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T3–4 squamous cell carcinoma of the larynx treated with radiation therapy alone
T3-4 Squamous Cell Carcinoma of the Larynx Treated With Radiation Therapy Alone William M. MendenhaU This article reviews the results of radiation therapy alone for T3-4 squamous cell carcinoma of the larynx. Local control after radiation therapy is approximately 65% for patients with T3 glottic and supraglottic carcinoma. The likelihood of local control is inversely related to tumor volume and, for those with glottic cancers, is adversely influenced by cartilage sclerosis on pretreat-
ment computed tomography of the larynx. Local control after radiotherapy is approximately 60% for T4 glottic cancers and 50% for T4 supraglottic carcinomas. The probability of severe complications is related to primary site and T-stage. Copyright 9 1998 by W.B. Saunders Company
of this discussion, ~ " or the purpose refers to T3 and T4 tumors. Patients
Europe, claims high local control rates after transoral laser excision, alone or combined with adjuvant radiation therapy. 4,5This article reviews the results of radiation therapy alone for T3 and T4 squamous cell carcinoma of the larynx.
advanced laryn-
geal cancer
with T1 and T2 tumors with clinically positive nodes have stage HI or 1V disease, but the management of the favorable primary tumor is conservative, and the likelihood of local control with larynx preservation is high. In contrast, the likelihood of local control with larynx preservation for advanced primary tumors is significantly lower. Depending on the site and extent of disease, treatment alternatives include partial laryngectomy, total laryngectomy, and radiation therapy alone or combined with adjuvant chemotherapy. The prevailing treatment philosophy varies considerably from one country to anotherJ Patients in the United States and Australia are usually treated surgically, which often necessitates total laryngectomyJ In contrast, patients in Canada and Great Britain are often treated with radiation therapy alone, with surgery reserved as salvage treatment for those who develop recurrent disease. Patients treated with radiotherapy in the United States often receive induction chemotherapy before irradiation. 2 The rationale for this strategy is based on the Veterans Affairs Laryngeal Cancer Study Group trial, which compared induction chemotherapy and radiation therapy (in the subset of patients who responded to chemotherapy) with initial laryngectomy and postoperative irradiation; survival rates were similar, and patients randomized to the induction chemotherapy arm had a higher rate of laryngeal voice preservation. 3 (See also the article by Forastiere in this issue.) An occasional head and neck surgeon, primarily in
From the Department of Radiation Oncology, University of Flerida CollegeofMedicine, GainesviUe,FL. Addressreprintrequeststo WilliamM. Mendenhall,MD, Departmentof Radiation Oncology,UniversityofFlorida Health ScienceCenter,PO Box 100385, 2000SW ArcherRoad, Gaiuesville,FL 32610-0385. 1053-4296/98/0804-000658.00/0
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Treatment Selection Glottic Carcinoma Glottic carcinomas with vocal cord fixation (T3) may be stratified into relatively favorable and unfavorable lesions. Patients with favorable tumors have disease mostly confined to one side of the larynx, have a good airway, and are reliable for close follow-up. 6,7Patients with unfavorable cancers usually have extensive bilateral disease, often associated with airway compromise. Patients with favorable tumors may he treated with radiation therapy or conservation surgery, which would necessitate an extended hemilaryngectomy or a near-total laryngectomy, The major disadvantage of partial laryngectomy is that a relatively small subset of patients (probably < 10%) is suitable for the procedure. 8 In contrast, 36 of 54 patients (67%) treated at the University of Florida between 1980 and 1988 for T3 glottic cancer received radiation therapy alone.6 Additionally, the functional outcome after partial laryngectomy may vary considerably, from that of a classic hemilaryngectomy to a controlled fistula for speaking with a permanent tracheostomy. Therefore, the preferred conservation treatment for patients with favorable T3 tumors is radiation therapy alone. Patients with unfavorable T3 cancers may be treated either with total laryngectomy and neck dissection, which is often followed by postoperative irradiation, or two to three cycles of induction chemotherapy followed by radiation therapy in those patients who have a partial (-->50% response) or com-
Seminars in Radiation Oncology, VoI 8, No 4 (October), 1998:pp 262-269
7'3-4 SCCr LarynxPreservedwith R T Alone
plete response to the chemotherapy. In addition to the physical findings that define the unfavorable cancer, pretreatment computed tomography (CT) of the larynx may be used to calculate the primary tumor volume and detect cartilage sclerosis; both are significantly related to the likelihood of tumor control with radiotherapy.9 Patients with T4 glottic carcinoma may be treated with either total laryngectomy and neck dissection combined with adjuvant radiotherapy or induction chemotherapy followed by irradiation in the subset of responders. Conservation surgery is not a realistic option, and irradiation alone is feasible only for the small subset of patients with low-volume disease who are staged as having T4 tumors based on minimal cartilage involvement or minimal extension into the soft tissues of the neck (usually through the cricothyroid membrane). My philosophy is to treat patients with advanced T4 cancers with total laryngectomy and to treat patients who have relatively low-volume tumors with induction chemotherapy followed by irradiation for those whose tumors respond.
Supraglottic Carcinoma Favorable T3 cancers are low-volume, exophytic lesions with involvement of the preepiglottic space or minimal involvement of the medial wall of the pyriform sinus, l~ Unfavorable T3 tumors are highvolume, endophytic lesions that are often associated with vocal cord fixation and airway compromise, t~ Patients with favorable T3 cancers are treated with either supraglottic laryngectomy or radiation therapy. Compared with irradiation alone, supraglottic laryngectomy results in a better local control rate but is associated with an increased risk of complications: In approximately 5% of patients taken to surgery, the procedure is converted to a total laryngectomy because of the anatomic extent of the lesion) ~ Most patients with T3 lesions are unsuitable for conservation surgery, however, because of their medical condition (cardiac or pulmonary disease) or anatomic extent of the primary tumor. Approximately 15% to 20% are suitable for supraglottic laryngectomy; the remainder are treated with irradiation. Patients with unfavorable T3 cancers are treated with total laryngectomy and neck dissection or induction chemotherapy, followed by irradiation in those whose tumors respond. Few such patients are suitable for conservation surgery. T4 supraglottic cancers are treated with total laryngectomy and dissection followed by postoperative irradiation. Patients with low-volume T4 tumors,
263
usually because of modest involvement of the base of tongue or pharyngeal wall, are treated with irradiation alone or preceded by induction chemotherapy.
Radiation TherapyTechnique Glottic Carcinoma Patients are treated with parallel-opposed fields that include the primary lesion and internal jugular lymph nodes (levels II, IN, and IV). 11,12The anterior aspect of the neck is tangentially irradiated because of the proximity of the anterior commissure to the anterior skin surface (usually approximately 1 cm); the inferior border is 2 cm below the inferior extent of the primary tumor (usually 1 to 2 cm below the bottom of the cricoid cartilage) (Fig 1). Patients receive 1.2 Gy per fraction twice daily with a minimum 6-hour interfraction interval to a total dose of 74.4 Gy; the dose is usually specified to an isodose line that includes the tumor with minimal, if any, margin (usually the 95% isodose line, normalized to Dmax at the central axis of the fields). The fields are weighted 3:2 to the side of the lesion (if it is lateralized) and reduced at 45.6 Gy and 60 Gy. The low neck receives 50 Gy in 25 fractions, once-daily fractionation, specified at Dmax, with a thin midline trachea block (Fig 2).
Supraglottic Carcinoma The portals for supraglottic carcinoma are similar to those used for advanced glottic cancer except that the anterior neck skin may sometimes be spared, and the inferior border is usually at the bottom of the cricoid cartilage (Fig 3). 13 The likelihood of positive retropharyngeal lymph nodes is low; however, if clinically positive neck nodes are present, the risk is increased, and the superior border of the field is placed at the jugular foramen. 14 The dose fractionation schedule is the same as that described for T3-4 glottic cancers.
Treatment of the Neck The risk of subclinical disease in the cervical lymph nodes exceeds 20% for patients with T3-4 laryngeal cancer.15 Therefore, the internal jugular lymph nodes (levels II and IV) are electively irradiated bilaterally. Patients with N1 or early N2B neck disease with the positive nodes located within the high-dose fields are treated with irradiation alone) 6 Patients with more advanced neck disease undergo a planned neck dissection after radiation therapy. 16,17
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William M. Mendenhall
rates after surgical salvage of failures at 5 years were 63% and 86%. The local control rates according to fractionation schedule are shown in Table 1. There is a modest improvement in local control for the subset of patients treated with twice-daily fractionation. Thirty-seven patients who were evaluable for local control after irradiation had pretreatment computed tomography (CT) scans available to calculate the primary tumor volume. 7 The likelihood of local control is inversely related to tumor volume: 3.5 cm 3 or less, 20 of 23 (87%), compared with greater than 3.5 cm 3, 4 of 14 (29%) (P < .001). Pameijer et al 9 have found that cartilage sclerosis, in addition to tumor volume, is a useful determinant of local control after irradiation. The relationship of vocal cord mobility, at various points during and after radiotherapy, to local control after irradiation is listed in Table 2. 7Whether the vocal cord becomes mobile or remains fixed does not appear to affect the probability of local control. The local control rates after irradiation and ultimate local control rates from various institutions, including the University of Florida, are summarized in Table 3) o Wang 18 reported a 67% rate of local control after radiotherapy for 41 patients treated with twice-daily fractionation, compared with 42% in 24 patients treated with once-daily irradiation. The 5-year local-regional control and ultimate 1. Radiation treatment technique for carcinoma of glottic lm'ynx, stage T3-4N0. The patient is treated supine, and the field is shaped with Lipowitz's metal. Anteriorly, the field is allowed to fall off. The entire pre-epiglottic space is included by encompassing hyoid bone and epiglottis. The superior border (just above the angle of the mandible) includes jugulodigastric lymph nodes. Posteriorly, a portion of spinal cord must be included within the field to ensure adequate coverage of midjugular lymph nodes: Spinal accessory lymph nodes themselves are at little risk of involvement. The lower border is slanted (1) to facilitate matching with the low neck field and (2) to reduce length of spinal cord in the high-dose field. The inferior border is placed at the bottom of the cricoid cartilage if the patient has no subglottic spread; in the presence of subglottic extension, the inferior border must be lowered according to disease extent. (Reprinted with permissiong) Figure
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Treatment Results Glottic Carcinoma Seventy-five patients were treated with radiation therapy alone for T3 squamous cell carcinoma of the glottic larynx at the University of Florida between 1966 and 1994; no patient received adjuvant chemotherapy] The local control and ultimate local control
F i g u r e 2. Example of a portal for T3N0 glottic carcinoma.
Low neck portal. The main nodes at risk are the lowjugular and lateral paratracheal nodes. The delphian node would be in the primary portal. A narrow and short midline shield is used. (Reprinted with permission. 43)
265
T3-4 SCCa: Larynx Preservedwith R T Alone
Table 2. T3 Vocal Cord Carcinoma: Local Control After Irradiation Versus Vocal Cord Mobility (No. Controlled/No. Treated)*
Local Control CordMobility Assessed At 50 Gy
End of irradiation
1-month follow-up
Mobility
No.
%
Mobile Impaired Fixed No data Mobile Impaired Fixed No data Mobile Impaired Fixed No data
7/10 9/17 21/34 3/4 14/23 8/14 16/25 2/3 18/28 8/13 14/24 0/0
70 53 62 75 61 57 64 67 64 62 58 --
*Note: Excludes 8 patients who died within 2 years of irradiation with the primarytumor site continuouslydisease-free,one patient who had a total laryngectomyat 5 months for suspected recurrence (laryngectomy specimen negative for tumor), and one patient who had a total laryngectomyat 8 months for chondronecrosis. Reprintedwith permission] Figure 3. Example of a portal for a lesion of the lower epiglottis or false vocal cord and a clinically negative neck. The subdigastric nodes are included but not the junctional nodes. Depending on the anatomy and tumor extent, the anterior border may fall off (ie, flash) or a small strip of skin may be shielded. (Reprinted with permission. 43) local-regional control rates for patients treated at the University of Florida were 61% and 86%. 7 The 5-year absolute and cause-specific survival rates were 54% and 78%. Foote et al e reported on 81 patients treated with surgery alone for previously untreated T3 glottic
carcinoma at the Mayo Clinic between 1979 and 1981; 6 patients (7%) underwent a near-total laryngectomy, and the remainder underwent total laryngectomy. The investigators observed a 74% 5-year local-regional control rate and 5-year absolute and cause-specific survival rates of 54% and 78%. The major difference between irradiation and surgery is that radiotherapy is associated with a significantly increased likelihood of laryngeal voice preservation.7,8
Table 1. T3 Vocal Cord Carcinoma: Local Control After Radiotherapy Versus Fractionation Schedule Controlled/Treated Fractionation Schedule Once daily Continuous course Split course Total Twice dally, continuous course 1.2/1.2 Gyt 1.2/1.4 Gy~ Total Overall total
Exclusions*
Salvaged~Attempted
Ultimate Local Control
No.
%
No.
%
No.
%
4 0 4
8/15 1/2 9/17
53 50 53
3/6 0/1 3/7
50 0 43
11/15 1/2 12/17
73 50 71
5 1 6 10
25/41 6/7 31/48 40/65
61 86 65 62
11/13 1/1 12/14 15/21
85 100 86 71
36/41 7/7 43/48 55/65
88 100 90 85
*Excludeseight patientswhodiedwithin2 years of irradiationwith the primarytumor site continuouslydisease-free,one patient who had a total laryngectomyat 5 months for suspected local recurrence (laryngectomyspecimennegativefor tumor), and one patient who had a total laryngectomyat 8 monthsfor chondronecrosis. t 1.2/1.2 = 1.2 Gy per fractionationthroughoutthe radiotherapycourse. :~1.2/1.4= 1.2 Gy per fractionto 60 Gy; 1.4Gy per fractionto 74 Gy. Reprintedwith permission.7
William M. Mendenhall
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Table 3. Stage T3 Glottic Carcinoma Treated With Irradiation
Investigator
Institution
No. Patients
Harwood et al24 Wang 18 Fletcher et a125 Skolyszewski and Reinfuss 26 Stewart et a127 Mills28 Mendenhall et al7
Princess Margaret (Toronto) Massachusetts General (Boston) M. D. Anderson (Houston) 15 European centers Manchester (England) Capetown (South Africa) University of Florida (Gainesville)
112 65 17 91 67 18 75
Minimum Local Follow-Up Control (yr) (%) 3 Notstated 2 3 10 2 2
51 57 77 50 57 44 63
Ultimate Control After Salvage Surgery (%) 77 --67 78 86
Reprinted with permission.l~
Nine patients with T4 glottic carcinomas were treated with radical irradiation at the University of Florida between 1964 and 1994; in 8 of 9 patients, the disease was locally controlled after radiotherapy. 19 The results of radiation treatment from the University of Florida and several other institutions are summarized in Table 4; the tumor was locally controlled after irradiation in almost two thirds of patients. 19The cure rates after surgery or irradiation for T4 glottic cancers are summarized in Table 5. 2~
Supraglottie L a r y n x A total of 110 patients were treated with radical irradiation for T3 (89 patients) and T4 (21 patients) supraglottic carcinoma at the University of Florida between 1964 and 1992; 1 patient received induction chemotherapy, and the remainder underwent irradiation alone or combined with a planned neck dissection31 Fifty-six patients had American Joint Committee on Cancer (AJCC) stage III disease (T3N0-1) and 54 patients had stage 1V disease (T3-4N2-3). The 5-year local control rate after radiation therapy for 89 patients with T3 cancers was 68%. Excluding 19 patients who died less than 2 years from treatment with the primary site continuously disease-free, the local control and ultimate local control rates were 45 of 70 (64%) and 57 of 70 (81%). Local control after irradiation versus subsite within the supraglottis revealed the following: suprahyoid epiglottis, 2 of 3 (67%); infrahyoid epiglottis, 23 of 32 (72%); false vocal cord, 8 of 18 (44%); aryepiglottic fold, 11 of 16 (69%); and arytenoid, 1 of 1 (100%). Local control versus vocal cord mobility revealed the following: normal mobility, 34 of 48 (71%); impaired mobility, 6 of 11 (55%); and fixation, 4 of 9 (44%). False vocal cord tumors are probably more likely to be highvolume, endophytic lesions associated with reduced or absent vocal cord mobility and a lower probability
of cure after irradiation. Local control after radiotherapy was inversely related to tumor volume as calculated on pretreatment C T scans: less than 6 cm 3, 11 of 13 (85%), versus 6 cm 3 or greater, 9 of 19 (47%) (P = .04). Multivariate analysis of local control results revealed the following ranking of possible prognostic factors: twice-daily versus once-daily fractionation (P = .07), site within the supraglottis (P = .1), N stage (P = .078), sex (P = .18), T stage (P = .63), vocal cord mobility (P = .68), suitability for conservation surgery (P = .667), and pretreatment C T scan obtained (P = .77). Local control after radiotherapy at various institutions is illustrated in Table 6. W a n g et aF 2 reported a 76% 5-year local control rate in 51 patients treated with twice-daily fractionation; the ultimate local control rate was 88%. Local control was obtained in 4 of 10 patients (40%) who received irradiation once
Table 4. Literature Review: Treatment ofT4 Laryngeal Cancer With Radical Radiotherapy
No. Patients Glottis Parsons et a119 Sagerman et a129 Karim et al~0 Harwood et al2~ Total Supraglottis Parsons et a119 Karim et al3~ Bataini et aP 1 Issa32 Fletcher et aP 3 Harwood et al34 Sagerman et a129 Total Adapted with permission.19
Local Control
9 1 38 39 87
8 0 24 22 54 (62%)
21 79 61 20 26 168 11 386
8 55 20 6 14 81 3 187 (48%)
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T3-4 SCCa: Larynx Preservedwith R T Alone
Table 5. Treatment of Stage T4 Glottic Carcinoma Investigator
Tumor Stage
Jesse 35 Ogura et aP6 Skolnick et aP 7 Vermund38 Stewart and Jackson39 Harwood et al2~
T4N0-N+ T4N0 T4N0 T4N0 T4N0 T4N0
No. Patients
Methodof Treatment
Results (NED)
48 11 7 31 13 56
Laryngectomy Laryngectomy Laryngectomy Laryngectomy Radiotherapy with surgery for salvage Radiotherapy with surgery for salvage
54% at 4 yr 45% at 3 yr 30% at 5 yr 35% at 5 yr 38% at 5 yr 49% at 5 yr*
*Life-tablemethod: uncorrectedfor deaths fromintercurrent disease. Abbreviation:NED,no evidenceof disease. Modifiedwith permission.2~ daily at the University of Florida compared with 41 of 60 (68%) after twice-daily fractionation (P = .09). 21 Twenty-one patients with T4 supraglottic carcinomas had a 5-year local control rate of 56% after radiation therapy. 21 Local control rates after irradiation from a variety of institutions are summarized in Table 4. Overall, the disease was locally controlled in approximately 50% of patients, which is somewhat less than observed after treatment of T4 glottic cancer. 19 Local-regional control rates at 5 years for 110 patients with T3-4 cancers treated at the University of Florida were as follows: stage IN, 68%; stage IV, 51%; and overall, 60%. The 5-year cause-specific and absolute survival rates were as follows: stage Ill, 83% and 52%; stage IV, 48% and 28%; and overall, 66% and 40%.
Complications Glottic Carcinoma Severe complications are defined as those that necessitate an operation or hospitalization, or result in death. 23 Five of 75 patients (7%) treated with radia-
Table 6. T3 Supraglottic Carcinoma Treated With Irradiation
Investigator
Institution
University of Florida (Gainesville) Fletcher and M.D. Anderson Hamberger4~ (Houston) Ghossein et al41 Institut Curie (Paris) Wang et a122 Massachusetts General (Boston)
Local No. Control Patients (%)
Mendenhall et a121
tion therapy alone for T3 glottic cancer at the University of Florida experienced severe complications, including the following: laryngeal edema necessitating a temporary (1 patient) or permanent (1 patient) tracheostomy, chondronecrosis that necessitated total laryngectomy (1 patient), total laryngectomy for a suspected local recurrence with a pathologically negative specimen (1 patient), and fatal airway obstruction (1 patient). 7 Severe complications developed in 7 of 21 patients (33%) who underwent a salvage laryngectomy: wound dehiscence that necessitated a split-thickness skin graft (1 patient) and pharyngocutaneous fistula (6 patients). Therefore, 11 patients (15%) experienced severe complications after radiation therapy or salvage surgery. Foote et al s reported that 13 of 81 patients (16%) treated surgically at the Mayo Clinic experienced significant postoperative complications; one (1%) died postoperatively of a myocardial infarction. Ten of 65 patients (15%) treated with surgery alone or combined with adjuvant irradiation at the University of Florida experienced a severe complication; one (1%) died postoperatively of upper gastrointestinal bleeding and sepsis. 6 One of nine patients (11%) irradiated at the University of Florida for T4 vocal cord cancer experienced a severe treatment complication. 19
Supraglottic Carcinoma Eight of 110 patients irradiated for T3 (3 of 89, 3%) and T4 (5 of 21, 24%) carcinomas of the supraglottic larynx experienced severe complications. 21
89
68
29
62
Follow-Up
35
46
51
76
Patients return to undergo head and weeks for the first third year, every 6
report an interim history and neck examination every 4 to 8 2 years, every 3 months for the months for the fourth and fifth
268
William M. Mendenhall
years, and annually thereafter. Chest radiographs are obtained yearly.
Conclusions Pretreatment CT of the larynx can be used to select patients with favorable lesions for treatment with radiotherapy alone with a high likelihood of cure with larynx preservation. Those with unfavorable cancers are probably best treated by surgery or by induction chemotherapy followed by radiotherapy in patients whose tumors respond. Compared with induction chemotherapy, CT has the obvious advantages of lower cost and lower morbidity. The major disadvantage of pretreatment CT is that it is operator dependent, and information pertaining to tumor volume and cartilage sclerosis may not be obtained if the quality of the scan or diagnostic radiologist is suboptimal. The optimal dose fractionation schedule and whether concomitant chemotherapy offers improved local control rates compared with radiotherapy alone are under investigation. In the United States, multiinstitutional randomized trials are necessary to answer these questions. A disadvantage of multiinstitutional trials is that variability in treatment techniques may obscure any differences that might exist between treatment arms.
References 1. O'Sullivan B, Mackillop W, Gilbert R, et ah Controversies in the management of laryngeal cancer: Results of an international survey of patterns of care. Radiother Oncol 31:23-32, 1994 2. Harari PM: Why has induction chemotherapy for advanced head and neck cancer become a United States community standard ofpractice?J Clin Oncol 15:2050-2055, 1997 3. Department of Veterans Affairs Laryngeal Cancer Study Group: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N EnglJ Med 324:1685-1690, 1991 4. Steiner W: Results of curative laser microsurgery of laryngeal carcinomas. AmJ Otolaryngol 14:116-121, 1993 5. Thumfart WF, Scholtz AW, Eckel HE, et al: Early cancer of the larynx, in Shah JP, JohnsonJT (eds): Proceedings of the 4th International Conference on Head and Neck Cancer, July 28-August 1. 1996. Head and Neck Cancer. Arlington, VA, and Pittsburgh, PA, Society of Head and Neck Surgeons and American Society for Head and Neck Surgery, 1996, pp 289-297 6. Mendenhall WM, Parsons JT, Stringer SP, et al: Stage T3 squamous cell carcinoma of the glottic larynx: A comparison of laryngectomy and irradiation. Int J Radiat Oncol Biol Phys 23:725-732, 1992 7. Mendenhall WM, Parsons JT, Mancuso AA, et al: Definitive
radiotherapy for T3 squamous cell carcinoma of the glottic larynx.J Clin Oncol 15:2394-2402, 1997 8. Foote RL, Olsen KD, Buskirk SJ, et ah Laryngectomy alone for T3 glottic cancer. Head Neck 16:406-412, 1994 9. Pameijer FA, Mancuso AA, Mendenhall WM, et al: Can pretreatment computed tomography predict local control in T3 squamous cell carcinoma of the glottic larynx treated with definitive radiotherapy? Int J Radiat Oncol Biol Phys 37: 1011-1021, 1997 10. Mendenhall WM, Parsons JT, Mancuso AA, et al: Larynx, in Perez CA, Brady LW (eds): Principles and Practice of Radiation Oncology (ed 3). Philadelphia, PA, Lippincott-Raven, 1997, pp 1069-1093 11. Mendenhall WM, Million RR, Sharkey DE, et ah Stage T3 squamous cell carcinoma of the glottic larynx treated with surgery and/or radiation therapy. IntJ Radiat Oncol Biol Phys 10:357-363, 1984 12. Mendenhall WM, Million RR: Elective neck irradiation for squamous cell carcinoma of the head and neck: Analysis of time-dose factors and causes of failure. IntJ Radiat Oncol Biol Phys 12:741-746, 1986 13. Mendenha[1 WM, Million RR, Cassisi NJ: Squamous cell carcinoma of the supraglottic lai3~x treated with radical irradiation: Analysis of treatment parameters and results. Int J Radiat Oncol Biol Phys 10:2223-2230, 1984 14. McLaughlin MP, Mendenhall WM, Mancuso AA, et al: Retropharyngeal adenopathy as a predictor of outcome in squamous cell carcinoma of the head and neck. Head Neck 17:190-198, 1995 15. Mendenhall WM, Million RR, Cassisi NJ: Elective neck irradiation in squamous-cell carcinoma of the head and neck. Head Neck Surg 3:15-20, 1980 16. Mendenhall WM, Million RR, Cassisi NJ: Squamous cell carcinoma of the head and neck treated with radiation therapy: The role of neck dissection for clinically positive neck nodes. IntJ Radiat Oncol Biol Phys 12:733-740, 1986 17. Ellis ER, Mendenhall WM, Rao PV, et al: Incisional or excisional neck-node biopsy before definitive radiotherapy, alone or followed by neck dissection. Head Neck 13:177-183, 1991 18. Wang CC: Carcinoma of the larynx, in Wang CC (ed): Radiation Therapy for Head and Neck Neoplasms (ed 3). New York, NY, Wiley-Liss, 1997, pp 221-255 19. ParsonsJT, Mendenhall WM, Stringer SP, et al: T4 laryngeal carcinoma: Radiotherapy alone with surgery reserved for salvage. IntJ Radiat Oncol Biol Phys 40:549-552, 1998 20. Harwood AR, Beale FA, Cummings BJ, et al: T4NOM0 glottic cancer: An analysis of dose-time-volume factors. Int J Radiat Oncol Biol Phys 7:1507-1512, 1981 21. Mendenhall WM, Parsons JT, Mancuso AA, et ah Radiotherapy for squamous cell carcinoma of the supraglottic larynx: An alternative to surgery. Head Neck 18:24-35, t996 22. Wang CC, Nakfoor BM, Spiro IJ, et al: Role of accelerated fractionated irradiation for supraglottic carcinoma: Assessment of results. CancerJ Sci Am 3:88-91, 1997 23. Taylor JMG, Mendenhall WM, Lavey RS: Dose, time, and fraction size issues for late effects in head and neck cancers. IntJ Radiat Oncol Biol Phys 22:3-11, 1991 24. Harwood AR, Beale FA, Cummings BJ, et ah T3 glottic cancer: An analysis of dose-time-volume factors. Int J Radiat Oncol Biol Phys 6:675-680, 1980 25. Fletcher GH, Lindberg RD, Jesse RH: Radiation therapy for
T3-4 SCCa" Larynx Preservedwith R T Alone
cancer of the larynx and pyriform sinus. Eye Ear Nose Throat Digest 31:58-67, 1969 26. Skolyszewski J, Reinfuss M: The results of radiotherapy of cancer of the larynx in six European countries. Radiobiol Radiother (Berl) 22:32-43, 1981 27. StewartJG, Brown JR, Palmer MK, et al: The management of glottic carcinoma by primary irradiation with surgery in reserve. Laryngoscope 85:1477-1484, 1975 28. Mills EE: Early glottic carcinoma: Factors affecting radiation failure, results of treatment and sequelae. Int J Radiat Oncol Biol Phys 5:811-817, 1979 29. Sagerman RH, Chung CT, King GA, et al: High dose preoperative irradiation for advanced laryngeal-hypopharyngeal cancer. Ann Otol Rhinol Laryngol 88(2 Pt 1):178-182, 1979 30. Karim AB, KralendonkJH, Njo KH, et al: Radiation therapy for advanced (T3T4N0-N3M0) laryngeal carcinoma: The need for a change of strategy: A radiotherapeutic viewpoint. Int J Radiat Oncol Biol Phys 13:1625-1633, 1987 31. BatainiJP, BrugereJ,Jaulerry CH, et al: Radiation treatment of lateral epilaryngeal cancer: Prognostic factors and results. AmJ Clin Oncol 7:641-645, 1984 32. Issa PY: Cancer of the supraglottic larynx treated by radiotherapy exclusively. Int J Radiat Oncol Biol Phys 15:843-850, 1988 33. Fletcher GH, Lindberg RD, Hamberger A, et al: Reasons for irradiation failure in squamous cell carcinoma of the larynx. Laryngoscope 85:987-1003, 1975 34. Harwood AR, Beale FA, Cummings BJ, et al: Supraglottic laryngeal carcinoma: An analysis of dose-time-volume factors in 410 patients. IntJ Radiat Oncol Biol Phys 9:311-319, 1983
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35. Jesse RH: The evaluation of treatment of patients with extensive squamous cancer of the vocal cords. Laryngoscope 85:1424-1429, 1975 36. Ogura JH, Sessions DG, Spector GJ: Analysis of surgical therapy for epidermoid carcinoma of the laryngeal glottis. Laryngoscope 85:1522-1530, 1975 37. Skolnik EM, Yee KF, Wheatley MA, et al: Carcinoma of the laryngeal glottis: Therapy and end results. Laryngoscope 85:1453-1466, 1975 38. Vermund H: Role of radiotherapy in cancer of the larynx as related to the TNM system of staging: A review. Cancer 25:485-504, 1970 39. Stewart JG,Jackson AW: The steepness of the dose response curve both for tumor cure and normal tissue injury. Laryngoscope 85:1107-1111, 1975 40. Fletcher GH, Hamberger AD: Causes of failure in irradiation ofsquamous-cell carcinoma of the supraglottic larynx. Radiology 111:697-700, 1974 41. G-hossein NA, BatainiJP, Ennuyer A, et al: Local control and site of failure in radically irradiated supraglottic laryngeal cancer. Radiology 112:187-192, 1974 42. ParsonsJT, Mendenhall WM, Mancuso AA, et al: Twice-a-day radiotherapy for squamous cell carcinoma of the glottic larynx. Head Neck 11:123-128, 1989 43. Million RR, Cassisi NJ, Mancuso AA, et al: Management of the neck for squamous cell carcinoma, in Million RR, Cassisi NJ (eds): Management of Head and Neck Cancer: A Multidisciplinary Approach (ed 2). Philadelphia, PA, Lippincott, 1994, pp 75-143
ment computed tomography of the larynx. Local control after radiotherapy is approximately 60% for T4 glottic cancers and 50% for T4 supraglottic carcinomas. The probability of severe complications is related to primary site and T-stage. Copyright 9 1998 by W.B. Saunders Company
of this discussion, ~ " or the purpose refers to T3 and T4 tumors. Patients
Europe, claims high local control rates after transoral laser excision, alone or combined with adjuvant radiation therapy. 4,5This article reviews the results of radiation therapy alone for T3 and T4 squamous cell carcinoma of the larynx.
advanced laryn-
geal cancer
with T1 and T2 tumors with clinically positive nodes have stage HI or 1V disease, but the management of the favorable primary tumor is conservative, and the likelihood of local control with larynx preservation is high. In contrast, the likelihood of local control with larynx preservation for advanced primary tumors is significantly lower. Depending on the site and extent of disease, treatment alternatives include partial laryngectomy, total laryngectomy, and radiation therapy alone or combined with adjuvant chemotherapy. The prevailing treatment philosophy varies considerably from one country to anotherJ Patients in the United States and Australia are usually treated surgically, which often necessitates total laryngectomyJ In contrast, patients in Canada and Great Britain are often treated with radiation therapy alone, with surgery reserved as salvage treatment for those who develop recurrent disease. Patients treated with radiotherapy in the United States often receive induction chemotherapy before irradiation. 2 The rationale for this strategy is based on the Veterans Affairs Laryngeal Cancer Study Group trial, which compared induction chemotherapy and radiation therapy (in the subset of patients who responded to chemotherapy) with initial laryngectomy and postoperative irradiation; survival rates were similar, and patients randomized to the induction chemotherapy arm had a higher rate of laryngeal voice preservation. 3 (See also the article by Forastiere in this issue.) An occasional head and neck surgeon, primarily in
From the Department of Radiation Oncology, University of Flerida CollegeofMedicine, GainesviUe,FL. Addressreprintrequeststo WilliamM. Mendenhall,MD, Departmentof Radiation Oncology,UniversityofFlorida Health ScienceCenter,PO Box 100385, 2000SW ArcherRoad, Gaiuesville,FL 32610-0385. 1053-4296/98/0804-000658.00/0
262
Treatment Selection Glottic Carcinoma Glottic carcinomas with vocal cord fixation (T3) may be stratified into relatively favorable and unfavorable lesions. Patients with favorable tumors have disease mostly confined to one side of the larynx, have a good airway, and are reliable for close follow-up. 6,7Patients with unfavorable cancers usually have extensive bilateral disease, often associated with airway compromise. Patients with favorable tumors may he treated with radiation therapy or conservation surgery, which would necessitate an extended hemilaryngectomy or a near-total laryngectomy, The major disadvantage of partial laryngectomy is that a relatively small subset of patients (probably < 10%) is suitable for the procedure. 8 In contrast, 36 of 54 patients (67%) treated at the University of Florida between 1980 and 1988 for T3 glottic cancer received radiation therapy alone.6 Additionally, the functional outcome after partial laryngectomy may vary considerably, from that of a classic hemilaryngectomy to a controlled fistula for speaking with a permanent tracheostomy. Therefore, the preferred conservation treatment for patients with favorable T3 tumors is radiation therapy alone. Patients with unfavorable T3 cancers may be treated either with total laryngectomy and neck dissection, which is often followed by postoperative irradiation, or two to three cycles of induction chemotherapy followed by radiation therapy in those patients who have a partial (-->50% response) or com-
Seminars in Radiation Oncology, VoI 8, No 4 (October), 1998:pp 262-269
7'3-4 SCCr LarynxPreservedwith R T Alone
plete response to the chemotherapy. In addition to the physical findings that define the unfavorable cancer, pretreatment computed tomography (CT) of the larynx may be used to calculate the primary tumor volume and detect cartilage sclerosis; both are significantly related to the likelihood of tumor control with radiotherapy.9 Patients with T4 glottic carcinoma may be treated with either total laryngectomy and neck dissection combined with adjuvant radiotherapy or induction chemotherapy followed by irradiation in the subset of responders. Conservation surgery is not a realistic option, and irradiation alone is feasible only for the small subset of patients with low-volume disease who are staged as having T4 tumors based on minimal cartilage involvement or minimal extension into the soft tissues of the neck (usually through the cricothyroid membrane). My philosophy is to treat patients with advanced T4 cancers with total laryngectomy and to treat patients who have relatively low-volume tumors with induction chemotherapy followed by irradiation for those whose tumors respond.
Supraglottic Carcinoma Favorable T3 cancers are low-volume, exophytic lesions with involvement of the preepiglottic space or minimal involvement of the medial wall of the pyriform sinus, l~ Unfavorable T3 tumors are highvolume, endophytic lesions that are often associated with vocal cord fixation and airway compromise, t~ Patients with favorable T3 cancers are treated with either supraglottic laryngectomy or radiation therapy. Compared with irradiation alone, supraglottic laryngectomy results in a better local control rate but is associated with an increased risk of complications: In approximately 5% of patients taken to surgery, the procedure is converted to a total laryngectomy because of the anatomic extent of the lesion) ~ Most patients with T3 lesions are unsuitable for conservation surgery, however, because of their medical condition (cardiac or pulmonary disease) or anatomic extent of the primary tumor. Approximately 15% to 20% are suitable for supraglottic laryngectomy; the remainder are treated with irradiation. Patients with unfavorable T3 cancers are treated with total laryngectomy and neck dissection or induction chemotherapy, followed by irradiation in those whose tumors respond. Few such patients are suitable for conservation surgery. T4 supraglottic cancers are treated with total laryngectomy and dissection followed by postoperative irradiation. Patients with low-volume T4 tumors,
263
usually because of modest involvement of the base of tongue or pharyngeal wall, are treated with irradiation alone or preceded by induction chemotherapy.
Radiation TherapyTechnique Glottic Carcinoma Patients are treated with parallel-opposed fields that include the primary lesion and internal jugular lymph nodes (levels II, IN, and IV). 11,12The anterior aspect of the neck is tangentially irradiated because of the proximity of the anterior commissure to the anterior skin surface (usually approximately 1 cm); the inferior border is 2 cm below the inferior extent of the primary tumor (usually 1 to 2 cm below the bottom of the cricoid cartilage) (Fig 1). Patients receive 1.2 Gy per fraction twice daily with a minimum 6-hour interfraction interval to a total dose of 74.4 Gy; the dose is usually specified to an isodose line that includes the tumor with minimal, if any, margin (usually the 95% isodose line, normalized to Dmax at the central axis of the fields). The fields are weighted 3:2 to the side of the lesion (if it is lateralized) and reduced at 45.6 Gy and 60 Gy. The low neck receives 50 Gy in 25 fractions, once-daily fractionation, specified at Dmax, with a thin midline trachea block (Fig 2).
Supraglottic Carcinoma The portals for supraglottic carcinoma are similar to those used for advanced glottic cancer except that the anterior neck skin may sometimes be spared, and the inferior border is usually at the bottom of the cricoid cartilage (Fig 3). 13 The likelihood of positive retropharyngeal lymph nodes is low; however, if clinically positive neck nodes are present, the risk is increased, and the superior border of the field is placed at the jugular foramen. 14 The dose fractionation schedule is the same as that described for T3-4 glottic cancers.
Treatment of the Neck The risk of subclinical disease in the cervical lymph nodes exceeds 20% for patients with T3-4 laryngeal cancer.15 Therefore, the internal jugular lymph nodes (levels II and IV) are electively irradiated bilaterally. Patients with N1 or early N2B neck disease with the positive nodes located within the high-dose fields are treated with irradiation alone) 6 Patients with more advanced neck disease undergo a planned neck dissection after radiation therapy. 16,17
264
William M. Mendenhall
rates after surgical salvage of failures at 5 years were 63% and 86%. The local control rates according to fractionation schedule are shown in Table 1. There is a modest improvement in local control for the subset of patients treated with twice-daily fractionation. Thirty-seven patients who were evaluable for local control after irradiation had pretreatment computed tomography (CT) scans available to calculate the primary tumor volume. 7 The likelihood of local control is inversely related to tumor volume: 3.5 cm 3 or less, 20 of 23 (87%), compared with greater than 3.5 cm 3, 4 of 14 (29%) (P < .001). Pameijer et al 9 have found that cartilage sclerosis, in addition to tumor volume, is a useful determinant of local control after irradiation. The relationship of vocal cord mobility, at various points during and after radiotherapy, to local control after irradiation is listed in Table 2. 7Whether the vocal cord becomes mobile or remains fixed does not appear to affect the probability of local control. The local control rates after irradiation and ultimate local control rates from various institutions, including the University of Florida, are summarized in Table 3) o Wang 18 reported a 67% rate of local control after radiotherapy for 41 patients treated with twice-daily fractionation, compared with 42% in 24 patients treated with once-daily irradiation. The 5-year local-regional control and ultimate 1. Radiation treatment technique for carcinoma of glottic lm'ynx, stage T3-4N0. The patient is treated supine, and the field is shaped with Lipowitz's metal. Anteriorly, the field is allowed to fall off. The entire pre-epiglottic space is included by encompassing hyoid bone and epiglottis. The superior border (just above the angle of the mandible) includes jugulodigastric lymph nodes. Posteriorly, a portion of spinal cord must be included within the field to ensure adequate coverage of midjugular lymph nodes: Spinal accessory lymph nodes themselves are at little risk of involvement. The lower border is slanted (1) to facilitate matching with the low neck field and (2) to reduce length of spinal cord in the high-dose field. The inferior border is placed at the bottom of the cricoid cartilage if the patient has no subglottic spread; in the presence of subglottic extension, the inferior border must be lowered according to disease extent. (Reprinted with permissiong) Figure
,
,",
I\\t ,/J-A' ~A\'," ~
,/ :'-:" / / ~/J
"', ,/i
_-_ ~'-~ ~
' ,'
"s \
/ ~ / / c"IN\ ' ~ "~ / ; J I
LN: .............
/
Treatment Results Glottic Carcinoma Seventy-five patients were treated with radiation therapy alone for T3 squamous cell carcinoma of the glottic larynx at the University of Florida between 1966 and 1994; no patient received adjuvant chemotherapy] The local control and ultimate local control
F i g u r e 2. Example of a portal for T3N0 glottic carcinoma.
Low neck portal. The main nodes at risk are the lowjugular and lateral paratracheal nodes. The delphian node would be in the primary portal. A narrow and short midline shield is used. (Reprinted with permission. 43)
265
T3-4 SCCa: Larynx Preservedwith R T Alone
Table 2. T3 Vocal Cord Carcinoma: Local Control After Irradiation Versus Vocal Cord Mobility (No. Controlled/No. Treated)*
Local Control CordMobility Assessed At 50 Gy
End of irradiation
1-month follow-up
Mobility
No.
%
Mobile Impaired Fixed No data Mobile Impaired Fixed No data Mobile Impaired Fixed No data
7/10 9/17 21/34 3/4 14/23 8/14 16/25 2/3 18/28 8/13 14/24 0/0
70 53 62 75 61 57 64 67 64 62 58 --
*Note: Excludes 8 patients who died within 2 years of irradiation with the primarytumor site continuouslydisease-free,one patient who had a total laryngectomyat 5 months for suspected recurrence (laryngectomy specimen negative for tumor), and one patient who had a total laryngectomyat 8 months for chondronecrosis. Reprintedwith permission] Figure 3. Example of a portal for a lesion of the lower epiglottis or false vocal cord and a clinically negative neck. The subdigastric nodes are included but not the junctional nodes. Depending on the anatomy and tumor extent, the anterior border may fall off (ie, flash) or a small strip of skin may be shielded. (Reprinted with permission. 43) local-regional control rates for patients treated at the University of Florida were 61% and 86%. 7 The 5-year absolute and cause-specific survival rates were 54% and 78%. Foote et al e reported on 81 patients treated with surgery alone for previously untreated T3 glottic
carcinoma at the Mayo Clinic between 1979 and 1981; 6 patients (7%) underwent a near-total laryngectomy, and the remainder underwent total laryngectomy. The investigators observed a 74% 5-year local-regional control rate and 5-year absolute and cause-specific survival rates of 54% and 78%. The major difference between irradiation and surgery is that radiotherapy is associated with a significantly increased likelihood of laryngeal voice preservation.7,8
Table 1. T3 Vocal Cord Carcinoma: Local Control After Radiotherapy Versus Fractionation Schedule Controlled/Treated Fractionation Schedule Once daily Continuous course Split course Total Twice dally, continuous course 1.2/1.2 Gyt 1.2/1.4 Gy~ Total Overall total
Exclusions*
Salvaged~Attempted
Ultimate Local Control
No.
%
No.
%
No.
%
4 0 4
8/15 1/2 9/17
53 50 53
3/6 0/1 3/7
50 0 43
11/15 1/2 12/17
73 50 71
5 1 6 10
25/41 6/7 31/48 40/65
61 86 65 62
11/13 1/1 12/14 15/21
85 100 86 71
36/41 7/7 43/48 55/65
88 100 90 85
*Excludeseight patientswhodiedwithin2 years of irradiationwith the primarytumor site continuouslydisease-free,one patient who had a total laryngectomyat 5 months for suspected local recurrence (laryngectomyspecimennegativefor tumor), and one patient who had a total laryngectomyat 8 monthsfor chondronecrosis. t 1.2/1.2 = 1.2 Gy per fractionationthroughoutthe radiotherapycourse. :~1.2/1.4= 1.2 Gy per fractionto 60 Gy; 1.4Gy per fractionto 74 Gy. Reprintedwith permission.7
William M. Mendenhall
266
Table 3. Stage T3 Glottic Carcinoma Treated With Irradiation
Investigator
Institution
No. Patients
Harwood et al24 Wang 18 Fletcher et a125 Skolyszewski and Reinfuss 26 Stewart et a127 Mills28 Mendenhall et al7
Princess Margaret (Toronto) Massachusetts General (Boston) M. D. Anderson (Houston) 15 European centers Manchester (England) Capetown (South Africa) University of Florida (Gainesville)
112 65 17 91 67 18 75
Minimum Local Follow-Up Control (yr) (%) 3 Notstated 2 3 10 2 2
51 57 77 50 57 44 63
Ultimate Control After Salvage Surgery (%) 77 --67 78 86
Reprinted with permission.l~
Nine patients with T4 glottic carcinomas were treated with radical irradiation at the University of Florida between 1964 and 1994; in 8 of 9 patients, the disease was locally controlled after radiotherapy. 19 The results of radiation treatment from the University of Florida and several other institutions are summarized in Table 4; the tumor was locally controlled after irradiation in almost two thirds of patients. 19The cure rates after surgery or irradiation for T4 glottic cancers are summarized in Table 5. 2~
Supraglottie L a r y n x A total of 110 patients were treated with radical irradiation for T3 (89 patients) and T4 (21 patients) supraglottic carcinoma at the University of Florida between 1964 and 1992; 1 patient received induction chemotherapy, and the remainder underwent irradiation alone or combined with a planned neck dissection31 Fifty-six patients had American Joint Committee on Cancer (AJCC) stage III disease (T3N0-1) and 54 patients had stage 1V disease (T3-4N2-3). The 5-year local control rate after radiation therapy for 89 patients with T3 cancers was 68%. Excluding 19 patients who died less than 2 years from treatment with the primary site continuously disease-free, the local control and ultimate local control rates were 45 of 70 (64%) and 57 of 70 (81%). Local control after irradiation versus subsite within the supraglottis revealed the following: suprahyoid epiglottis, 2 of 3 (67%); infrahyoid epiglottis, 23 of 32 (72%); false vocal cord, 8 of 18 (44%); aryepiglottic fold, 11 of 16 (69%); and arytenoid, 1 of 1 (100%). Local control versus vocal cord mobility revealed the following: normal mobility, 34 of 48 (71%); impaired mobility, 6 of 11 (55%); and fixation, 4 of 9 (44%). False vocal cord tumors are probably more likely to be highvolume, endophytic lesions associated with reduced or absent vocal cord mobility and a lower probability
of cure after irradiation. Local control after radiotherapy was inversely related to tumor volume as calculated on pretreatment C T scans: less than 6 cm 3, 11 of 13 (85%), versus 6 cm 3 or greater, 9 of 19 (47%) (P = .04). Multivariate analysis of local control results revealed the following ranking of possible prognostic factors: twice-daily versus once-daily fractionation (P = .07), site within the supraglottis (P = .1), N stage (P = .078), sex (P = .18), T stage (P = .63), vocal cord mobility (P = .68), suitability for conservation surgery (P = .667), and pretreatment C T scan obtained (P = .77). Local control after radiotherapy at various institutions is illustrated in Table 6. W a n g et aF 2 reported a 76% 5-year local control rate in 51 patients treated with twice-daily fractionation; the ultimate local control rate was 88%. Local control was obtained in 4 of 10 patients (40%) who received irradiation once
Table 4. Literature Review: Treatment ofT4 Laryngeal Cancer With Radical Radiotherapy
No. Patients Glottis Parsons et a119 Sagerman et a129 Karim et al~0 Harwood et al2~ Total Supraglottis Parsons et a119 Karim et al3~ Bataini et aP 1 Issa32 Fletcher et aP 3 Harwood et al34 Sagerman et a129 Total Adapted with permission.19
Local Control
9 1 38 39 87
8 0 24 22 54 (62%)
21 79 61 20 26 168 11 386
8 55 20 6 14 81 3 187 (48%)
267
T3-4 SCCa: Larynx Preservedwith R T Alone
Table 5. Treatment of Stage T4 Glottic Carcinoma Investigator
Tumor Stage
Jesse 35 Ogura et aP6 Skolnick et aP 7 Vermund38 Stewart and Jackson39 Harwood et al2~
T4N0-N+ T4N0 T4N0 T4N0 T4N0 T4N0
No. Patients
Methodof Treatment
Results (NED)
48 11 7 31 13 56
Laryngectomy Laryngectomy Laryngectomy Laryngectomy Radiotherapy with surgery for salvage Radiotherapy with surgery for salvage
54% at 4 yr 45% at 3 yr 30% at 5 yr 35% at 5 yr 38% at 5 yr 49% at 5 yr*
*Life-tablemethod: uncorrectedfor deaths fromintercurrent disease. Abbreviation:NED,no evidenceof disease. Modifiedwith permission.2~ daily at the University of Florida compared with 41 of 60 (68%) after twice-daily fractionation (P = .09). 21 Twenty-one patients with T4 supraglottic carcinomas had a 5-year local control rate of 56% after radiation therapy. 21 Local control rates after irradiation from a variety of institutions are summarized in Table 4. Overall, the disease was locally controlled in approximately 50% of patients, which is somewhat less than observed after treatment of T4 glottic cancer. 19 Local-regional control rates at 5 years for 110 patients with T3-4 cancers treated at the University of Florida were as follows: stage IN, 68%; stage IV, 51%; and overall, 60%. The 5-year cause-specific and absolute survival rates were as follows: stage Ill, 83% and 52%; stage IV, 48% and 28%; and overall, 66% and 40%.
Complications Glottic Carcinoma Severe complications are defined as those that necessitate an operation or hospitalization, or result in death. 23 Five of 75 patients (7%) treated with radia-
Table 6. T3 Supraglottic Carcinoma Treated With Irradiation
Investigator
Institution
University of Florida (Gainesville) Fletcher and M.D. Anderson Hamberger4~ (Houston) Ghossein et al41 Institut Curie (Paris) Wang et a122 Massachusetts General (Boston)
Local No. Control Patients (%)
Mendenhall et a121
tion therapy alone for T3 glottic cancer at the University of Florida experienced severe complications, including the following: laryngeal edema necessitating a temporary (1 patient) or permanent (1 patient) tracheostomy, chondronecrosis that necessitated total laryngectomy (1 patient), total laryngectomy for a suspected local recurrence with a pathologically negative specimen (1 patient), and fatal airway obstruction (1 patient). 7 Severe complications developed in 7 of 21 patients (33%) who underwent a salvage laryngectomy: wound dehiscence that necessitated a split-thickness skin graft (1 patient) and pharyngocutaneous fistula (6 patients). Therefore, 11 patients (15%) experienced severe complications after radiation therapy or salvage surgery. Foote et al s reported that 13 of 81 patients (16%) treated surgically at the Mayo Clinic experienced significant postoperative complications; one (1%) died postoperatively of a myocardial infarction. Ten of 65 patients (15%) treated with surgery alone or combined with adjuvant irradiation at the University of Florida experienced a severe complication; one (1%) died postoperatively of upper gastrointestinal bleeding and sepsis. 6 One of nine patients (11%) irradiated at the University of Florida for T4 vocal cord cancer experienced a severe treatment complication. 19
Supraglottic Carcinoma Eight of 110 patients irradiated for T3 (3 of 89, 3%) and T4 (5 of 21, 24%) carcinomas of the supraglottic larynx experienced severe complications. 21
89
68
29
62
Follow-Up
35
46
51
76
Patients return to undergo head and weeks for the first third year, every 6
report an interim history and neck examination every 4 to 8 2 years, every 3 months for the months for the fourth and fifth
268
William M. Mendenhall
years, and annually thereafter. Chest radiographs are obtained yearly.
Conclusions Pretreatment CT of the larynx can be used to select patients with favorable lesions for treatment with radiotherapy alone with a high likelihood of cure with larynx preservation. Those with unfavorable cancers are probably best treated by surgery or by induction chemotherapy followed by radiotherapy in patients whose tumors respond. Compared with induction chemotherapy, CT has the obvious advantages of lower cost and lower morbidity. The major disadvantage of pretreatment CT is that it is operator dependent, and information pertaining to tumor volume and cartilage sclerosis may not be obtained if the quality of the scan or diagnostic radiologist is suboptimal. The optimal dose fractionation schedule and whether concomitant chemotherapy offers improved local control rates compared with radiotherapy alone are under investigation. In the United States, multiinstitutional randomized trials are necessary to answer these questions. A disadvantage of multiinstitutional trials is that variability in treatment techniques may obscure any differences that might exist between treatment arms.
References 1. O'Sullivan B, Mackillop W, Gilbert R, et ah Controversies in the management of laryngeal cancer: Results of an international survey of patterns of care. Radiother Oncol 31:23-32, 1994 2. Harari PM: Why has induction chemotherapy for advanced head and neck cancer become a United States community standard ofpractice?J Clin Oncol 15:2050-2055, 1997 3. Department of Veterans Affairs Laryngeal Cancer Study Group: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N EnglJ Med 324:1685-1690, 1991 4. Steiner W: Results of curative laser microsurgery of laryngeal carcinomas. AmJ Otolaryngol 14:116-121, 1993 5. Thumfart WF, Scholtz AW, Eckel HE, et al: Early cancer of the larynx, in Shah JP, JohnsonJT (eds): Proceedings of the 4th International Conference on Head and Neck Cancer, July 28-August 1. 1996. Head and Neck Cancer. Arlington, VA, and Pittsburgh, PA, Society of Head and Neck Surgeons and American Society for Head and Neck Surgery, 1996, pp 289-297 6. Mendenhall WM, Parsons JT, Stringer SP, et al: Stage T3 squamous cell carcinoma of the glottic larynx: A comparison of laryngectomy and irradiation. Int J Radiat Oncol Biol Phys 23:725-732, 1992 7. Mendenhall WM, Parsons JT, Mancuso AA, et al: Definitive
radiotherapy for T3 squamous cell carcinoma of the glottic larynx.J Clin Oncol 15:2394-2402, 1997 8. Foote RL, Olsen KD, Buskirk SJ, et ah Laryngectomy alone for T3 glottic cancer. Head Neck 16:406-412, 1994 9. Pameijer FA, Mancuso AA, Mendenhall WM, et al: Can pretreatment computed tomography predict local control in T3 squamous cell carcinoma of the glottic larynx treated with definitive radiotherapy? Int J Radiat Oncol Biol Phys 37: 1011-1021, 1997 10. Mendenhall WM, Parsons JT, Mancuso AA, et al: Larynx, in Perez CA, Brady LW (eds): Principles and Practice of Radiation Oncology (ed 3). Philadelphia, PA, Lippincott-Raven, 1997, pp 1069-1093 11. Mendenhall WM, Million RR, Sharkey DE, et ah Stage T3 squamous cell carcinoma of the glottic larynx treated with surgery and/or radiation therapy. IntJ Radiat Oncol Biol Phys 10:357-363, 1984 12. Mendenhall WM, Million RR: Elective neck irradiation for squamous cell carcinoma of the head and neck: Analysis of time-dose factors and causes of failure. IntJ Radiat Oncol Biol Phys 12:741-746, 1986 13. Mendenha[1 WM, Million RR, Cassisi NJ: Squamous cell carcinoma of the supraglottic lai3~x treated with radical irradiation: Analysis of treatment parameters and results. Int J Radiat Oncol Biol Phys 10:2223-2230, 1984 14. McLaughlin MP, Mendenhall WM, Mancuso AA, et al: Retropharyngeal adenopathy as a predictor of outcome in squamous cell carcinoma of the head and neck. Head Neck 17:190-198, 1995 15. Mendenhall WM, Million RR, Cassisi NJ: Elective neck irradiation in squamous-cell carcinoma of the head and neck. Head Neck Surg 3:15-20, 1980 16. Mendenhall WM, Million RR, Cassisi NJ: Squamous cell carcinoma of the head and neck treated with radiation therapy: The role of neck dissection for clinically positive neck nodes. IntJ Radiat Oncol Biol Phys 12:733-740, 1986 17. Ellis ER, Mendenhall WM, Rao PV, et al: Incisional or excisional neck-node biopsy before definitive radiotherapy, alone or followed by neck dissection. Head Neck 13:177-183, 1991 18. Wang CC: Carcinoma of the larynx, in Wang CC (ed): Radiation Therapy for Head and Neck Neoplasms (ed 3). New York, NY, Wiley-Liss, 1997, pp 221-255 19. ParsonsJT, Mendenhall WM, Stringer SP, et al: T4 laryngeal carcinoma: Radiotherapy alone with surgery reserved for salvage. IntJ Radiat Oncol Biol Phys 40:549-552, 1998 20. Harwood AR, Beale FA, Cummings BJ, et al: T4NOM0 glottic cancer: An analysis of dose-time-volume factors. Int J Radiat Oncol Biol Phys 7:1507-1512, 1981 21. Mendenhall WM, Parsons JT, Mancuso AA, et ah Radiotherapy for squamous cell carcinoma of the supraglottic larynx: An alternative to surgery. Head Neck 18:24-35, t996 22. Wang CC, Nakfoor BM, Spiro IJ, et al: Role of accelerated fractionated irradiation for supraglottic carcinoma: Assessment of results. CancerJ Sci Am 3:88-91, 1997 23. Taylor JMG, Mendenhall WM, Lavey RS: Dose, time, and fraction size issues for late effects in head and neck cancers. IntJ Radiat Oncol Biol Phys 22:3-11, 1991 24. Harwood AR, Beale FA, Cummings BJ, et ah T3 glottic cancer: An analysis of dose-time-volume factors. Int J Radiat Oncol Biol Phys 6:675-680, 1980 25. Fletcher GH, Lindberg RD, Jesse RH: Radiation therapy for
T3-4 SCCa" Larynx Preservedwith R T Alone
cancer of the larynx and pyriform sinus. Eye Ear Nose Throat Digest 31:58-67, 1969 26. Skolyszewski J, Reinfuss M: The results of radiotherapy of cancer of the larynx in six European countries. Radiobiol Radiother (Berl) 22:32-43, 1981 27. StewartJG, Brown JR, Palmer MK, et al: The management of glottic carcinoma by primary irradiation with surgery in reserve. Laryngoscope 85:1477-1484, 1975 28. Mills EE: Early glottic carcinoma: Factors affecting radiation failure, results of treatment and sequelae. Int J Radiat Oncol Biol Phys 5:811-817, 1979 29. Sagerman RH, Chung CT, King GA, et al: High dose preoperative irradiation for advanced laryngeal-hypopharyngeal cancer. Ann Otol Rhinol Laryngol 88(2 Pt 1):178-182, 1979 30. Karim AB, KralendonkJH, Njo KH, et al: Radiation therapy for advanced (T3T4N0-N3M0) laryngeal carcinoma: The need for a change of strategy: A radiotherapeutic viewpoint. Int J Radiat Oncol Biol Phys 13:1625-1633, 1987 31. BatainiJP, BrugereJ,Jaulerry CH, et al: Radiation treatment of lateral epilaryngeal cancer: Prognostic factors and results. AmJ Clin Oncol 7:641-645, 1984 32. Issa PY: Cancer of the supraglottic larynx treated by radiotherapy exclusively. Int J Radiat Oncol Biol Phys 15:843-850, 1988 33. Fletcher GH, Lindberg RD, Hamberger A, et al: Reasons for irradiation failure in squamous cell carcinoma of the larynx. Laryngoscope 85:987-1003, 1975 34. Harwood AR, Beale FA, Cummings BJ, et al: Supraglottic laryngeal carcinoma: An analysis of dose-time-volume factors in 410 patients. IntJ Radiat Oncol Biol Phys 9:311-319, 1983
269
35. Jesse RH: The evaluation of treatment of patients with extensive squamous cancer of the vocal cords. Laryngoscope 85:1424-1429, 1975 36. Ogura JH, Sessions DG, Spector GJ: Analysis of surgical therapy for epidermoid carcinoma of the laryngeal glottis. Laryngoscope 85:1522-1530, 1975 37. Skolnik EM, Yee KF, Wheatley MA, et al: Carcinoma of the laryngeal glottis: Therapy and end results. Laryngoscope 85:1453-1466, 1975 38. Vermund H: Role of radiotherapy in cancer of the larynx as related to the TNM system of staging: A review. Cancer 25:485-504, 1970 39. Stewart JG,Jackson AW: The steepness of the dose response curve both for tumor cure and normal tissue injury. Laryngoscope 85:1107-1111, 1975 40. Fletcher GH, Hamberger AD: Causes of failure in irradiation ofsquamous-cell carcinoma of the supraglottic larynx. Radiology 111:697-700, 1974 41. G-hossein NA, BatainiJP, Ennuyer A, et al: Local control and site of failure in radically irradiated supraglottic laryngeal cancer. Radiology 112:187-192, 1974 42. ParsonsJT, Mendenhall WM, Mancuso AA, et al: Twice-a-day radiotherapy for squamous cell carcinoma of the glottic larynx. Head Neck 11:123-128, 1989 43. Million RR, Cassisi NJ, Mancuso AA, et al: Management of the neck for squamous cell carcinoma, in Million RR, Cassisi NJ (eds): Management of Head and Neck Cancer: A Multidisciplinary Approach (ed 2). Philadelphia, PA, Lippincott, 1994, pp 75-143