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T1-T2N0 Squamous Cell Carcinoma of the Glottic Larynx Treated With Radiation Therapy

From the Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL.

Address correspondence to William M. Mendenhall, MD, Department of Radiation Oncology, PO Box 100385, Gainesville, FL 32610-0385; email: mendewil{at}shands.ufl.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The end results after radiation therapy for T1-T2N0 glottic carcinoma vary considerably. We analyze patient-related and treatment-related parameters that may influence the likelihood of cure.

PATIENTS AND METHODS: Five hundred nineteen patients were treated with radiation therapy and had follow-up for 2 years. Three patients who were disease-free were lost to follow-up at 7 months, 21 months, and 10.5 years. No other patients were lost to follow-up.

RESULTS: Local control rates at 5 years after radiation therapy were as follows: T1A, 94%; T1B, 93%; T2A, 80%; and T2B, 72%. Multivariate analysis of local control revealed that the following parameters significantly influenced this end point: overall treatment time (P < .0001), T stage (P = .0003), and histologic differentiation (P = .013). Patients with poorly differentiated cancers fared less well than those with better differentiated lesions. Rates of local control with laryngeal preservation at 5 years were as follows: T1A and T1B, 95%; T2A, 82%; and T2B, 76%. Cause-specific survival rates at 5 years were as follows: T1A and T1B, 98%; T2A, 95%; and T2B, 90%. One patient with a T1N0 cancer and three patients with T2N0 lesions experienced severe late radiation complications.

CONCLUSION: Radiation therapy cures a high percentage of patients with T1-T2N0 glottic carcinomas and has a low rate of severe complications. The major treatment-related parameter that influences the likelihood of cure is overall treatment time.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE GOALS OF treatment for early vocal cord cancer include cure, laryngeal voice preservation, and optimal voice quality with minimal morbidity, expense, and inconvenience. The treatment of choice is controversial. Options include radiation therapy,¹ open partial laryngectomy,² and transoral laser excision.³ The selection of treatment depends on the location and extent of the tumor, the medical condition of the patient, the philosophy of the physicians, and the wishes of the patient.^1,4-6 Discussion among physicians about the optimal treatment modality may be rather animated, and there is a tendency to selectively quote data from the literature to support one’s bias. Significant variability in end results for the various modalities are probably related to selection bias and treatment techniques. This variability and the fact that few physicians actually analyze the end results of treatment of their patients further complicate the process of treatment selection. The purpose of this article is to analyze parameters that may influence end results in patients treated with radiation therapy and to discuss these findings relative to the pertinent literature.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Five hundred nineteen patients with previously untreated T1N0 and T2N0 biopsy-proven squamous cell carcinoma of the glottic larynx who were treated with radiation therapy alone at the University of Florida between October 1964 and July 1998 were analyzed. The treatment of choice at the University of Florida for patients with T1 and T2 vocal cord cancers has been, and remains, radiation therapy alone, so that this represents a relatively unselected series of patients. Patients were excluded if they had clinically positive neck nodes (five patients with T2 cancers) or a synchronous head and neck primary malignancy (six patients). Patients were treated with planned continuous-course radiation therapy (RT) with curative intent; four patients treated with the planned split-course technique between 1970 and 1974 were also excluded.⁷ Split-course RT is no longer used at the University of Florida.

Patients were followed-up for 2 years, with the exception of two patients who were lost to follow-up at 7 months and 21 months, respectively. One additional patient was lost to follow-up 10.5 years after radiation therapy. All three patients were clinically disease-free and were censored at the time of last follow-up. No other patients were lost to follow-up. The follow-up on living patients ranged from 7 months to 35 years (median, 9.87 years).

Patients ranged in age from 22 to 86 years (median, 63 years). The characteristics of the patient population are listed in Table 1. Patients were clinically staged according to the 1998 American Joint Committee on Cancer.⁸ Stage T2 was further stratified depending on whether vocal cord mobility was normal (T2A) or impaired (T2B). Patients were also stratified according to the surgical procedure that would have been necessary if the patient had undergone an open surgical procedure as the first step in treatment. The anatomic limitations of these procedures have been described and are outlined in Table 2. The authors recognize that some lesions that are unsuitable for a cordectomy or hemilaryngectomy may be suitable for an open extended partial laryngectomy or a transoral laser excision.^3,9 However, many head and neck surgeons do not perform these extended operations, and the limitations of the procedure may vary with the physician.

Patients were treated in the lateral decubitus position. The fields were set up daily and checked on the table by the attending physician. The typical borders for a T1 lesion that involved the anterior two thirds of one or both cords would be the middle of the thyroid notch, the bottom of the cricoid cartilage, 1 cm behind the posterior border of the thyroid ala, and falling off 1.5 cm anteriorly (Fig 1).^1,13 Fields were enlarged depending on extension off of the true vocal cord for patients with T2 tumors. The fields were not routinely reduced in size at any point in the treatment course. Early in the study, patients were treated with a single ipsilateral field. Subsequently, a parallel-opposed two-field technique was used. A three-field technique was used consistently over at least the past 20 years and consisted of parallel-opposed fields to give approximately 90% of the dose and an anterior field to give the remainder. The fields were weighted 3:2 for lateralized cancers, and the anterior boost field was centered on the tumor. The dose was specified at an isodose line that just encompassed the cancer and usually was 95% of the maximum dose. Patients were treated with ⁶⁰Co or 2-MV x-rays early in our experience. Our preference has been to use ⁶⁰Co in recent years except with a small subset of patients treated, for the most part at a satellite facility, with higher energy beams. No patient was treated with orthovoltage irradiation.

View larger version (61K): [in this window] [in a new window]   Fig 1. Patient with a T1N0 squamous cell carcinoma confined to the anterior two-thirds of the vocal cord. (A) Patient in the lateral chicken-wing position. Reprinted from Mendenhall et al.1 (B) Schematic diagram of the field. (C) Computer-generated dosimetry. Parts B and C reprinted from Million et al.13

Elective neck RT was not used for any patient with a T1 cancer. Thirteen patients with bulky T2 tumors received elective RT to the internal jugular lymph nodes, depending on the inclination of the attending physician.

Acute complications during RT were defined as severe if an unplanned treatment break was necessary. There were no planned treatment splits. Late complications were defined as severe if they necessitated a surgical procedure or resulted in death.¹⁴ The placement of a tracheostomy tube or gastrostomy tube would be defined as a severe complication.

The probabilities of local control, local control with laryngeal voice preservation, neck control, distant metastases, and survival were calculated by the Kaplan-Meier product-limit method.^15,16 All 519 patients were included in the analyses of end results. The log-rank test was used for univariate comparison among curves.^16,17 Multivariate analyses were performed using the forward stepwise log-rank tests of association of covariates.^16,18 The following parameters were included in the multivariate analyses of local control, local control with laryngeal voice preservation, and survival: T stage, surgical alternative (cordectomy v hemilaryngectomy v total laryngectomy), anterior commissure invasion, histologic differentiation (well, moderate, or not otherwise specified v poor), total dose (continuous variable), fractionation (once v twice daily), overall treatment time (continuous variable), and beam energy (⁶⁰Co or 2-MV x-rays v 6-MV x-rays or other). The multivariate analysis of neck control included T stage, surgical alternative, anterior commissure invasion, histologic differentiation, elective neck RT (no v yes), and continuous local control after RT (yes v no).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Local Control
Local control after RT is depicted in Fig 2. The 5-year local control rates after RT for the subset of 384 patients treated after December 1977 were as follows: T1A, 95%; T1B, 94%; T2A, 82%; and T2B, 70%. The 5-year local control rates after RT for 182 patients with T2 cancers treated after December 1977 with once-daily versus twice-daily fractionation were as follows: T2A, 82% and 83%, respectively (P = .88); and T2B, 71% and 69%, respectively (P = .80). The 5-year local control rates after irradiation and including patients who were successfully treated after a local recurrence were 87% and 97%, respectively, for the overall group. Multivariate analysis of local control revealed that the following parameters significantly impacted this end point: overall treatment time (P < .0001), T stage (P = .0003), and histologic differentiation (P = .013). Fractionation schedule marginally influenced local control (P = .07). The fact that this parameter was marginally significant despite the similarity in the 5-year local control rates comparing once-daily with twice-daily fractionation may reflect selection bias because patients with more favorable cancers tended to be treated after the former schedule. Variables that did not significantly influence local control were as follows: beam energy (P = .216), anterior commissure invasion (P = .350), surgical alternative (P = .450), and irradiation dose (P = .678).

View larger version (15K): [in this window] [in a new window]   Fig 2. Local control after radiation therapy. Local control rates at 5 years were as follows: T1A, 94%; T1B, 93%; T2A, 80%; and T2B, 72%.

Fifty-one patients with T2 cancers experienced a local recurrence after RT. Forty-nine underwent salvage surgery, and two patients were inoperable. Seven patients, who would initially have been suitable for a total laryngectomy (n = 6) or hemilaryngectomy (n = 1), underwent a salvage hemilaryngectomy, which was successful in four patients. Forty-two patients underwent salvage total laryngectomy, which was successful in 36 patients.

The ultimate rates of local control, including patients who were successfully treated after a local recurrence, are shown in Fig 3. Multivariate analysis of ultimate local control revealed that T stage (P = .062) and irradiation dose (P = .072) marginally influenced this end point. Parameters that did not significantly impact ultimate local control included histologic differentiation (P = .102), anterior commissure invasion (P = .266), fractionation schedule (P = .348), beam energy (P = .383), surgical alternative (P = .792), and overall treatment time (P = .934).

View larger version (16K): [in this window] [in a new window]   Fig 3. Ultimate local control after treatment. Ultimate local control rates at 5 years were as follows: T1A, 98%; T1B, 98%; T2A, 96% and T2B, 96%.

View larger version (16K): [in this window] [in a new window]   Fig 4. Local control with laryngeal voice preservation. Local control with laryngeal preservation rates at 5 years were as follows: T1A, 95%; T1B, 95%; T2A, 82%; and T2B, 76%.

View larger version (15K): [in this window] [in a new window]   Fig 5. Control of disease in the neck after treatment. The 5-year rates of neck disease control for patients who did not receive elective neck irradiation were as follows: T1A and T1B, 99%; T2A, 95%; and T2B, 87%.

Seventeen patients with T2 cancers experienced recurrent disease in the neck. Seven patients experienced recurrent cancer in the neck with the primary site continuously disease-free; five patients experienced remission after neck dissection. Ten patients who had local recurrence also experienced recurrent cancer in the neck; six patients were successfully treated after neck dissection.

The ultimate rates of neck control, including patients who were successfully treated after recurrence in the neck, are depicted in Fig 6. The ultimate rate of neck disease control at 5 years for the entire group of patients was 99%.

View larger version (14K): [in this window] [in a new window]   Fig 6. Ultimate rates of control of disease in the neck. The 5-year rates of ultimate neck control were as follows: T1A and T1B, 99%; and T2A and T2B, 98%.

View larger version (14K): [in this window] [in a new window]   Fig 7. Distant metastasis-free survival. The 5-year rates of distant metastasis-free survival were as follows: T1A and T1B, 99%; and T2A and T2B, 97%.

View larger version (15K): [in this window] [in a new window]   Fig 8. Absolute survival. The 5-year absolute survival rates were as follows: T1AN0, 82%; T1BN0, 79%; T2AN0, 77%; and T2BN0, 77%.

View larger version (15K): [in this window] [in a new window]   Fig 9. Cause-specific survival. The 5-year cause-specific survival rates were as follows: T1AN0, 98%; T1BN0, 98%; T2AN0, 95%; and T2BN0, 90%.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The local control rates after RT for T1-T2 vocal cord cancer vary considerably.^1,5,19 Patient-related parameters that may influence local control after RT include sex, tumor extent, histologic differentiation, pretreatment hemoglobin, and p53 status. These factors cannot be manipulated by the physician but may influence the likelihood of cure after RT or surgery and, thus, may influence the selection of treatment.

T stage and surgical alternative are both methods of stratifying tumor extent. Anterior commissure invasion and impaired vocal cord mobility are also useful in defining tumor extent; the latter is part of the T-staging system and is used to stratify T2 cancers. The likelihood of local control decreases as tumor extent increases and with impaired vocal cord mobility.^1,20 T stage seems to be more predictive of local control after RT than surgical alternative. Although anterior commissure involvement has been reported by some to be associated with decreased local control after RT and, thus, is a reason to operate, this has not been our experience. It seems that anterior commissure invasion has no significant effect on local control after RT.

Women are generally thought to have a prognosis as good as or better than men do after treatment for most head and neck cancers. The reasons for this are unclear.

Histologic differentiation has been reported to influence local control after RT. Multivariate analyses of our data indicated that histologic differentiation significantly influenced local control and cause-specific survival. The small subset of patients with poorly differentiated cancers may fare better if treated with more aggressive altered fractionation schedules.

Other parameters that may affect the likelihood of cure include pretreatment hemoglobin,^21,22 Karnofsky performance status, and p53 status.²³ Because data pertaining to these parameters were not available for the vast majority of our patients, these factors were not analyzed. We currently obtain pretreatment complete blood cell counts and record the Karnofsky performance status for all patients with head and neck cancers.

Treatment-related parameters that may influence local-regional control may be altered by the radiation oncologist and include overall treatment time,^19,20,24-31 fraction size,^1,20,32-34 beam energy,^35-38 and the use of elective neck RT.³⁹ Field size has also been reported to influence the likelihood of local control after RT.⁴⁰ However, it is difficult to understand how field size would affect local control so long as the portals are carefully arranged to include the primary cancer and avoid a marginal miss. As has been previously observed, RT works, and it works best if the entire tumor is included in the treatment fields. It is important to analyze treatment-related parameters because they, along with selection bias, explain the variability in local control rates after RT that range from approximately 80% to 95% for patients with T1 cancers, and from 50% to 80% for those with T2 lesions.^1,4,5

Overall treatment time has been shown to be significantly related to the likelihood of local control after RT for a variety of head and neck cancers. Indeed, reduction of overall treatment time to diminish tumor repopulation during the RT course is one of the major features of altered fractionation schedules that have been shown to be superior to conventional once-daily RT.⁴¹ Although the reduction in the probability of local control with a protracted treatment course is probably greatest for locally advanced tumors,⁷ an adverse effect has even been seen in patients with T1 glottic malignancies.

The influence of fraction size on local control is related to overall time. Simply increasing the dose per fraction and treating to the same or slightly lower total dose will necessarily shorten the overall treatment time if the same number of fractions is delivered per week. There is convincing evidence that, for patients treated once-daily 5 days per week, fractionation schedules using doses of 2 Gy per fraction are superior to those using 1.8 Gy per fraction.^32,33

Recent altered fractionation studies using once-daily treatments of 1.8 to 2.0 Gy per fraction, administered 6 or 7 days a week, suggest that it is possible to overcome the adverse effects of a relatively low-dose per fraction by treating more than 5 days a week.^41,42 Given the likely resistance to routine treatment of patients on the weekends in the United States, a more attractive alternative is to either increase the once-daily fraction size or to treat two fractions per day. Sufficient evidence exists to indicate that once-daily schedules of 1.8 Gy per treatment 5 days per week are suboptimal. It has been our practice to treat T1 and T2 vocal cord cancers at 2.25 Gy per fraction once daily or, in most recent years, some patients with T2 lesions with hyperfractionated RT. Although the multivariate analysis of local control in our patients revealed a marginally significant impact of fractionation schedule on this end point, our more aggressive altered fractionation schedules did not clearly result in an improvement, compared with once-daily fractionation at 2.25 Gy per fraction. It is possible that altered fractionation schedules might result in better local control compared with a less aggressive once-daily treatment course using 2-Gy fractions. Our current policy is to treat patients with T2 cancers with once-daily irradiation. Although it might be tempting to add concomitant chemotherapy to the regimen, our bias is that the additional morbidity is not warranted in patients with relatively early-stage disease.

Much of the data pertaining to the use of radiotherapy for early vocal cord cancer is based on patients treated with ⁶⁰Co or 4-MV x-rays. Indeed, the vast majority of patients treated in the present series were treated with ⁶⁰Co, and it remains our beam of choice. However, ⁶⁰Co and 4-MV machines are not available in most radiation therapy departments in the United States. The lowest energy photon beam is usually 6-MV. The concern is that, because the anterior commissure is only approximately 1 cm from the skin of the anterior neck, tumors in this location could be underdosed by a 6-MV x-ray beam. However, a dosimetric evaluation at our institution comparing 6-MV x-rays with ⁶⁰Co revealed no significant difference in the dose received at any point along the vocal cords.³⁸ The only difference was several millimeters below the skin of the anterior neck, where 6-MV X-rays delivered a lower dose than ⁶⁰Co. This would not be an issue for properly staged patients with T1-T2 vocal cord cancers. Tumors in this location would likely be associated with T4 tumors. More important than a dosimetric comparison of 6-MV x-rays and ⁶⁰Co in a phantom are the end results of patients treated with 6-MV beams. All other factors being equal, patients treated with 6-MV x-rays are probably approximately as likely to be cured as those treated with ⁶⁰Co.³⁷

The probability of local control with laryngeal voice preservation in our series compares favorably with surgical series. Voice quality after successful irradiation is probably better than after open partial laryngectomy. However, many patients with early-stage lesions are operated on using transoral laser surgery and have better voice quality compared with those undergoing open partial laryngectomy, depending on how much of the larynx is removed. We are unable to address the issue of voice quality after irradiation in our series because we did not routinely assess this end point before and after treatment.

The likelihood of occult disease in the neck nodes is acknowledged to be nil for patients with T1 glottic cancers.³⁹ However, some authors recommend elective neck RT for some patients with T2 lesions with adverse features, such as impaired vocal cord mobility. Our experience indicates that the likelihood of occult disease in the neck nodes is low for all patients with T2 vocal cord cancers as long as the primary site remains controlled after treatment. Although we have rarely succumbed to a gut feeling and used elective neck RT for a patient with an unfavorable T2 cancer, there are no data to support doing so. On the other hand, if cancer recurs at the primary site, the likelihood of occult disease in the neck nodes is relatively high for patients who initially had T1 as well as T2 cancers, so that salvage laryngectomy should be combined with a neck dissection.³⁹

Radiation therapy alone cures a relatively high (but variable) percentage of patients with T1 and T2 vocal cord cancer. The likelihood of cure is related to both patient-related and treatment-related parameters. The most important of the treatment-related parameters within the constraints of this study seems to be overall treatment time. To offer the patient the best chance of cure and for RT to compete favorably with partial laryngectomy, the treatment-related RT parameters must be optimized.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Mendenhall WM, Parsons JT, Million RR, et al: T1-T2 squamous cell carcinoma of the glottic larynx treated with radiation therapy: Relationship of dose-fractionation factors to local control and complications. Int J Radiat Oncol Biol Phys 15: 1267-1273, 1988[Medline]

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Submitted February 12, 2001; accepted May 23, 2001.

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