Clin. Otoluryngol. (1990), 15, 193-195
EDITORIAL Adjuvant chemotherapy in head and neck cancer Adjuvant chemotherapy may be used in three ways in the treatment of squamous cell carcinoma of the head and neck: as induction therapy before other forms of treatment; synchronously with radiotherapy; or as maintenance therapy after radical radiotherapy and/or surgery. Its place has been reviewed by several authors'-s who have mostly concluded that adjuvant chemotherapy does not improve the survival rate achieved by conventional surgery or radiotherapy. However, a review must satisfy certain criteria before we can accept its findings. In particular it ought to encompass all published (and, if possible, unpublished) reports; otherwise, it may be seriously biased. Most of the above papers review only some of the reports. For example, one review of induction chemotherapy considers only two of the eight published series? the validity of a review which ignores three-quarters of the published material must be questioned. A review should be comprehensive and should cover the following topics: The size of the trial and whether it is large enough to detect the minimal likely increase in survival. Exclusion of eligible patients before randomization or analysis. Only Tannock and Browman' consider these two points. The method of survival analysis, that is, whether total mortality or cancer mortality was analysed. Analysis of cancer deaths alone can give an unduly favourable impression because it does not take into account the 'swings and roundabouts' effect of deaths due to toxicity.
The extent and direction of any change in survival. Most of the above reviews regard a better survival rate in the chemotherapy arm as indicating an improvement, whereas they regard a worse survival rate as indicating no effect. This is illogical: there is no reason to suppose that chemotherapy may not decrease survival, and a review should take into account both the direction of any change in survival, and its magnitude. If most of the trials show an improvement in survival in the same direction but none is significant, there may be an overall significant effect which can be revealed by a meta-analysis, a technique in which the results of several trials are pooled. However, if about half the trials show improvement and the other half of equally sized and equally reliable trials show the opposite, intuitively one feels that such a treatment is valueless, and a meta-analysis is then likely to show that such treatment is indeed ineffective.' The site of failure: it is hoped that adjuvant chemotherapy might reduce the rate of regional failure, even if it does not affect survival. There is also concern that it might increase the rate of distant metastases. Only two reviews consider the question of the site of f a i l ~ r e . ~ , ~ Toxicity is considered by all reviews, bar ~ W O ,although ~J~ none report the death rate from toxicity. Twenty-four prospective randomized controlled trials with survival data of adjuvant chemotherapy in head and neck cancer have been published in E n g l i ~ h : ' ~ ~ ' 193
194
EDITORIAL
over 3500 patients were admitted to these trials. A complete overview is presented elsewhere36of all these trials from the point of view of design o f the trial, analysis of survival, response rates, meta-analysis, site of failure and toxicity and will be summarized here. The minimal increase in survival that could be detected ranged from 11 to 52%, with a median of 25%. No trial was big enough to detect the likely increase of survival, which is in the order of 5%. It may safely be assumed that any method of treatment producing an increase in survival of 25% would become rapidly established without the need for a trial. Many trials excluded some eligible patients before randomization, the proportion being 21 % in those series with details. A further 10% of treated patients were excluded from analysis, so that almost onethird of all eligible patients were excluded from the ultimate analysis, a major source of bias in favour of the chemotherapy arm. Most authors analysed cancer deaths rather than total mortality, omitting deaths due to toxicity, again providing bias in favour of chemotherapy. Only three papers gave full details of toxicity with grading: these showed a high toxicity rate. The mortality rate from chemotherapy in nine series averaged 6.5%. Clearly this effect must be taken into account in calculating the potential benefit of treatment, and calculations of survival must therefore be based on total mortality. Response rates were quoted in four induction studies. The response rate was 47% but the chemotherapy arms in these four studies had a 7% higher cancer mortality. Meta-analysis showed a decrease of cancer mortality of 3%, which was just significant. Induction chemotherapy and induction/maintenance chemotherapy did not affect cancer mortality whereas synchronous and synchronous/maintenance therapy were effective. Cisplatinum, 5FU and a variety of other regimens did not
affect the death rate from cancer, whereas methotrexate and bleomycin significantly reduced it and the combination of VBM significantly increased it. Single-agent chemotherapy produced a significant reduction in cancer deaths whereas combination chemotherapy produced a nonsignificant increase. There was a significant reduction in cancer deaths in patients with mouth cancer but not in patients with tumours at other sites. The rate of locoregional failure was significantly lower in the treated arms, whereas the metastatic rate was similar in both arms. In summary, in all the series reported so far adjuvant chemotherapy has reduced cancer mortality by 3%. Against this must be set the death rate from toxicity: if the average rate of 6.5% in those trials where toxicity is reported applies to all trials, adjuvant chemotherapy for squamous carcinoma of the head and neck has reduced survival by 3.5%.
P. M. Stell
References 1 CACHINY. (1982) Adjuvant chemotherapy in head
and neck carcinoma. Clin. Otolaryngol. 3, 121-132. 2 CHANGT.M. (1988) Induction chemotherapy for advanccd head and neck cancers: a literature review. Head Neck Surg. 10, 15&159 A.A. (1986) Review: Management of 3 FORESTIERE advanced stage squamous cell carcinoma of the head and neck. Am. J. Med. Sci. 291,405415 S.G.IV. (1981) Integration 4 GLICKJ.H. & TAYLOR of chemotherapy into a combined modality treatment plan for head and neck cancer: a review. Int. J . Radiat. Oncol. Biol. Phys. 7, 229-242 HONGW.K. (1988) Editorial. Induction chemotherapy for advanced head and neck cancer. Head Neck Surg. 10, 147-149 C. (1982) Changing role of MEADG.M. &JACOBS chemotherapy in treatment of head and neck cancer. Am. J . Med. 73, 582-595 TANNOCKI.F. & BROWMANG. (1986) Lack of evidence for a role of chemotherapy in the routine management of locally advanced head and neck cancer. 2. CJin. Oncol. 4, 1121-1 126 SNOWG.B. & VERMORKEN J.B. (1989) Review: Neo-adjuvant chemotherapy in head and neck cancer: state of the art, 1988. J . Clin. Oncol. 14, 371-376 PETO R. (1987) Why do we need systematic overviews of randomized trials? Stat. Med. 6, 233-240 ARCANCELI G., NEKVIC., RIGHINIR.E., CRETON R., MIRRIM.A. & GLJFKRA A. (1983) Combined I
,
-
Adjuvant chemotherapy in head and neck cancer radiation and drugs: The effect of intra-arterial chemotherapy followed by radiotherapy in head and neck cancer. Radiotherapy Oncol. I, 101-107 I I CACHINY., JORTRAY A. & SANCHOS H. (1977) Preliminary results of a randomised E.O.R.T.C. study comparing radiotherapy and concomitant bleomycin, to radiotherapy alone in epidermoid carcinomas of the oropharynx. Eur. J . Cancer 13, 1389-1395 12 ERVINT.J., CLARKJ.R. & WEICHSELBAUM R.R. (1987) An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous cell carcinoma of the head and neck. J . Clin. Oncol. 5, 10-20 13 FAZEKAS J.T., SOMMER C. & KRAMERS. (1980) Adjuvant intravenous Methotrexate or definitive radiotherapy alone for advanced squamous cancers of the oral cavity, oropharynx, supraglottic larynx or hypopharynx. Znt. J. Rudiut. Oncol. Biol. Phys. 6, 535-541 14 Fu K.K., PHILIPS T.L. & SILVERBERG I.J. (1987) Combined radiotherapy and chemotherapy with Bleomycin and Methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group Randomized Trial. J . Clin. Oncol. 5, 1410-1418 15 GOLLINF.F., ANSFIELD F.J., BRANDENBURG J.H., H. (1972) Combined RAMIREZG. & VERMUND therapy in advanced head and neck cancer: a randomized study. Am. J . Roentgenol. 114, 83-88 P.M. 16 GUPTAN.K., POINTON R.C.S. & WILKINSON (1987) A randomised clinical trial to contrast radiotherapy with radiotherapy and Methotrexate given synchronously in head and neck cancer. Clin. Radiol. 38, 575-581 PROGRAM. (1987) 17 HEAD AND NECK CONTRACTS Adjuvant chemotherapy for advanced head and neck squamous carcinoma. Cancer 60, 301-31 1 18 HOLOYEP.Y., GROSSMAN T.W. & TOOHILL R.J. (1985) Randomized study of adjuvant chemotherapy for head and neck cancer. Otolaryngol. Head Neck Surg. 93, 112 19 HUSSEYD.H. & ABRAMSJ.P. (1975) Combined therapy in advanced head and neck cancer: hydroxyurea and radiotherapy. Prog. Clin. Cancer 6, 79-86 20 KNOWLTON A.H., F’ERCARPIO B., BOBROWS. & FISCHER J.J. (1975) Methotrexate and radiation therapy in the treatment of advanced head and neck tumors. Therapeutic Radiol. 116, 709-712 21 Lo T.C., WILEYA.L. & ANSFIELDF.J. (1976) Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharynx. A randomized study. Am. J . Roentgenol. 126, 229-235 D. 22 MARTINM., MAZERONJ.J. & GLAUBIGER (1 986) Neo-adjuvant poiychemotherapy of head and neck cancer: preliminary results of a randomized study. Proc. ASCO 5, 141, Abstract 551 W.R., DE 23 NISSENBAUM M., BROWDEA,, BEZWODA
195 MOORN.G. & DERMAN D.P. (1984) Treatment of advanced head and neck cancer: multiple daily dose fractionated radiation therapy and sequential multimodal treatment approach. Medical Pediat. Oncol. 12, 204208 N.W., JOHNSON F.B. & BRAUNT.J. 24 PEARLMAN (1985) A prospective study of preoperative chemotherapy and split-course irradiation for locally advanced or recurrent oral/pharyngeal squamous carcinoma Am. J. Clin. Oncol. 8, 490. Z., BLOCKJ. & KUISKH. (1981) A 25 PETROVICH randomised comparison of radiotherapy with a radiotherapy-chemotherapy combination in Stage IV carcinoma of the head and neck. Cancer 47, 2259-2264 26 RENTSCHLER R.E., WILBURD.W. & PETTIG.H. (1987) Adjuvant methotrexate escalated to toxicity for resectable stage I11 and IV squamous head and neck carcinomas-a prospective randomized study. J. Clin. Oncol. 5, 278-285 27 SCHULLER D.E., STEIND.W. & METCHB. (1989) Analysis of treatment failure patterns. Arch. Otolaryngol. Head Neck Surg. 115, 834-836 V. & KRISHNAMURTHI S. (1980) Combined 28 SHANTA bleomycin and radiotherapy in oral cancer. Clin. Radiol. 31, 617-620 29 STEFANIA., EELLS R.W. & ABBATEJ. (1971) Hydroxyurea and radiotherapy in head and neck cancer. Radiology 101, 391-396 30 STEFAN~ A. & CHUNGT.S. (1980) Hydroxyurea and radiotherapy in head and neck cancer-long term results of a double blind randomised prospective study. Radiui. Oncol. Biof. Phys. 6, 1398. R., FRASER 31 STELLP.M., DALBYJ.E., STRICKLAND J.G., BRADLEY P.J. & FLOOD L.M. (1983) Sequential chemotherapy and radiotherapy in advanced head and neck cancer. Clin. Radiol. 34, 463467 32 STOLW~JK C., WACENER D.J., VANDENBROEKP., I. (1983) LEVENDAG P.C., KAZEMI. & BRUASET Randomized adjuvant chemotherapy trial for advanced head and neck cancer. Netherlands J . Med. 28, 347 E. & SHOWELJ.L. 33 TAYLORS.G., APPLEBAUM (1985) A randomized trial of adjuvant chemotherapy in head and neck cancer. J . Clin. Oncol. 3, 672-679 34 TOOLHILLR.J., ANDERSON T. & BYHARDTR.W. (1987) Cisplatin and fluorouracil as neoadjuvant therapy in head and neck cancer. Arch. Otolaryngol. Head Neck Surg. 113, 758-761 O., WINTHERF., TRAUSIO 35 VERMUND H., KAALHUS R. (1985) Bleomycin J., THORUDE. & HARANG and radiation therapy in squamous cell carcinoma of the upper aero-digestive tract: a phase 111 clinical trial. Znt. J . Rudiui. OnCOl. Biol, Phys. 11, 1877-1886 36 STELLP.M. & RAWSON N.S.B. (1990) Adjuvant chemotherapy in head and neck cancer. Br. J . Cancer 61, 719-187
EDITORIAL Adjuvant chemotherapy in head and neck cancer Adjuvant chemotherapy may be used in three ways in the treatment of squamous cell carcinoma of the head and neck: as induction therapy before other forms of treatment; synchronously with radiotherapy; or as maintenance therapy after radical radiotherapy and/or surgery. Its place has been reviewed by several authors'-s who have mostly concluded that adjuvant chemotherapy does not improve the survival rate achieved by conventional surgery or radiotherapy. However, a review must satisfy certain criteria before we can accept its findings. In particular it ought to encompass all published (and, if possible, unpublished) reports; otherwise, it may be seriously biased. Most of the above papers review only some of the reports. For example, one review of induction chemotherapy considers only two of the eight published series? the validity of a review which ignores three-quarters of the published material must be questioned. A review should be comprehensive and should cover the following topics: The size of the trial and whether it is large enough to detect the minimal likely increase in survival. Exclusion of eligible patients before randomization or analysis. Only Tannock and Browman' consider these two points. The method of survival analysis, that is, whether total mortality or cancer mortality was analysed. Analysis of cancer deaths alone can give an unduly favourable impression because it does not take into account the 'swings and roundabouts' effect of deaths due to toxicity.
The extent and direction of any change in survival. Most of the above reviews regard a better survival rate in the chemotherapy arm as indicating an improvement, whereas they regard a worse survival rate as indicating no effect. This is illogical: there is no reason to suppose that chemotherapy may not decrease survival, and a review should take into account both the direction of any change in survival, and its magnitude. If most of the trials show an improvement in survival in the same direction but none is significant, there may be an overall significant effect which can be revealed by a meta-analysis, a technique in which the results of several trials are pooled. However, if about half the trials show improvement and the other half of equally sized and equally reliable trials show the opposite, intuitively one feels that such a treatment is valueless, and a meta-analysis is then likely to show that such treatment is indeed ineffective.' The site of failure: it is hoped that adjuvant chemotherapy might reduce the rate of regional failure, even if it does not affect survival. There is also concern that it might increase the rate of distant metastases. Only two reviews consider the question of the site of f a i l ~ r e . ~ , ~ Toxicity is considered by all reviews, bar ~ W O ,although ~J~ none report the death rate from toxicity. Twenty-four prospective randomized controlled trials with survival data of adjuvant chemotherapy in head and neck cancer have been published in E n g l i ~ h : ' ~ ~ ' 193
194
EDITORIAL
over 3500 patients were admitted to these trials. A complete overview is presented elsewhere36of all these trials from the point of view of design o f the trial, analysis of survival, response rates, meta-analysis, site of failure and toxicity and will be summarized here. The minimal increase in survival that could be detected ranged from 11 to 52%, with a median of 25%. No trial was big enough to detect the likely increase of survival, which is in the order of 5%. It may safely be assumed that any method of treatment producing an increase in survival of 25% would become rapidly established without the need for a trial. Many trials excluded some eligible patients before randomization, the proportion being 21 % in those series with details. A further 10% of treated patients were excluded from analysis, so that almost onethird of all eligible patients were excluded from the ultimate analysis, a major source of bias in favour of the chemotherapy arm. Most authors analysed cancer deaths rather than total mortality, omitting deaths due to toxicity, again providing bias in favour of chemotherapy. Only three papers gave full details of toxicity with grading: these showed a high toxicity rate. The mortality rate from chemotherapy in nine series averaged 6.5%. Clearly this effect must be taken into account in calculating the potential benefit of treatment, and calculations of survival must therefore be based on total mortality. Response rates were quoted in four induction studies. The response rate was 47% but the chemotherapy arms in these four studies had a 7% higher cancer mortality. Meta-analysis showed a decrease of cancer mortality of 3%, which was just significant. Induction chemotherapy and induction/maintenance chemotherapy did not affect cancer mortality whereas synchronous and synchronous/maintenance therapy were effective. Cisplatinum, 5FU and a variety of other regimens did not
affect the death rate from cancer, whereas methotrexate and bleomycin significantly reduced it and the combination of VBM significantly increased it. Single-agent chemotherapy produced a significant reduction in cancer deaths whereas combination chemotherapy produced a nonsignificant increase. There was a significant reduction in cancer deaths in patients with mouth cancer but not in patients with tumours at other sites. The rate of locoregional failure was significantly lower in the treated arms, whereas the metastatic rate was similar in both arms. In summary, in all the series reported so far adjuvant chemotherapy has reduced cancer mortality by 3%. Against this must be set the death rate from toxicity: if the average rate of 6.5% in those trials where toxicity is reported applies to all trials, adjuvant chemotherapy for squamous carcinoma of the head and neck has reduced survival by 3.5%.
P. M. Stell
References 1 CACHINY. (1982) Adjuvant chemotherapy in head
and neck carcinoma. Clin. Otolaryngol. 3, 121-132. 2 CHANGT.M. (1988) Induction chemotherapy for advanccd head and neck cancers: a literature review. Head Neck Surg. 10, 15&159 A.A. (1986) Review: Management of 3 FORESTIERE advanced stage squamous cell carcinoma of the head and neck. Am. J. Med. Sci. 291,405415 S.G.IV. (1981) Integration 4 GLICKJ.H. & TAYLOR of chemotherapy into a combined modality treatment plan for head and neck cancer: a review. Int. J . Radiat. Oncol. Biol. Phys. 7, 229-242 HONGW.K. (1988) Editorial. Induction chemotherapy for advanced head and neck cancer. Head Neck Surg. 10, 147-149 C. (1982) Changing role of MEADG.M. &JACOBS chemotherapy in treatment of head and neck cancer. Am. J . Med. 73, 582-595 TANNOCKI.F. & BROWMANG. (1986) Lack of evidence for a role of chemotherapy in the routine management of locally advanced head and neck cancer. 2. CJin. Oncol. 4, 1121-1 126 SNOWG.B. & VERMORKEN J.B. (1989) Review: Neo-adjuvant chemotherapy in head and neck cancer: state of the art, 1988. J . Clin. Oncol. 14, 371-376 PETO R. (1987) Why do we need systematic overviews of randomized trials? Stat. Med. 6, 233-240 ARCANCELI G., NEKVIC., RIGHINIR.E., CRETON R., MIRRIM.A. & GLJFKRA A. (1983) Combined I
,
-
Adjuvant chemotherapy in head and neck cancer radiation and drugs: The effect of intra-arterial chemotherapy followed by radiotherapy in head and neck cancer. Radiotherapy Oncol. I, 101-107 I I CACHINY., JORTRAY A. & SANCHOS H. (1977) Preliminary results of a randomised E.O.R.T.C. study comparing radiotherapy and concomitant bleomycin, to radiotherapy alone in epidermoid carcinomas of the oropharynx. Eur. J . Cancer 13, 1389-1395 12 ERVINT.J., CLARKJ.R. & WEICHSELBAUM R.R. (1987) An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous cell carcinoma of the head and neck. J . Clin. Oncol. 5, 10-20 13 FAZEKAS J.T., SOMMER C. & KRAMERS. (1980) Adjuvant intravenous Methotrexate or definitive radiotherapy alone for advanced squamous cancers of the oral cavity, oropharynx, supraglottic larynx or hypopharynx. Znt. J. Rudiut. Oncol. Biol. Phys. 6, 535-541 14 Fu K.K., PHILIPS T.L. & SILVERBERG I.J. (1987) Combined radiotherapy and chemotherapy with Bleomycin and Methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group Randomized Trial. J . Clin. Oncol. 5, 1410-1418 15 GOLLINF.F., ANSFIELD F.J., BRANDENBURG J.H., H. (1972) Combined RAMIREZG. & VERMUND therapy in advanced head and neck cancer: a randomized study. Am. J . Roentgenol. 114, 83-88 P.M. 16 GUPTAN.K., POINTON R.C.S. & WILKINSON (1987) A randomised clinical trial to contrast radiotherapy with radiotherapy and Methotrexate given synchronously in head and neck cancer. Clin. Radiol. 38, 575-581 PROGRAM. (1987) 17 HEAD AND NECK CONTRACTS Adjuvant chemotherapy for advanced head and neck squamous carcinoma. Cancer 60, 301-31 1 18 HOLOYEP.Y., GROSSMAN T.W. & TOOHILL R.J. (1985) Randomized study of adjuvant chemotherapy for head and neck cancer. Otolaryngol. Head Neck Surg. 93, 112 19 HUSSEYD.H. & ABRAMSJ.P. (1975) Combined therapy in advanced head and neck cancer: hydroxyurea and radiotherapy. Prog. Clin. Cancer 6, 79-86 20 KNOWLTON A.H., F’ERCARPIO B., BOBROWS. & FISCHER J.J. (1975) Methotrexate and radiation therapy in the treatment of advanced head and neck tumors. Therapeutic Radiol. 116, 709-712 21 Lo T.C., WILEYA.L. & ANSFIELDF.J. (1976) Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharynx. A randomized study. Am. J . Roentgenol. 126, 229-235 D. 22 MARTINM., MAZERONJ.J. & GLAUBIGER (1 986) Neo-adjuvant poiychemotherapy of head and neck cancer: preliminary results of a randomized study. Proc. ASCO 5, 141, Abstract 551 W.R., DE 23 NISSENBAUM M., BROWDEA,, BEZWODA
195 MOORN.G. & DERMAN D.P. (1984) Treatment of advanced head and neck cancer: multiple daily dose fractionated radiation therapy and sequential multimodal treatment approach. Medical Pediat. Oncol. 12, 204208 N.W., JOHNSON F.B. & BRAUNT.J. 24 PEARLMAN (1985) A prospective study of preoperative chemotherapy and split-course irradiation for locally advanced or recurrent oral/pharyngeal squamous carcinoma Am. J. Clin. Oncol. 8, 490. Z., BLOCKJ. & KUISKH. (1981) A 25 PETROVICH randomised comparison of radiotherapy with a radiotherapy-chemotherapy combination in Stage IV carcinoma of the head and neck. Cancer 47, 2259-2264 26 RENTSCHLER R.E., WILBURD.W. & PETTIG.H. (1987) Adjuvant methotrexate escalated to toxicity for resectable stage I11 and IV squamous head and neck carcinomas-a prospective randomized study. J. Clin. Oncol. 5, 278-285 27 SCHULLER D.E., STEIND.W. & METCHB. (1989) Analysis of treatment failure patterns. Arch. Otolaryngol. Head Neck Surg. 115, 834-836 V. & KRISHNAMURTHI S. (1980) Combined 28 SHANTA bleomycin and radiotherapy in oral cancer. Clin. Radiol. 31, 617-620 29 STEFANIA., EELLS R.W. & ABBATEJ. (1971) Hydroxyurea and radiotherapy in head and neck cancer. Radiology 101, 391-396 30 STEFAN~ A. & CHUNGT.S. (1980) Hydroxyurea and radiotherapy in head and neck cancer-long term results of a double blind randomised prospective study. Radiui. Oncol. Biof. Phys. 6, 1398. R., FRASER 31 STELLP.M., DALBYJ.E., STRICKLAND J.G., BRADLEY P.J. & FLOOD L.M. (1983) Sequential chemotherapy and radiotherapy in advanced head and neck cancer. Clin. Radiol. 34, 463467 32 STOLW~JK C., WACENER D.J., VANDENBROEKP., I. (1983) LEVENDAG P.C., KAZEMI. & BRUASET Randomized adjuvant chemotherapy trial for advanced head and neck cancer. Netherlands J . Med. 28, 347 E. & SHOWELJ.L. 33 TAYLORS.G., APPLEBAUM (1985) A randomized trial of adjuvant chemotherapy in head and neck cancer. J . Clin. Oncol. 3, 672-679 34 TOOLHILLR.J., ANDERSON T. & BYHARDTR.W. (1987) Cisplatin and fluorouracil as neoadjuvant therapy in head and neck cancer. Arch. Otolaryngol. Head Neck Surg. 113, 758-761 O., WINTHERF., TRAUSIO 35 VERMUND H., KAALHUS R. (1985) Bleomycin J., THORUDE. & HARANG and radiation therapy in squamous cell carcinoma of the upper aero-digestive tract: a phase 111 clinical trial. Znt. J . Rudiui. OnCOl. Biol, Phys. 11, 1877-1886 36 STELLP.M. & RAWSON N.S.B. (1990) Adjuvant chemotherapy in head and neck cancer. Br. J . Cancer 61, 719-187
