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Squamous Cell Carcinoma of the Oropharynx Surgery, Radiation Therapy, or Both
James T. Parsons, M.D.1 William M. Mendenhall, M.D.2 Scott P. Stringer, M.D.3 Robert J. Amdur, M.D.2 Russell W. Hinerman, M.D.2 Douglas B. Villaret, M.D.3 Giselle J. Moore-Higgs, M.S.N.2 Bruce D. Greene, M.D.1 Tod W. Speer, M.D.1 Nicholas J. Cassisi, D.D.S., M.D.3 Rodney R. Million, M.D.2 1
Department of Radiation Oncology, Bethesda Memorial Hospital, Boynton Beach, Florida.
2
Department of Radiation Oncology, University of Florida, Gainesville, Florida.
3
Department of Otolaryngology, University of Florida College of Medicine, Gainesville, Florida.
Address for correspondence: William M. Mendenhall, M.D., Department of Radiation Oncology, University of Florida Health Science Center, P.O. Box 100385, Gainesville, FL 32610-0385; Fax: (352) 265-0759. E-mail:
[email protected] Received July 20, 2001; revision received January 7, 2002; accepted January 22, 2002. © 2002 American Cancer Society
BACKGROUND. The treatment of patients with squamous cell carcinoma (SCC) of the oropharynx remains controversial. No randomized trial has addressed adequately the question of whether surgery (S), radiation therapy (RT), or combined treatment is most effective. METHODS. Treatment results from North American academic institutions that used S with or without adjuvant RT (S ⫾ RT) or used RT alone or followed by neck dissection (RT ⫾ ND) for patients with SCC of the tonsillar region or the base of tongue were compiled through a MEDLINE search (from 1970 to August, 2000) and from the references cited in each report. Studies were eligible for inclusion if they contained direct, actuarial (life-table), or Kaplan–Meier calculations for the following end points: local control, local-regional control, 5-year absolute survival, 5-year cause specific survival, or severe or fatal treatment complications. Weighted average results, which took into account series size, were calculated for each end point for the purposes of treatment comparison. Results and conclusions were based on data from 51 reported series, representing the treatment of approximately 6400 patients from the United States and Canada. RESULTS. The results for patients with SCC of the base of tongue who underwent S ⫾ RT versus RT ⫾ ND, respectively, were as follows: local control, 79% versus 76% (P ⫽ 0.087); local-regional control, 60% versus 69% (P ⫽ 0.009); 5-year survival, 49% versus 52% (P ⫽ 0.2); 5-year cause specific survival, 62% versus 63% (P ⫽ 0.4); severe complications, 32% versus 3.8% (P ⬍ 0.001); and fatal complications, 3.5% versus 0.4% (P ⬍ 0.001). The results for patients with SCC in the tonsillar region who underwent S ⫾ RT versus RT ⫾ ND, respectively, were as follows: local control, 70% versus 68% (P ⫽ 0.2); local-regional control, 65% versus 69% (P ⫽ 0.1); 5-year survival, 47% versus 43% (P ⫽ 0.2); 5-year cause specific survival, 57% versus 59% (P ⫽ 0.3); severe complications, 23% versus 6% (P ⬍ 0.001); and fatal complications, 3.2% versus 0.8% (P ⬍ 0.001). CONCLUSIONS. The information in this article provides a useful benchmark for evidence-based counseling of patients with SCC of the oropharynx. The rates of local control, local-regional control, 5-year survival, and 5-year cause specific survival were similar for patients who underwent S ⫾ RT or RT ⫾ ND, whereas the rates of severe or fatal complications were significantly greater for the S ⫾ RT group. Furthermore, available data on the functional consequences of treatment suggest the superiority of RT ⫾ ND. The authors conclude that RT ⫾ ND is preferable for the majority of patients with SCC of the oropharynx. Cancer 2002;94:2967– 80. © 2002 American Cancer Society. DOI 10.1002/cncr.10567 KEYWORDS: oropharyngeal neoplasms, squamous cell carcinoma, surgery, radiotherapy, combined-modality therapy, treatment outcome.
T
he oropharynx consists of the tonsillar region (pillars and fossae), base of tongue, soft palate, and posterior and lateral oropharyngeal walls. Carcinoma arising from these sites usually is squamous in
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origin and is related strongly to smoking and, to a lesser degree, alcohol ingestion. Most commonly, carcinoma affects patients in the fifth through seventh decades in life: The incidence in men is two to five times greater than the incidence observed in women. In 2001, there will be approximately 30,100 new diagnoses of oral or pharyngeal carcinoma in the United States, resulting in 7800 deaths.1 The management of patients with primary oropharyngeal squamous cell carcinoma (SCC) remains controversial.2–12 It is often stated that radiation therapy (RT) and surgery (S) are equally effective for the treatment of patients with early-stage disease, whereas a combination of the two modalities is the standard of care for patients with advanced disease, with the presumption that two radical treatments are more effective than one. There are insufficient randomized data that adequately address the question of RT alone versus combined-modality treatment. The only randomized trial was conducted by the Radiation Therapy Oncology Group.13 Seventy patients with oropharyngeal carcinoma received definitive RT (24 patients), preoperative RT and S (23 patients), or S and postoperative RT (23 patients). There were no significant differences in the end results. Tumor control and survival are the usual measures of treatment efficacy. For patients with SCC of the oropharynx, local (primary site) control is particularly relevant. If ultimate local control is not achieved, then the patient likely will suffer a miserable death, with intractable pain, bleeding, infection, malodor, trismus, inability to handle secretions, suffocation, and wasting—a scenario not appreciably different than when President Ulysses S. Grant died of tonsillar carcinoma 115 years ago.14 For this reason, if it can be proven clearly that S, RT, or combinedmodality treatment is the superior local treatment, then the finding would be of considerable significance. In addition to tumor control and survival, therapies for patients with malignant disease are judged by the complications, morbidity, and mortality that they induce. The choice between S and RT is not trivial, because these treatments produce different toxicities and functional outcomes. In the absence of randomized trials, treatment decisions are based on retrospective data. The purpose of this article was to review the North American experience with RT alone or followed by neck dissection (RT ⫾ ND) or S with or without adjuvant RT (S ⫾ RT ) for patients with SCC of the base of tongue or tonsil. There were insufficient published data on patients with soft palate and pharyngeal wall tumors to make meaningful comparisons.
MATERIALS AND METHODS Treatment results from North American academic institutions that used S ⫾ RT or RT ⫾ ND for patients with SCC of the tonsillar region or the base of tongue were compiled from a MEDLINE search (1970 to August 2000) and from references cited in each study. Studies were eligible for inclusion if they contained direct, actuarial (life-table), or Kaplan–Meier calculations for the following end points: local control, localregional (primary site and neck) control, 5-year absolute or cause specific survival, or severe or fatal treatment complications. Few reports contained all information. All available data for each selected end point are presented. Some institutions have published results more than once; the dates of patient treatment are included for each such report. In some instances, the dates of patient inclusion overlapped slightly, indicating that some patients were reported more than once. Entries in each table are chronological, according to year of publication. Included in the tables are the percentages of patients who had T4 tumors (advanced primary disease) or Stage IV tumors (advanced primary and/or neck disease). During the 30-year study period, the staging definitions have undergone several modifications.15–17 In general, however, throughout the study period, the T4 designation usually implied the presence of one or more of the following findings: extension of primary tumor into soft tissues of the neck, trismus, tongue deviation or fixation (usually with dysarthria), bone destruction, or cranial nerve paralysis (the latter two are rare in patients with oropharyngeal tumors). Stage IV has generally meant T4 primary disease and/or the presence of lymph node metastases measuring ⬎ 3 cm, multiple lymph node metastases, or bilateral or contralateral lymph node involvement. Weighted average results, which take into account series size, were calculated for ease of data comparison. Thus, the impact of each series was scaled in importance according to the number of patients treated. For each end point, a weighted average was calculated as follows: for each series, the number of patients treated was multiplied by the percentage of patients who satisfied the selected end point (for example, 5-year survival). The total number of patients who satisfied that end point from all series combined was then divided by the total number of all patients who were treated in the respective series. Series for which no data were available for a particular end point were excluded from both the numerator and the denominator. For comparison of two proportions, significance was calculated by a modified chi-square test.18 Patients who developed local and/or regional recur-
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TABLE 1 Base of Tongue Carcinoma: Local Control According to T Stagea Local control (%) Institution S with or without adjuvant RT Washington University, St. Louis, MO (1983)19 Stanford University, Palo Alto, CA (1974–1982) (1985)20 M. D. Anderson Cancer Center, Houston, TX (1974–1984) (1990)3 University of Pittsburgh, Pittsburgh, PA (1992)6 Memorial Sloan-Kettering Cancer Center, New York, NY (1973–86) 199221 Memorial Sloan-Kettering Cancer Center, New York, NY (1979–89) 199322 University of Pennsylvania, Philadelphia, PA (1997)23 Mayo Clinic, Rochester, MN (1971–1993) (1998)24 Weighted average RT with or without neck dissection M. D. Anderson Cancer Center, Houston, TX (1954–1971) (1976)25 University of California, San Francisco, CA (1979)26 Stanford University, Palo Alto, CA (1974–1982) (1985)20 M. D. Anderson Cancer Center, Houston, TX (1974–1984) (1990)3 M. D. Anderson Cancer Center, Houston, TX (1984–1992) (1995)27 Massachusetts General Hospital, Boston (b.i.d.) (1995)28 William Beaumont Hospital, Royal Oak, MI (1996)29 Memorial Sloan-Kettering Cancer Center, New York, NY (1981–1995) (1998)30 University of Florida, Gainesville, FL (2000)31 Weighted average
No. of patients
T4 (%)
Boost technique
101 14 35 13 31 100 17 79 390
9 0 ND 0 39 19 41 0 13
NA NA NA NA NA NA NA NA —
174 48 14 121 54 90 20 68 217 806
17 10 14 ND 2 0 25 3 19 13
EBRT EBRT 192 Ir EBRT EBRT EBRT 192 Ir 192 Ir EBRT —
T1
T2
T3
T4
Overall
ND ND
ND 3/3
ND 43
ND ND
100 84b ND
ND 86b ND
84 —
87 —
76 —
ND —
74 60 80 100 84b 82b 77 82 79
91 100 ND
71 56 ND
78 32 ND 59 67 54 100 82 81 —
52 20 ND 44 ND ND 80 2/2 38 —
74 48 86 68 85 ND 88 89 79 76
83 100 ND ND
79
77
80
89 100 85 100 87 96 —
ND 84b ND
96 85 89 93 91 —
NA: not applicable; ND: no data; 192Ir: iridium 192 interstitial brachytherapy boost; EBRT: external beam radiation therapy; b.i.d.: twice a day; S: surgery; RT: radiation therapy. a Modified from Table 1 in Mendenhall et al., 2000.31 b First site of failure.
rences were scored as failures even if, subsequently, they were salvaged successfully by S and/or RT. Patients who survived for 5 years were scored as survivors irrespective of their disease status at that time and irrespective of any prior failures and/or salvage procedures. Serious complications of RT included conditions that required operation or hospitalization or that resulted in severe debility, including severe osteoradionecrosis, soft tissue necrosis, permanent gastrostomy, severe edema, serious neurologic injury, radiationinduced sarcoma, and complications of planned neck dissection or salvage surgery, when reported. Severe complications of S consisted of severe wound breakdown or fistula requiring surgical repair, osteomyelitis, permanent gastrostomy, permanent tracheostomy, chronic aspiration, carotid artery rupture, myocardial infarction, or other severe cardiopulmonary or central nervous system events. Results and conclusions are based on data from 51 reported series, representing treatment administered to approximately 6400 patients across the United States and Canada.
RESULTS Base of Tongue Local control The local control rates in patients with SCC of the base of the tongue after undergoing S ⫾ RT (390 patients; 13% had T4 lesions) or external-beam RT with or without an interstitial implant (806 patients; 13% had T4 lesions) are shown in Table 1.3,6,19 –31 The weightedaverage local control rate was 79% in the S ⫾ RT group compared with 76% in the RT alone group (P ⫽ 0.087) for all stages.
Local-regional control The local-regional control rates in patients with SCC of the base of the tongue after undergoing S ⫾ RT (370 patients) or RT ⫾ ND (370 patients) are shown in Table 2.17,19,20,22–24,27,31–34 Although the RT series had a significantly greater proportion of patients with Stage IV disease (66% vs. 42%; P ⬍ 0.001), weighted-average, local-regional control rates for all stages were greater after RT ⫾ ND (69%) than after S ⫾ RT (60%; P ⫽ 0.009).
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TABLE 2 Base of Tongue Carcinoma: Local-Regional Control According to the American Joint Committee on Cancer Staging Systema Local-regional control (%) Institution S with or without adjuvant RT M. D. Anderson Cancer Center, Houston, TX (1964–1973) (1978)32 Massachusetts General Hospital, Boston, MA (1962–1976) (1983)33 Washington University, St. Louis, MO (1983)19 Stanford University, Palo Alto, CA (1974–1982) (1985)20 Memorial Sloan-Kettering Cancer Center, New York, NY (1979–1989) (1993)22 University of Pennsylvania, Philadelphia, PA (1997)23 Mayo Clinic, Rochester, MN (1971–1993) (1998)24 Weighted average RT with or without neck dissection Massachusetts General Hospital, Boston, MA (1962–1976) (1983)33 Memorial Medical Center, Long Beach, CA (1988)34 M. D. Anderson Cancer Center, Houston, TX (1984–1992) (1995)27 University of Florida, Gainesville, FL (2000)31 Weighted average
No. of patients
Stage IV (%)
Stage I
Stage II
Stage III
Stage IV
Overall
34 25 101 14 100 17 79 370
76 40 45 21 36 59 33 42
ND 67 100 ND ND ND 56 —
ND 80 75 100 ND ND 79 —
ND 29 67 33 ND ND 55 —
ND 20 40 33 ND 50 54 —
56 40 57 43 72b 68 59 60
29 70 54 217 370
52 57 63 71 66
ND ND ND 100 —
20 100 100 100 —
22 78 79 83 —
7 73 72 65c —
14 77 76 72 69
ND: no data. a See American Joint Committee on Cancer, 1998.17 Modified from Table 2 in Mendenhall et al., 2000.31 b First site of failure. c Stage IVA, 64%; Stage IVB, 66%.
TABLE 3 Base of Tongue Carcinoma: Five-Year Survivala Survival (%) Institution S with or without adjuvant RT Mayo Clinic, Rochester, MN (1960–1967) (1972)35 Washington University, St. Louis, MO (1983)19 Stanford University, Palo Alto, CA (1974–1982) (1985)20 Memorial Sloan-Kettering Cancer Center, New York, NY (1979–1989) (1993)22 University of Pennsylvania, Philadelphia, PA (1997)23 Mayo Clinic, Rochester, MN (1971–1993) (1998)24 University of Pittsburgh, Pittsburgh, PA (1980–1987) (2000)36 Weighted average RT with or without neck dissection Stanford University, Palo Alto, CA (1958–1980) (1983)37 Memorial Medical Center, Long Beach, CA (1988)34 M. D. Anderson Cancer Center, Houston, TX (1984–1992) (1995)27 Memorial Sloan-Kettering Cancer Center, New York, NY (1981–1995) (1998)30 University of Florida, Gainesville, FL (2000)31 Weighted average
No. of patients
T4 (%)
Stage IV (%)
Absolute
Cause specific
102 101 14 100 17 79 87 500
ND 9 0 19 41 0 ND 11
7 45 21 36 59 33 ND 31
44 45 51 55 46 (3 yr) 51 49 49
ND ND ND 65 ND 65 56 62
64 70 54 68 217 473
ND 17 2 3 19 14
50 57 63 51 71 62
35 35 59 87 50 52
ND 60 65 ND 64 63
ND: no data. a Modified from Table 3 in Mendenhall et al., 2000.31
Absolute and cause specific survival The absolute and cause specific survival rates in patients with SCC of the base of the tongue after undergoing S ⫾ RT (500 patients) or RT ⫾ ND (473 patients) are shown in Table 3.19,20,22–24,27,30,31,34 –37 Twice as many patients in the RT ⫾ ND group had Stage IV
disease (62% vs. 31%; P ⬍ 0.001). Despite this bias, the 5-year, weighted, cause specific survival rates were 62% in the S ⫾ RT group compared with 63% in the RT ⫾ ND group (P ⫽ 0.4). The 5-year absolute survival rates were 49% in the S ⫾ RT group compared with 52% in the RT ⫾ ND group (P ⫽ 0.2).
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TABLE 4 Base of Tongue: Severe Complicationsa Complications (%) Institution S with or without adjuvant RT M. D. Anderson Cancer Center, Houston, TX (1964–1973) (1978)32 Indiana University, Indianapolis, IN (1983)38 Washington University, St. Louis, MO (1983)19 Stanford University, Palo Alto, CA (1985)20 M. D. Anderson Cancer Center, Houston, TX (1974–1984) (1990)3 University of California, Los Angeles, CA (1990)39 University of Pittsburgh, Pittsburgh, PA (1992)6 Memorial Sloan-Kettering Cancer Center, New York, NY (1979–1989) (1993)22 Mayo Clinic, Rochester, MN (1971–1986) (1993)2 University of Pennsylvania, Philadelphia, PA (1997)23 Weighted average RT with or without neck dissection Stanford University, Palo Alto, CA (1956–1973) (1976)40 M. D. Anderson Cancer Center, Houston, TX (1954–1971) (1976)25 Stanford University, Palo Alto, CA (1974–1982) (1985)20 Memorial Medical Center, Long Beach, CA (1988)34 M. D. Anderson Cancer Center, Houston, TX (1974–1984) (1990)3 M. D. Anderson Cancer Center, Houston, TX (1984–1992) (1995)27 William Beaumont Hospital, Royal Oak, MI (1996)29 Memorial Sloan-Kettering Cancer Center, New York, NY (1981–95) (1998)30 University of Florida, Gainesville, FL (2000)31 Weighted average
No. of patients
T4 (%)
34 8 101 14 51 13 14 100 55 17 407
41 38 9 0 ND 0 0 19 0 41 15
104 174 14 70 121 54 20 68 217 842
ND 17 14 17 ND 2 25 3 19 14
Boost technique
Severe
Fatal
NA NA NA NA NA NA NA NA NA NA
26 38 28 64 28 23 0 ND 49 29 32
18 12 4 0 2 0 0 0 4 0 3.5
EBRT EBRT 192 Ir 192 Ir EBRT EBRT 192 Ir 192 Ir EBRT —
7 3 7 6 2 0 10 3 4 3.8
1 0 0 0 0 0 0 0 1 0.4
NA: not applicable; ND: no data; EBRT: external beam radiation therapy; 192Ir: iridium 192 interstitial brachytherapy boost; S: surgery; RT: radiation therapy. a Modified from Table 4 in Mendenhall et al., 2000.31
Severe or fatal complications The severe or fatal complication rates in patients with SCC of the base of the tongue after undergoing S ⫾ RT (407 patients) or RT ⫾ ND (842 patients) are shown in Table 4.2,3,6,19,20,22,23,25,27,29 –32,34,38 – 40 Severe complications were noted in 32% of patients in the S ⫾ RT group compared with 3.8% in the RT ⫾ ND group (P ⬍ 0.001). Fatal complications occurred in 3.5% of patients in the S ⫾ RT group compared with 0.4% of patients in the RT ⫾ ND group (P ⬍ 0.001). Most of the excess mortality after S was reported in the early series.
Tonsillar Region Local control The local control rates for patients with SCC of the tonsillar region after undergoing S ⫾ RT (406 patients; 12% had T4 lesions) or RT alone (1833 patients; 14% had T4 lesions) are shown in Table 5.21,28,41–53 Local control rates were similar (70% after S ⫾ RT vs. 68% after RT; P ⫽ 0.2).
Local-regional control The local-regional control rates for patients with SCC of the tonsillar region after undergoing S ⫾ RT (281
patients) or RT ⫾ ND (858 patients) are shown in Table 6.41,42,48,50,52–57 A greater proportion of patients in the RT ⫾ ND group had Stage IV disease (52% vs. 31%; P ⬍ 0.001). Despite this bias, local-regional control rates (65% after S ⫾ RT; 69% after RT ⫾ ND) were similar (P ⫽ 0.1).
Five-year absolute and cause specific survival The 5-year absolute and cause specific survival rates for patients with SCC of the tonsillar region after undergoing S ⫾ RT (321 patients; 44% had Stage IV disease) or RT ⫾ ND (2276 patients; 49% had Stage IV disease) are shown in Table 7.21,40,42,45– 47,49,50,52,53,57– 64 The absolute survival rates were 47% in the S ⫾ RT group compared with 43% in the RT ⫾ ND group (P ⫽ 0.2). The cause specific survival rates were 57% in the S ⫾ RT group compared with 59% in the RT ⫾ ND group (P ⫽ 0.3)
Severe or fatal complication rates The severe or fatal complication rates for patients with SCC of the tonsillar region after undergoing S ⫾ RT (616 patients) or RT ⫾ ND (2308 patients) are listed in Table 8.41,44,46,48,50,54 –58,61,63– 67 Severe complications (23% in the S ⫾ RT group vs. 6% in the RT ⫾ ND group;
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TABLE 5 Tonsillar Squamous Cell Carcinoma: Local Control According to Tumor Statusa Local control (%) Series S with or without adjuvant RT Memorial Sloan-Kettering Cancer Center, New York, NY (1973–1986) (1992)21 Mayo Clinic, Rochester, MN (1970–1988) (1994)41 Roswell Park Cancer Institute, Buffalo, NY (1998)42 University of California Medical Center, Los Angeles, CA (1998)43 Washington University Medical Center, St. Louis, MO (1998)44 Weighted average RT with or without neck dissection University of Michigan, Ann Arbor, MI (1955–1963) (1971)45 University of Michigan, Ann Arbor, MI (1960–1976) (1983)46 University of Maryland Hospital, Baltimore, MA (1984)47 Memorial Medical Center, Long Beach, CA (1985)48 M. D. Anderson Cancer Center, Houston, TX (1968–1983) (1989)49 Mayo Clinic, Rochester, MN (1970–1988) (1994)50 Massachusetts General Hospital, Boston, MA (b.i.d) (1995)28 University of Virginia, Charlottesville, VA (1995)51 Washington University Medical Center, St. Louis, MO (1998)44 University of California, Los Angeles, CA (1998)43 Vancouver Cancer Center, Vancouver, BC (1999)52 University of Florida, Gainesville, FL (2000)53 Weighted average
No. of patients
T4 (%)
T1
T2
T3
T4
Overall
S with or without RT S with or without RT S S and RT S and RT
20 72 56 28 230 406
20 3 ND ND 14 12
ND 78 ND
4/4 76 ND
100 44 ND
50 0/2 ND
71 —
65 —
58 —
89 71 75 64 68 70
RT RT RT RT, 192Ir RT RT RT RT RT RT Ipsilateral RT RT —
102 353 185 80 150 21 102 53 154 55 178 400 1833
14 16 14 24 5 43 0 0 23 ND 5 17 14
78 63
39 50 51 ND 67 100 80 ND 59
29 25 19 ND 63 56 ND ND 33
79 81 —
58 74 —
Treatment
80 80 —
61
77 92 94 ND 94 ND
77 80 ND 81 80 91
83 76 65 94 83 —
31 56 60 —
65 62 58 84 75 76 ND 81 56 44 75 76 68
S: Surgery; RT: radiation therapy; ND: no data; 192Ir: iridium 192 intestitial brachytherapy boost; b.i.d.: twice a day. a Modified from Table 2 in Mendenhall et al., 2000.53
P ⬍ 0.001) and fatal complications (3.2% vs. 0.8%, respectively; P ⬍ 0.001) were both significantly more frequent in the S ⫾ RT group.
Additional Analyses Considering the rather wide range of reported outcomes, especially in the early years, we suspect some heterogeneity of treatment technique and/or patient selection among the various institutions. To minimize the impact of including data that may be considered unrepresentative of the current state of the art, each end point was analyzed four additional ways for each treatment type: 1) analysis limited to the three largest patient series, 2) analysis limited to the three series reporting the most favorable results, 3) analysis limited to the three most recent series, and 4) analysis limited to eight U.S. institutions widely recognized for expertise in the management of patients with carcinoma of the head and neck that have published their data on multiple occasions and that represent all geographic regions of the United States (Memorial SloanKettering Cancer Center, New York, NY; Stanford University, Palo Alto, CA; M. D. Anderson Cancer Center, Houston, TX; University of Florida, Gainesville, FL; University of California, San Francisco, CA; Mayo
Clinic, Rochester, MN; Washington University, St. Louis, MO; and Massachusetts General Hospital, Boston, MA). Reanalysis by these methods resulted in no change in any conclusion and provided reassurance that the conclusions were not distorted or diluted by the inclusion of heterogeneous, unrepresentive patient series. Whenever significant differences were noted between S and RT, as noted below, the differences were always in favor of the RT ⫾ ND group compared with the S ⫾ RT group. Table 9 shows local control, local-regional control, survival, and complication data for the three largest RT series and the three largest S series for each end point for which data were available on both base of tongue carcinoma and tonsillar carcinoma. Of 12 data comparisons between S ⫾ RT and RT ⫾ ND, results significantly favored RT ⫾ ND in five instances and S ⫾ RT in none (P ⬍ 0.05). Table 10 shows local control, local-regional control, survival, and complication data for the three most recently reported RT series and the three most recently reported S series for each end point for which data were available for both base of tongue carcinoma and tonsillar carcinoma. Of 12 data comparisons, re-
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TABLE 6 Tonsillar Squamous Cell Carcinoma: Local-Regional Control According to the American Joint Committee on Cancer Staging Systema Local-regional control (%)
Series S with or without adjuvant RT University of California School of Medicine, San Francisco, CA (1986)54 Memorial Sloan-Kettering Cancer Center, New York, NY (1969–1983) (1989)55 Mayo Clinic, Rochester, MN (1970–1988) (1994)41 Roswell Park Cancer Institute, Buffalo, NY (1998)42 Weighted average RT with or without neck dissection University of Washington, Seattle, WA (1982)56 Memorial Medical Center, Long Beach, CA (1985)48 Mayo Clinic, Rochester, MN (1970–1988) (1994)50 M. D. Anderson Cancer Center, Houston, TX (1983–1992) (1997)57 Vancouver Cancer Center, Vancouver, BC (1999)52 University of Florida, Gainesville, FL (2000)53 Weighted average
Treatment
No. of patients
Stage IV (%)
S with or without RT
40
ND
S with or without RT S with or without RT S —
113 72 56 281
35 25 29 31
RT R 192Ir RT RT Ipsilateral RT RT —
104 80 21 83 170 400 858
35 49 57 53 ND 56 52
Stage I
Stage II
5/5
64 83
Stage III
Stage IV
68
Overall
73
69
71 53
—
—
—
—
73 63 48 65
100 3/3 ND ND 92 63 —
74 100 ND 76 75 73 —
49 85 100 65 55 85 —
33 56 60 87 59 65, 52b —
54 75 77 77 ND 70 69
73 78
68 56 43
S: surgery; RT: radiation therapy; ND: no data; 192Ir: iridium 192 interstitial brachytherapy boost. a See American Joint Committee on Cancer, 1998.17 Modified from Table 3 in Mendenhall et al., 2000.53 b Stage IVA, 65%; Stage IVB, 52%.
sults significantly favored RT ⫾ ND in five instances and S ⫾ RT in none. Table 11 shows local control, local-regional control, survival, and complication data for the three RT series that reported the most favorable results for each endpoint for which data were available compared with the same data for the most favorable S series for both base of tongue carcinoma and tonsillar carcinoma. Of 12 data comparisons, results significantly favored RT ⫾ ND in six instances and S ⫾ RT in none. Table 12 shows local control, local-regional control, survival, and complication data for eight geographically distributed cancer centers in the United States that are recognized widely for their expertise in the management of patients with carcinoma of the head and neck. Not all centers reported results for each end point. Some centers reported data more than once. All available reports were used to compile final results for both base of tongue carcinoma and tonsillar carcinoma. Of 11 data comparisons, results significantly favored RT ⫾ ND in four instances and S ⫾ RT in none.
DISCUSSION This report presents a retrospective, nonrandomized, multi-institutional, pooled analysis of therapeutic results from over 6000 patients from U.S. and Canadian academic institutions who were treated with RT ⫾ ND or S ⫾ RT for SCC of the base of the tongue or the
tonsillar region. There are problems in comparing data from nonrandomized patient series, including the influence of patient selection as well as differences in staging systems, treatment delivery, and end results reporting. Nevertheless, because there are no adequate randomized data, we believe that this information represents a useful benchmark for evidencebased counseling of patients with SCC of the oropharynx, and we also believe that this is the first serious attempt to compile all evidence, both favorable and unfavorable, relative to the efficacy, complications, and morbidity of S or RT. The reality for patients with oropharyngeal carcinoma is that treatment selection often depends on where the patient is referred: Patients who are referred to institutions that favor RT usually receive that treatment, whereas patients who are referred to institutions that favor S undergo an operation. The usual basis for such decision making is institutional preference, prior training, recent experience (positive or negative) with a similar patient, or a recent journal article. Although some statisticians may challenge the methods and conclusions of the current article and their utility as a means of treatment selection, probably few would argue that the aforementioned institutional bias justifications for recommending one treatment over another are more valid. The number of publications in the field of oncology is increasing rapidly. Most clinicians cannot re-
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TABLE 7 Tonsillar Squamous Cell Carcinoma: Survivala Five-year survival (%) Series S with or without adjuvant RT University of Virginia Medical Center, Charlottesville, VA (1981)58 Upstate Medical Center, Syracuse, NY (1982)59 University of Cincinnati Medical Center, OH (1985)60 East Orange VA Medical Center, NJ (1986)61 Memorial Sloan-Kettering Cancer Center, New York, NY (1973–1986) (1992)21 Mayo Clinic, Rochester, MN (1970–1988) (1994)50 Roswell Park Cancer Institute, Buffalo, NY (1998)42 Weighted average RT with or without neck dissection University of Michigan, Ann Arbon, MI (1955–1963) (1971)45 Stanford University, Palo Alto, CA (1956–1973) (1976)40 Yale University, New Haven, CT (1977)62 University of Virginia Medical Center, Charlottesville, VA (1981)58 University of Michigan, Ann Arbor, MI (1960–1976) (1983)46 University of Maryland Medical Center, Baltimore, MD (1984)47 Princess Margaret Hospital, Toronto, Ontario (1985)63 East Orange VA Medical Center, NJ (1986)61 M. D. Anderson Cancer Center, Houston, TX (1968–1983) (1989)49 Stanford University, Palo Alto, CA (1975–1990) (1993)64 Mayo Clinic, Rochester, MN (1970–1988) (1994)50 M. D. Anderson Cancer Center, Houston, TX (1983–1992) (1997)57 Vancouver Cancer Center, Vancouver, BC (1999)52 University of Florida, Gainesville, FL (2000)53 Weighted average
Treatment
No. of patients
Stage IV (%)
Absolute
Cause specific
S with or without RT S and RT S and RT S with or without RT S and RT S and RT S —
37 47 82 63 20 16 56 321
51 45 39 48 65 56 29 44
ND ND ND 38 54 74 ND 47
54 57 56 ND ND ND 61 57
RT RT RT RT RT RT RT RT RT RT RT RT RT RT —
102 140 65 45 353 185 372 81 150 37 21 83 242 400 2276
ND ND ND 51 31 46 54 60 ND 51 57 53 ND 56 49
34 33 37 ND 53 30 38 20 ND 63 31 60 48 49 43
40 ND ND 27 ND 42 54 ND 70 ND 77 71 62 70 59
S: surgery; RT: radiation therapy; ND: no data. a Modified from Table 4 in Medenhall et al., 2000.53
main abreast of all relevant information, which is scattered widely through the medical literature and often is fragmented, confusing, or biased. Summary articles traditionally are informal reviews that reflect one or another school of thought rather than an entire data base, as presented herein. Although randomized trials or meta-analyses are the gold standards for guiding treatment, literature reviews like the current report have considerable potential to improve clinical practice when no randomized trials exist. We believe it is unlikely that the questions addressed in this article will ever be studied in a randomized trial. The most striking findings in this review were 1) the marked similarities in rates of local control, localregional control, absolute survival, and cause specific survival between the two treatment modalities and 2) the marked disparity in rates of severe or fatal complications, both of which occurred four to nine times more frequently after S ⫾ RT than after RT ⫾ ND. Tables 4 and 8 summarize the rates of readily measurable complications, such as osteoradionecrosis, soft tissue necrosis, carotid artery rupture, and pharyngocutaneous fistula. The tables do not address the much
more difficult to quantify frequencies of other types of functional or cosmetic losses. The individual and collective morbidities of S and RT are difficult to categorize and transcend any single definition. Physicians generally define complications as unexpected adverse sequelae. To the patient, however, some expected sequelae, although not statistically scored as complications, may be equally debilitating. Successful treatment by S or by RT may produce very different end results as perceived by the patient. For example, a patient with T4 base of tongue carcinoma who has undergone total glossectomy, total laryngectomy, bilateral ND, and postoperative RT who heals uneventfully and experiences no postirradiation complication is scored statistically as complication free, despite suffering considerable physiologic, psychologic, and socioeconomic injury. The same patient treated with RT ⫾ ND remains more intact anatomically and, assuming treatment is successful and free of complications, retains better function. Conversely, a patient with a T1 or superficial T2 tonsillar region tumor with minimal or absent lymph node metastasis may have a better functional outcome after S plus
Squamous Cell Carcinoma of the Oropharynx/Parsons et al.
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TABLE 8 Tonsillar Squamous Cell Carcinoma: Severe Complicationsa Complications (%) Institution S with or without adjuvant RT University of Cincinnati, Cincinnati, OH (1971)65 University of Okalahoma, Oklahoma City, OK (1973)66 University of Virginia Medical Center, Charlottsville, VA (1981)58 University of California Medical Center, San Francisco, CA (1986)54 East Orange VA Medical Center, East Orange, NJ (1986)61 Memorial Sloan-Kettering Cancer Center, New York, NY (1969–1983) (1989)55 Mayo Clinic, Rochester, MN (1970–1988) (1994)41 Washington University Medical Center, St. Louis, MO (1998)44 Weighted average RT with or without neck dissection Massachusetts General Hospital, Boston, MA (1972)67 University of Virginia Medical Center, Charlottsville, VA (1981)58 University of Washington, Seattle, WA (1982)56 University of Michigan, Ann Arbor, MI (1963–1976) (1983)46 Memorial Medical Center, Long Beach, CA (1985)48 Princess Margaret Hospital, Toronto, Ontario (1985)63 East Orange VA Medical Center, East Orange, NJ (1986)61 University of California School of Medicine, San Francisco, CA (1986)54 Stanford University, Palo Alto, CA (1975–1990) (1993)64 Mayo Clinic, Rochester, MN (1994)50 M. D. Anderson Cancer Center, Houston, TX (1983–1992) (1997)57 Washington University Medical Center, St. Louis, MO (1998)44 Vancouver Cancer Center, Vancouver, BC (1999)52 University of Florida, Gainesville, FL (2000)53 Weighted average
No. of patients
Severe
Fatal
Preop RT and S Preop RT and S S with or without RT Preop RT and S Preop RT and S S with or without RT S with or without RT Preop RT and S S and Postop RT
32 30 52 34 49 117 72 144 86 616
34 ND 23 18 31 18 21 24 24 23
0 10 ND 6 8 0 0 5 2 3.2
RT RT RT RT RT, 192Ir RT RT RT RT RT RT RT Ipsilateral RT RT —
262 52 104 353 80 372 81 131 37 21 83 154 178 400 2308
11 11 4 2 3 3 22 5 5 5 2 10 3 8 6
ND ND 2 0.2 0 0 9 ND 0 0 0 1 0 1 0.8
Treatment
S: surgery; RT: radiation therapy; Preop: preoperative; Postop: postoperative; ND: no data; 192Ir: iridium-192 interstitial brachytherapy boost. a Modified from Table 5 in Mendenhall et al., 2000.53
ipsilateral ND than with high-dose RT, thus avoiding the expected sequelae of xerostomia. Quality-of-life outcomes are critical measures of a patient’s well being that should be included in comprehensive assessments of treatment outcome. Functional losses may result from anatomic deficits caused by resection of tissues or from xerostomia, taste changes, fibrosis, pain, or trismus, all of which affect ability to eat and communicate. In modern surgical series for base of tongue carcinoma, 15–20% of patients have required total laryngectomy;2,3,22 15–20% of patients have required mandibulectomy;3,22,23 and 10 –25% of patients have required permanent gastrostomy, tracheostomy, or both.2,7,23 Approximately 15– 20% of patients with tonsillar carcinoma who undergo S require segmental mandibulectomy.41 There is a paucity of literature on functional outcome in patients who are treated for oropharyngeal malignancies. Harrison et al.68 performed detailed functional assessments on 30 patients who underwent
external plus interstitial RT ⫾ ND at Memorial SloanKettering Cancer Center for base of tongue carcinoma using the performance scale of List et al.69 Patients analyzed their ability to eat in public, understandability of speech, and normalcy of diet (scoring range, 0 –100, with 100 representing no impairment). Although the assessment was subjective, it provided important information about patient perception of outcome. Mean scores were 83%, 93%, and 75%, respectively. The latter score was related mainly to xerostomia, an expected sequelae of RT. Seven of eight patients with T3 tumors rated understandability of speech at 100%, a result difficult to achieve with S, which would require at least partial glossectomy. In a separate article, Harrison et al.70 noted that the majority of working patients maintained their prediagnosis employment status and earning potential after RT. Horwitz et al.,29 using the same performance status scale, noted mean scores of 89% and 94% for understandability of speech and normalcy of diet, respec-
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TABLE 9 Local Control, Local-Regional Control, Survival, and Complication Rates for the Three Largest Radiation Therapy and Surgical Series S with or without RT
Variable
No. of patients
TABLE 10 Local Control, Local-Regional Control, Survival, and Complication Rates for the Three most Recent Radiation Therapy and Surgical Series
RT with or without ND
%
No. of patients
S with or without RT %
P value Variable
Local control Base of tongue Tonsil Local-regional control Base of tongue Tonsil Five-year survival Base of tongue Absolute Cause specific Tonsil Absolute Cause specific Complications Base of tongue Severe Fatal Tonsil Severe Fatal
280 358
79 70
512 938
75 67
0.14 0.36
280 241
63 64
337 587
74 68
0.002 0.289
303 266
48 58
355 341
54 63
0.11 0.17
99 185
47 58
1125 1014
47 62
0.86 0.26
207 256
34 2.4
512 512
3.2 0.4
⬍ 0.0001 0.02
419 419
22 2
1125 1125
4.4 0.4
⬍ 0.0001 0.0036
Local control Base of tongue Tonsil Local-regional control Base of tongue Tonsil Five-year survival Base of tongue Absolute Cause specific Tonsil Absolute Cause specific Complications Base of tongue Severe Fatal Tonsil Severe Fatal
RT with or without ND
No. of patients
%
No. of patients
%
P value
196 314
82 69
305 633
82 73
0.92 0.32
196 241
66 64
337 498
75 72
0.046 0.028
266 266
52 62
339 341
59 63
0.080 0.74
99 185
47 58
725 725
50 67
0.65 0.022
86 172
37 1.3
305 305
4.2 0.7
⬍ 0.0001 0.62
419 419
22 2
732 732
7.2 0.7
⬍ 0.0001 0.06
S. surgery; RT. radiation therapy; ND. neck dissection. S. surgery; RT. radiation therapy; ND. neck dissection.
tively, in an analysis of 20 patients who were treated with external plus interstitial RT at William Beaumont Hospital (Royal Oak, MI). At the University of Florida, Moore et al.71 used the same performance scale to analyze functional outcome in 49 patients with base of tongue carcinoma who were alive and free of disease 2–23 years after external beam RT ⫾ ND. Functional results were similar to those reported by Harrison et al.68 and Horwitz et al.29 after external plus interstitial RT. Function after both types of RT was superior to reported functional results after S and postoperative RT at Memorial Sloan-Kettering Cancer Center;72 this was true for both patients with early-stage disease (T1–T2) and patients with advanced-stage disease (T3–T4). In all three RT series, there were nonsignificant trends toward declining function with increasing T stage; for patients who underwent S and postoperative RT at Memorial Sloan-Kettering Cancer Center, functional status deteriorated markedly when comparing patients who had T1–T2 disease with patients who had T3–T4 disease (P ⫽ 0.0014). This is consistent with the fact that larger tumors require more extensive operations. Because RT does not involve tissue resection, the observed functional decline with increasing T
stage suggests more extensive tumor-related tissue destruction and scar formation as the reasons. Functional results after RT at the University of Florida did not deteriorate with follow-up beyond 5 years. Planned postradiotherapy ND had no impact on function scores. Nisi et al.73 performed the same functional analysis on 21 patients (S alone, 13 patients; S and postoperative RT, 8 patients) who underwent operation at the Mayo Clinic. Eighty-one percent of patients had early-stage disease (T1–T2). For patients who underwent S alone, performance scores were similar to those reported after RT. Patients who underwent S and received postoperative RT had worse function. In separate analyses, the same authors2,24 showed that S alone seldom was applicable to this patient group, because local-regional failure rates, even for patients with early-stage disease (clinical Stage I–II), were 40% when postoperative RT was not administered, rendering the functional results of S alone largely irrelevant. We are not aware of detailed quality-of-life assessments after treatment for tonsillar carcinoma. Functional impairment caused by resection of large oropharyngeal lesions represents a significant
Squamous Cell Carcinoma of the Oropharynx/Parsons et al. TABLE 11 Local Control, Local-Regional Control, Survival, and Complication Rates for the Three Radiation Therapy and Surgical Series Reporting the Most Favorable Results S with or without RT
Variable Local control Base of tongue Tonsil Local-regional control Base of tongue Tonsil Five-year survival Base of tongue Absolute Cause specific Tonsil Absolute Cause specific Complications Base of tongue Severe Fatal Tonsil Severe Fatal
No. of patients
TABLE 12 Local Control, Local-Regional Control, Survival, and Complication Rates for Eight U.S. Hospitals S with or without RT
RT with or without ND
%
No. of patients
Variable %
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RT with or without ND
No. of patients
%
No. of patients
%
P value
360 322
79 70
696 725
75 72
0.19 0.57
353 225
60 70
300 504
67 71
0.056 0.651
396 179
49 65
403 271
55 64
0.085 0.89
36 n.d.
63 n.d.
681 654
47 70
0.051 n.d.
255 355
34 3.8
752 752
3.5 0.4
⬍ 0.0001 ⬍ 0.0001
453 453
22 2.4
1088 695
8.0 0.8
⬍ 0.0001 0.034
P value
223 148
83 75
102 154
88 83
0.005 0.11
218 225
65 70
337 184
75 76
0.014 0.006
193 266
53 62
331 341
59 63
0.115 0.74
99 185
47 58
473 641
55 70
0.175 0.0016
61 145
19 0
349 191
2.2 0.0
⬍ 0.0001 1.0
223 223
19 0
1065 771
2.6 0.0
⬍ 0.0001 1.0
Local control Base of tongue Tonsil Local-regional control Base of tongue Tonsil Five-year survival Base of tongue Absolute Cause specific Tonsil Absolute Cause specific Complications Base of tongue Severe Fatal Tonsil Severe Fatal
S: surgery; RT: radiation therapy; ND: neck dissection n.d. no data. S: surgery; RT: radiation therapy; ND: neck dissection.
challenge, despite the sophistication of modern surgical reconstruction. Regional lymphatic metastasis from these tumors is often bilateral, at multiple levels, or massive. The morbidities from extensive neck dissection(s) and postoperative RT in such patients invariably require further compound rehabilitative and reconstructive challenges. For patients with base of tongue carcinoma (which has an 85% incidence of lymph node metastases and a 35% incidence of bilateral nodal involvement at diagnosis), treatment limited to the ipsilateral neck represents incomplete therapy.24 The ease and success of bilateral neck irradiation is another factor that favors RT for these patients. For patients with tonsillar carcinoma, the majority of lymph node metastasis in early-stage disease is to the ipsilateral neck. T1 and superficial T2 lesions are suitable for S and ipsilateral ND with little or no functional impairment. If neck disease is minimal or absent, then RT may be avoided. S for patients with more advanced lesions requires complex reconstruction,10 does not eliminate the need for postoperative RT, does not increase the cure rate compared with RT ⫾ ND, is associated with a greater incidence of complications,
and, we believe, results in less satisfactory function than RT ⫾ ND. In summary, this review does not support the claim that S ⫾ RT optimizes the chances for the successful treatment of patients with oropharyngeal carcinoma. For no stage or site of disease did S ⫾ RT produce clearly superior rates of tumor control or survival compared with RT ⫾ ND. The incidences of severe and/or fatal complications were several-fold greater in patients who underwent operation. Furthermore, although post-treatment function has been studied incompletely, available data suggest the superiority of RT ⫾ ND. These findings lead us to conclude that RT ⫾ ND is preferable to S ⫾ RT for most patients with SCC of the oropharynx. The authors hasten to mention that the results and conclusions of the current article, which addresses only patients with carcinoma of the oropharynx, are not generalizable to patients with carcinoma at other head and neck sites. Different conclusions may be reached in analyses of other anatomic regions because rates of local control, long-term morbidity, and function after S or RT differ for each anatomic region based on different tumor sensitivities, anatomic constraints, and functional anatomy. For exam-
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ple, it is the authors’ opinion that most patients with tumors of the oral cavity (e.g., tumors of the oral tongue, floor of mouth, buccal mucosa, retromolar trigone, alveolar ridge, and hard palate) are managed better by S ⫾ RT than RT ⫾ ND. Although local control rates for patients with T1–T2 tumors of the floor of the mouth or the oral tongue who were treated with primary RT were similar to the rates achieved by patients who underwent S, we believe that long-term complication rates (mostly bone and/or soft tissue necrosis) were greater after high-dose RT (which often involves an interstitial implant) than after S ⫾ RT. For patients with tumors at other oral cavity sites (e.g., tumors of the alveolar ridge, retromolar trigone, buccal mucosa, and hard palate), the local control rates after RT ⫾ ND were inferior to those after S ⫾ RT. Just as surgical options and ingenious reconstructive techniques have evolved over the years, so have radiotherapeutic options. Increasingly, patients with early-stage tonsil carcinoma are treated with ipsilateral RT techniques that limit morbidity, especially xerostomia, by using mixed-beam, wedge pair, threedimensional conformal or intensity-modulated RT techniques. Hyperfractionation74,75 and accelerated fractionation have been proven superior to conventional fractionation in randomized trials. Neoadjuvant chemotherapy before RT is an effective organ-sparing strategy for patients with SCC of the larynx76 and hypopharynx77,78 and showed promise as an organsparing tool in a retrospective analysis of patients with T4 oropharyngeal SCC at the University of Florida.79 Concurrent chemotherapy and RT regimens have consistently produced higher rates of both local-regional control and survival compared with the rates produced by RT alone in randomized trials80 – 85 and hold promise for continued improvement in both tumor control and functional outcome.
7.
8.
9.
10. 11. 12. 13.
14. 15. 16. 17.
18. 19.
20.
21.
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