role external radiotherapy and/or brachytherapy currently play in limited disease. For patients with locally advanced HNSCC the recommendations to address the questions about better treatment in resectable and unresectable tumors are based on more than 100 randomized Phase III trials included in six meta-analyses on chemo-radiotherapy and/or altered fractionation. Data from phase II trials and cohort studies help interpret the advances in intensity-modulated radiotherapy.

Results

External radiotherapy and/or brachytherapy are crucial treatment options in patients with early stage HNSCC. For patients with locally advanced HNSCC, where outcome with conventional radiotherapy is poor, meta-analyses and collective data showed that loco-regional control may be improved at high level of evidence by altered fractionation radiotherapy, chemo-radiotherapy with concomitant approach or association of selected hypoxic cell radiosensitizer with radiotherapy. For these patients, overall survival may be improved at high level of evidence by concomitant chemo-radiotherapy or hyperfractionated RT delivered with increased total dose. Also EGFR-inhibitors (cetuximab)-radiotherapy strategy offers at a lower level of evidence better loco-regional control and overall survival than radiotherapy alone. Chemo-radiotherapy programs can achieve an improved larynx-function preservation program without the risk of overall survival reduction, for patients with larynx or hypopharynx tumors who are candidates to radical surgery followed by radiotherapy. Recently, strong evidence for an improved outcome for high-risk resected patients has been shown by the use of adjuvant concomitant chemo-radiotherapy. Despite improved results, a higher severe toxicity has been largely evidenced with concomitant chemo-radiotherapy by reducing the gain in the therapeutic index with new treatment strategies. Three-dimensional conformal radiotherapy is the minimal standard of technique in HNSCC: however, as advances are promising, intensity-modulated radiotherapy should be largely implemented.

Conclusions

Stepwise improvements in HNSCC non-surgical therapy have shown favorable impact on loco-regional control and overall survival. However, despite hundreds of clinical trials in patients with advanced disease, there is no absolute consensus about patient selection for altered fractionation regimens, type of chemo-radiotherapy association, radiation or chemotherapy dose schedule. Nevertheless, many well-conducted clinical studies have expanded therapy options besides standard radiotherapy and have contributed to defining the evolving standard of care for patients with HNSCC.

Section snippets

Goals in head and neck SCC management

The management of patients with HNSCC should be a multidisciplinary approach, including mainly surgeons, radiation oncologists, medical oncologists, clinical nurse specialists, speech and language specialists, and dieticians [57]. Several methods for the treatment of HNSCC are employed including surgery, radiotherapy, chemotherapy and novel targeted therapies. Factors that influence the choice of treatment are the primary site, grade of differentiation, stage classification, patient’ age and

Search strategy and selection criteria

Data for this review were identified by search of PubMed and references from articles using the search terms “head and neck cancer”, “radiotherapy” and “randomized trial”. Only relevant papers published in English from 1995 to September 2006 were included. Literature data concerning treatment of nasopharynx cancer were not included in this review.

Open questions

The following questions about HNSCC are frequently addressed in the radiotherapy community:

  • (1)

    Is radiotherapy a treatment option in patients with early disease?

  • (2)

    Is conventional radiotherapy still a treatment option in advanced disease?

  • (3)

    Is altered fractionation radiotherapy (hyperfractionation/accelerated regimen) better than conventional RT in advanced disease?

  • (4)

    Is chemo-radiotherapy better than conventional RT in advanced disease? Can chemo-radiotherapy offer reasonable potential for larynx-function

EBM for radiotherapy in early disease

For patients with early stage HNSCC no level 1 study exists in which radiation therapy is compared with conservative surgery for the evaluation of local control or survival. Only evidence from prospective and retrospective cohort studies is available to evaluate the role external radiotherapy and/or brachytherapy currently play in limited disease. Conventional radiotherapy has remained a mainstay in the treatment of patients with early disease for decades; the doses historically employed (60–70 

Summary of evidenced treatment options for clinical management

To draw definitive conclusions on the basis of evidence-based radiotherapy in Head and Neck Cancer is not an easy task since different strategies have shown similar results in clinically advanced disease [4], [18], [31]. To better interpret the literature data the NCI evidence-based levels [76], [89] of different treatment options in locally advanced HNSCC are presented in Table 4. In details, according to different clinical end-points, specific sites or programs, collected data have proven the

Criticisms on chemo-radiotherapy and perspectives

As concomitant chemo-radiotherapy appears to be the major treatment of choice for the patients with locally advanced HNSCC [81] many critical aspects exist, briefly reported as follows:

  • 1.

    no clear indications exist that combining radiation with multiagent chemotherapy is better than irradiation plus high dose cisplatin [18];

  • 2.

    the optimal time-dose regimen has not yet been defined for this approach [4];

  • 3.

    chemo-radiotherapy significantly increases the intensity and length of mucosal reaction [18], [25]

Conclusions

Stepwise improvements in head and neck cancer therapy have shown favorable impact on these complex malignancies. Nevertheless, though the recent outcome improvements with altered radiation fractionation and chemo-radiotherapy for advanced disease appear quite clear, the overall impact on the broad HNSCC population is still not acceptable. Specifically, therapeutic ratio of different strategies may remain low since acute and consequential toxicity induced by intensified therapies critically

References (103)

  • F. Eschwege et al.

    Results of a European trial of etanidazole combined with radiotherapy in head and neck carcinomas

    Int J Radiat Oncol Biol Phys

    (1997)
  • J. Fazekas et al.

    Failure of misonidazole-sensitized radiotherapy to impact upon Stage III–IV squamous cancers of the head and neck

    Int J Radiat Oncol Biol Phys

    (1987)
  • J.F. Fowler et al.

    Loss of local control with prolongation in radiotherapy

    Int J Radiat Oncol Biol Phys

    (1992)
  • K.K. Fu et al.

    A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003

    Int J Radiat Oncol Biol Phys

    (2000)
  • D.R. Gandara et al.

    Tirapazamine: the prototype for a novel class of therapeutic agent targeting tumor hypoxia

    Semin Oncol

    (2002)
  • V. Gregoire et al.

    CT-based delineation of lymph node levels and related CTVs in the node negative neck: DAHANCA, EORTC, GORTEC, NCIC, RTOG consensus guidelines

    Radiother Oncol

    (2003)
  • V. Gregoire et al.

    Intensity Modulated Radiation Therapy in head and neck squamous cell carcinoma: state of art and future challenges

    Cancer Radiother

    (2005)
  • V. Gregoire et al.

    Proposal for the delineation of the nodal CTV in the node-positive and post-operative neck

    Radiother Oncol

    (2006)
  • P.M. Harari

    Promising new advances in head and neck radiotherapy

    Ann Oncol

    (2005)
  • T. Hehr et al.

    Hyperfractionated, accelerated chemoradiation with concurrent mitomycin-C and cisplatin in locally advanced head and neck cancer, a phase I/II study

    Radiother Oncol

    (2006)
  • S. Kumar et al.

    Concomitant boost radiotherapy with concurrent weekly cisplatin in advanced head and neck cancers: a phase I–II trial

    Radiother Oncol

    (2005)
  • G. Lammering

    Molecular predictor and promising target: will EGFR now become a star in radiotherapy?

    Radiother Oncol

    (2005)
  • M. Lapeyre et al.

    Propositions for the selection and the delineation of peritumoral microscopic disease volumes in oral cavity and oropharyngeal cancers (lymph nodes excluded)

    Cancer Radiother

    (2005)
  • T.S. Lawrence et al.

    The mechanism of action of radiosensitization of conventional chemotherapeutic agents

    Semin Radiat Oncol

    (2003)
  • D.J. Lee et al.

    Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinoma

    Int J Radiat Oncol Biol Phys

    (1995)
  • L. Licitra et al.

    Is there still a role for neo-adjuvant chemotherapy in head and neck cancer?

    Ann Oncol

    (2004)
  • J.A. Medina et al.

    A phase II study of concomitant boost radiation plus concurrent weekly cisplatin for locally advanced unresectable head and neck carcinomas

    Radiother Oncol

    (2006)
  • M. Nordsmark et al.

    Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy: an international multi-center study

    Radiother Oncol

    (2005)
  • J. Overgaard et al.

    Misonidazole combined with split-course radiotherapy in the treatment of invasive carcinoma of the larynx and pharynx: report from the DAHANCA 2 study

    Int J Radiat Oncol Biol Phys

    (1989)
  • J. Overgaard et al.

    A randomized double-blind phase III study of nimorazole as hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results from the Danish Head and Neck Cancer Study (DAHANCA). Protocol 5–85

    Radiother Oncol

    (1998)
  • J. Overgaard et al.

    Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of the head and neck: DAHANCA 6 & 7 randomised controlled trial

    Lancet

    (2003)
  • J. Overgaard et al.

    Plasma osteopontin, hypoxia and response to the hypoxia sensitizer nimorazole in radiotherapy of head and neck cancer: results from the DAHANCA 5 randomises double-blind placebo-controlled trial

    Lancet Oncol

    (2005)
  • J.P. Pignon et al.

    Chemotherapy added to loco-regional treatment for head and neck squamous cell carcinoma: three meta-analyses of update individual data

    Lancet

    (2000)
  • J.P. Pignon et al.

    Individual patient data meta-analyses in head and neck carcinoma: what have we learnt?

    Cancer Radiother

    (2005)
  • G. Sanguineti et al.

    Accelerated versus conventional fractionated postoperative radiotherapy for advanced head and neck cancer: results of a multicenter Phase III study

    Int J Radiat Oncol Biol Phys

    (2005)
  • K. Saarilahti et al.

    Intensity modulated radiotherapy for head and neck cancer: evidence for preserved salivary gland function

    Radiother Oncol

    (2005)
  • K. Skladowski et al.

    Clinical radiobiology of glottic T1 squamous cell carcinoma

    Radiother Oncol

    (1999)
  • L. Smid et al.

    Postoperative concomitant irradiation and chemotherapy with mitomycin C and bleomycin for advanced head and neck carcinoma

    Int J Radiat Oncol Biol Phys

    (2003)
  • J. Widder et al.

    Hyperfractionated accelerated radiochemotherapy (HFA-RCT) with mitomycin C for advanced head and neck cancer

    Radiother Oncol

    (2004)
  • R. Suwinski et al.

    Randomized clinical trial on continuous 7-day-a week postoperative radiotherapy for high risk squamous cell head and neck cancer: a report on acute normal tissue reactions

    Radiother Oncol

    (2005)
  • J.C. Wadsley et al.

    Investigation of relationship between change in loco-regional control and change in overall survival in randomized controlled trials or modified radiotherapy in head and neck cancer

    Int J Radiat Oncol Biol Phys

    (2004)
  • D.J. Adelstein et al.

    An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer

    J Clin Oncol

    (2003)
  • D.J. Adelstein et al.

    Multiagent concurrent chemoradiotherapy for locoregionally advanced Squamous Cell Head and Neck Cancer: mature results from a single institution

    J Clin Oncol

    (2006)
  • Green FL, Page DL, Fleming ID et al., editors. AJCC cancer staging manual. 6th ed. New York: Springer;...
  • M. Al-Sarraf

    Treatment of locally advanced head and neck cancer: historical and critical review

    Cancer Control

    (2002)
  • K.K. Ang et al.

    Impact of epidermal growth factor receptor overexpression on survival and pattern of relapse in patients with advanced head and neck carcinoma

    Cancer Res

    (2002)
  • P. Antognoni et al.

    Altered fractionation radiotherapy in head and neck cancer: clinical issues and pitfalls of “evidence-based medicine”

    Tumori

    (2005)
  • Y. Belkacemy et al.

    Assessment of tumor radiosensitivity using functional and metabolic nuclear imaging in research and clinical practice

    Cancer Radiother

    (2006)
  • S.M. Bentzen et al.

    Epidermal Growth Factor Receptor Expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial

    J Clin Oncol

    (2005)
  • J. Bernier et al.

    Postoperative irradiation with or without concomitant chemotherapy for locally advanced Head and Neck Cancer

    N Engl J Med

    (2004)

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