Chemotherapy as an adjunct to radiotherapy in locally advanced nasopharyngeal carcinoma

Bertrand Baujat; Hélène Audry; Jean Bourhis; Anthony TC Chan; Haluk Onat; Daniel TT Chua; Dora LW Kwong; Muhyi Al‐Sarraf; Kwan‐Hwa Chi; Masato Hareyama; Singh F Leung; Kullathorn Thephamongkhol; Jean Pierre Pignon; MAC‐NPC Collaborative Group

doi:10.1002/14651858.CD004329.pub2

Chemotherapy as an adjunct to radiotherapy in locally advanced nasopharyngeal carcinoma

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References

References to studies included in this review

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excluded studies
awaiting assessment
ongoing studies
additional references

Al‐Sarraf M, LeBlanc M, Shanker PG, Fu KK, Cooper J, Vuong T, et al. Chemotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. Journal of Clinical Oncology 1998;16:1310‐7.

Chan ATC, Teo PML, Leung TW, Leung SF, Lee WY, Yeo W, et al. A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. International Journal of Radiation Oncology, Biology, Physics 1995;33:569‐77.

Chan ATC, Teo PML, Ngan RK, Leung TW, Lau WH, Zee B, et al. Concurrent chemotherapy‐radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma : Progression‐free survival analysis of a phase III randomized trial. Journal of Clinical Oncology 2002;20:2038‐44.

Chi KH, Chang Y, Guo W, Shiau C, Wang L, Hsu M, et al. A phase III study of adjuvant chemotherapy in advanced stage nasopharyngeal carcinoma patients. International Journal of Radiation Oncology, Biology, Physics 2002;52:1238‐44.

Chua DT, Ma J, Sham JS, Mai HQ, Choy DT, Hong MH, et al. Improvement of survival after addition of induction chemotherapy to radiotherapy in patients with early‐stage nasopharyngeal carcinoma: Subgroup analysis of two Phase III trials. International Journal of Radiation Oncology, Biology, Physics 2006;65(5):1300‐6. Epub 2006 Jun 5.

Chua DT, Sham JS, Choy D, Lorvidhaya V, Sumitsawan Y, Thongprasert S, et al. Preliminary report of the Asian‐Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Cancer 1998;83:2270‐83.

Cvitkovic E, Eschwege F, Rahal M, Dosen D, Mersic Z, Krajina Z, et al. Preliminary results of trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs radiotherapy alone in stage IV ( N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression free survival. International Journal of Radiation Oncology, Biology, Physics 1996;35:463‐9.

Hareyama M, Sakata K, Shirato H, Nishioka T, Nishio M, Suzuki K, et al. A prospective randomized trial comparing neoadjuvant chemotherapy with radiotherapy alone in advanced nasopharyngeal carcinoma. Cancer 2002;94:2217‐23.

Kwong DLW, Sham JST, Au GKH, Chua DTT, Kwong PWK, Cheng ACK, et al. Concurrent and adjuvant Chemotherapy for Nasopharyngeal carcinoma: a factorial study. Journal of Clinical Oncology 2004;22:2643‐53.

References to studies excluded from this review

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included studies
awaiting assessment
ongoing studies
additional references

Lin JC, Jan JS, Hsu CY, Liang WM, Jiang RS, Wang WY. Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression‐free survival. Journal of Clinical Oncology 2003;21:631‐7.

Ma J, Mai HQ, Hong MH, Min HQ, Mao ZD, Cui NJ, et al. Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma. Journal of Clinical Oncology 2001;19:1350‐7.

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References to studies awaiting assessment

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excluded studies
ongoing studies
additional references

Chen Y, Liu MZ, Liang SB, Zong JF, Mao YP, Tang LL, et al. Preliminary results of a prospective randomized trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of China. International Journal of Radiation Oncology, Biology, Physics 2008;71(5):1356‐64.

Hui EP, Ma BB, Leung SF, King AD, Mo F, Kam MK, et al. Randomized phase II trial of concurrent cisplatin‐radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. Journal of Clinical Oncology 2009;27(2):242‐9.

Lee AW, Lau WH, Tung SY, Chua D, Chappell R, Xu L, Siu L, et al. Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally advanced Nasopharyngeal Carcinoma: NPC‐9901 trial by the Hong‐Kong Nasopharyngeal Cancer Study Group. Journal of Clinical Oncology 2005;23:6966‐75.

Wee J, Tan EH, Tia BC, Wong HB, Leong SS, Tan T, Chua ET, Yang E, Lee K M, Fong KW, et al. Phase III randomized trial of radiotherapy versus concurrent chemo‐radiotherapy followed by adjuvant chemotherapy in patients with AJCC/UICC (1997) stage 3 and 4 nasopharyngeal cancer of the endemic variety. Journal of Clinical Oncology 2005;23:6730‐8.

References to ongoing studies

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included studies
excluded studies
awaiting assessment
additional references

Lee AW, Tung SY, Chan AT, Chappell R, Fu YT, Lu TX, Tan T, et al. Preliminary results of a randomized study (NPC‐9902 Trial) on therapeutic gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal carcinoma. International Journal of Radiation Oncology, Biology, Physics 2006;66:142‐51.

VUMCA II. Ongoing study1996.

Zhang L, Zhao C, Peng PJ, Lu LX, Han F, Wu SX. Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. Journal of Clinical Oncology 2005;23:8461‐8.

Additional references

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ongoing studies

Ali H, Al‐Sarraf M. Chemotherapy in advanced nasopharyngeal cancer. Oncology (Huntingt) 2000;14:1223‐30.

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Baujat B, Hélène Audry H, Jean Bourhis J, Chan ATC, Onat H, Chua DTT, Kwong DLW, Al‐Sarraf M, Chi K‐H, Hareyama M, Leung SF, Thephamongkhol K, Pignon JP, on behalf of the MAC‐NPC Collaborative Group. Chemotherapy in locally advanced nasopharyngeal carcinoma. An individual patient data meta‐analysis of 8 randomised trials and 1753 patients. International Journal of Radiation Oncology, Biology, Physics 2006;64:47‐56.

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Langedijk JA, Leemans R, Buter J, Berkhof J, Slotman BJ. The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta‐analysis of the published literature. Journal of Clinical Oncology 2004;22:4604‐12.

MAC‐NPC (Meta‐Analysis of Chemotherapy in Naso‐Pharynx Carcinoma) Group. Chemotherapy for nasopharyngeal carcinoma. Cochrane Database of Systematic Reviews 2004, Issue 3. [Art. No.: CD004329. DOI: 10.1002/14651858.CD004329]

The Non‐Small Cell Lung Cancer Collaborative Group. Chemotherapy in non‐small cell lung cancer: a meta‐analysis using updated individual patient data from 52 randomised clinical trials. British Medical Journal 1995;311:899‐909.

Pignon JP, Bourhis J, Domenge C, Désigné L on behalf of the MACH‐NC Collaborative Group. Chemotherapy added to locoregional treatment for head and neck squamous‐cell carcinoma: three meta‐analysis of updated individual data. The Lancet 2000;255:949‐55.

Pignon JP, Hill C. Meta‐analysis of randomised clinical trials in oncology. The Lancet Oncology 2001;2:475‐82.

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Stewart LA, Parmar MKB. Meta‐analysis of the literature or of individual data: is there a difference?. The Lancet 1993;341:418‐22.

Thephamongkhol K, Zhou J, Browman G, Wong RKW, Chan JCK, Zeng Y, Thabane L, Hodson I, Oliver T. Chemo‐radiotherapy versus radiotherapy alone for nasopharyngeal carcinoma: A meta‐analysis of 78 randomized controlled trials (RCTs) from English and non‐English databases. Journal of Clinical Oncology 2004;22 (Supplement: abstract proceeding):5522.

Vokes EE, Liebowitz DN, Weichselbaum RR. Nasopharyngeal carcinoma. The Lancet 1997;350:1087‐91.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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excluded studies
awaiting classification
ongoing studies

Al‐Sarraf 1998

Methods	Inclusion period: 1989 to 1995. Median follow up: 110 months.
Participants	193 patients. Stages III to IV (AJCC < 1997). Histology WHO 1 to 3.
Interventions	Radiotherapy: Tumor: 70 Gray/7 weeks. N‐ 50 Gray, N+ 66 to 70 Gray +/‐ concomitant Cisplatin: 100 mg/m² x 3 and adjuvant Cisplatin: 80 mg/m² x 3 cycles and Fluorouracil: 4000 mg/m² x 3 cycles, continuous infusion.
Outcomes	Overall survival, event‐free survival.
Notes	24% of type 1 histology, concomitant cisplatin every 3 weeks, adjuvant cisplatin + 5‐fluorouracil every 4 weeks.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Chan 1995

Methods	Inclusion period: 1988 to 1991. Median follow up: 35 months.
Participants	77 patients. Stage III to IV (Ho classification). Histology WHO 3.
Interventions	Radiotherapy: Tumor: 66 Gray/6.5 weeks. N‐ 58 Gray, N+ 65.5 Gray +/‐ induction and adjuvant chemotherapy: Cisplatin: 100 mg/m² x (induction 2 cycles and adjuvant 4 cycles) and Fluorouracil: 3000 mg/m² x (induction 2 cycles and adjuvant 4 cycles), continuous infusion.
Outcomes	Overall survival, event‐free survival.
Notes	2 cycles of induction and 4 cycles of adjuvant chemotherapy. Radiotherapy : nasopharynx, equivalent of 66 Gy with conventional fractionation + 20 Gy boost if parapharyngeal disease + 18 to 24 Gy using 192Ir if residual disease 4 weeks after radiotherapy; neck: 58 Gy for lower neck, 66 Gy for upper neck.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Chan 2002

Methods	Inclusion period: 1994 to 1999. Median follow up: 67 months.
Participants	350 patients. Stages II to IV (AJCC 1997). Histology WHO 1 to 3.
Interventions	Radiotherapy: Tumor: 66 Gray/6.5 weeks. N‐ 58 Gray, N+ 65.5 Gray +/‐ concomitant Cisplatin: 40 mg/m² , weekly.
Outcomes	Overall survival, event‐free survival.
Notes	10 or 20 Gy (depending on the centre) boost if parapharyngeal disease, 21 to 24 Gy using 192Ir if residual local disease after radiotherapy, 7.5 Gy boost if residual nodal disease, radical neck dissection if proven residual neck nodes.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Chi 2002

Methods	Inclusion period: 1994 to 1999. Median follow up: 72 months.
Participants	158 patients. Stage IV (AJCC < 1997). Histology WHO 1 to 3.
Interventions	Radiotherapy: Tumor: 70 to 72 Gray/7 to 8 weeks. N‐ 50 Gray lower neck +/‐ Adjuvant Cisplatin: 20 mg/m² x 9 weekly, Fluorouracil: 2200 mg/m² x 9 weekly, Leucovorin acid: 120 mg/m² x 9 weekly.
Outcomes	Overall survival, event‐free survival.
Notes	All drugs provided by continuous injections.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Chua 1998

Methods	Inclusion period: 1989 to 1993. Median follow up: 65 months.
Participants	334 patients. Stages II to IV (AJCC < 1997). Histology WHO 2 to 3.
Interventions	Radiotherapy: Tumor 66 to 74 Gray/6.5 to 7.5 weeks. N‐ 60 to 66 Gray, N+ 66 to 76 Gray. +/‐ Induction chemotherapy: Cisplatin: 60 mg/m² x 2 to 3; Epirubicin: 110 mg/m² x 2 to 3.
Outcomes	Overall survival, event‐free survival.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Cvitkovic 1996

Methods	Inclusion period: 1989 to 1993. Median follow up: 84 months.
Participants	339 patients. Stages III to IV (AJCC < 1997). Histology WHO 1 to 3.
Interventions	Radiotherapy: Tumor 65 to 70 Gray/6.5 to 7.5 weeks. N‐ 50 Gray, N+ 65 Gray. +/‐ Induction chemotherapy: Bleomycin: 15 mg/m² x 3; Bleomycin: 60 mg/m² x 3, continuous injection; Epirubicin: 70 mg/m² x 3; Cisplatin: 100 mg/m² x 3.
Outcomes	Overall survival, event‐free survival.
Notes	110 patients treated with conventional radiotherapy and 176 patients with hypofractionated radiotherapy, 2.5 Gy x 3/weeks followed by 3.5 Gy x 3/week.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Hareyama 2002

Methods	Inclusion period: 1991 to 1998. Median follow up: 74 months.
Participants	80 patients. Stages I to IV (AJCC < 1997). Histology WHO 1 to 3.
Interventions	Radiotherapy: Tumor: 66 to 68 Gray/6.5 to 7 weeks. N‐ 50 Gray, N+ 66 to 68 Gray +/‐ induction chemotherapy: Cisplatin: 80 mg/m² x 2 cycles and Fluorouracil: 3200 mg/m² x 2 cycles, continuous infusion.
Outcomes	Overall survival, event‐free survival.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Kwong 2004a

Methods	Inclusion period: 1995 to 2000. Median follow up: 57 months
Participants	222 patients. Stages II to IV (AJCC 1997). Histology WHO 1 to 3.
Interventions	Radiotherapy: Tumor: 62.5 to 68 Gray/7 weeks. N 62.5 to 66 Gray/7weeks +/‐ boost 10 Gray +/‐ concomitant UFT 600 mg daily po / Adjuvant Cisplatin: 100 mg/m² x 3, Fluorouracil: 3000 mg/m² x 3, Vincristine: 2mg x 3, Bleomycin: 30 mg x 3, Methotrexate: 150 mg/m² x 3
Outcomes	Overall survival, Event‐free survival
Notes	2 X 2 design, concomitant chemotherapy versus none, adjuvant chemotherapy versus none, concomitant+adjuvant chemotherapy versus adjuvant chemotherapy, concomitant +adjuvant chemotherapy versus concomitant chemotherapy ; for adjuvant chemotherapy, alternating cycles of cisplatin + 5‐fluorouracil and vincristine + bleomycin + methotrexate. +/‐ 10 Gy additional boost in case of parapharyngeal space involvement and/or palpable residual nodes.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Kwong 2004b

Methods	See Kwong 2004a
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Kwong 2004c

Methods	See Kwong 2004a
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Kwong 2004d

Methods	See Kwong 2004a
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Kwong 2004a (QMH‐95 conc), Kwong 2004b (QMH‐95adj), Kwong 2004c (QMH‐95adj+), Kwong 2004d (QMH‐95conc+): 4 comparisons issued from QMH‐95 2x2 trial.

Characteristics of excluded studies [ordered by study ID]

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included studies
awaiting classification
ongoing studies

Study	Reason for exclusion
Lin 2003	Allocation: not properly randomised.
Ma 2001	Allocation: not properly randomised.
Pan 2000	Allocation: not properly randomised.
Rossi 1988	Individual data lost by the institution.

Characteristics of studies awaiting assessment [ordered by study ID]

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excluded studies
ongoing studies

Chen 2008

Methods	Randomized phase III trial
Participants	316 (158 per group) locoregionally advanced nasopharyngeal carcinomas
Interventions	Radiotherapy (70 Grays in 7 weeks) plus concurrent cisplatin (40 mg/m² weekly) followed by adjuvant cisplatin (80 mg/m² on day 1) + 5 Fluoro‐Uracil (800 mg/m² on days 1 to 5) every 4 weeks for 3 cycles versus same radiotherapy
Outcomes	Significant benefit in favour of chemotherapy arm on: 2‐year overall survival rate (89.8% versus 79.7%, P = 0.003) 2‐year failure‐free survival rate (84.6% versus 72.5%, P = 0.001) 2‐year distant failure‐free survival rate (86.5% versus 78.7% P = 0.024) 2‐year locoregional failure‐free survival rate (98% versus 91.9%, P = 0.007)
Notes	Notes: more toxicity and lower compliance in the chemotherapy arm

Hui 2009

Methods	Randomized phase II trial
Participants	65 (34 CT + CRT versus 31 CRT) stage III to IVb nasopharyngeal carcinomas
Interventions	Induction docetaxel (75 mg/m²) + cisplatin (75 mg/m²) every 3 weeks for 2 cycles followed by radiotherapy (conventional or IMRT) + concurrent cisplatin (40 mg/m²) weekly versus same radiotherapy + same concurrent cisplatin
Outcomes	Significant benefit on overall survival in favour of induction chemotherapy arm: 3‐year overall survival: 94.1% versus 67.7%, Hazard Ratio = 0.24 (95% CI 0.078 to 0.73), P = 0.012 3‐year progression‐free survival 88.2% versus 59.5%, Hazard Ratio = 0.49 (95% CI 0.20 to 1.19), P = 0.12
Notes	Notes: induction CT followed by concurrent RT + CT was well tolerated

Lee 2005

Methods
Participants	335
Interventions	RT versus RT + Concomitant Cisplatin + Adjuvant Cisplatin + 5FU versus RT + Induction CT
Outcomes	No significant benefit on overall survival
Notes	See footnotes

Wee 2005

Methods
Participants	221
Interventions	RT versus RT + Concomitant Cisplatin + Adjuvant Cisplatin + 5FU
Outcomes	Significant benefit from CT
Notes	See footnotes

Characteristics of ongoing studies [ordered by study ID]

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included studies
excluded studies
awaiting classification

Lee 2006

Trial name or title	NPC99‐02
Methods
Participants	189
Interventions	RT versus accelerated RT versus RT + Concomitant Cisplatin + Adjuvant Cisplatin + 5FU versus accelerated RT + Concomitant Cisplatin + Adjuvant Cisplatin + 5FU
Outcomes	Preliminary results in favour of accelerated RT + chemotherapy
Starting date	1999
Contact information	Lee AW, Hong Kong Nasopharyngeal Cancer Study Group and the Princess Margaret Hospital in Canada
Notes	See footnotes

VUMCA II

Trial name or title	VUMCA II
Methods
Participants	509
Interventions	Induction CT+ RT versus Induction CT + RT + concomitant CT
Outcomes	Not ready for analysis
Starting date	1996
Contact information	Institut Gustave‐Roussy Dr E. Benhamou
Notes

Zhang 2005

Trial name or title	Sun Yat‐Sen University
Methods
Participants	77
Interventions	RT versus RT + concomitant oxaliplatin
Outcomes	Significant benefit from CT
Starting date	2001
Contact information	Cancer Centre of Sun Yat Sen University
Notes	See footnotes

Recently published as a full paper:
‐ Lee AW, Lau W H, Tung S Y, Chua D, Chappell R, Xu L, Siu L et al. Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally advanced Nasopharyngeal Carcinoma: NPC‐9901 trial by the Hong‐Kong Nasopharyngeal Cancer Study Group. J Clin Oncol 2005; 23: 6966‐75.
‐ Wee J, Tan EH, Tia BC, Wong H B, Leong S S, Tan T, Chua E T, Yang E, Lee K M,.Fong KW et al. Phase III randomized trial of radiotherapy versus concurrent chemo‐radiotherapy followed by adjuvant chemotherapy in patients with AJCC/UICC (1997) stage 3 and 4 nasopharyngeal cancer of the endemic variety. J Clin Oncol 2005; 23: 6730‐38.
‐ Zhang L, Zhao C, Peng PJ, Lu LX, Han F, Wu SX. Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol 2005; 23: 8461‐68.
‐ Lee AW, Tung SY, Chan AT, Chappell R, Fu YT, Lu TX, Tan T, Chua DT, O'Sullivan B, Xu SL, Pang ES, Sze WM, Leung TW, Kwan WH, Chan PT, Liu XF, Tan EH, Sham JS, Siu L, Lau WH. Preliminary results of a randomized study (NPC‐9902 Trial) on therapeutic gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2006 ;66:142‐51.

Data and analyses

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Comparison 1. Radiotherapy versus radiotherapy + chemotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Effect of chemotherapy on overall survival, hazard ratio of death by timing of chemotherapy Show forest plot	11	1975	Peto Odds Ratio (95% CI)	0.82 [0.71, 0.95]
Open in figure viewer Analysis 1.1 Comparison 1 Radiotherapy versus radiotherapy + chemotherapy, Outcome 1 Effect of chemotherapy on overall survival, hazard ratio of death by timing of chemotherapy.
1.1 Induction +/‐ adjuvant chemotherapy	4	830	Peto Odds Ratio (95% CI)	0.99 [0.80, 1.21]
1.2 Concomitant +/‐ adjuvant chemotherapy	4	765	Peto Odds Ratio (95% CI)	0.60 [0.48, 0.76]
1.3 Adjuvant chemotherapy	3	380	Peto Odds Ratio (95% CI)	0.97 [0.68, 1.38]
2 Effect of chemotherapy on event‐free survival, hazard ratio of tumour failure or death by timing of chemo. Show forest plot	11	1975	Peto Odds Ratio (95% CI)	0.76 [0.67, 0.86]
Open in figure viewer Analysis 1.2 Comparison 1 Radiotherapy versus radiotherapy + chemotherapy, Outcome 2 Effect of chemotherapy on event‐free survival, hazard ratio of tumour failure or death by timing of chemo..
2.1 Induction +/‐ adjuvant chemotherapy	4	830	Peto Odds Ratio (95% CI)	0.82 [0.68, 0.97]
2.2 Concomitant +/‐adjuvant chemotherapy	4	765	Peto Odds Ratio (95% CI)	0.63 [0.51, 0.78]
2.3 Adjuvant chemotherapy	3	380	Peto Odds Ratio (95% CI)	0.90 [0.67, 1.20]
3 Effect of chemotherapy on loco‐regional control, HR of loco‐regional failure by timing of chemotherapy Show forest plot	10	1782	Peto Odds Ratio (95% CI)	0.76 [0.63, 0.91]
Open in figure viewer Analysis 1.3 Comparison 1 Radiotherapy versus radiotherapy + chemotherapy, Outcome 3 Effect of chemotherapy on loco‐regional control, HR of loco‐regional failure by timing of chemotherapy.
3.1 Induction +/‐ adjuvant chemotherapy	4	830	Peto Odds Ratio (95% CI)	0.76 [0.60, 0.97]
3.2 Concomitant +/‐ adjuvant chemotherapy	3	572	Peto Odds Ratio (95% CI)	0.81 [0.55, 1.18]
3.3 Adjuvant chemotherapy	3	380	Peto Odds Ratio (95% CI)	0.71 [0.48, 1.04]
4 Effect of chemotherapy on distant control, hazard ratio of distant failure by timing of chemotherapy Show forest plot	10	1782	Peto Odds Ratio (95% CI)	0.72 [0.59, 0.87]
Open in figure viewer Analysis 1.4 Comparison 1 Radiotherapy versus radiotherapy + chemotherapy, Outcome 4 Effect of chemotherapy on distant control, hazard ratio of distant failure by timing of chemotherapy.
4.1 Induction +/‐ adjuvant chemotherapy	4	830	Peto Odds Ratio (95% CI)	0.65 [0.49, 0.86]
4.2 Concomitant +/‐ adjuvant chemotherapy	3	572	Peto Odds Ratio (95% CI)	0.69 [0.49, 0.97]
4.3 Adjuvant chemotherapy	3	380	Peto Odds Ratio (95% CI)	1.11 [0.66, 1.85]

Analysis 1.1

Comparison 1 Radiotherapy versus radiotherapy + chemotherapy, Outcome 1 Effect of chemotherapy on overall survival, hazard ratio of death by timing of chemotherapy.

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Analysis 1.2

Comparison 1 Radiotherapy versus radiotherapy + chemotherapy, Outcome 2 Effect of chemotherapy on event‐free survival, hazard ratio of tumour failure or death by timing of chemo..

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Analysis 1.3

Comparison 1 Radiotherapy versus radiotherapy + chemotherapy, Outcome 3 Effect of chemotherapy on loco‐regional control, HR of loco‐regional failure by timing of chemotherapy.

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Analysis 1.4

Comparison 1 Radiotherapy versus radiotherapy + chemotherapy, Outcome 4 Effect of chemotherapy on distant control, hazard ratio of distant failure by timing of chemotherapy.

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Table 1. Patient characteristics by treatment group

Characteristics	RT + CT	RT
n = 1975	n = 990	n = 985
Gender: male	75%	74%
Age: < 40 or equal	33%	29%
41 to 50	31%	33%
51+	36%	38%
Perform. status (n = 1468)*: 0	52%	50%
1	46%	47%
2	2%	3%
Tumour stage: T1	46%	47%
T2	27%	28%
T3,4	27%	25%
Nodal stage (n = 1 898)**: N0	10%	9%
N1,2	65%	68%
N3	25%	23%
Histology (n = 1636)***: WHO 1	4%	3%
WHO 2	18%	18%
WHO 3	78%	79%
* Data missing from three trials. Data missing from one trial, using Ho's classification. * Data missing from one trial, that did not distinguish between WHO histologic type 2 and 3 but did not include type 1.

Table 1. Patient characteristics by treatment group

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Table 2. Treatment effect on overall and event‐free survival according to patient charact

Characteristics	n. patients RT+CT/RT	HR of death (95%CI)	P‐value	HR tum. failur/death	P‐value
Gender: Male	742/727	0.81 (0.69 to 0.95)		0.76 (0.66 to 0.87)
Gender: Female	248/258	0.85 (0.62 to 1.16)	0.81	0.74 (0.58 to 0.96)	0.89
Age < 40 or equal	326/285	0.85 (0.63 to 1.14)		0.67 (0.52 to 0.85)
41 to 50	308/327	0.77 (0.59 to 1.01)		0.80 (0.64 to 1.00)
> 50	356/373	0.86 (0.70 to 1.05)	0.85 (t for trend)	0.79 (0.66 to 0.95)	0.31 (t for trend)
Performance status: 0	380/368	0.89 (0.71 to 1.11)		0.78 (0.64 to 0.94)
1	342/340	0.71 (0.55 to 0.92)		0.66 (0.53 to 0.83)
2	17/21	1.55 (0.65 to 3.69)	0.73 (t for trend)	1.40 (0.65 to 3.02)	0.92 (t for trend)
T stage (AJCC97): T1	267/272	0.68 (0.51 to 0.90)		0.69 (0.54 to 0.87)
T2	350/363	0.83 (0.64 to 1.07)		0.82 (0.66 to 1.02)
T3/T4	373/350	0.90 (0.73 to 1.12)	0.12 (t for trend)	0.73 (0.60 to 0.88)	0.80 (t for trend)
N stage (AJCC97): N0	91/83	1.02 (0.61 to 1.69)		0.65 (0.42 to 1.00)
N1/N2	620/643	0.82 (0.68 to 0.99)		0.79 (0.68 to 0.93)
N3	242/219	0.68 (0.52 to 0.88)	0.24 (t for trend)	0.64 (0.51 to 0.81)	0.47 (t for trend)
WHO type 1	29/26	0.30 (0.15 to 0.59)		0.18 (0.09 to 0.36)
WHO type 2 to 3	958/959	0.85 (0.73 to 0.98)	0.003	0.78 (0.69 to 0.89)	< 0.0001
Total	990/985	0.82 (0.71 to 0.94)	0.006	0.76 (0.67 to 0.86)	< 0.0001

Table 2. Treatment effect on overall and event‐free survival according to patient charact

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Table 3. Sensitivity analyses

Trials included	N patients RT+CT/RT	OS. HR. 95%CI	OS. HR. p‐value	OS. heterogeneity I²	OS. Hetero. p‐value	EFS. HR. 95%CI	EFS. HR. p‐value	EFS. hetero. I²	EFS. Hetero. p‐value
All trials	990/985	0.82 (0.71 to 0.94)	0.006	50%	0.03	0.76 (0.67 to 0.86)	< 0.0001	32%	0.14
Without Al‐Sarraf 1998 (INT‐0099)	893/889	0.90 (0.77 to 1.05)	0.17	0%	0.37	0.82 (0.72 to 0.93)	0.002	0%	0.99
Without patients with WHO 1 carcinoma	958/959	0.85 (0.73 to 0.98)	0.03	38%	0.09	0.78 (0.69 to 0.89)	0.0001	0%	0.58
Without one small trial (Chan 1995 (PWH‐88))	953/945	0.81 (0.70 to 0.93)	0.003	51%	0.03	0.75 (0.66 to 0.85)	< 0.0001	36%	0.12
Without QMH‐95 combined arms (Kwong 2004d (QMH‐95conc+), Kwong 2004c (QMH‐95adj+))	876/875	0.84 (0.73 to 0.98)	0.02	53%	0.03	0.75 (0.66 to 0.85)	< 0.0001	43%	0.08
Without Chan 1995 (PWH‐88), QMH95: follow up < 5 years	729/725	0.80 (0.68 to 0.93)	0.004	58%	0.04	0.73 (0.64 to 0.84)	< 0.0001	32%	0.03

Table 3. Sensitivity analyses

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Comparison 1. Radiotherapy versus radiotherapy + chemotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Effect of chemotherapy on overall survival, hazard ratio of death by timing of chemotherapy Show forest plot	11	1975	Peto Odds Ratio (95% CI)	0.82 [0.71, 0.95]

1.1 Induction +/‐ adjuvant chemotherapy	4	830	Peto Odds Ratio (95% CI)	0.99 [0.80, 1.21]
1.2 Concomitant +/‐ adjuvant chemotherapy	4	765	Peto Odds Ratio (95% CI)	0.60 [0.48, 0.76]
1.3 Adjuvant chemotherapy	3	380	Peto Odds Ratio (95% CI)	0.97 [0.68, 1.38]
2 Effect of chemotherapy on event‐free survival, hazard ratio of tumour failure or death by timing of chemo. Show forest plot	11	1975	Peto Odds Ratio (95% CI)	0.76 [0.67, 0.86]

2.1 Induction +/‐ adjuvant chemotherapy	4	830	Peto Odds Ratio (95% CI)	0.82 [0.68, 0.97]
2.2 Concomitant +/‐adjuvant chemotherapy	4	765	Peto Odds Ratio (95% CI)	0.63 [0.51, 0.78]
2.3 Adjuvant chemotherapy	3	380	Peto Odds Ratio (95% CI)	0.90 [0.67, 1.20]
3 Effect of chemotherapy on loco‐regional control, HR of loco‐regional failure by timing of chemotherapy Show forest plot	10	1782	Peto Odds Ratio (95% CI)	0.76 [0.63, 0.91]

3.1 Induction +/‐ adjuvant chemotherapy	4	830	Peto Odds Ratio (95% CI)	0.76 [0.60, 0.97]
3.2 Concomitant +/‐ adjuvant chemotherapy	3	572	Peto Odds Ratio (95% CI)	0.81 [0.55, 1.18]
3.3 Adjuvant chemotherapy	3	380	Peto Odds Ratio (95% CI)	0.71 [0.48, 1.04]
4 Effect of chemotherapy on distant control, hazard ratio of distant failure by timing of chemotherapy Show forest plot	10	1782	Peto Odds Ratio (95% CI)	0.72 [0.59, 0.87]

4.1 Induction +/‐ adjuvant chemotherapy	4	830	Peto Odds Ratio (95% CI)	0.65 [0.49, 0.86]
4.2 Concomitant +/‐ adjuvant chemotherapy	3	572	Peto Odds Ratio (95% CI)	0.69 [0.49, 0.97]
4.3 Adjuvant chemotherapy	3	380	Peto Odds Ratio (95% CI)	1.11 [0.66, 1.85]

Comparison 1. Radiotherapy versus radiotherapy + chemotherapy

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References

References to studies included in this review

Al‐Sarraf 1998 {published and unpublished data}

Chan 1995 {published and unpublished data}

Chan 2002 {published and unpublished data}

Chi 2002 {published and unpublished data}

Chua 1998 {published and unpublished data}

Cvitkovic 1996 {published and unpublished data}

Hareyama 2002 {published and unpublished data}

Kwong 2004a {published and unpublished data}

Kwong 2004b {published and unpublished data}

Kwong 2004c {published and unpublished data}

Kwong 2004d {published and unpublished data}

References to studies excluded from this review

Lin 2003 {published and unpublished data}

Ma 2001 {published and unpublished data}

Pan 2000 {published and unpublished data}

Rossi 1988 {published data only}

References to studies awaiting assessment

Chen 2008 {published data only}

Hui 2009 {published data only}

Lee 2005 {published and unpublished data}

Wee 2005 {published data only}

References to ongoing studies

Lee 2006 {unpublished data only}

VUMCA II {published data only}

Zhang 2005 {published and unpublished data}

Additional references

Ali 2000

Auperin 1999

Baujat 2006

Chua 2000

EBCTCG 1990

Higgins 2002

Langedijk 2004

MAC‐NPC 2004

NSCLCCG 1995

Pignon 2000

Pignon 2001

Schemper 1996

Stewart 1993

Thephamongkhol 2004

Vokes 1997

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of studies awaiting assessment [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Data and analyses

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