- Email: [email protected]
Induction chemotherapy prior to surgery did not improve survival, but may reduce mandibulectomy over surgery alone in locally advanced squamous cell cancer of the oral cavity
CANCER TREATMENT REVIEWS 2003; 29: 341–344 doi:10.1016/S0305-7372(03)00136-1
EVIDENCE-BASED ONCOLOGY
Induction chemotherapy prior to surgery did not improve survival, but may reduce mandibulectomy over surgery alone in locally advanced squamous cell cancer of the oral cavity Abstracted from: Licitra L, Grandi C, Guzzo M et al. Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. J Clin Oncol 2003; 21: 327–33.
Background There is little evidence about the most effective treatments for oral cavity cancer. Most research in this area examines ‘head and neck cancer’ more generally. Tumours recur in about half of people with locally advanced squamous cell cancer of the oral cavity treated with surgery and radiotherapy. It remains unclear whether induction chemotherapy before surgery improves survival or functional outcomes in locally advanced oral cavity cancer. Objective To assess whether induction chemotherapy prior to surgery increases 5-year survival in advanced tumours of the oral cavity. Setting Four hospitals in Italy; June 1989 to December 1999. Method Multi-centre randomised controlled trial. Participants One hundred and ninety-five people with untreatable resectable biopsy-proven stage T2-T4, N0-N2, M0 squamous cell carcinoma of the oral cavity. T2 tumours were included if they were larger than 3 cm. Tumours extending to the oropharynx (where chemoradiation is preferable to surgery) were eligible if more than 50% of the lesion volume was contained in the oral cavity. Mean age 55 years; 16% women. Exclusion criteria were Karnofsky performance status less than 70; abnormal serum creatinine; inadequate nutritional, pulmonary or cardiac status; platelet count less than or equal to 100,000 mm3 ; and white blood cell count less than or equal to 4000 mm3 .
0305-7372/$ - see front matter
C
Intervention Three cycles of 100 mg/m2 cisplatin plus 1000 mg/ m2 fluorouracil given as a 120-h infusion every 21 days, followed by surgery (chemotherapy group) or surgery alone (controls). Chemotherapy group The timing of surgery in the chemotherapy group varied according to response to chemotherapy. All participants received two cycles of chemotherapy. Participants who had 50% or greater tumour regression received a third cycle of chemotherapy (63%). Participants with progressive or stable disease after two cycles were scheduled for immediate surgical resection, without a third cycle of chemotherapy (37%). All participants In all participants, surgery was modulated depending on the proximity of the tumour to the mandible. Postoperative radiotherapy was reserved for high risk patients (for instance progressive disease). Median follow up was 76 months. Main outcomes Five-year survival; complete response (complete disappearance of clinically evident tumour); partial response (50% or greater reduction in diameter); event free survival.
Main results Survival Five-year survival was 55% in both groups. Overall 5-year event free survival was 57% in the chemotherapy group and 46% for controls (p < 0:05; Table 1).
2003 ELSEVIER SCIENCE LTD. ALL RIGHTS RESERVED.
342
EVIDENCE-BASED ONCOLOGY
TA B L E 1 Survival and relapse among people with advanced oral cavity carcinoma receiving induction chemotherapy or surgery alone
Five-year event free survival Local regional relapse Distant relapse Distant primary tumours
Induction chemotherapy % (n ¼ 98)
Surgery alone controls % (n ¼ 97)
57 31 7 6
46 32 9 13
Absolute risk change % (95% CI)
Relative risk change % (95% CI)
11 ABI (3 ABR to 25 ABI) 24 RBI (10 RBR to 58 RBI) 1 ARR (12 ARI to 14 ARR) 3 RRR (37 RRI to 43 RRR) 2 ARR (6 ARI to 10 ARR) 22 RRR (52 RRI to 97 RRR) 7 ARR (1 ARI to 15 ARR) 54 RRR (10 to 97 RRR)
Note. ABI/RBI, absolute/relative benefit increase with induction chemotherapy; ABR/RBR, absolute/relative benefit reduction with induction chemotherapy; ARI/ARR, absolute risk increase/reduction with induction chemotherapy; RRR/RRI, relative risk reduction/relative risk increase. Numbers needed to treat have not been calculated because differences are not statistically significant.
Response to chemotherapy Twenty-seven percent of the chemotherapy group had complete remission (primary tumour and neck nodes). The objective response rate was 82% (33% complete response, 49% partial response). Ninetyfive percent of the chemotherapy group developed some toxicity. This was severe (grade 3 or 4) in 37%. There were three toxic deaths. Other outcomes Thirty-one percent of the chemotherapy group and 52% of controls underwent mandible resection (21% difference, 95% CI 7% to 34%, p < 0:05). Adjuvant postoperative radiotherapy was required in 33% of the chemotherapy group compared with 46% of controls (13% difference, 95% CI 0% to 27%). Postoperative morbidity was similar between groups (Table 2), as were days spent in hospital (21 days for chemotherapy v 23 days controls). Authors’ conclusions Induction chemotherapy does not improve survival over surgery alone in people with advanced oral cavity carcinoma, but may reduce the need for mandibulectomy and radiotherapy.
Method notes Power calculation
The study has 78% power to detect a 20% absolute risk reduction in 5-year cancer recurrence in the chemotherapy group, assuming 50% recurrence among controls (5% level of significance for 2-sided test). The authors aimed for 90% power, but recruitment was terminated early due to difficulties with patient accrual
Blinding
It is unclear whether outcome assessors were blind to treatment allocation. Patients and physicians could not be blinded
Generation of allocation sequence
Adequate. Generated at central co-ordinating institution
Allocation concealment
Adequate
Balanced groups
Adequate. Groups were balanced for gender, age, tumour site and tumour stage
Analysis
Intention to treat analysis
Sources of funding: CNR-ACRO; Associazione Italiana Ricerca Cancro. For correspondence: L Licitra, Istituto Nazionale Tumori, Milan, Italy. E-mail: [email protected]. Abstract provided by Bazian Ltd., London.
EVIDENCE-BASED ONCOLOGY
343
TA B L E 2 Postoperative morbidity among people with advanced oral cavity carcinoma receiving induction chemotherapy or surgery alone
No morbidity Partial transposed flap necrosis Mucosal dehiscence Regional infection Partial skin necrosis Oro-cutaneous fistula Pneumonia Bleeding Toxic or postoperative death
Induction chemotherapy % (n ¼ 98)
Surgery alone controls % (n ¼ 97)
Absolute risk change % (95% CI)
Relative risk change % (95% CI)
55.1 13.3
48.4 18.5
7 ABI (7 ABR to 21 ABI) 5 ARR (5 ARI to 15 ARR)
14 RBI (17 RBR to 45 RBI) 28 RRR (19 RRI to 75 RRR)
12.2 7.1 5.1 5.1 2.1 2.1 3
17.5 4.1 7.2 6.1 3.1 1.1 0
5 ARR (5 ARI to 15 ARR) 3 ARI (3 ARR to 9 ARI) 2 ARR (5 ARI to 9 ARR) 1 ARR (5 ARI to 7 ARR) 1 ARR (3 ARI to 5 ARR) 1 ARI (3 ARR to 5 ARI) 3 ARI (0 to 6 ARI)
30 RRR (17 RRI to 78 RRR) 73 RRI (135 RRR to 281 RRI) 29 RRR (50 RRI to 108 RRR) 16 RRR (80 RRI to 113 RRR) 32 RRR (86 RRI to 151 RRR) 91 RRI (352 RRR to 534 RRI) Not calculable
Note. ABI/RBI, absolute/relative benefit increase with induction chemotherapy; ARR/ARI, absolute risk reduction/absolute risk increase with induction chemotherapy; RRR/RRI, relative risk reduction/relative risk increase; ABR/RBR, absolute/relative benefit reduction with induction chemotherapy. Numbers needed to treat have not been calculated because differences are not statistically significant.
Commentary Adverse effects of treatment for head and neck cancer include facial disfigurement, psychosocial morbidity and speech and eating dysfunction. Treatment decisions are complicated because of the difficult balance between benefits and risks, even when the disease is life threatening (1). This study examines the role of neoadjuvant induction chemotherapy in resectable squamous cell oral cavity cancer. Tumour response to neoadjuvant chemotherapy is greater in induction chemotherapy in resectable oral cavity cancer compared with other cancers in the head and neck area (about 80% for oral cavity v 70% in other areas). This study examines whether improved tumour response translates into improved survival, improved functional outcomes, or both. Other literature There is little reliable data on induction chemotherapy in oral cavity cancer. Pignon and colleagues (2) conducted a meta-analysis on the role of induction chemotherapy in head and neck cancer (not exclusively of the oral cavity). They found that neoadjuvant induction chemotherapy increased long term survival by 2% over surgery alone. Survival was similar with definitive radiotherapy in people who responded to chemotherapy compared with radical surgery in nonresponders. The effects of chemotherapy differed among tumour sites. Chemotherapy had no significant benefits for tumours of the larynx, but appeared to be beneficial for hypopharyngeal tumours. Few systematic reviews or controlled studies have focused specifically on the oral cavity. Retrospective studies and commentaries in people with oral cavity cancer have provoked interest in chemotherapy for
oral cavity cancer (3,4). For example, one recent retrospective analysis of 204 consecutive patients with locally advanced cancer of the oral cavity found that two courses of chemotherapy following local treatment reduced the need for radical surgery (5). People treated with either definitive or adjuvant radiation therapy had better outcomes. Randomised trials were needed to help to confirm these findings. This study’s contribution This elegant study by Licitra and colleagues assesses survival and organ preservation in people with a homogeneous tumour location. Survival outcomes were similar to those obtained in other tumour sites. In the chemotherapy arm, the response rate was high (82%), resulting in a reduced need for radiotherapy. This reduction in postoperative radiotherapy may be based on chemotherapy-induced tumour shrinkage, resulting in ‘downstaging’ and improvement in local control. Other trials have reported reductions in distant metastases using induction chemotherapy. This finding was not replicated by Licitra and colleagues, although there was a slight reduction in second primary tumours (6% chemotherapy v 13% controls). Clinical implications Despite the high response rate to induction chemotherapy, there was no difference in overall long term survival. This may suggest that chemotherapy is of little benefit. On the other hand, the lack of difference between groups may be because people receiving chemotherapy were under-treated. After ‘downstaging’ from primary chemotherapy, some participants who did not receive adjuvant radiotherapy may have received less global treatment
344
EVIDENCE-BASED ONCOLOGY
than required. Other possible explanations are based on the Gompertzian growth curve. In bulky tumours, more cells may be in a resting state and not sensitive to induction chemotherapy. Early use of chemotherapy may also be associated with the development of drug resistance. Animal models suggest that as the tumour burden increases, tumours become a heterogeneous population with increased numbers of drug resistant cells. Importantly, the trial found that chemotherapy allowed for more organ-preserving surgery. Mandibulectomy was undertaken less often in people receiving chemotherapy (31% chemotherapy v 52% controls). The authors assume that reducing the need for demolitive surgery and postoperative radiotherapy may improve quality of life. This has yet to be confirmed. It is likely that organ and function-preserving approaches obtain better mastication and cosmetic results. Both can be accomplished as a consequence of sparing the mandible. In conclusion, this well designed trial has clarified the role of induction chemotherapy in cancer of the oral cavity, among relatively homogeneous patients. Until now, there has been little high quality evidence in this patient group. Although induction chemotherapy did not improve survival, primary chemotherapy may be associated with greater rates of organ-preserving surgery. It may also be used to avoid adjuvant radiation therapy and its sequelae, although this has to be balanced with the possible acute toxic effect of chemotherapy.
Quality Assessment (scale 1 ¼ fair, 4 ¼ excellent) Relevance Validity Applicability Feasibility Impact Knowledge context
3 2 3 4 2 4
Juan J. Grau, M D Associate Professor of Oncology Clinic of Hematology-Oncology University of Barcelona Hospital Clinic Barcelona, Spain E-mail: [email protected]
References 1. Schenck DP. Ethical considerations in the treatment of head and neck cancer. Cancer Control 2002; 9: 410–419. 2. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamouscell carcinoma: three meta-analyses of updated individual data. Lancet 2000; 355: 949–955. 3. Koch WM, Lee DJ, Eisele DW, et al. Chemoradiotherapy for organ preservation in oral and pharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 1995; 121: 974–980. 4. Marks SC. Surgical management of head and neck cancer. Hematol Oncol Clin North Am 1999; 13: 655–667. 5. Grau JJ, Domingo J, Blanch JL, et al. Multidisciplinary approach in advanced cancer of the oral cavity: outcome with neoadjuvant chemotherapy according to the intention-tothreat local therapy. Oncology 2002; 63: 338–345.
EVIDENCE-BASED ONCOLOGY
Induction chemotherapy prior to surgery did not improve survival, but may reduce mandibulectomy over surgery alone in locally advanced squamous cell cancer of the oral cavity Abstracted from: Licitra L, Grandi C, Guzzo M et al. Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. J Clin Oncol 2003; 21: 327–33.
Background There is little evidence about the most effective treatments for oral cavity cancer. Most research in this area examines ‘head and neck cancer’ more generally. Tumours recur in about half of people with locally advanced squamous cell cancer of the oral cavity treated with surgery and radiotherapy. It remains unclear whether induction chemotherapy before surgery improves survival or functional outcomes in locally advanced oral cavity cancer. Objective To assess whether induction chemotherapy prior to surgery increases 5-year survival in advanced tumours of the oral cavity. Setting Four hospitals in Italy; June 1989 to December 1999. Method Multi-centre randomised controlled trial. Participants One hundred and ninety-five people with untreatable resectable biopsy-proven stage T2-T4, N0-N2, M0 squamous cell carcinoma of the oral cavity. T2 tumours were included if they were larger than 3 cm. Tumours extending to the oropharynx (where chemoradiation is preferable to surgery) were eligible if more than 50% of the lesion volume was contained in the oral cavity. Mean age 55 years; 16% women. Exclusion criteria were Karnofsky performance status less than 70; abnormal serum creatinine; inadequate nutritional, pulmonary or cardiac status; platelet count less than or equal to 100,000 mm3 ; and white blood cell count less than or equal to 4000 mm3 .
0305-7372/$ - see front matter
C
Intervention Three cycles of 100 mg/m2 cisplatin plus 1000 mg/ m2 fluorouracil given as a 120-h infusion every 21 days, followed by surgery (chemotherapy group) or surgery alone (controls). Chemotherapy group The timing of surgery in the chemotherapy group varied according to response to chemotherapy. All participants received two cycles of chemotherapy. Participants who had 50% or greater tumour regression received a third cycle of chemotherapy (63%). Participants with progressive or stable disease after two cycles were scheduled for immediate surgical resection, without a third cycle of chemotherapy (37%). All participants In all participants, surgery was modulated depending on the proximity of the tumour to the mandible. Postoperative radiotherapy was reserved for high risk patients (for instance progressive disease). Median follow up was 76 months. Main outcomes Five-year survival; complete response (complete disappearance of clinically evident tumour); partial response (50% or greater reduction in diameter); event free survival.
Main results Survival Five-year survival was 55% in both groups. Overall 5-year event free survival was 57% in the chemotherapy group and 46% for controls (p < 0:05; Table 1).
2003 ELSEVIER SCIENCE LTD. ALL RIGHTS RESERVED.
342
EVIDENCE-BASED ONCOLOGY
TA B L E 1 Survival and relapse among people with advanced oral cavity carcinoma receiving induction chemotherapy or surgery alone
Five-year event free survival Local regional relapse Distant relapse Distant primary tumours
Induction chemotherapy % (n ¼ 98)
Surgery alone controls % (n ¼ 97)
57 31 7 6
46 32 9 13
Absolute risk change % (95% CI)
Relative risk change % (95% CI)
11 ABI (3 ABR to 25 ABI) 24 RBI (10 RBR to 58 RBI) 1 ARR (12 ARI to 14 ARR) 3 RRR (37 RRI to 43 RRR) 2 ARR (6 ARI to 10 ARR) 22 RRR (52 RRI to 97 RRR) 7 ARR (1 ARI to 15 ARR) 54 RRR (10 to 97 RRR)
Note. ABI/RBI, absolute/relative benefit increase with induction chemotherapy; ABR/RBR, absolute/relative benefit reduction with induction chemotherapy; ARI/ARR, absolute risk increase/reduction with induction chemotherapy; RRR/RRI, relative risk reduction/relative risk increase. Numbers needed to treat have not been calculated because differences are not statistically significant.
Response to chemotherapy Twenty-seven percent of the chemotherapy group had complete remission (primary tumour and neck nodes). The objective response rate was 82% (33% complete response, 49% partial response). Ninetyfive percent of the chemotherapy group developed some toxicity. This was severe (grade 3 or 4) in 37%. There were three toxic deaths. Other outcomes Thirty-one percent of the chemotherapy group and 52% of controls underwent mandible resection (21% difference, 95% CI 7% to 34%, p < 0:05). Adjuvant postoperative radiotherapy was required in 33% of the chemotherapy group compared with 46% of controls (13% difference, 95% CI 0% to 27%). Postoperative morbidity was similar between groups (Table 2), as were days spent in hospital (21 days for chemotherapy v 23 days controls). Authors’ conclusions Induction chemotherapy does not improve survival over surgery alone in people with advanced oral cavity carcinoma, but may reduce the need for mandibulectomy and radiotherapy.
Method notes Power calculation
The study has 78% power to detect a 20% absolute risk reduction in 5-year cancer recurrence in the chemotherapy group, assuming 50% recurrence among controls (5% level of significance for 2-sided test). The authors aimed for 90% power, but recruitment was terminated early due to difficulties with patient accrual
Blinding
It is unclear whether outcome assessors were blind to treatment allocation. Patients and physicians could not be blinded
Generation of allocation sequence
Adequate. Generated at central co-ordinating institution
Allocation concealment
Adequate
Balanced groups
Adequate. Groups were balanced for gender, age, tumour site and tumour stage
Analysis
Intention to treat analysis
Sources of funding: CNR-ACRO; Associazione Italiana Ricerca Cancro. For correspondence: L Licitra, Istituto Nazionale Tumori, Milan, Italy. E-mail: [email protected]. Abstract provided by Bazian Ltd., London.
EVIDENCE-BASED ONCOLOGY
343
TA B L E 2 Postoperative morbidity among people with advanced oral cavity carcinoma receiving induction chemotherapy or surgery alone
No morbidity Partial transposed flap necrosis Mucosal dehiscence Regional infection Partial skin necrosis Oro-cutaneous fistula Pneumonia Bleeding Toxic or postoperative death
Induction chemotherapy % (n ¼ 98)
Surgery alone controls % (n ¼ 97)
Absolute risk change % (95% CI)
Relative risk change % (95% CI)
55.1 13.3
48.4 18.5
7 ABI (7 ABR to 21 ABI) 5 ARR (5 ARI to 15 ARR)
14 RBI (17 RBR to 45 RBI) 28 RRR (19 RRI to 75 RRR)
12.2 7.1 5.1 5.1 2.1 2.1 3
17.5 4.1 7.2 6.1 3.1 1.1 0
5 ARR (5 ARI to 15 ARR) 3 ARI (3 ARR to 9 ARI) 2 ARR (5 ARI to 9 ARR) 1 ARR (5 ARI to 7 ARR) 1 ARR (3 ARI to 5 ARR) 1 ARI (3 ARR to 5 ARI) 3 ARI (0 to 6 ARI)
30 RRR (17 RRI to 78 RRR) 73 RRI (135 RRR to 281 RRI) 29 RRR (50 RRI to 108 RRR) 16 RRR (80 RRI to 113 RRR) 32 RRR (86 RRI to 151 RRR) 91 RRI (352 RRR to 534 RRI) Not calculable
Note. ABI/RBI, absolute/relative benefit increase with induction chemotherapy; ARR/ARI, absolute risk reduction/absolute risk increase with induction chemotherapy; RRR/RRI, relative risk reduction/relative risk increase; ABR/RBR, absolute/relative benefit reduction with induction chemotherapy. Numbers needed to treat have not been calculated because differences are not statistically significant.
Commentary Adverse effects of treatment for head and neck cancer include facial disfigurement, psychosocial morbidity and speech and eating dysfunction. Treatment decisions are complicated because of the difficult balance between benefits and risks, even when the disease is life threatening (1). This study examines the role of neoadjuvant induction chemotherapy in resectable squamous cell oral cavity cancer. Tumour response to neoadjuvant chemotherapy is greater in induction chemotherapy in resectable oral cavity cancer compared with other cancers in the head and neck area (about 80% for oral cavity v 70% in other areas). This study examines whether improved tumour response translates into improved survival, improved functional outcomes, or both. Other literature There is little reliable data on induction chemotherapy in oral cavity cancer. Pignon and colleagues (2) conducted a meta-analysis on the role of induction chemotherapy in head and neck cancer (not exclusively of the oral cavity). They found that neoadjuvant induction chemotherapy increased long term survival by 2% over surgery alone. Survival was similar with definitive radiotherapy in people who responded to chemotherapy compared with radical surgery in nonresponders. The effects of chemotherapy differed among tumour sites. Chemotherapy had no significant benefits for tumours of the larynx, but appeared to be beneficial for hypopharyngeal tumours. Few systematic reviews or controlled studies have focused specifically on the oral cavity. Retrospective studies and commentaries in people with oral cavity cancer have provoked interest in chemotherapy for
oral cavity cancer (3,4). For example, one recent retrospective analysis of 204 consecutive patients with locally advanced cancer of the oral cavity found that two courses of chemotherapy following local treatment reduced the need for radical surgery (5). People treated with either definitive or adjuvant radiation therapy had better outcomes. Randomised trials were needed to help to confirm these findings. This study’s contribution This elegant study by Licitra and colleagues assesses survival and organ preservation in people with a homogeneous tumour location. Survival outcomes were similar to those obtained in other tumour sites. In the chemotherapy arm, the response rate was high (82%), resulting in a reduced need for radiotherapy. This reduction in postoperative radiotherapy may be based on chemotherapy-induced tumour shrinkage, resulting in ‘downstaging’ and improvement in local control. Other trials have reported reductions in distant metastases using induction chemotherapy. This finding was not replicated by Licitra and colleagues, although there was a slight reduction in second primary tumours (6% chemotherapy v 13% controls). Clinical implications Despite the high response rate to induction chemotherapy, there was no difference in overall long term survival. This may suggest that chemotherapy is of little benefit. On the other hand, the lack of difference between groups may be because people receiving chemotherapy were under-treated. After ‘downstaging’ from primary chemotherapy, some participants who did not receive adjuvant radiotherapy may have received less global treatment
344
EVIDENCE-BASED ONCOLOGY
than required. Other possible explanations are based on the Gompertzian growth curve. In bulky tumours, more cells may be in a resting state and not sensitive to induction chemotherapy. Early use of chemotherapy may also be associated with the development of drug resistance. Animal models suggest that as the tumour burden increases, tumours become a heterogeneous population with increased numbers of drug resistant cells. Importantly, the trial found that chemotherapy allowed for more organ-preserving surgery. Mandibulectomy was undertaken less often in people receiving chemotherapy (31% chemotherapy v 52% controls). The authors assume that reducing the need for demolitive surgery and postoperative radiotherapy may improve quality of life. This has yet to be confirmed. It is likely that organ and function-preserving approaches obtain better mastication and cosmetic results. Both can be accomplished as a consequence of sparing the mandible. In conclusion, this well designed trial has clarified the role of induction chemotherapy in cancer of the oral cavity, among relatively homogeneous patients. Until now, there has been little high quality evidence in this patient group. Although induction chemotherapy did not improve survival, primary chemotherapy may be associated with greater rates of organ-preserving surgery. It may also be used to avoid adjuvant radiation therapy and its sequelae, although this has to be balanced with the possible acute toxic effect of chemotherapy.
Quality Assessment (scale 1 ¼ fair, 4 ¼ excellent) Relevance Validity Applicability Feasibility Impact Knowledge context
3 2 3 4 2 4
Juan J. Grau, M D Associate Professor of Oncology Clinic of Hematology-Oncology University of Barcelona Hospital Clinic Barcelona, Spain E-mail: [email protected]
References 1. Schenck DP. Ethical considerations in the treatment of head and neck cancer. Cancer Control 2002; 9: 410–419. 2. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamouscell carcinoma: three meta-analyses of updated individual data. Lancet 2000; 355: 949–955. 3. Koch WM, Lee DJ, Eisele DW, et al. Chemoradiotherapy for organ preservation in oral and pharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 1995; 121: 974–980. 4. Marks SC. Surgical management of head and neck cancer. Hematol Oncol Clin North Am 1999; 13: 655–667. 5. Grau JJ, Domingo J, Blanch JL, et al. Multidisciplinary approach in advanced cancer of the oral cavity: outcome with neoadjuvant chemotherapy according to the intention-tothreat local therapy. Oncology 2002; 63: 338–345.