Radiotherapy with or without chemotherapy for patients with T1-T2 glottic carcinoma: retrospective analysis
- Naoki Hirasawa†1Email author,
- Yoshiyuki Itoh†1,
- Shunichi Ishihara1,
- Seiji Kubota1,
- Junji Itoh1,
- Yasushi Fujimoto2,
- Tsutomu Nakashima2 and
- Shinji Naganawa1
© Hirasawa et al; licensee BioMed Central Ltd. 2010
Received: 6 July 2010
Accepted: 30 July 2010
Published: 30 July 2010
To assess the results for local control (LC) and survival in patients with early-stage glottic cancer (GC) who were treated by radiotherapy (RT) with or without chemotherapy.
Fifty-eight patients with T1-T2 squamous cell carcinoma of the glottis who were treated between 2001 and 2006 were analyzed retrospectively. Potential prognostic factors for LC were evaluated by univariate analysis.
The 5-year LC rate in all patients was 84.3%. The overall 5-year LC rates for patients with T1a, Tb, and T2 GC were 85.9%, 83%, and 85%, respectively. Of the 58 patients, eight developed recurrent disease at the primary site, and one had lymph node recurrences on the neck. In the final analysis, the total laryngectomy-free survival rate was 93% at five years, and the ultimate LC rates for T1a, Tb, and T2 were 100%, 90.9%, and 95.2%, respectively. In a univariate analysis of 55 patients, there was no statistical significance between the LC rate for RT alone and that for chemoradiation. Only two patients died of laryngeal carcinoma, and one died of intercurrent disease. Fifty-five patients were living disease-free at the end of the study period. The 5-year overall survival (OS) rate for all patients was 88.1%, and the 5-year OS rates for T1a, Tb, and T2 were 91.6%, 77.8%, and 89.9%, respectively.
The retrospective analysis showed a high rate of LC and larynx preservation in patients with T1-T2 GC by means of RT with or without chemotherapy. There was, however, no statistical difference in LC rates for the two types of therapy.
Glottic carcinoma (GC), the most common laryngeal cancer, and is usually detected early because of the symptomatic occurrence of hoarse voice. The recommended strategies for early GC with the intent of larynx preservation are radiation therapy (RT), transoral laser therapy, and partial laryngectomy [1, 2].
RT is the preferred therapeutic method in early GC. The advantages of RT in terms of preservation of the structure and function of the larynx have been documented extensively, and RT currently is the initial treatment of choice in most institutions, with surgery being reserved as a salvage option for local failure. For T1 GC, the LC rate for RT alone has been reported to be about 80-90% [3–8], whereas for T2 GC, the LC rate has been about 65-80% [4, 5, 7, 8]. Based on our previously reported data for 1990-1997, the LC rate of T2 GC by RT alone was 65% at our institute.
The purpose of this study was to review retrospectively our experience in the treatment of T1 and T2 GC through RT with or without chemotherapy from 2001 to 2006.
Total no. of patients
Age median (range)
64 y.o. (44-92)
Performance status (ECOG)
squamous cell carcinoma
Chemotherapy and these regimen
Low dose CDDP
Low dose CDDP/5FU
High dose CDDP/5FU
In three patients treated with chemoradiotherapy (two cases) or RT alone (one case), tumor responses were very poor. For these patients, treatments were discontinued at 18 Gy, 36 Gy, and 52 Gy, and partial laryngectomies were performed.
In our basic concept, the regimens of a low dose of CDDP, Carboplatin, UFT, or a low dose of CDDP/5-FU were mainly used for bulky T1 and T2 tumor, on the other hand, the regimens of a high dose of CDDP or alternative CDDP/5-FU were used for unfavorable T2 tumor (maybe, near T3).
LC and total laryngectomy-free survival were assessed from the beginning of RT until evidence of recurrence or until laryngectomy. Survival curves were calculated using the method of Kaplan and Meier, and log-rank tests were used to define the statistical significance of the observed differences in survival and LC based on univariate analysis. The results were considered statistically significant at the level of P < 0.05. In the univariate analysis, the variables analyzed included age (63 > vs. ≤ 63), T category (T1 vs. T2), overall treatment time (> 49 vs. ≤ 49), and chemotherapy (combined. vs. not combined).
After RT alone or combined with chemotherapy, the patients were evaluated at 1-month intervals for the first year, at 2-month intervals during the second year, every 3 months during the third year, every 4 months during the fourth year, and every 6 months thereafter. The patients who presented with recurrence of disease in the follow-up time submitted to salvage treatment by total or partial laryngectomy. The interval time between these events was recorded.
Local control and patterns of failure
For all 58 patients, the 5-year LC rate was 84.3%. The 5-year LC rates for T1a, Tb, and T2 were 85.9%, 83%, and 85%, respectively. The difference between the sub-stage LC rates was not statistically significant.
Local control rate and survival according to the T stage
5-year local control rates without surgery
5-year local control rates after surgery
5-year Overall survival
5-year Cause-specific survival
Overall survival (OS) and cause-specific survival (CSS) rates
The 5-year OS rate for all patients was 88.1%, and the 5-year OS rates for T1a, Tb, and T2 were 91.6%, 77.8%, and 89.9% respectively. The 5-year CSS rate in the 58 patients was 95.8%, and the 5-year CSS rates for T1a, Tb, and T2 were 100%, 87.5%, and 95.2%, respectively (Table 4).
Univariate Analysis (in 55 patients)
5-year local control rate(%)
T1N0 (n = 36)
T2N0 (n = 19)
Overall treatment times
> 49 days (n = 27)
≤ 49 days (n = 28)
combined (n = 17)
none (n = 38)
> 63 y.o. (n = 27)
≤ 63 y.o. (n = 28)
There were no severe acute complications. No late complications such as chondronecrosis were seen, and no patients required hospitalization due to complications.
Second primary cancers
Incidence of secondary primary cancers in this study
The goals of treatment for early GC include cure and laryngeal voice preservation.
In this study, the 5-year LC rate for all patients was 84.3%, and the 5-year LC rates for T1a, Tb, and T2 were 85.9%, 83%, and 85%, respectively. The difference between the sub-stage LC rates was not statistically significant. These results are favorable. In particular, the outcome of LC for T2 GC was better than our previous results (1990-1997) as mentioned in introduction, however, in the univariate analysis for combined chemotherapy for LC, the difference had no statistical significance (p = 0.52). The 5-year LC rate with chemoradiation was 93.7% (Table 5).
According to recently published guidelines [1, 2] for head and neck cancer treatment, all patients with T1-T2 laryngeal cancer should be treated, at least initially, with the intent of larynx preservation. Chemoradiotherapy is not recommended for early GC. However, several analyses of the risk of local failure after RT for early GC have shown the probability of success to be closely related to the volume or bulk of the lesion [9–11]. Moreover, recent studies have shown an improvement in LC for patients with T1 and T2 GC when total radiation is delivered in a shorter overall treatment time with a high-dose fractionation [4, 12] or hyperfractionation schedule [13–15]. Therefore, we treated several cases on a hyperfractionation schedule during the early period of this analysis.
Therefore, we conducted chemoradiation for bulky T1 and T2 GC with the intent to improve LC. The 5-year LC rate with chemoradiation was 93.7%. The result was favorable, but the difference had no statistical significance.
Our study had several limitations. First, we were unable to determine the best combination of therapies using anticancer drugs because this study was not prospective and various chemotherapy regimens were used at different times. Second, therapies of three patients were discontinued due to poor responses, and these cases were counted as recurrences in the statistical analyses. Two patients, one with a bulky T1b tumor and the other with an unfavorable T2 tumor, responded poorly in spite of chemoradiation with low-dose CDDP and 5-FU. Perhaps bulky tumors and unfavorable T2 tumors require more intensive and powerful anticancer drugs. Because many regimens of chemotherapy were used in the cases presented in this study, consideration must be made of the choice of anticancer drugs, and a prospective trial must be conducted in which chemoradiation is used on an optimal dosing schedule for T1 bulky or T2 GC. A phase II study of chemoradiotherapy with S-1(per oral anti-cancer drug) for T2GC is currently underway.
Many recent studies have suggested novel markers of radiosensitivity, such as DNA ploidy , expression of epidermal growth factor , p53 [22, 23], Bcl-2 , and microvessel density . Regarding microvessel density, the biological effects of ionizing radiation are critically dependent on the existence of oxygen in tissues, which may be another reason for the poor responses. The cases of poor response are considered to involve radioresistant tumors, said to account for 6-30% of all tumors . If poor responses to radiotherapy with or without chemotherapy can be predicted, surgery or another procedure may be selected.
In the present study, a second malignancy occurred in more than 20% of the cases, 75% of which were in the upper aerodigestive tract. Additionally, the prognoses for patients with a second malignancy were poorer than those of patients with a single malignancy, though the difference was not statistically significant.
By means of radiotherapy with or without chemotherapy, we achieved a high rate of LC in patients with T1-T2 GC. Although the combination therapy yielded the most favorable results, there was no statistical difference in the LC rates.
- Laryngeal Cancer Treatment. PDQ® - NCI's Comprehensive Cancer Database. [http://www.cancer.gov/cancertopics/pdq/treatment/laryngeal/healthprofessional]
- Pfister DG, Laurie SA, Weinstein GS, Mendenhall WM, Adelstein DJ, Ang KK, Clayman GL, Fisher SG, Forastiere AA, Harrison LB, et al: American Society of Clinical Oncology clinical practice guideline for the use of larynx-preservation strategies in the treatment of laryngeal cancer. J Clin Oncol. 2006, 24: 3693-3704. 10.1200/JCO.2006.07.4559.View ArticlePubMedGoogle Scholar
- Jin J, Liao Z, Gao L, Huang X, Xu G: Analysis of prognostic factors for T(1)N(0)M(0) glottic cancer treated with definitive radiotherapy alone: experience of the cancer hospital of Peking Union Medical College and the Chinese Academy Of Medical Sciences. Int J Radiat Oncol Biol Phys. 2002, 54: 471-478. 10.1016/S0360-3016(02)03493-4.View ArticlePubMedGoogle Scholar
- Mendenhall WM, Amdur RJ, Morris CG, Hinerman RW: T1-T2N0 squamous cell carcinoma of the glottic larynx treated with radiation therapy. J Clin Oncol. 2001, 19: 4029-4036.PubMedGoogle Scholar
- Dinshaw KA, Sharma V, Agarwal JP, Ghosh S, Havaldar R: Radiation therapy in T1-T2 glottic carcinoma: influence of various treatment parameters on local control/complications. Int J Radiat Oncol Biol Phys. 2000, 48: 723-735. 10.1016/S0360-3016(00)00635-0.View ArticlePubMedGoogle Scholar
- Cellai E, Frata P, Magrini SM, Paiar F, Barca R, Fondelli S, Polli C, Livi L, Bonetti B, Vitali E, et al: Radical radiotherapy for early glottic cancer: Results in a series of 1087 patients from two Italian radiation oncology centers. I. The case of T1N0 disease. Int J Radiat Oncol Biol Phys. 2005, 63: 1378-1386. 10.1016/j.ijrobp.2005.05.018.View ArticlePubMedGoogle Scholar
- Frata P, Cellai E, Magrini SM, Bonetti B, Vitali E, Tonoli S, Buglione M, Paiar F, Barca R, Fondelli S, et al: Radical radiotherapy for early glottic cancer: Results in a series of 1087 patients from two Italian radiation oncology centers. II. The case of T2N0 disease. Int J Radiat Oncol Biol Phys. 2005, 63: 1387-1394. 10.1016/j.ijrobp.2005.05.013.View ArticlePubMedGoogle Scholar
- Mendenhall WM, Hinerman RW, Amdur RJ, Mancuso AA, Villaret DB, Werning JW: Larynx. Perez and Brady's Principles and Practice of Radiation Oncology. Edited by: Halperin EC, Perez CA, Brady LW. 2007, Philadelphia: Lippincott Williams & Wilkins, 975-995. 5Google Scholar
- Reddy SP, Mohideen N, Marra S, Marks JE: Effect of tumor bulk on local control and survival of patients with T1 glottic cancer. Radiother Oncol. 1998, 47: 161-166. 10.1016/S0167-8140(97)00196-5.View ArticlePubMedGoogle Scholar
- Reddy SP, Hong RL, Nagda S, Emami B: Effect of tumor bulk on local control and survival of patients with T1 glottic cancer: a 30-year experience. Int J Radiat Oncol Biol Phys. 2007, 69: 1389-1394. 10.1016/j.ijrobp.2007.05.077.View ArticlePubMedGoogle Scholar
- Karim AB, Kralendonk JH, Yap LY, Njo KH, Tierie AH, Tiwari RM, Snow GB, Gerritsen GJ, Hasman A: Heterogeneity of stage II glottic carcinoma and its therapeutic implications. Int J Radiat Oncol Biol Phys. 1987, 13: 313-317. 10.1016/0360-3016(87)90004-6.View ArticlePubMedGoogle Scholar
- Yamazaki H, Nishiyama K, Tanaka E, Koizumi M, Chatani M: Radiotherapy for early glottic carcinoma (T1N0M0): results of prospective randomized study of radiation fraction size and overall treatment time. Int J Radiat Oncol Biol Phys. 2006, 64: 77-82. 10.1016/j.ijrobp.2005.06.014.View ArticlePubMedGoogle Scholar
- Haugen H, Johansson KA, Mercke C: Hyperfractionated-accelerated or conventionally fractionated radiotherapy for early glottic cancer. Int J Radiat Oncol Biol Phys. 2002, 52: 109-119. 10.1016/S0360-3016(01)01812-0.View ArticlePubMedGoogle Scholar
- Garden AS, Forster K, Wong PF, Morrison WH, Schechter NR, Ang KK: Results of radiotherapy for T2N0 glottic carcinoma: does the "2" stand for twice-daily treatment?. Int J Radiat Oncol Biol Phys. 2003, 55: 322-328. 10.1016/S0360-3016(02)03938-X.View ArticlePubMedGoogle Scholar
- Trotti A, Pajak T, Emami B, Hammond E, Jones C, Morrison W, Sagar S, Ridge J, Fu KK, Ang K: A Randomized Trial of Hyperfractionation Versus Standard Fractionation In T2 Squamous Cell Carcinoma of The Vocal Cord. Int J Radiat Oncol Biol Phys. 2006, 66: S15-View ArticleGoogle Scholar
- Akimoto T, Nonaka T, Kitamoto Y, Ishikawa H, Ninomiya H, Chikamatsu K, Furuya N, Hayakawa K, Mitsuhashi N, Nakano T: Radiation therapy for T2N0 laryngeal cancer: A retrospective analysis for the impact of concurrent chemotherapy on local control. Int J Radiat Oncol Biol Phys. 2006, 64: 995-1001. 10.1016/j.ijrobp.2005.10.003.View ArticlePubMedGoogle Scholar
- Itoh Y, Fuwa N: Retrospective analysis: concurrent chemoradiotherapy using protracted continuous infusion of low-dose cisplatin and 5-fluorouracil for T2N0 glottic cancer. Radiat Med. 2006, 24: 277-281. 10.1007/s11604-005-1517-1.View ArticlePubMedGoogle Scholar
- Kumamoto Y, Masuda M, Kuratomi Y, Toh S, Shinokuma A, Chujo K, Yamamoto T, Komiyama S: "FAR" chemoradiotherapy improves laryngeal preservation rates in patients with T2N0 glottic carcinoma. Head Neck. 2002, 24: 637-642. 10.1002/hed.10114.View ArticlePubMedGoogle Scholar
- Tsuji H, Kiba T, Nagata M, Inoue T, Yukawa H, Yamashita T, Shimode Y, Murata H, Nagata K, Tomoda K: A phase I study of concurrent chemoradiotherapy with S-1 for T2N0 glottic carcinoma. Oncology. 2006, 71: 369-373. 10.1159/000108385.View ArticlePubMedGoogle Scholar
- Niibe Y, Nakayama M, Matsubayashi T, Takahashi H, Kitano M, Okamoto M, Hayakawa K: Effectiveness of concurrent radiation therapy with UFT or TS-1 for T2N0 glottic cancer in Japan. Anticancer Res. 2007, 27: 3497-3500.PubMedGoogle Scholar
- Ii N, Fuwa N, Ando M, Itoh Y, Nomoto Y, Takeda K: DNA ploidy analysis performed prospectively using fresh tumor samples in early glottic carcinoma treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2002, 52: 415-419. 10.1016/S0360-3016(01)02612-8.View ArticlePubMedGoogle Scholar
- Ahmed WA, Suzuki K, Imaeda Y, Horibe Y: Ki-67, p53 and epidermal growth factor receptor expression in early glottic cancer involving the anterior commissure treated with radiotherapy. Auris Nasus Larynx. 2008, 35: 213-219.View ArticlePubMedGoogle Scholar
- Narayana A, Vaughan AT, Kathuria S, Fisher SG, Walter SA, Reddy SP: P53 overexpression is associated with bulky tumor and poor local control in T1 glottic cancer. Int J Radiat Oncol Biol Phys. 2000, 46: 21-26. 10.1016/S0360-3016(99)00348-X.View ArticlePubMedGoogle Scholar
- Condon LT, Ashman JN, Ell SR, Stafford ND, Greenman J, Cawkwell L: Overexpression of Bcl-2 in squamous cell carcinoma of the larynx: a marker of radioresistance. Int J Cancer. 2002, 100: 472-475. 10.1002/ijc.10503.View ArticlePubMedGoogle Scholar
- Zhang S, Hayashi R, Fujii M, Hasegawa Y, Yoshino K, Fukayama M, Ochiai A: Total microvessel perimeter per tumor area is a predictor of radiosensitivity in early-stage glottic carcinoma. Int J Radiat Oncol Biol Phys. 2009, 73: 1104-1109. 10.1016/j.ijrobp.2008.05.038.View ArticlePubMedGoogle Scholar
- Fujita M, Rudoltz MS, Canady DJ, Patel P, Machtay M, Pittard MQ, Mohiuddin M, Regine WF: Second malignant neoplasia in patients with T1 glottic cancer treated with radiation. Laryngoscope. 1998, 108: 1853-1855. 10.1097/00005537-199812000-00016.View ArticlePubMedGoogle Scholar
- Franchin G, Minatel E, Gobitti C, Talamini R, Vaccher E, Sartor G, Politi D, Trovo MG, Barzan L: Radiotherapy for patients with early-stage glottic carcinoma: univariate and multivariate analyses in a group of consecutive, unselected patients. Cancer. 2003, 98: 765-772. 10.1002/cncr.11575.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.