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Survival evaluation of treatment modality in squamous cell carcinoma of the oral cavity and oropharynx
Journal of Cranio-Maxillofacial Surgery (2000) 28, 49±55 # 2000 European Association for Cranio-Maxillofacial Surgery doi:10.1054/jcms.1999.0091, available online at http://www.idealibrary.com on
Survival evaluation of treatment modality in squamous cell carcinoma of the oral cavity and oropharynx Josep Pericot,1 Josep M. EscribaÁ,2 AndreÂs ValdeÂs,3 MarõÂ a J. Biosca,1 Antoni Monner,1 Xavier CastellsagueÂ,4 Ramon Galiana,5 Pere Piulachs,1 Eloi Escutia1, Antoni Mari 1
Department of Maxillofacial Surgery (Head: Prof. Dr. J. Pericot), Ciutat SanitaÁria UniversitaÁria de Bellvitge, L'Hospitalet de Ll., Barcelona, Spain; 2 Primary Assistance Direction, Institut CatalaÁ de la Salut; 3 Department of Maxillofacial Surgery (Head: Prof. Dr. R. L. Ots), University of Alicante, Alicante, Spain; 4 Department of Cancer Epidemiology (Head: Prof. Dr. X. Bosch), Hospital Duran Reynals, C.S.U.B., Institut CatalaÁ d'OncologõÂa L'Hospitalet de LL., Barcelona, Spain; 5Department of Radiation Oncology (Head: Prof. Dr. F. Guedea), Ciutat SanitaÁria UniversitaÁria de Bellvitge, L'Hospitalet de Ll., Barcelona, Spain SUMMARY. The treatment of squamous cell carcinoma of the mouth and oropharynx continues to change. In this primary report, we compared the results obtained by combined surgery and radiation therapy, or either modality alone. Other methods such as brachytherapy, or hyperfractionated radiotherapy, were not included in our protocols. A statistical analysis of the 3- and 5-year survival rates in relation to location and size of the primary tumour, stage at initial presentation, treatment modality and recurrence, was carried out in 88 patients with squamous cell carcinoma of the oral cavity or oropharynx. The overall survival rate was 73.8% at 3 years and 66.3% at 5 years. Size of tumour and stage at presentation were signi®cant when P value was adjusted by site. Survival was signi®cantly associated with type of treatment (combined approach obtained superior results), location of primary tumour, and recurrence. The type of neck dissection did not show any eect. Therapeutic modality used, stage, and location of primary tumour signi®cantly in¯uenced survival. A more selective combined initial treatment according to site and stage (distribution) is recommended. # 2000 European Association for Cranio-Maxillofacial Surgery INTRODUCTION
consecutive patients with squamous cell carcinoma of the oral cavity or oropharynx on the 3- and 5-year survival rates. The results obtained were also analyzed according to major indicators of prognosis, such as location of the primary tumour, surface size, stage at initial presentation, therapeutic approach, type of neck dissection, and tumour recurrence. In another paper we shall attempt to compare the survival rates accomplished with the new additional therapies, such as brachytherapy, hyperfractionated radiotherapy, and others that were not in our routine treatment protocols at the time of this study.
The prognosis of patients with oral cancer remains uncertain, despite re®nements in conventional therapy and more recent protocols using alternative treatment modalities. Although squamous cell carcinomas or the oral cavity are often treated as a single entity, they are a heterogeneous group of tumours, the natural history and prognosis being strongly in¯uenced by the anatomic site of the primary tumour. Although the addition of radiation therapy to extirpative surgery has represented a major advancement in the treatment of oral cancer (Mac Comb and Fletcher, 1957; Southwick et al., 1960; Jesse and Lindberg, 1975; Mendelson et al., 1976; Farr et al., 1980; White and Byers, 1980; Byers, 1985; Jesse et al., 1987; Okamoto et al., 1988), there has been only a moderate improvement in survival over the past few decades despite more sophisticated radiation therapy, improvement in surgical techniques (Jacobs, 1979; Bocca et al., 1985; Ariyan, 1980; Pearlman et al., 1985) and the advent of aggressive chemotherapy protocols. The concept of combining surgery and irradiation to the neck and primary location has been widely applied since the early 1960s, but opinions dier about the indications and sequence of such combination treatment. The aim of this preliminary report was to assess the eect of therapeutic modalities used in a series of 88
MATERIAL AND METHODS Between July 1983 and December 1989, a total of 123 consecutive patients were treated at the Department of Maxillofacial Surgery of our institution for squamous cell cancer of the oral cavity and/or oropharynx. After review of the medical records, 35 (28.4%) were excluded because of partial treatment elsewhere, incomplete information, or no follow-up available. The remaining 88 previously untreated patients with a histopathological diagnosis of squamous cell carcinoma who underwent de®nite treatment for primary cancer in the oral cavity and/or oropharynx form the basis of this study. Follow-up examinations took place regularly at intervals of 3, 6, 49
50 Journal of Cranio-Maxillofacial Surgery
and 12 months after treatment at then annually. All patients were followed for at least 3 years (maximum 9 years), or until their deaths. The last follow-ups were completed by 1 July 1992. All information was obtained by three head and neck surgeons from clinical visits, correspondence or telephone interview with the patient, the patient's family, or the referring physician; or autopsy data. The following items were recorded: age, sex, site of primary tumour, size of primary lesion, clinical staging by the UICC-TNM classi®cation system (Hermanek and Sobin, 1992) treatment, type of neck dissection, and tumour recurrence. Treatment modalities included combined surgery and postoperative radiotherapy (in patients with locally advanced tumours, evidence of neck node metastasis, and suspicion of actual positive marginal extirpative), surgery alone, or radiation therapy alone. Dierent types of neck dissection were carried out according to the stage of the disease. The `ampli®ed radical neck dissection' was done in one case (including retroauricular nodes, parotidectomy, and facial skin) due to major tumour invasion of the neck and retromandibular area. Modi®ed neck dissection was carried out as a supraomohyoid neck dissection, including nodes at the levels I, II, and III with preservation of the sterno-cleido-mastoid muscle, internal jugular vein, carotid artery, and the spinal accessory nerve for patients who were clinically N0, and with primary tumours less than 3 cm in diameter. If there was suspicion of invasion in more than two nodes, extranodal invasion, or nodes bigger than 3 cm then an extended supraomohyoid neck dissection was performed, including level IV nodes, and part of the level V territory (middle posterior ceryvical nodes) dissected beneath the sterno-cleido-mastoid muscle. In some cases, the modi®ed neck dissection converted to a radical neck dissection. A bilateral neck dissection was undertaken simultaneously (Ballantyne and Jackson, 1982), but only when a clear tumour invasion of the midline was observed, or bilaterally positive nodes were found clinically. With regard to radiotherapy technique, the patients were mostly treated with disintegrated photons of Cobalt 60, and complementary irradiation for the neck, with electrons from a linear accelerator. The treatment ®eld included the entire primary tumour area, all extensions of the surgical scar and the upper and middle lymphatic drainage area, with two laterocervical opposing ®elds, and one anterior direct supraclavicular ®eld with glottic protection for subclavian and lower lymphatic chains. The patients were treated with a sessional dose of 2 Gy daily, ®ve days each week. The total dose at the primary site was 60±66 Gy, according to the limits of the surgical borders obtained. In the lymph mode area the doses were between 50 and 66 Gy, according to the type of node invasion observed surgically and on histopathological diagnosis following neck dissection. Radiotherapy was considered an essential part of the treatment for eradicating subclinical neck disease as well as of the tumour itself: patients with tumours
greater than 4 cm (pT3 UICC) or a tumour with positive margins or with malignant cells near the limits of the surgical resection (less than 10 mm), were always treated with postoperative radiotherapy. Combined surgery and radiotherapy was also employed in cases of undierentiated tumours, in tumours with speci®c malignant histopathological trends (nerve and vessel in®ltration), and in all cases of salvage surgery following local recurrence. Regarding the neck combined radiotherapy was used in any patient with pN+, and as an elective modality in pN0 patients exhibiting a primary tumour of more than 3.5 cm in diameter. A comprehensive indication for this combination therapy was also in those patients in whom it was dicult to perform follow-ups (because of social habits or distant residence). At the present time we use surgery as the primary treatment only in pN1 neck disease patients without extracapsular invasion, or any other poor prognostic factor (aggressive clinical or histopathologic in®ltration). In some patients, radiotherapy or chemotherapy was initially used when radical surgery could not be performed due to the patient's general condition, or when the patient refused an operation. Statistical analysis The probability of survival was calculated using the Kaplan-Meier estimates. Dierences in the probabilities of survival were calculated with the log-rank test (Cox-Mantel test). Cox proportional hazards regression analysis was used to estimate risk ratio of mortality in association with dierent variables. The statistical signi®cance of these estimates was assessed by the 95% con®dence interval. RESULTS The clinical characteristics and treatment modality of the patients are shown in Table 1. Among the dierent parameters studied we listed: a high incidence in males with a majority of patients under the age of 55 years; the most frequent presentations were stage III oral carcinoma (39.7%), and stage IV cases of oropharyngeal carcinoma (33.3%). (Neck disease at that time was only evaluated by clinical palpation with N0 encountered most often and a higher incidence of N3 nodes for the orpharyngeal lesions.) The recurrence rate was 25.9% for oral and 40% for oropharyngeal primaries. Recurrences in the neck were found to be much lower, with 1.7% and 3.3% for oral and oropharyngeal carcinomas respectively (see Table 1). The overall 5-year survival rate was 79.5% for patients with oral and 39.6% for the group with oropharyngeal carcinomata (Fig. 1). In the univariate analysis the survival probability was studied in relation to the parameters mentioned, and the results
Survival evaluation of treatment modality 51 Table 1 ± Characteristics of 88 patients with squamous cell carcinoma of the oral cavity and oropharynx Prognostic factors
Oral
Oropharyngeal
n
%
Deaths
n
%
Deaths
Sex Male Female
48 10
82.8 17.2
9 5
25 5
83.3 16.7
13 3
Age (yrs) 555 55±65 465
24 21 11
42.9 37.5 19.6
3 8 2
12 11 3
46.2 42.3 11.5
5 6 3
Stage I II III IV
8 12 23 15
13.8 20.7 39.7 25.9
0 3 5 6
4 4 6 16
13.3 13.3 20.0 33.3
2 1 3 10
Size T1 T2 T3 T4
9 25 16 8
15.5 43.1 27.6 13.8
0 5 6 3
3 9 6 12
10.0 30.0 20.0 40.0
1 4 3 8
Neck disease N0 N1 N2 N3
26 21 9 2
44.8 36.2 15.5 3.4
5 4 4 1
11 8 4 7
36.7 26.7 13.3 23.3
5 5 4 2
Treatment modality Surgery & radiotherapy Surgery alone Radiotherapy alone
40 16 2
69.0 27.6 3.4
9 4 1
21 4 5
70.0 13.3 16.7
11 2 3
Neck surgery Modi®ed neck dissection Radical neck dissection Ampli®ed radical neck dissection No neck dissection
28 19 1 10
48.3 32.8 1.7 17.2
2 7 1 4
13 10 0 7
43.3 33.3 0.0 23.3
7 6 0 3
Recurrence Primary Simultaneous primary and neck Neck Distant metastasis No relapse
15 2 1 1 39
25.9 3.4 1.7 1.7 67.2
8 1 0 1 4
12 1 1 1 15
40.0 3.3 3.3 3.3 50.0
9 1 1 1 4
Cause of death Oral cancer Other causes
14 7
66.7 33.3
16 2
88.9 11.1
are shown in Table 2. The statistically signi®cant factors were site of the primary tumour, size of the tumour and the incidence of recurrence. Treatment modality was close to statistical signi®cance (P=0.0759; Fig. 2). In the strati®ed univariate analysis of the two main groups of patients (oral and oropharyngeal), we found the following prognostically important factors: age, especially in oro-pharynx patients (P=0.02), with an adjusted P value by site of 0.06. Other important factors with an adjusted P value by site were: size (P=0.04), therapeutic modality (P=0.15), with a dierence of maximum survival for surgery plus postoperative radiotherapy (85.9%) and minimal survival for radiotherapy alone (50%) in the oral cancer patients (these dierences were not signi®cant in the oropharynx group). Recurrence showed values of P=0.0000 and of P=0.006 in the oral and the orpharynx groups respectively. In relation to N (nodes) the value was P=0.006.
The results of the multivariate analysis are shown in Table 3. A marginal signi®cance is observed according to the primary location, and statistically signi®cant dierences were found with radiotherapy alone (only 2 oral cavity and 5 oropharynx cases), stage IV disease, and recurrence indicating a poor chance of survival. DISCUSSION Squamous cell carcinoma of the oral cavity remains to be one of the most dicult malignancies to control. In the study of Farr and co-workers (1980) of a historical series of 1034 cases of epidermoid carcinoma of the mouth, the 5-year survival was 41% for carcinoma of the mouth and pharynx, with 47.5% for patients with stage II lesions and 19% for those with stage III & IV disease. Franceschi et al. (1993) reviewed the records of 297 consecutive patients who underwent primary treatment of a squamous cell
52 Journal of Cranio-Maxillofacial Surgery
Fig. 1 ± Kaplan-Meier estimates of survival after treatment for the overall group of patients with squamous cell cancer of the oral cavity and/ or oropharynx, and the subgroup of patients with tumour relapse.
Table 2 ± Survival rates after 1, 3 and 5 years of the initial treatment in 88 patients with squamous cell carcinoma of the oral cavity and/or oropharynx (with univariate analysis of prognostic factors) Survival probability Prognostic factors
n
Deaths
1 yr
Sex Male Female
73 15
22 8
88.6 93.3
Age (yrs) 555 55±65 465
36 32 14
8 14 5
Stage I II III IV
12 16 29 31
Site Oral Oropharyngeal
3 yr
Log rank test 5 yr
P
75.4 66.7
68.1 59.3
0.24
94.3 90.4 78.6
82.3 67.8 70.7
75.3 59.3 61.9
0.18
2 4 8 16
100 86.7 96.4 80.1
100 79.4 78.3 56.7
81.8 69.5 78.3 47.9
0.0115
58 30
14 16
91.1 86.3
81.9 58.7
79.5 39.6
0.0012
Size T1 T2 T3 T4
12 34 22 20
1 9 9 11
100 87.9 85.7 89.7
100 72.4 66.3 68.6
90.9 72.4 66.3 42.8
0.0049
Neck disease N0±N1 N2±N3
66 22
19 11
92.1 81.8
80.8 54.6
72.5 49.6
0.025
Treatment modality Surgery & radiotherapy Surgery alone Radiotherapy alone
61 20 7
20 6 4
93.3 89.5 57.1
79.5 67.4 42.9
69.6 67.4 42.9
0.0759
Neck surgery No neck dissection Radical neck dissection Modi®ed & ampli®ed radical neck dissection
17 29 42
7 13 10
76.5 92.9 92.6
64.7 67.7 82.3
64.7 55.9 75.8
0.1357
Recurrence No Yes
54 34
8 22
92.5 84.5
84.7 56.3
84.7 36.4
0.0000
Survival evaluation of treatment modality 53
Fig. 2 ± Probability of survival for the dierent treatment modalities including a combined approach with surgery and postoperative radiation therapy (1), surgery and other forms of radiation (2), surgery alone (3), and radiation therapy alone (4).
Table 3 ± Risk ratio of death in the multivariate Cox regression analysis Prognostic factors
Hazard rate*
95% CI
Site Oral Oropharyngeal
1 2.66
0.99±7.13
Stage I II III IV
1 4.94 4.75 8.28
0.86±28.36 0.78±29.01 1.46±47.00
Treatment Surgery & radiotherapy Surgery alone Radiotherapy alone
1 2.80 5.74
0.99±7.89 1.06±31.12
1 11.96
3.80±37.68
Recurrence No Yes
* Hazard rate estimates in a Cox regression model containing site, stage, treatment modality and recurrence.
cancer of the tongue. Five-year survival was 65% overall. In this series, surgical removal of the tongue lesion was performed in 279 (94%) patients. Of these, 207 patients had surgery alone and 67 patients had surgery plus postoperative radiotherapy. In the study of Levy et al. (1991) a 5-year survival rate of 68.3% was reported in a group of 75 patients with carcinoma of the oral tongue (51 of whom were treated by a combination of surgery and radiation therapy). Our 5-year survival rate of 79.5% for the oral carcinoma group (58 patients, 72.4% tongue and ¯oor of the mouth and 27.6% all other oral sites), appears similar to the data of these other authors. In our group of 30 patients with carcinoma of the oropharynx, we found an overall 5-year survival rate of 39.6%, with 3-year and 5-year survival rates of 50% and 55.6% for T1 plus T2 tumours, as
compared with 50% and 22.9% for T3 plus T4. Some of the series published in the literature are restricted to carcinoma of the base of the tongue. Lusinchi et al. (1989) obtained a 5-year survival rate of 26% in 108 patients treated with external radiation plus curietherapy boost. Similarly, Jaulerry et al. (1991) achieved a 5-year survival rate of 27% in 166 patients receiving external beam radiation, whereas Foote et al. (1990) in 84 patients with base of tongue cancer who also underwent external beam radiation, reported 5-year relapse-free and absolute survival rates of 58% and 43%, respectively. On the other hand, in a group of 55 base of tongue cancer patients treated with surgery alone, the overall 5-year survival rate obtained by Foote et al. (1993) was even better (55%). They also found that local control of the disease was not in¯uenced by the following factors: clinical or pathological involvement of adjacent structures, grade of cell dierentiation, tumour size (in cm), status of the primary surgical margins, and type of operation performed. In the experience of Shaha et al. (1984) with 320 patients treated for squamous cell carcinoma of the ¯oor of the mouth (67% had T1 or T2 tumours), the 5 year cure for the entire group was 65%, a somewhat lower percentage that our 5-year survival rate of 79.5% for oral carcinoma. This may be indicative of the poor prognosis of some speci®c locations such as the ¯oor of the mouth. We found as mentioned already by Lindberg et al. (1974) Jesse and Fletcher (1977) Bartelink et al. (1983) that the possibility of survival was signi®cantly associated with the modality of treatment. The better results were achieved with a combination of surgery and postoperative radiotherapy as opposed to surgery alone, and especially to radiotherapy alone. By contrast, Ildstad et al. (1989) in 542 patients with
54 Journal of Cranio-Maxillofacial Surgery
squamous cell carcinoma of the head and neck found that the type of therapy used did not signi®cantly in¯uence survival after adjusting for stage. Combined therapy in these series, however, consisted of preoperative irradiation followed by surgery. In the study of O'Brien et al. (1986) with 179 patients with squamous cell carcinoma (of lip, oral cavity, and oropharynx in 127 cases), the predicted cumulative survival rate at 5 years for the entire group was 56%. The addition of radiotherapy to the surgical treatment of these patients altered the pattern of recurrence (higher index relapse in the ipsilateral neck without the use of radiotherapy) but did not signi®cantly alter survival in any subgroup of patients. As pointed out by Ildstad et al. (1983), the prognosis was signi®cantly better in primary tumours when compared to recurrences. Several reports have described an association between outcome and stage of the patients at the time of initial diagnosis. According to Ildstad et al. (1989) stage at initial diagnosis was the single-most important factor in¯uencing survival for all tumour locations (P50.0001). We also found a statistical signi®cance for stage with a P value adjusted by site of 0.047. In 155 consecutive oral squamous cell cancers, treated by surgery, radiation, or a combination of these, Moore et al. (1986) concluded that surface size, when greater than 2 cm, was an unreliable predictor of tumour behaviour per se, although small surface size (5 2 cm) correlated well with good survival. Foote et al. (1993) found that relapse in neck disease was in¯uenced by sex and clinical and histological N stage but not by extent or grade of primary tumour and extracapsular nodal extension. O'Brien et al. (1986) and Franceschi et al. (1993) found that among patients with involved nodes, survival was signi®cantly lower when more than two nodes were involved, or when extracapsular spread was present. In our study, survival was not in¯uenced by the type of neck dissection given the same stage of neck disease. Other investigators have reported similar ®ndings (Jesse et al., 1987; Bocca et al., 1980; Hanley, 1980). The clinical behaviour of the disease after treatment in our series, is consistent with a higher index of recurrences in the oropharynx carcinomas especially in base of the tongue lesions (40% of recurrence). This high incidence may be explained by the size of the primary tumour (60% were T3 and T4), and the diculty in obtaining margins free of disease, after surgical resection in this location. At the present time, wider primary tumour resections together with skilful reconstructive procedures using predicled or free ¯aps, and new therapeutic modalities in combination with surgery, e.g. brachytherapy, and chemotherapy associated with hyperfractionated radiotherapy, seem to improve the control of this type of recurrence. Better control of the primary was obtained in oral cavity carcinoma, except in a subgroup of patients with in®ltrating tumours of the ¯oor of the mouth. We did not observe any case of osteoradionecrosis in this series. Finally control of disease in the neck was
reasonable with two cases of recurrence only in the neck (2.2%), and three more cases with recurrences in the neck as well as of the primary (3.4%). CONCLUSION The fact that survival was in¯uenced signi®cantly by the therapeutic modality used, the site of the primary tumour, the stage, and the incidence of recurrence emphasizes the need for an early diagnosis, and more selective treatment planning, according to these parameters. Our results are consistent with those reported by other authors and future studies should compare the results of classical treatment modalities, with innovative therapeutic modalities (such as branchytherapy, hyperfractionated radiotherapy, preoperative chemotherapy, etc.). Acknowledgements The authors are indebted to Marta Pulido, MD, for editing the manuscript and editorial assistance.
References Ariyan S. Functional radical neck dissection. Plast Reconstr Surg 65: 768±776, 1980 Ballantyne AJ, Jackson GL. Synchronous bilatreal neck dissection. Am J Surg 144: 152±155, 1987 Bartelink H, Breur K, Hart G, Annyas B, Van Slooten E, Snow G. The value of postoperative radiotherapy as an adjuvant to radical neck dissection. Cancer 52: 1008±1013, 1983 Bocca E, Pignataro O, Sasaki CT. Functional neck dissection (a description of operative technique). Arch Ortolaryngol 106: 524±527, 1980 Byers RM. Modi®ed neck dissection. A study of 967 cases from 1970 to 1980. Am J Surg 150: 414±421, 1985. Farr HW, Glodfarb PM, Farr CM. Epidermoid carcinoma of the mouth and pharynx at Memorial Sloan-Kettering Cancer Center, 1965±1969, Am J Surg 140: 563±567, 1980 Franceschi D, Gupta R, Spiro RH, Shah JP. Improved survival in the treatment sof squamous carcinoma of the oral tongue. Am J Surg 166: 360±365, 1993 Foote RL, Parson JT, Mendenhall WM, Million RR, Cassisi NJ, Stringer SP. Is interstitial implantation essential for successful radiotherapeutic treatment of the base of the tongue? Int J Radiat Oncol Biol Phys 18: 1293±1298, 1990 Foote RL, Olsen KD, Davis DL, Buskirk SJ, Stanley RJ, Kunselman SJ, Schaid DJ, De Santo LW. Base of the tongue carcinoma: patterns of failure and predictors of recurrence after surgery alone. Head Neck Surg 15: 300±307, 1993 Hanley DJ. Supraomohyoid neck dissection. Br J Plast Surg 33: 136±137, 1980 Hermanek P, Sobin LH. UICC TNM classi®cation of malignant tumours, 4th edition, 2nd revision. Berlin: Springer, 1992 Ildstad ST, Bigelow ME, Remensnyder JP. Intra-oral cancer at the Massachusetts General Hospital. Squamous cell carcinoma of the ¯oor of the mouth. Ann Surg 197: 34±41, 1983 Ildstad ST, Tollerud DJ, Bigelow ME, Remensnyder JP. A multivariate analysis of determinants of survival for patients with squamous cell carcinoma of the head and neck. Ann Surg 209: 237±241, 1989 Jacobs HG. Views on the relative indications for suprahyoid and radical neck dissection. J Cranio-maxfac Surg 7: 307±314, 1979 Jaulerry C, Rodriquez J, Brunin F, Mosseri V, Pontvert D, Brugere J, Bataini JP. Results of radiation therapy in carcinoma of the base of tongue. Cancer 67: 1532±1538, 1991
Survival evaluation of treatment modality 55 Jesse RJ, Lindberg RD. The eciency of combining radiation therapy with a surgical procedure in patients with cervical metastases from squamous cancer of the oropharynx and hypopharynx. Cancer 35: 1163±1166, 1975 Jesse RH, Fletcher GH. Treatment of the neck in patients with squamous carcinoma of the head and neck. Cancer 39: 868± 872, 1977 Jesse RH, Ballantyne AJ, Larson D. Radical or modi®ed neck dissection: a therapeutic dilemma. Am J Surg 136: 516±519, 1987 Levy R, Sefal K, Hadar T, Shvero J, Abraham A. Squamous cell carcinoma of the oral tongue. Eur J Surg Oncol 17: 330±334, 1991 Lindberg RD, Jesse RH, Fletcher GH. Radiotherapy before or after surgery? In: Proceedings of the 17th Annual Clinical Conference on Cancer 1972, The University of Texas M.D. Anderson Hospital and Tumor Institute. Neoplasia of Head and Neck. Chicago: Year Book Medical Publisher, 1974; 47±58 Lusinchi A, Eskandari J, Son Y, Gerbaulet A, Haie C, Mamelle G, Eschwege F, Chassagne D. External irradiation plus curietherapy boost in 108 base of the tongue carcinomas. Int J Radiat Oncol Biol Phys 17: 1191±1197, 1989 Mac Comb WS, Fletcher GH. Planned combination of surgery and radiation in treatment of advanced primary head and neck cancers. Am J Roentgenol 77: 397±414, 1957 Mendelson BC, Woods JE, Beahrs OH. Neck dissection in the treatment of the carcinomas of the anterior two-thirds of the tongue. Surg Gynecol Obstet 143: 75±80, 1976 Moore C, Flynn MB, Greenberg RA. Evaluation of size in prognosis of oral cancer. Cancer 58: 158±162, 1986 O'Brien CJ, Smith JW, Soong S-J, Urist MM, Maddox WA. Neck dissection with and without radiotherapy: prognostic factors,
patterns of recurrence, and survival. Am J Surg 152: 456±463, 1986 Okamoto M, Ozeki S, Watanobe T, Iida Y, Tashiro H. Cervical lymph node metastasis in carcinoma of the tongue. Correlation between clinical and histopathological ®ndings and metastasis. J Carnio-maxfac Surg 16: 31±34, 1988 Pearlman NW, Johnson FB, Kennaugh RC. Modi®ed radical neck dissection and postoperative radiotherapy in squamous cell head and neck cancer. Am J Surg 150: 488±490, 1985 Shaha AR, Spiro RH, Shah JP, Strong EW. Squamous carcinoma of the ¯oor of the mouth. Am J Surg 148: 455±459, 1984 Southwick HW, Slauthter DP, Trevino ET. Elective neck dissection for intraoral cancer. Arch Surg 80: 905±909, 1960 White D. Byers RM. What is the preferred initial method of treatment for squamous carcinoma of the tongue? Am J Surg 140: 553±555, 1980
J. Pericot Institut ClõÂ nica Corachan C/BuõÈ gas 19 E-08017 Barcelona Spain Tel: +34 3 2800022 Fax: +34 3 2801455 Paper received 8 June 1999 Accepted 1 December 1999
Survival evaluation of treatment modality in squamous cell carcinoma of the oral cavity and oropharynx Josep Pericot,1 Josep M. EscribaÁ,2 AndreÂs ValdeÂs,3 MarõÂ a J. Biosca,1 Antoni Monner,1 Xavier CastellsagueÂ,4 Ramon Galiana,5 Pere Piulachs,1 Eloi Escutia1, Antoni Mari 1
Department of Maxillofacial Surgery (Head: Prof. Dr. J. Pericot), Ciutat SanitaÁria UniversitaÁria de Bellvitge, L'Hospitalet de Ll., Barcelona, Spain; 2 Primary Assistance Direction, Institut CatalaÁ de la Salut; 3 Department of Maxillofacial Surgery (Head: Prof. Dr. R. L. Ots), University of Alicante, Alicante, Spain; 4 Department of Cancer Epidemiology (Head: Prof. Dr. X. Bosch), Hospital Duran Reynals, C.S.U.B., Institut CatalaÁ d'OncologõÂa L'Hospitalet de LL., Barcelona, Spain; 5Department of Radiation Oncology (Head: Prof. Dr. F. Guedea), Ciutat SanitaÁria UniversitaÁria de Bellvitge, L'Hospitalet de Ll., Barcelona, Spain SUMMARY. The treatment of squamous cell carcinoma of the mouth and oropharynx continues to change. In this primary report, we compared the results obtained by combined surgery and radiation therapy, or either modality alone. Other methods such as brachytherapy, or hyperfractionated radiotherapy, were not included in our protocols. A statistical analysis of the 3- and 5-year survival rates in relation to location and size of the primary tumour, stage at initial presentation, treatment modality and recurrence, was carried out in 88 patients with squamous cell carcinoma of the oral cavity or oropharynx. The overall survival rate was 73.8% at 3 years and 66.3% at 5 years. Size of tumour and stage at presentation were signi®cant when P value was adjusted by site. Survival was signi®cantly associated with type of treatment (combined approach obtained superior results), location of primary tumour, and recurrence. The type of neck dissection did not show any eect. Therapeutic modality used, stage, and location of primary tumour signi®cantly in¯uenced survival. A more selective combined initial treatment according to site and stage (distribution) is recommended. # 2000 European Association for Cranio-Maxillofacial Surgery INTRODUCTION
consecutive patients with squamous cell carcinoma of the oral cavity or oropharynx on the 3- and 5-year survival rates. The results obtained were also analyzed according to major indicators of prognosis, such as location of the primary tumour, surface size, stage at initial presentation, therapeutic approach, type of neck dissection, and tumour recurrence. In another paper we shall attempt to compare the survival rates accomplished with the new additional therapies, such as brachytherapy, hyperfractionated radiotherapy, and others that were not in our routine treatment protocols at the time of this study.
The prognosis of patients with oral cancer remains uncertain, despite re®nements in conventional therapy and more recent protocols using alternative treatment modalities. Although squamous cell carcinomas or the oral cavity are often treated as a single entity, they are a heterogeneous group of tumours, the natural history and prognosis being strongly in¯uenced by the anatomic site of the primary tumour. Although the addition of radiation therapy to extirpative surgery has represented a major advancement in the treatment of oral cancer (Mac Comb and Fletcher, 1957; Southwick et al., 1960; Jesse and Lindberg, 1975; Mendelson et al., 1976; Farr et al., 1980; White and Byers, 1980; Byers, 1985; Jesse et al., 1987; Okamoto et al., 1988), there has been only a moderate improvement in survival over the past few decades despite more sophisticated radiation therapy, improvement in surgical techniques (Jacobs, 1979; Bocca et al., 1985; Ariyan, 1980; Pearlman et al., 1985) and the advent of aggressive chemotherapy protocols. The concept of combining surgery and irradiation to the neck and primary location has been widely applied since the early 1960s, but opinions dier about the indications and sequence of such combination treatment. The aim of this preliminary report was to assess the eect of therapeutic modalities used in a series of 88
MATERIAL AND METHODS Between July 1983 and December 1989, a total of 123 consecutive patients were treated at the Department of Maxillofacial Surgery of our institution for squamous cell cancer of the oral cavity and/or oropharynx. After review of the medical records, 35 (28.4%) were excluded because of partial treatment elsewhere, incomplete information, or no follow-up available. The remaining 88 previously untreated patients with a histopathological diagnosis of squamous cell carcinoma who underwent de®nite treatment for primary cancer in the oral cavity and/or oropharynx form the basis of this study. Follow-up examinations took place regularly at intervals of 3, 6, 49
50 Journal of Cranio-Maxillofacial Surgery
and 12 months after treatment at then annually. All patients were followed for at least 3 years (maximum 9 years), or until their deaths. The last follow-ups were completed by 1 July 1992. All information was obtained by three head and neck surgeons from clinical visits, correspondence or telephone interview with the patient, the patient's family, or the referring physician; or autopsy data. The following items were recorded: age, sex, site of primary tumour, size of primary lesion, clinical staging by the UICC-TNM classi®cation system (Hermanek and Sobin, 1992) treatment, type of neck dissection, and tumour recurrence. Treatment modalities included combined surgery and postoperative radiotherapy (in patients with locally advanced tumours, evidence of neck node metastasis, and suspicion of actual positive marginal extirpative), surgery alone, or radiation therapy alone. Dierent types of neck dissection were carried out according to the stage of the disease. The `ampli®ed radical neck dissection' was done in one case (including retroauricular nodes, parotidectomy, and facial skin) due to major tumour invasion of the neck and retromandibular area. Modi®ed neck dissection was carried out as a supraomohyoid neck dissection, including nodes at the levels I, II, and III with preservation of the sterno-cleido-mastoid muscle, internal jugular vein, carotid artery, and the spinal accessory nerve for patients who were clinically N0, and with primary tumours less than 3 cm in diameter. If there was suspicion of invasion in more than two nodes, extranodal invasion, or nodes bigger than 3 cm then an extended supraomohyoid neck dissection was performed, including level IV nodes, and part of the level V territory (middle posterior ceryvical nodes) dissected beneath the sterno-cleido-mastoid muscle. In some cases, the modi®ed neck dissection converted to a radical neck dissection. A bilateral neck dissection was undertaken simultaneously (Ballantyne and Jackson, 1982), but only when a clear tumour invasion of the midline was observed, or bilaterally positive nodes were found clinically. With regard to radiotherapy technique, the patients were mostly treated with disintegrated photons of Cobalt 60, and complementary irradiation for the neck, with electrons from a linear accelerator. The treatment ®eld included the entire primary tumour area, all extensions of the surgical scar and the upper and middle lymphatic drainage area, with two laterocervical opposing ®elds, and one anterior direct supraclavicular ®eld with glottic protection for subclavian and lower lymphatic chains. The patients were treated with a sessional dose of 2 Gy daily, ®ve days each week. The total dose at the primary site was 60±66 Gy, according to the limits of the surgical borders obtained. In the lymph mode area the doses were between 50 and 66 Gy, according to the type of node invasion observed surgically and on histopathological diagnosis following neck dissection. Radiotherapy was considered an essential part of the treatment for eradicating subclinical neck disease as well as of the tumour itself: patients with tumours
greater than 4 cm (pT3 UICC) or a tumour with positive margins or with malignant cells near the limits of the surgical resection (less than 10 mm), were always treated with postoperative radiotherapy. Combined surgery and radiotherapy was also employed in cases of undierentiated tumours, in tumours with speci®c malignant histopathological trends (nerve and vessel in®ltration), and in all cases of salvage surgery following local recurrence. Regarding the neck combined radiotherapy was used in any patient with pN+, and as an elective modality in pN0 patients exhibiting a primary tumour of more than 3.5 cm in diameter. A comprehensive indication for this combination therapy was also in those patients in whom it was dicult to perform follow-ups (because of social habits or distant residence). At the present time we use surgery as the primary treatment only in pN1 neck disease patients without extracapsular invasion, or any other poor prognostic factor (aggressive clinical or histopathologic in®ltration). In some patients, radiotherapy or chemotherapy was initially used when radical surgery could not be performed due to the patient's general condition, or when the patient refused an operation. Statistical analysis The probability of survival was calculated using the Kaplan-Meier estimates. Dierences in the probabilities of survival were calculated with the log-rank test (Cox-Mantel test). Cox proportional hazards regression analysis was used to estimate risk ratio of mortality in association with dierent variables. The statistical signi®cance of these estimates was assessed by the 95% con®dence interval. RESULTS The clinical characteristics and treatment modality of the patients are shown in Table 1. Among the dierent parameters studied we listed: a high incidence in males with a majority of patients under the age of 55 years; the most frequent presentations were stage III oral carcinoma (39.7%), and stage IV cases of oropharyngeal carcinoma (33.3%). (Neck disease at that time was only evaluated by clinical palpation with N0 encountered most often and a higher incidence of N3 nodes for the orpharyngeal lesions.) The recurrence rate was 25.9% for oral and 40% for oropharyngeal primaries. Recurrences in the neck were found to be much lower, with 1.7% and 3.3% for oral and oropharyngeal carcinomas respectively (see Table 1). The overall 5-year survival rate was 79.5% for patients with oral and 39.6% for the group with oropharyngeal carcinomata (Fig. 1). In the univariate analysis the survival probability was studied in relation to the parameters mentioned, and the results
Survival evaluation of treatment modality 51 Table 1 ± Characteristics of 88 patients with squamous cell carcinoma of the oral cavity and oropharynx Prognostic factors
Oral
Oropharyngeal
n
%
Deaths
n
%
Deaths
Sex Male Female
48 10
82.8 17.2
9 5
25 5
83.3 16.7
13 3
Age (yrs) 555 55±65 465
24 21 11
42.9 37.5 19.6
3 8 2
12 11 3
46.2 42.3 11.5
5 6 3
Stage I II III IV
8 12 23 15
13.8 20.7 39.7 25.9
0 3 5 6
4 4 6 16
13.3 13.3 20.0 33.3
2 1 3 10
Size T1 T2 T3 T4
9 25 16 8
15.5 43.1 27.6 13.8
0 5 6 3
3 9 6 12
10.0 30.0 20.0 40.0
1 4 3 8
Neck disease N0 N1 N2 N3
26 21 9 2
44.8 36.2 15.5 3.4
5 4 4 1
11 8 4 7
36.7 26.7 13.3 23.3
5 5 4 2
Treatment modality Surgery & radiotherapy Surgery alone Radiotherapy alone
40 16 2
69.0 27.6 3.4
9 4 1
21 4 5
70.0 13.3 16.7
11 2 3
Neck surgery Modi®ed neck dissection Radical neck dissection Ampli®ed radical neck dissection No neck dissection
28 19 1 10
48.3 32.8 1.7 17.2
2 7 1 4
13 10 0 7
43.3 33.3 0.0 23.3
7 6 0 3
Recurrence Primary Simultaneous primary and neck Neck Distant metastasis No relapse
15 2 1 1 39
25.9 3.4 1.7 1.7 67.2
8 1 0 1 4
12 1 1 1 15
40.0 3.3 3.3 3.3 50.0
9 1 1 1 4
Cause of death Oral cancer Other causes
14 7
66.7 33.3
16 2
88.9 11.1
are shown in Table 2. The statistically signi®cant factors were site of the primary tumour, size of the tumour and the incidence of recurrence. Treatment modality was close to statistical signi®cance (P=0.0759; Fig. 2). In the strati®ed univariate analysis of the two main groups of patients (oral and oropharyngeal), we found the following prognostically important factors: age, especially in oro-pharynx patients (P=0.02), with an adjusted P value by site of 0.06. Other important factors with an adjusted P value by site were: size (P=0.04), therapeutic modality (P=0.15), with a dierence of maximum survival for surgery plus postoperative radiotherapy (85.9%) and minimal survival for radiotherapy alone (50%) in the oral cancer patients (these dierences were not signi®cant in the oropharynx group). Recurrence showed values of P=0.0000 and of P=0.006 in the oral and the orpharynx groups respectively. In relation to N (nodes) the value was P=0.006.
The results of the multivariate analysis are shown in Table 3. A marginal signi®cance is observed according to the primary location, and statistically signi®cant dierences were found with radiotherapy alone (only 2 oral cavity and 5 oropharynx cases), stage IV disease, and recurrence indicating a poor chance of survival. DISCUSSION Squamous cell carcinoma of the oral cavity remains to be one of the most dicult malignancies to control. In the study of Farr and co-workers (1980) of a historical series of 1034 cases of epidermoid carcinoma of the mouth, the 5-year survival was 41% for carcinoma of the mouth and pharynx, with 47.5% for patients with stage II lesions and 19% for those with stage III & IV disease. Franceschi et al. (1993) reviewed the records of 297 consecutive patients who underwent primary treatment of a squamous cell
52 Journal of Cranio-Maxillofacial Surgery
Fig. 1 ± Kaplan-Meier estimates of survival after treatment for the overall group of patients with squamous cell cancer of the oral cavity and/ or oropharynx, and the subgroup of patients with tumour relapse.
Table 2 ± Survival rates after 1, 3 and 5 years of the initial treatment in 88 patients with squamous cell carcinoma of the oral cavity and/or oropharynx (with univariate analysis of prognostic factors) Survival probability Prognostic factors
n
Deaths
1 yr
Sex Male Female
73 15
22 8
88.6 93.3
Age (yrs) 555 55±65 465
36 32 14
8 14 5
Stage I II III IV
12 16 29 31
Site Oral Oropharyngeal
3 yr
Log rank test 5 yr
P
75.4 66.7
68.1 59.3
0.24
94.3 90.4 78.6
82.3 67.8 70.7
75.3 59.3 61.9
0.18
2 4 8 16
100 86.7 96.4 80.1
100 79.4 78.3 56.7
81.8 69.5 78.3 47.9
0.0115
58 30
14 16
91.1 86.3
81.9 58.7
79.5 39.6
0.0012
Size T1 T2 T3 T4
12 34 22 20
1 9 9 11
100 87.9 85.7 89.7
100 72.4 66.3 68.6
90.9 72.4 66.3 42.8
0.0049
Neck disease N0±N1 N2±N3
66 22
19 11
92.1 81.8
80.8 54.6
72.5 49.6
0.025
Treatment modality Surgery & radiotherapy Surgery alone Radiotherapy alone
61 20 7
20 6 4
93.3 89.5 57.1
79.5 67.4 42.9
69.6 67.4 42.9
0.0759
Neck surgery No neck dissection Radical neck dissection Modi®ed & ampli®ed radical neck dissection
17 29 42
7 13 10
76.5 92.9 92.6
64.7 67.7 82.3
64.7 55.9 75.8
0.1357
Recurrence No Yes
54 34
8 22
92.5 84.5
84.7 56.3
84.7 36.4
0.0000
Survival evaluation of treatment modality 53
Fig. 2 ± Probability of survival for the dierent treatment modalities including a combined approach with surgery and postoperative radiation therapy (1), surgery and other forms of radiation (2), surgery alone (3), and radiation therapy alone (4).
Table 3 ± Risk ratio of death in the multivariate Cox regression analysis Prognostic factors
Hazard rate*
95% CI
Site Oral Oropharyngeal
1 2.66
0.99±7.13
Stage I II III IV
1 4.94 4.75 8.28
0.86±28.36 0.78±29.01 1.46±47.00
Treatment Surgery & radiotherapy Surgery alone Radiotherapy alone
1 2.80 5.74
0.99±7.89 1.06±31.12
1 11.96
3.80±37.68
Recurrence No Yes
* Hazard rate estimates in a Cox regression model containing site, stage, treatment modality and recurrence.
cancer of the tongue. Five-year survival was 65% overall. In this series, surgical removal of the tongue lesion was performed in 279 (94%) patients. Of these, 207 patients had surgery alone and 67 patients had surgery plus postoperative radiotherapy. In the study of Levy et al. (1991) a 5-year survival rate of 68.3% was reported in a group of 75 patients with carcinoma of the oral tongue (51 of whom were treated by a combination of surgery and radiation therapy). Our 5-year survival rate of 79.5% for the oral carcinoma group (58 patients, 72.4% tongue and ¯oor of the mouth and 27.6% all other oral sites), appears similar to the data of these other authors. In our group of 30 patients with carcinoma of the oropharynx, we found an overall 5-year survival rate of 39.6%, with 3-year and 5-year survival rates of 50% and 55.6% for T1 plus T2 tumours, as
compared with 50% and 22.9% for T3 plus T4. Some of the series published in the literature are restricted to carcinoma of the base of the tongue. Lusinchi et al. (1989) obtained a 5-year survival rate of 26% in 108 patients treated with external radiation plus curietherapy boost. Similarly, Jaulerry et al. (1991) achieved a 5-year survival rate of 27% in 166 patients receiving external beam radiation, whereas Foote et al. (1990) in 84 patients with base of tongue cancer who also underwent external beam radiation, reported 5-year relapse-free and absolute survival rates of 58% and 43%, respectively. On the other hand, in a group of 55 base of tongue cancer patients treated with surgery alone, the overall 5-year survival rate obtained by Foote et al. (1993) was even better (55%). They also found that local control of the disease was not in¯uenced by the following factors: clinical or pathological involvement of adjacent structures, grade of cell dierentiation, tumour size (in cm), status of the primary surgical margins, and type of operation performed. In the experience of Shaha et al. (1984) with 320 patients treated for squamous cell carcinoma of the ¯oor of the mouth (67% had T1 or T2 tumours), the 5 year cure for the entire group was 65%, a somewhat lower percentage that our 5-year survival rate of 79.5% for oral carcinoma. This may be indicative of the poor prognosis of some speci®c locations such as the ¯oor of the mouth. We found as mentioned already by Lindberg et al. (1974) Jesse and Fletcher (1977) Bartelink et al. (1983) that the possibility of survival was signi®cantly associated with the modality of treatment. The better results were achieved with a combination of surgery and postoperative radiotherapy as opposed to surgery alone, and especially to radiotherapy alone. By contrast, Ildstad et al. (1989) in 542 patients with
54 Journal of Cranio-Maxillofacial Surgery
squamous cell carcinoma of the head and neck found that the type of therapy used did not signi®cantly in¯uence survival after adjusting for stage. Combined therapy in these series, however, consisted of preoperative irradiation followed by surgery. In the study of O'Brien et al. (1986) with 179 patients with squamous cell carcinoma (of lip, oral cavity, and oropharynx in 127 cases), the predicted cumulative survival rate at 5 years for the entire group was 56%. The addition of radiotherapy to the surgical treatment of these patients altered the pattern of recurrence (higher index relapse in the ipsilateral neck without the use of radiotherapy) but did not signi®cantly alter survival in any subgroup of patients. As pointed out by Ildstad et al. (1983), the prognosis was signi®cantly better in primary tumours when compared to recurrences. Several reports have described an association between outcome and stage of the patients at the time of initial diagnosis. According to Ildstad et al. (1989) stage at initial diagnosis was the single-most important factor in¯uencing survival for all tumour locations (P50.0001). We also found a statistical signi®cance for stage with a P value adjusted by site of 0.047. In 155 consecutive oral squamous cell cancers, treated by surgery, radiation, or a combination of these, Moore et al. (1986) concluded that surface size, when greater than 2 cm, was an unreliable predictor of tumour behaviour per se, although small surface size (5 2 cm) correlated well with good survival. Foote et al. (1993) found that relapse in neck disease was in¯uenced by sex and clinical and histological N stage but not by extent or grade of primary tumour and extracapsular nodal extension. O'Brien et al. (1986) and Franceschi et al. (1993) found that among patients with involved nodes, survival was signi®cantly lower when more than two nodes were involved, or when extracapsular spread was present. In our study, survival was not in¯uenced by the type of neck dissection given the same stage of neck disease. Other investigators have reported similar ®ndings (Jesse et al., 1987; Bocca et al., 1980; Hanley, 1980). The clinical behaviour of the disease after treatment in our series, is consistent with a higher index of recurrences in the oropharynx carcinomas especially in base of the tongue lesions (40% of recurrence). This high incidence may be explained by the size of the primary tumour (60% were T3 and T4), and the diculty in obtaining margins free of disease, after surgical resection in this location. At the present time, wider primary tumour resections together with skilful reconstructive procedures using predicled or free ¯aps, and new therapeutic modalities in combination with surgery, e.g. brachytherapy, and chemotherapy associated with hyperfractionated radiotherapy, seem to improve the control of this type of recurrence. Better control of the primary was obtained in oral cavity carcinoma, except in a subgroup of patients with in®ltrating tumours of the ¯oor of the mouth. We did not observe any case of osteoradionecrosis in this series. Finally control of disease in the neck was
reasonable with two cases of recurrence only in the neck (2.2%), and three more cases with recurrences in the neck as well as of the primary (3.4%). CONCLUSION The fact that survival was in¯uenced signi®cantly by the therapeutic modality used, the site of the primary tumour, the stage, and the incidence of recurrence emphasizes the need for an early diagnosis, and more selective treatment planning, according to these parameters. Our results are consistent with those reported by other authors and future studies should compare the results of classical treatment modalities, with innovative therapeutic modalities (such as branchytherapy, hyperfractionated radiotherapy, preoperative chemotherapy, etc.). Acknowledgements The authors are indebted to Marta Pulido, MD, for editing the manuscript and editorial assistance.
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J. Pericot Institut ClõÂ nica Corachan C/BuõÈ gas 19 E-08017 Barcelona Spain Tel: +34 3 2800022 Fax: +34 3 2801455 Paper received 8 June 1999 Accepted 1 December 1999