Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19805 patients, on behalf of MACH-NC group.

BACKGROUND AND PURPOSE The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. MATERIALS AND METHODS Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. RESULTS For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p<0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend=0.03). OS was not increased by the addition of induction (HR=0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend=0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR=0.84 [0.74; 0.95], p=0.005). CONCLUSION The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.

[1]  M. Parmar,et al.  Predictive classifier for intensive treatment of head and neck cancer , 2020, Cancer.

[2]  C. García-Girón,et al.  Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial , 2020, Clinical and Translational Oncology.

[3]  Rajesh Kumar,et al.  Randomized Controlled Study Comparing Efficacy and Toxicity of Weekly vs. 3-Weekly Induction Chemotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma , 2020, Frontiers in Oncology.

[4]  J. Pignon,et al.  Role of chemotherapy in 5000 patients with head and neck cancer treated by curative surgery: A subgroup analysis of the meta-analysis of chemotherapy in head and neck cancer. , 2019, Oral oncology.

[5]  Christopher U. Jones,et al.  Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial , 2019, The Lancet.

[6]  C. R. Leemans,et al.  Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial , 2019, The Lancet.

[7]  J. Pignon,et al.  Impact of missing individual patient data on 18 meta-analyses of randomised trials in oncology: Gustave Roussy experience , 2018, BMJ Open.

[8]  J. Bourhis,et al.  Induction Chemotherapy Followed by Cetuximab Radiotherapy Is Not Superior to Concurrent Chemoradiotherapy for Head and Neck Carcinomas: Results of the GORTEC 2007-02 Phase III Randomized Trial. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  R. Orecchia,et al.  Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II–III trial , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[10]  M. Parmar,et al.  Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis. , 2017, The Lancet. Oncology.

[11]  V. Grégoire,et al.  Long-term update of the 24954 EORTC phase III trial on larynx preservation. , 2016, European journal of cancer.

[12]  V. Budach,et al.  Standard or split TPF induction chemotherapy followed by bioradiation: ICRAT randomized phase II study. , 2016 .

[13]  P. Pai,et al.  Conventional radiotherapy versus concurrent chemoradiotherapy versus accelerated radiotherapy in locoregionally advanced carcinoma of head and neck: Results of a prospective randomized trial , 2016, Head & neck.

[14]  Jian Sun,et al.  Long-term results of a randomized phase III trial of TPF induction chemotherapy followed by surgery and radiation in locally advanced oral squamous cell carcinoma , 2015, Oncotarget.

[15]  Jun Ma,et al.  Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. , 2015, The Lancet. Oncology.

[16]  Richard D Riley,et al.  Preferred Reporting Items for a Systematic Review and Meta-analysis of Individual Participant Data: The PRISMA-IPD Statement , 2015 .

[17]  E. Hitre,et al.  Docetaxel, cisplatin and 5-fluorouracil induction chemotherapy followed by chemoradiotherapy or chemoradiotherapy alone in stage III–IV unresectable head and neck cancer , 2015, Strahlentherapie und Onkologie.

[18]  E. Vokes,et al.  Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  C. García-Girón,et al.  A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  Pierre Blanchard,et al.  Taxane-cisplatin-fluorouracil as induction chemotherapy in locally advanced head and neck cancers: an individual patient data meta-analysis of the meta-analysis of chemotherapy in head and neck cancer group. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  F. Khuri,et al.  Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. , 2013, The Lancet. Oncology.

[22]  R. Weber,et al.  Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  W. Guo,et al.  Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  K. Ang,et al.  Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. , 2012, International journal of radiation oncology, biology, physics.

[25]  J. Bernier,et al.  Concomitant cisplatin and hyperfractionated radiotherapy in locally advanced head and neck cancer: 10-year follow-up of a randomized phase III trial (SAKK 10/94). , 2010, International journal of radiation oncology, biology, physics.

[26]  J. Cooper,et al.  Phase III study of radiation therapy with or without cis-platinum in patients with unresectable squamous or undifferentiated carcinoma of the head and neck: an intergroup trial of the Eastern Cooperative Oncology Group (E2382). , 2011, International journal of radiation oncology, biology, physics.

[27]  N. Datta,et al.  8512 POSTER DISCUSSION A Three-Arm Randomized Trial Comparing Neo-Adjuvant or Concurrent Weekly Cisplatin to Radiotherapy Alone for Locally Advanced Head and Neck Squamous Cell Cancer (HNSCC) , 2011 .

[28]  J F Tierney,et al.  A critical review of methods for the assessment of patient-level interactions in individual participant data meta-analysis of randomized trials, and guidance for practitioners. , 2011, Journal of clinical epidemiology.

[29]  J. Bourhis,et al.  Accelerated radiotherapy and concomitant high dose chemotherapy in non resectable stage IV locally advanced HNSCC: results of a GORTEC randomized trial. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[30]  B. Mohanti,et al.  Concomitant chemoradiation versus radical radiotherapy in advanced squamous cell carcinoma of oropharynx and nasopharynx using weekly cisplatin: a phase II randomized trial. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[31]  A. Paccagnella,et al.  Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[32]  R. Orecchia,et al.  Radiotherapy Alone or with Concomitant Daily Low-Dose Carboplatin in Locally Advanced, Unresectable Head and Neck Cancer: Definitive Results of a Phase III Study with a Follow-Up Period of up to Ten Years , 2010, Tumori.

[33]  A. Hackshaw,et al.  Chemoradiotherapy for locally advanced head and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial , 2009, The Lancet. Oncology.

[34]  J. Pignon,et al.  Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. , 2009, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[35]  J. Horiot,et al.  Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy. , 2009, Journal of the National Cancer Institute.

[36]  G. Calais,et al.  Randomized clinical trial of post-operative radiotherapy versus concomitant carboplatin and radiotherapy for head and neck cancers with lymph node involvement. , 2008, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[37]  D. Heron,et al.  Long‐Term Results of a Phase III Randomized Trial of Postoperative Radiotherapy With or Without Carboplatin in Patients With High‐Risk Head and Neck Cancer , 2008, The Laryngoscope.

[38]  M. Žargi,et al.  Patterns of failure in patients with locally advanced head and neck cancer treated postoperatively with irradiation or concomitant irradiation with Mitomycin C and Bleomycin. , 2007, International journal of radiation oncology, biology, physics.

[39]  N. Magné,et al.  French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC-GORTEC). , 2006, International journal of radiation oncology, biology, physics.

[40]  P. Wust,et al.  Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer: final results of the radiotherapy cooperative clinical trials group of the German , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  K. Rufibach,et al.  Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  A. Paccagnella,et al.  Randomized phase III trial of neoadjuvant chemotherapy in head and neck cancer: 10-year follow-up. , 2004, Journal of the National Cancer Institute.

[43]  J. Jacobs,et al.  Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. , 2004, The New England journal of medicine.

[44]  Jacques Bernier,et al.  Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. , 2004, The New England journal of medicine.

[45]  L. Kowalski,et al.  A randomized trial of neoadjuvant vs concomitant chemotherapy vs radiotherapy alone in the treatment of stage IV head and neck squamous cell carcinoma , 1992, European Archives of Oto-Rhino-Laryngology.

[46]  George Fountzilas,et al.  Concomitant radiochemotherapy vs radiotherapy alone in patients with head and neck cancer , 2004, Medical oncology.

[47]  G. Calais,et al.  Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  R. Weber,et al.  Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. , 2003, The New England journal of medicine.

[49]  C. Grau,et al.  Radiotherapy with or without mitomycin c in the treatment of locally advanced head and neck cancer: results of the IAEA multicentre randomised trial. , 2003, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[50]  V. Torri,et al.  Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial. , 2003, International journal of radiation oncology, biology, physics.

[51]  J. Ensley,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. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  J. Giralt,et al.  A phase III double-blind randomized placebo controlled study of porfiromycin and radiation therapy in patients with head and neck cancer , 2002 .

[53]  S. Thompson,et al.  Quantifying heterogeneity in a meta‐analysis , 2002, Statistics in medicine.

[54]  R. Swindell,et al.  Concomitant methotrexate and radiotherapy in advanced head and neck cancer: 15-year follow-up of a randomized clinical trial. , 2001, Clinical oncology (Royal College of Radiologists (Great Britain)).

[55]  A. Dietz,et al.  Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer. , 2001, International journal of radiation oncology, biology, physics.

[56]  B. Coche-Déquéant,et al.  Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma , 2000, British Journal of Cancer.

[57]  J. Naude,et al.  Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancers. , 2000, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[58]  B. Jeremic,et al.  Hyperfractionated Radiation Therapy With or Without Concurrent Low-Dose Daily Cisplatin in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Prospective Randomized Trial , 2000 .

[59]  J. Bourhis,et al.  Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data , 2000, The Lancet.

[60]  M. Secic,et al.  Mature results of a Phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with Stage III and IV squamous cell carcinoma of the head and neck , 2000, Cancer.

[61]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[62]  A. Huang,et al.  Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. , 1998, The New England journal of medicine.

[63]  T. Wendt,et al.  Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  B. Jeremic,et al.  Radiation therapy alone or with concurrent low-dose daily either cisplatin or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck: a prospective randomized trial. , 1997, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[65]  U. Ringborg,et al.  Neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the head and neck: a randomized phase III study. , 1997, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[66]  E. Cohen-Jonathan,et al.  Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. , 1996, International journal of radiation oncology, biology, physics.

[67]  M Schemper,et al.  A note on quantifying follow-up in studies of failure time. , 1996, Controlled clinical trials.

[68]  V. Vitale,et al.  Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. , 1996, Journal of the National Cancer Institute.

[69]  J. Mazeron,et al.  Comparaison d'une association radiothérapie-chimiothérapie concomitante et d'une radiothérapie seule dans les cancers avancés des voies aérodigestives supérieures: résultat d'un essai randomisé , 1996 .

[70]  D. Belpomme,et al.  Cancers de la base de langue et de l'hypopharynx: résultats d'un essai multicentrique randomisé de chimiothérapie avant traitement locorégional , 1996 .

[71]  N. Datta,et al.  Feasibility of non-cisplatin-based induction chemotherapy and concurrent chemoradiotherapy in advanced head and neck cancer. , 1996, Acta oncologica.

[72]  Anthony Howell,et al.  Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. , 1995, The New England journal of medicine.

[73]  L. Stewart,et al.  Practical methodology of meta-analyses (overviews) using updated individual patient data. Cochrane Working Group. , 1995, Statistics in medicine.

[74]  M. Žargi,et al.  Radiotherapy, combined with simulataneous chemotherapy with Mitomycin C and bleomycin for inoperable head and neck cancer—preliminary report , 1995 .

[75]  A. Geater,et al.  Combination chemotherapy as induction therapy for advanced resectable head and neck cancer , 1995, Journal of surgical oncology.

[76]  L. Eapen,et al.  Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[77]  V. Deshmane,et al.  Perioperative chemotherapy in patients with oral cancer. , 1994, American journal of surgery.

[78]  H. Sakamoto,et al.  [Multiple cooperative study of UFT-adjuvant chemotherapy for malignant tumor in the jaw and oral cavities. The Oral Surgery Malignant Tumor Research Association in Kanto Kohshinetsu District]. , 1994, Gan to kagaku ryoho. Cancer & chemotherapy.

[79]  E. Stennert,et al.  Induction chemotherapy in primary resectable head and neck tumors - a prospective randomized trial. , 1994, International journal of oncology.

[80]  A. Paccagnella,et al.  Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. , 1994, Journal of the National Cancer Institute.

[81]  E. Vokes,et al.  Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[82]  J. Mazeron,et al.  A randomized study of CDDP and 5-FU as Neo-Adjuvant chemotherapy in head and neck cancer: an interim analysis , 1994 .

[83]  J. Depondt,et al.  Neoadjuvant chemotherapy with carboplatin/5-fluorouracil in head and neck cancer. , 1993, Oncology.

[84]  B. O'Sullivan,et al.  A randomized trial of radiation therapy compared to split course radiation therapy combined with mitomycin C and 5 fluorouracil as initial treatment for advanced laryngeal and hypopharyngeal squamous carcinoma. , 1993, International journal of radiation oncology, biology, physics.

[85]  S. Rockwell,et al.  Mitomycin C as an adjunct to postoperative radiation therapy in squamous cell carcinoma of the head and neck: results from two randomized clinical trials. , 1993, International journal of radiation oncology, biology, physics.

[86]  G. Sanguineti,et al.  Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. , 1992, The New England journal of medicine.

[87]  J. Aguiar,et al.  Induction chemotherapy with carboplatin and ftorafur in advanced head and neck cancer. A randomized study. , 1992, American journal of clinical oncology.

[88]  F. Baillet,et al.  Neoadjuvant combination of carboplatin and 5-FU in head and neck cancer: a randomized study. , 1992, Annals of oncology : official journal of the European Society for Medical Oncology.

[89]  B. Qaqish,et al.  Simultaneous chemoradiation in the treatment of advanced head and neck cancer. , 1992, Archives of otolaryngology--head & neck surgery.

[90]  B. Morrica,et al.  [Chemo-radiotherapy in advanced head and neck tumors. Personal experience]. , 1992, La Radiologia medica.

[91]  P. Piedbois,et al.  Induction chemotherapy in head and neck cancer: Results of a phase III trial , 1992, Head & neck.

[92]  Early Breast Cancer Trialists' Collaborative Group.  Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy 133 randomised trials involving 31 000 recurrences and 24 000 deaths among 75 000 women , 1992, The Lancet.

[93]  P. Validire,et al.  Induction chemotherapy in advanced head and neck tumors: results of two randomized trials. , 1992, International journal of radiation oncology, biology, physics.

[94]  J. Jacobs,et al.  Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: report on Intergroup Study 0034. , 1992, International journal of radiation oncology, biology, physics.

[95]  T. Kozuka,et al.  [A comparative clinical study of adjuvant chemotherapy of tumors in the head and neck areas by means of HCFU]. , 1991, Gan to kagaku ryoho. Cancer & chemotherapy.

[96]  U. Nastasi,et al.  [The use of cisplatin as radiosensitizing agent in advanced tumors of the head and neck. Randomized study]. , 1991, La Radiologia medica.

[97]  A. Kramar,et al.  Randomised EORTC head and neck cooperative group trial of preoperative intra-arterial chemotherapy in oral cavity and oropharynx carcinoma. , 1991, European journal of cancer.

[98]  R. Corvò,et al.  Combined chemotherapy and radiation therapy in advanced inoperable squamous cell carcinoma of the head and neck. The final report of a randomized trial , 1991, Cancer.

[99]  J. Torner,et al.  Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer. , 1990, International journal of radiation oncology, biology, physics.

[100]  J. Mazeron,et al.  Randomized study of 5 fluorouracil and cis platin as neoadjuvant therapy in head and neck cancer: a preliminary report. , 1990, International journal of radiation oncology, biology, physics.

[101]  O. Dalesio,et al.  A randomized EORTC study on the effect of preoperative polychemotherapy in pyriform sinus carcinoma treated by pharyngolaryngectomy and irradiation. Results from 5 to 10 years. , 1990, Acta chirurgica Belgica.

[102]  D. Adelstein,et al.  Simultaneous versus sequential combined technique therapy for squamous cell head and neck cancer , 1990, Cancer.

[103]  S. Rockwell,et al.  Randomized clinical trial of mitomycin C as an adjunct to radiotherapy in head and neck cancer. , 1989, International journal of radiation oncology, biology, physics.

[104]  B. Asselain,et al.  Induction chemotherapy in advanced head and neck cancer. Preliminary results of a randomized study. , 1989, Acta oncologica.

[105]  D. Schuller,et al.  Preoperative chemotherapy in advanced resectable head and neck cancer: Final report of the southwest oncology group , 1988, The Laryngoscope.

[106]  F. Eschwège,et al.  Ten-year results of randomized trial comparing radiotherapy and concomitant bleomycin to radiotherapy alone in epidermoid carcinomas of the oropharynx: experience of the European Organization for Research and Treatment of Cancer. , 1988, NCI monographs : a publication of the National Cancer Institute.

[107]  P. Wilkinson,et al.  A randomised clinical trial to contrast radiotherapy with radiotherapy and methotrexate given synchronously in head and neck cancer. , 1987, Clinical radiology.

[108]  J. Cox,et al.  Cisplatin and fluorouracil as neoadjuvant therapy in head and neck cancer. A preliminary report. , 1987, Archives of otolaryngology--head & neck surgery.

[109]  R. Hoffmann,et al.  The effects of delay in standard treatment due to induction chemotherapy in two randomized prospective studies , 1987, The Laryngoscope.

[110]  R. Makuch,et al.  Adjuvant chemotherapy for advanced head and neck squamous carcinoma. Final report of the Head and Neck Contracts Program. , 1986, Cancer.

[111]  R. Weichselbaum,et al.  An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck. , 1987, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[112]  R. Hoffmann,et al.  A randomized study of adjuvant chemotherapy for cancer of the upper aerodigestive tract. , 1986, International journal of radiation oncology, biology, physics.

[113]  A randomized trial of combined multidrug chemotherapy and radiotherapy in advanced squamous cell carcinoma of the head and neck. An interim report from the SECOG participants. South-East Co-operative Oncology Group. , 1986, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[114]  A. Meyers,et al.  A prospective study of preoperative chemotherapy and split‐course irradiation for locally advanced or recurrent oral/pharyngeal squamous carcinoma , 1985, American journal of clinical oncology.

[115]  R. G. Hoffman,et al.  Randomized Study of Adjuvant Chemotherapy for Head and Neck Cancer , 1985, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[116]  O. Kaalhus,et al.  Bleomycin and radiation therapy in squamous cell carcinoma of the upper aero-digestive tract: a phase III clinical trial. , 1985, International journal of radiation oncology, biology, physics.

[117]  R. Peto,et al.  Beta blockade during and after myocardial infarction: an overview of the randomized trials. , 1985, Progress in cardiovascular diseases.

[118]  L. Parvinen,et al.  Combined bleomycin treatment and radiation therapy in squamous cell carcinoma of the head and neck region. , 1985, Acta radiologica. Oncology.

[119]  W. Bezwoda,et al.  Treatment of advanced head and neck cancer: multiple daily dose fractionated radiation therapy and sequential multimodal treatment approach. , 1984, Medical and pediatric oncology.

[120]  J. Fazekas,et al.  Adjuvant intravenous methotrexate or definitive radiotherapy alone for advanced squamous cancers of the oral cavity, oropharynx, supraglottic larynx or hypopharynx. , 1980, International journal of radiation oncology, biology, physics.

[121]  K. Morita.  Clinical significance of radiation therapy combined with chemotherapy. , 1980, Strahlentherapie.

[122]  V. Shanta,et al.  Combined bleomycin and radiotherapy in oral cancer. , 1980, Clinical radiology.

[123]  W. Bezwoda,et al.  Treatment of advanced head and neck cancer by means of radiation therapy plus chemotherapy--a randomised trial. , 1979, Medical and pediatric oncology.

[124]  G. Bonadonna,et al.  Adjuvant Therapies and Markers of Post-Surgical Minimal Residual Disease I , 1979, Recent Results in Cancer Research.

[125]  C. Chastang,et al.  Adjvant treatment of tongue and floor of the mouth cancers. , 1978, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[126]  S. Rennaes,et al.  Combined preoperative treatment with cobalt and bleomycin in patients with head and neck carcinoma--a controlled clinical study. , 1978, International journal of radiation oncology, biology, physics.

[127]  D. Hussey,et al.  Combined therapy in advanced head and neck cancer: hydroxyurea and radiotherapy. , 1975, Progress in clinical cancer.

[128]  B. Pierquin,et al.  Intra‐arterial methotrexate chemotherapy and telecobalt therapy in cancer of the oral cavity and oropharynx , 1974, Cancer.