Squamous cell carcinoma of the oropharynx

Surgery, radiation therapy, or both

Authors


Abstract

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

The 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 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 combined-modality 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, local-regional (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 recurrences 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, radiation-induced 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 weighted-average local control rate was 79% in the S ± RT group compared with 76% in the RT alone group (P = 0.087) for all stages.

Table 1. Base of Tongue Carcinoma: Local Control According to T Stagea
InstitutionNo. of patientsT4 (%)Boost techniqueLocal control (%)
T1T2T3T4Overall
  • 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.

S with or without adjuvant RT
 Washington University, St. Louis, MO (1983) 191019NANDNDNDND74
 Stanford University, Palo Alto, CA (1974–1982) (1985) 20140NAND3/343ND60
 M. D. Anderson Cancer Center, Houston, TX (1974–1984) (1990) 335NDNA837980
 University of Pittsburgh, Pittsburgh, PA (1992) 6130NA100100NDND100
 Memorial Sloan-Kettering Cancer Center, New York, NY (1973–86) 1992 213139NAND84b86b84b84b
 Memorial Sloan-Kettering Cancer Center, New York, NY (1979–89) 1993 2210019NANDNDNDND82b
 University of Pennsylvania, Philadelphia, PA (1997) 231741NA778077
 Mayo Clinic, Rochester, MN (1971–1993) (1998) 24790NA848776ND82
 Weighted average3901379
RT with or without neck dissection
 M. D. Anderson Cancer Center, Houston, TX (1954–1971) (1976) 2517417EBRT9171785274
 University of California, San Francisco, CA (1979) 264810EBRT10056322048
 Stanford University, Palo Alto, CA (1974–1982) (1985) 201414192IrNDNDNDND86
 M. D. Anderson Cancer Center, Houston, TX (1974–1984) (1990) 3121NDEBRT89594468
 M. D. Anderson Cancer Center, Houston, TX (1984–1992) (1995) 27542EBRT1009667ND85
 Massachusetts General Hospital, Boston (b.i.d.) (1995) 28900EBRT858554NDND
 William Beaumont Hospital, Royal Oak, MI (1996) 292025192Ir100891008088
 Memorial Sloan-Kettering Cancer Center, New York, NY (1981–1995) (1998) 30683192Ir8793822/289
 University of Florida, Gainesville, FL (2000) 3121719EBRT9691813879
 Weighted average8061376

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).

Table 2. Base of Tongue Carcinoma: Local-Regional Control According to the American Joint Committee on Cancer Staging Systema
InstitutionNo. of patientsStage IV (%)Local-regional control (%)
Stage IStage IIStage IIIStage IVOverall
  • 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%.

S with or without adjuvant RT
 M. D. Anderson Cancer Center, Houston, TX (1964–1973) (1978) 323476NDNDNDND56
 Massachusetts General Hospital, Boston, MA (1962–1976) (1983) 3325406780292040
 Washington University, St. Louis, MO (1983) 191014510075674057
 Stanford University, Palo Alto, CA (1974–1982) (1985) 201421ND100333343
 Memorial Sloan-Kettering Cancer Center, New York, NY (1979–1989) (1993) 2210036NDNDNDND72b
 University of Pennsylvania, Philadelphia, PA (1997) 231759NDNDND5068
 Mayo Clinic, Rochester, MN (1971–1993) (1998) 2479335679555459
 Weighted average3704260
RT with or without neck dissection
 Massachusetts General Hospital, Boston, MA (1962–1976) (1983) 332952ND2022714
 Memorial Medical Center, Long Beach, CA (1988) 347057ND100787377
 M. D. Anderson Cancer Center, Houston, TX (1984–1992) (1995) 275463ND100797276
 University of Florida, Gainesville, FL (2000) 31217711001008365c72
 Weighted average3706669

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).

Table 3. Base of Tongue Carcinoma: Five-Year Survivala
InstitutionNo. of patientsT4 (%)Stage IV (%)Survival (%)
AbsoluteCause specific
  • ND: no data.

  • a

    Modified from Table 3 in Mendenhall et al., 2000. 31

S with or without adjuvant RT
 Mayo Clinic, Rochester, MN (1960–1967) (1972) 35102ND744ND
 Washington University, St. Louis, MO (1983) 1910194545ND
 Stanford University, Palo Alto, CA (1974–1982) (1985) 201402151ND
 Memorial Sloan-Kettering Cancer Center, New York, NY (1979–1989) (1993) 2210019365565
 University of Pennsylvania, Philadelphia, PA (1997) 2317415946 (3 yr)ND
 Mayo Clinic, Rochester, MN (1971–1993) (1998) 24790335165
 University of Pittsburgh, Pittsburgh, PA (1980–1987) (2000) 3687NDND4956
 Weighted average50011314962
RT with or without neck dissection
 Stanford University, Palo Alto, CA (1958–1980) (1983) 3764ND5035ND
 Memorial Medical Center, Long Beach, CA (1988) 347017573560
 M. D. Anderson Cancer Center, Houston, TX (1984–1992) (1995) 27542635965
 Memorial Sloan-Kettering Cancer Center, New York, NY (1981–1995) (1998) 306835187ND
 University of Florida, Gainesville, FL (2000) 3121719715064
 Weighted average47314625263

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.

Table 4. Base of Tongue: Severe Complicationsa
InstitutionNo. of patientsT4 (%)Boost techniqueComplications (%)
SevereFatal
  • 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

S with or without adjuvant RT
 M. D. Anderson Cancer Center, Houston, TX (1964–1973) (1978) 323441NA2618
 Indiana University, Indianapolis, IN (1983) 38838NA3812
 Washington University, St. Louis, MO (1983) 191019NA284
 Stanford University, Palo Alto, CA (1985) 20140NA640
 M. D. Anderson Cancer Center, Houston, TX (1974–1984) (1990) 351NDNA282
 University of California, Los Angeles, CA (1990) 39130NA230
 University of Pittsburgh, Pittsburgh, PA (1992) 6140NA00
 Memorial Sloan-Kettering Cancer Center, New York, NY (1979–1989) (1993) 2210019NAND0
 Mayo Clinic, Rochester, MN (1971–1986) (1993) 2550NA494
 University of Pennsylvania, Philadelphia, PA (1997) 231741NA290
 Weighted average40715323.5
RT with or without neck dissection
 Stanford University, Palo Alto, CA (1956–1973) (1976) 40104NDEBRT71
 M. D. Anderson Cancer Center, Houston, TX (1954–1971) (1976) 2517417EBRT30
 Stanford University, Palo Alto, CA (1974–1982) (1985) 201414192Ir70
 Memorial Medical Center, Long Beach, CA (1988) 347017192Ir60
 M. D. Anderson Cancer Center, Houston, TX (1974–1984) (1990) 3121NDEBRT20
 M. D. Anderson Cancer Center, Houston, TX (1984–1992) (1995) 27542EBRT00
 William Beaumont Hospital, Royal Oak, MI (1996) 292025192Ir100
 Memorial Sloan-Kettering Cancer Center, New York, NY (1981–95) (1998) 30683192Ir30
 University of Florida, Gainesville, FL (2000) 3121719EBRT41
 Weighted average842143.80.4

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).

Table 5. Tonsillar Squamous Cell Carcinoma: Local Control According to Tumor Statusa
SeriesTreatmentNo. of patientsT4 (%)Local control (%)
T1T2T3T4Overall
  • 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

S with or without adjuvant RT
 Memorial Sloan-Kettering Cancer Center, New York, NY (1973–1986) (1992) 21S with or without RT2020ND4/41005089
 Mayo Clinic, Rochester, MN (1970–1988) (1994) 41S with or without RT7237876440/271
 Roswell Park Cancer Institute, Buffalo, NY (1998) 42S56NDNDNDNDND75
 University of California Medical Center, Los Angeles, CA (1998) 43S and RT28ND806164
 Washington University Medical Center, St. Louis, MO (1998) 44S and RT230148071655868
 Weighted average4061270
RT with or without neck dissection
 University of Michigan, Ann Arbor, MI (1955–1963) (1971) 45RT1021477392965
 University of Michigan, Ann Arbor, MI (1960–1976) (1983) 46RT353169277502562
 University of Maryland Hospital, Baltimore, MA (1984) 47RT185149480511958
 Memorial Medical Center, Long Beach, CA (1985) 48RT, 192Ir8024NDNDNDND84
 M. D. Anderson Cancer Center, Houston, TX (1968–1983) (1989) 49RT15059481676375
 Mayo Clinic, Rochester, MN (1970–1988) (1994) 50RT2143ND801005676
 Massachusetts General Hospital, Boston, MA (b.i.d) (1995) 28RT10209180NDND
 University of Virginia, Charlottesville, VA (1995) 51RT5308378NDND81
 Washington University Medical Center, St. Louis, MO (1998) 44RT154237663593356
 University of California, Los Angeles, CA (1998) 43RT55ND653144
 Vancouver Cancer Center, Vancouver, BC (1999) 52Ipsilateral RT17859479585675
 University of Florida, Gainesville, FL (2000) 53RT400178381746076
 Weighted average18331468

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).

Table 6. Tonsillar Squamous Cell Carcinoma: Local-Regional Control According to the American Joint Committee on Cancer Staging Systema
SeriesTreatmentNo. of patientsStage IV (%)Local-regional control (%)
Stage IStage IIStage IIIStage IVOverall
  • 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%.

S with or without adjuvant RT
 University of California School of Medicine, San Francisco, CA (1986) 54S with or without RT40ND5/5646873
 Memorial Sloan-Kettering Cancer Center, New York, NY (1969–1983) (1989) 55S with or without RT1133583716873
 Mayo Clinic, Rochester, MN (1970–1988) (1994) 41S with or without RT72257369535663
 Roswell Park Cancer Institute, Buffalo, NY (1998) 42S5629784348
 Weighted average2813165
RT with or without neck dissection
 University of Washington, Seattle, WA (1982) 56RT1043510074493354
 Memorial Medical Center, Long Beach, CA (1985) 48R 192Ir80493/3100855675
 Mayo Clinic, Rochester, MN (1970–1988) (1994) 50RT2157NDND1006077
 M. D. Anderson Cancer Center, Houston, TX (1983–1992) (1997) 57RT8353ND76658777
 Vancouver Cancer Center, Vancouver, BC (1999) 52Ipsilateral RT170ND92755559ND
 University of Florida, Gainesville, FL (2000) 53RT4005663738565, 52b70
 Weighted average8585269

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)

Table 7. Tonsillar Squamous Cell Carcinoma: Survivala
SeriesTreatmentNo. of patientsStage IV (%)Five-year survival (%)
AbsoluteCause specific
  • S: surgery; RT: radiation therapy; ND: no data.

  • a

    Modified from Table 4 in Medenhall et al., 2000. 53

S with or without adjuvant RT
 University of Virginia Medical Center, Charlottesville, VA (1981) 58S with or without RT3751ND54
 Upstate Medical Center, Syracuse, NY (1982) 59S and RT4745ND57
 University of Cincinnati Medical Center, OH (1985) 60S and RT8239ND56
 East Orange VA Medical Center, NJ (1986) 61S with or without RT634838ND
 Memorial Sloan-Kettering Cancer Center, New York, NY (1973–1986) (1992) 21S and RT206554ND
 Mayo Clinic, Rochester, MN (1970–1988) (1994) 50S and RT165674ND
 Roswell Park Cancer Institute, Buffalo, NY (1998) 42S5629ND61
 Weighted average321444757
RT with or without neck dissection
 University of Michigan, Ann Arbon, MI (1955–1963) (1971) 45RT102ND3440
 Stanford University, Palo Alto, CA (1956–1973) (1976) 40RT140ND33ND
 Yale University, New Haven, CT (1977) 62RT65ND37ND
 University of Virginia Medical Center, Charlottesville, VA (1981) 58RT4551ND27
 University of Michigan, Ann Arbor, MI (1960–1976) (1983) 46RT3533153ND
 University of Maryland Medical Center, Baltimore, MD (1984) 47RT185463042
 Princess Margaret Hospital, Toronto, Ontario (1985) 63RT372543854
 East Orange VA Medical Center, NJ (1986) 61RT816020ND
 M. D. Anderson Cancer Center, Houston, TX (1968–1983) (1989) 49RT150NDND70
 Stanford University, Palo Alto, CA (1975–1990) (1993) 64RT375163ND
 Mayo Clinic, Rochester, MN (1970–1988) (1994) 50RT21573177
 M. D. Anderson Cancer Center, Houston, TX (1983–1992) (1997) 57RT83536071
 Vancouver Cancer Center, Vancouver, BC (1999) 52RT242ND4862
 University of Florida, Gainesville, FL (2000) 53RT400564970
 Weighted average2276494359

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; 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.

Table 8. Tonsillar Squamous Cell Carcinoma: Severe Complicationsa
InstitutionTreatmentNo. of patientsComplications (%)
SevereFatal
  • 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

S with or without adjuvant RT
 University of Cincinnati, Cincinnati, OH (1971) 65Preop RT and S32340
 University of Okalahoma, Oklahoma City, OK (1973) 66Preop RT and S30ND10
 University of Virginia Medical Center, Charlottsville, VA (1981) 58S with or without RT5223ND
 University of California Medical Center, San Francisco, CA (1986) 54Preop RT and S34186
 East Orange VA Medical Center, East Orange, NJ (1986) 61Preop RT and S49318
 Memorial Sloan-Kettering Cancer Center, New York, NY (1969–1983) (1989) 55S with or without RT117180
 Mayo Clinic, Rochester, MN (1970–1988) (1994) 41S with or without RT72210
 Washington University Medical Center, St. Louis, MO (1998) 44Preop RT and S144245
S and Postop RT86242
 Weighted average616233.2
RT with or without neck dissection
 Massachusetts General Hospital, Boston, MA (1972) 67RT26211ND
 University of Virginia Medical Center, Charlottsville, VA (1981) 58RT5211ND
 University of Washington, Seattle, WA (1982) 56RT10442
 University of Michigan, Ann Arbor, MI (1963–1976) (1983) 46RT35320.2
 Memorial Medical Center, Long Beach, CA (1985) 48RT, 192Ir8030
 Princess Margaret Hospital, Toronto, Ontario (1985) 63RT37230
 East Orange VA Medical Center, East Orange, NJ (1986) 61RT81229
 University of California School of Medicine, San Francisco, CA (1986) 54RT1315ND
 Stanford University, Palo Alto, CA (1975–1990) (1993) 64RT3750
 Mayo Clinic, Rochester, MN (1994) 50RT2150
 M. D. Anderson Cancer Center, Houston, TX (1983–1992) (1997) 57RT8320
 Washington University Medical Center, St. Louis, MO (1998) 44RT154101
 Vancouver Cancer Center, Vancouver, BC (1999) 52Ipsilateral RT17830
 University of Florida, Gainesville, FL (2000) 53RT40081
 Weighted average230860.8

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 Sloan-Kettering 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 9. Local Control, Local-Regional Control, Survival, and Complication Rates for the Three Largest Radiation Therapy and Surgical Series
VariableS with or without RTRT with or without NDPvalue
No. of patients%No. of patients%
  1. S. surgery; RT. radiation therapy; ND. neck dissection.

Local control
 Base of tongue28079512750.14
 Tonsil35870938670.36
Local-regional control
 Base of tongue28063337740.002
 Tonsil24164587680.289
Five-year survival
 Base of tongue
  Absolute30348355540.11
  Cause specific26658341630.17
 Tonsil
  Absolute99471125470.86
  Cause specific185581014620.26
Complications
 Base of tongue
  Severe207345123.2< 0.0001
  Fatal2562.45120.40.02
 Tonsil
  Severe4192211254.4< 0.0001
  Fatal419211250.40.0036

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, results significantly favored RT ± ND in five instances and S ± RT in none.

Table 10. Local Control, Local-Regional Control, Survival, and Complication Rates for the Three most Recent Radiation Therapy and Surgical Series
VariableS with or without RTRT with or without NDPvalue
No. of patients%No. of patients%
  1. S. surgery; RT. radiation therapy; ND. neck dissection.

Local control
 Base of tongue19682305820.92
 Tonsil31469633730.32
Local-regional control
 Base of tongue19666337750.046
 Tonsil24164498720.028
Five-year survival
 Base of tongue
  Absolute26652339590.080
  Cause specific26662341630.74
 Tonsil
  Absolute9947725500.65
  Cause specific18558725670.022
Complications
 Base of tongue
  Severe86373054.2< 0.0001
  Fatal1721.33050.70.62
 Tonsil
  Severe419227327.2< 0.0001
  Fatal41927320.70.06

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 11. Local Control, Local-Regional Control, Survival, and Complication Rates for the Three Radiation Therapy and Surgical Series Reporting the Most Favorable Results
VariableS with or without RTRT with or without NDPvalue
No. of patients%No. of patients%
  1. S: surgery; RT: radiation therapy; ND: neck dissection.

Local control
 Base of tongue22383102880.005
 Tonsil14875154830.11
Local-regional control
 Base of tongue21865337750.014
 Tonsil22570184760.006
Five-year survival
 Base of tongue
  Absolute19353331590.115
  Cause specific26662341630.74
 Tonsil
  Absolute9947473550.175
  Cause specific18558641700.0016
Complications
 Base of tongue
  Severe61193492.2< 0.0001
  Fatal14501910.01.0
 Tonsil
  Severe2231910652.6< 0.0001
  Fatal22307710.01.0

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.

Table 12. Local Control, Local-Regional Control, Survival, and Complication Rates for Eight U.S. Hospitals
VariableS with or without RTRT with or without NDPvalue
No. of patients%No. of patients%
  1. S: surgery; RT: radiation therapy; ND: neck dissection n.d. no data.

Local control
 Base of tongue36079696750.19
 Tonsil32270725720.57
Local-regional control
 Base of tongue35360300670.056
 Tonsil22570504710.651
Five-year survival
 Base of tongue
  Absolute39649403550.085
  Cause specific17965271640.89
 Tonsil
  Absolute3663681470.051
  Cause specificn.d.n.d.65470n.d.
Complications
 Base of tongue
  Severe255347523.5< 0.0001
  Fatal3553.87520.4< 0.0001
 Tonsil
  Severe4532210888.0< 0.0001
  Fatal4532.46950.80.034

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 evidence-based 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 remain 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, local-regional 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 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 Sloan-Kettering 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, respectively, 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 authors 2, 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 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 example, 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, three-dimensional conformal or intensity-modulated RT techniques. Hyperfractionation 74, 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 larynx 76 and hypopharynx 77, 78 and showed promise as an organ-sparing 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 trials 80–85 and hold promise for continued improvement in both tumor control and functional outcome.

Ancillary