Eur Arch Otorhinolaryngol DOI 10.1007/s00405-015-3658-x
HEAD AND NECK
Primary radiotherapy for squamous cell carcinoma of the pyriform sinus William M. Mendenhall1 • Robert J. Amdur1 • Christopher G. Morris1 Jessica Kirwan1 • Peter T. Dziegielewski2 • John W. Werning2
•
Received: 20 February 2015 / Accepted: 18 May 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract The objective of this study is to report the longterm outcomes of primary radiotherapy (RT) for patients with T1–T2 squamous cell carcinomas (SCC) of the pyriform sinus. Between November 1964 and March 2008, 135 patients with T1–T2 pyriform sinus SCC were treated with primary RT at the University of Florida. Adjuvant chemotherapy was employed in 21 patients (16 %) and 62 patients (46 %) underwent a planned neck dissection. Median follow-up was 3.5 years (range 0.2–24.7 years); median follow-up on living patients was 8.3 years (range 3.8–24.0 years). The 5-year outcomes were as follows: local control, 85 %; regional control, 81 %; local–regional control, 71 %; distant metastasis-free survival, 76 %; cause-specific survival, 62 %; and overall survival, 38 %. The 5-year local control rate was 88 % for T1 cancers and 84 % for those with T2 SCCs (p = 0.5429). Sixteen patients (12 %) experienced severe late complications. Primary RT results in a high probability of cure with a relatively modest risk of severe late complications for patients with T1–T2 SCCs of the pyriform sinus. Keywords Primary radiotherapy Head and neck Pyriform sinus Adjuvant chemotherapy Neck dissection
& William M. Mendenhall [email protected] 1
2
Radiation Oncology, University of Florida College of Medicine, 2000 SW Archer Rd., PO Box 100385, Gainesville, FL 32610-0385, USA Otolaryngology, University of Florida College of Medicine, Gainesville, FL, USA
Introduction Squamous cell carcinomas (SCC) of the pyriform sinus are relatively uncommon and frequently found in patients with a long history of tobacco and/or ethanol abuse. A small proportion of patients may have SCCs that are positive for high-risk human papilloma virus (HR-HPV) and have an improved prognosis compared with those who are HRHPV negative [1]. As has been observed with patients who present HR-HPV-positive oropharyngeal SCCs, they tend to be younger and are more likely to be non-smokers [1]. Patients usually present with local-regionally advanced disease and have a poor prognosis and a low probability of laryngeal preservation [2]. A small subset of patients present with T1–T2 SCCs and may be suitable for larynx preservation strategies with either partial laryngopharyngectomy alone or combined with adjuvant radiotherapy (RT) or primary RT alone or combined with adjuvant chemotherapy and/or planned neck dissection [3–19]. Comparing the relative advantages and disadvantages of these two strategies is difficult because T1–T2 cancers are uncommon and because they are often grouped with other hypopharyngeal sites and/or T stages when outcomes are reported [2, 4, 14, 19–23]. The aim of this paper is to update our experience in the treatment of patients with T1– T2 SCCs of the pyriform sinus with primary RT at the University of Florida [24].
Materials and methods Between November 1964 and March 2008, 135 patients with previously untreated T1–T2 N0–N3 M0 SCCs of the pyriform sinus were treated with primary RT at the University of Florida. Patients were staged according to the
123
Eur Arch Otorhinolaryngol
American Joint Committee on Cancer (AJCC) staging system, version 7 [25]. Patients with T2 cancers usually had low volume primary tumors (\6.5 cc) and fully mobile vocal cords. Those with more advanced lesions were usually treated with surgery and are not included in this series. A small subset of patients treated with planned split-course RT between 1969 and 1974 was excluded. The median follow-up was 3.5 years (range, 0.2–24.7 years); the median follow-up on living patients was 8.3 years (range, 3.8–24.0 years). The characteristics of the patent population are depicted in Table 1. The median age was 63 years (range, 43–83 years). One hundred twenty-three patients were treated with conventional RT techniques and 12 patients received intensity-modulated RT (IMRT). Fractionation schedules included the following: once-daily fractionation, 55 patients (41 %); twice-daily fractionation, 67 patients (49 %); and concomitant boost technique, 13 patients (10 %). The median dose in those treated once daily was 6960 cGy (range 5650–7500 cGy). Patients treated twice daily usually received 7440 cGy in 62 fractions. The concomitant boost technique consisted of 7200 cGy in 42 fractions over 30 treatment days [26]. All patients were treated with planned continuous-course RT. Adjuvant chemotherapy was administered to 21 patients (16 %). Induction chemotherapy usually consisted of 2–3 Table 1 Patient population Parameter
No. of patients
Percent
T stage T1
28
21
T2
107
79
N0
28
21
N1
22
16
N2A
11
8
N2B
36
27
N2C
15
11
N3
23
17
N stage
Overall stage I
8
6
II
18
13
III
23
17
IVA
62
46
IVB
24
18
Negative
93
69
Positive
31
23
No data
11
8
Apex involvement
123
cycles of fluorouracil and cisplatin and was administered in 4 patients (3 %). The use of induction chemotherapy was discontinued in approximately 1997. Concomitant chemotherapy, which has often been employed for node positive patients since 1997, usually consisted of weekly cisplatin 30 mg/and was received by 17 patients (13 %). A temporary nasogastric feeding tube was required during RT in 10 patients (7 %); 28 patients (21 %) required a temporary gastrostomy. Planned neck dissection was performed after RT on 62 patients (46 %) and was unilateral in 60 patients (44 %) and bilateral in 2 patients (2 %). Since approximately 1995, the addition of a planned neck dissection has been reserved for node positive patients with an incomplete response to RT based on a 4-week post-RT computed tomography (CT) scan and/or a 3-month post-RT positron emission tomography (PET)-CT scan. Pathologic evidence of residual SCC was detected in 32 of 62 patients (51 %) after RT (Table 2). Planned neck dissection was usually not performed prior to RT. Complications were coded as severe if they required hospitalization, necessitated surgical intervention, or resulted in death [27]. Additionally, patients who required a permanent tracheotomy and/or gastrostomy were coded as having a severe complication. SAS and JMP software were used for statistical analysis (SAS Institute, Cary, NC). The Kaplan–Meier product limit method provided estimates of freedom from selected endpoints. The log-rank test statistic assessed level of statistical significance between strata of selected prognostic factors.
Results Figure 1 depicts event-free survival rates. Time to recurrence Of 135 patients, 53 patients (39 %) developed a local, regional, and/or distant recurrence following treatment. Of the 53 patients with a recurrence, the time to recurrence was within 2 years in 47 patients (89 %), within 3 years in 52 patients (98 %), and within 5 years in 52 patients (98 %). Local control The local control rates at 5 years were as follows: T1, 88 %; T2, 84 %; and overall, 85 % (p = 0.5429). The 5-year ultimate local control rates, including patients successfully salvaged after a local recurrence, were as follows: T1, 92 %; T2, 92 %, and overall, 92 % (p = 0.9401).
Eur Arch Otorhinolaryngol Table 2 Literature review Series/institution
Number of patients
Treatment
Local control interval
Severe complications (%)
Holsinger et al. University of Paris V [16]
30
PLP ± PORT
79.6 % (5 years)
13
Plouin-Gaudin et al. Saint-Luc University [28]
34
PLP ± PORT
90 % (NS)
35
Makeieff et al. Hopital Gui de Chauliac [29]
87
PLP ± PORT
81 % (NS)
8
Chevalier et al. Lille University [9]
48a
PLP ± PORT
98 % (NS)
4
Steiner et al. University of Goettingen [8]
129
PLP ± PORT
82 % for I–II; 69 % for III–IV (5 years)
7
Bataini et al. Curie Institut [30]
62
RT
52 %
11
Nakajima et al. Osaka Medical Center [19]
91
RT
Lateral wall 87 %; Medial wall 82 % (3 years)
6b
Yoshimura et al. Tokyo Medical and Dental University [21]
77c
RT
76 % (5 years)
9
Blanchard et al. Institut Gustave Roussy [18]
107
RT
85 % (5 years)
20d
Mendenhall et al. Present Series
135
RT
85 % (5 years)
12
PLP: partial laryngopharyngectomy, PORT: postoperative radiotherapy, RT: radiotherapy, NS: not stated a
Includes 17 patients with aryepiglottic fold cancers
b
Includes 12 patients with posterior pharyngeal wall cancers (total 103 patients)
c
Includes 12 postcricoid and 15 pharyngeal wall cancers
d
Complications in 249 patients including 107 with T1–T2 cancers
71 % (p \ 0.0001). Seventeen patients had a local recurrence including 4 patients who also had a regional failure. Twelve patients underwent attempted surgical salvage, which was successful in 8 patients. Twenty-two patients had a regional failure, including 4 patients who also had a local recurrence. Eight patients underwent attempted surgical salvage, which was successful in 1 patient. The 5-year ultimate local–regional control rates were as follows: I–II, 92 %; III, 82 %; IVA, 85 %; IVB, 37 %; and overall, 78 % (p \ 0.0001). Distant metastasis-free survival rate Fig. 1 Event-free survival rates at 5 years
Regional control The 5-year regional control rates were as follows: N0, 92 %; N1, 95 %; N2A, 100 %; N2B, 90 %; N2C, 61 %; N3, 39 %; and overall, 81 % (p \ 0.0001). The 5-year ultimate regional control rates were as follows: N0, 92 %; N1, 95 %; N2A, 100 %; N2B, 90 %; N2C, 67 %; N3, 39 %; and overall, 82 % (p \ 0.0001).
The 5-year distant metastasis-free survival rates were as follows: I–II, 96 %; III, 90 %; IVA, 69 %; IVB, 59 %; and overall, 76 % (p = 0.0043). Cause-specific survival The 5-year cause-specific survival rates were as follows: I–II, 86 %; III, 75 %; IVA, 61 %; IVB, 22 %; and overall, 62 % (p \ 0.0001). Overall survival
Local–regional control The 5-year local–regional control rates were as follows: I–II, 87 %; III, 68 %; IVA, 81 %; IVB, 24 %; and overall,
The 5-year overall survival rates were as follows: I–II, 62 %; III, 48 %; IVA, 35 %; IVB, 13 %; and overall, 38 % (p = 0.0005).
123
Eur Arch Otorhinolaryngol
Complications Four patients (3 %) were hospitalized during or shortly after completing RT. Seventeen patients underwent either a salvage neck dissection (5 patients), a salvage partial pharyngectomy (1 patient), or a total laryngectomy combined with a partial or total pharyngectomy alone or combined with a neck dissection (11 patients). Severe postoperative complications occurred in 5 patients (29 %) and included pharyngocutaneous fistula (3 patients), wound breakdown and fatal carotid rupture (1 patient), and fatal myocardial infarction (1 patient). Severe late complications occurred in 16 patients (12 %) and included temporary tracheostomy for laryngeal edema (1 patient), permanent tracheostomy (2 patients), permanent gastrostomy (9 patients), permanent gastrostomy and tracheotomy (2 patients), and laryngopharyngectomy for necrosis (2 patients).
Discussion There are a variety of problems comparing the outcomes of retrospective studies reporting on the efficacy of partial laryngopharyngectomy versus primary RT. Some reporting the outcomes of partial laryngectomy employ a pathologic staging system that results in stage migration, which may lead to artificial improvement in outcomes within a tumor stage. One of the most significant problems is selection bias. Patients with more advanced neck disease are more likely to experience a regional and/or distant recurrence and have a lower probability of survival. For these reasons, the most useful outcomes to compare are local control and severe complications. Holsinger et al. reported on 30 patients who underwent a partial laryngopharyngectomy at the University of Paris V for T1 (16 patients) or T2 (14 patients) pyriform sinus SCC [16]. Preoperative chemotherapy was given to 8 patients and 22 patients received postoperative RT. Three patients (10 %) died postoperatively and one additional patient (3.3 %) experienced a severe complication. The 5-year local control rate was 79.6 %. Plouin-Glaudin et al. reported on 34 patients with SCC of the pyriform sinus who underwent a partial laryngopharyngectomy with or without postoperative RT between 1986 and 2001 at Saint-Luc University Hospital (Brussels, Belgium) [28]. Thirty-one patients had previously untreated T1–T2 cancers; 4 patients were operated for surgical salvage after failing RT. Three patients (8.8 %) died postoperatively and were excluded from the analysis of local–regional control. Nine additional patients (26 %) experienced postoperative infection and fistulae; 2 required
123
surgical intervention. The median follow-up was 45.2 months. Local control was obtained in 90 % of patients; 80 % had local control with larynx preservation. The local–regional control rate at 5 years was 86 %. Makeieff et al. reported on 87 patients with T1 (14 patients) and T2 (73 patients) SCC of the pyriform sinus and laryngeal margin who underwent a supraglottic hemipharyngo-laryngectomy between 1981 and 1998 at the Hopital Gui de Chauliac (Montpellier, France) [29]. Postoperative RT was administered to 80 patients. Two patients (2.3 %) died postoperatively. Five patients (5.7 %) developed complications after completion of postoperative RT including tracheotomy (3 patients) and necrosis (2 patients). Local control was achieved in 81 %. Chevalier et al. reported on 48 patients with SCC of the pyriform sinus (31 patients) and aryepiglottic fold (17 patients) treated with a supraglottic hemilaryngopharyngectomy between 1979 and 1994 at the Lille University Medical Center (Lille, France) [9]. Two patients (4 %) died postoperatively. Postoperative RT was administered to 43 patients (88 %). Local control was obtained in 47 patients (98 %). Steiner et al. reported on 129 patients who underwent transoral CO2 microsurgery for SCC of the pyriform sinus between 1981 and 1996 at the University of Goettingen [8]. Patients were pathologically staged, likely resulting in stage migration. The distribution of pT stage was: pT1, 24 patients; pT2, 74 patients; pT3, 17 patients; and pT4, 14 patients. Postoperative RT was administered to 58 % of patients. The median follow-up was 44 months. Major postoperative complications included bleeding (5 patients; 3.9 %) and laryngeal edema requiring surgery (1 patient; 0.8 %). Late complications were observed in 3 patients (2.3 %) who required a permanent gastronomy for aspiration (2 patients) and stenosis (1 patient). The 5-year local control rates were 82 % for patients with stage I–II SCCs and 69 % for those with III–IV cancers. Bataini et al. reported on 434 patients with SCCs of the pyriform sinus treated with primary RT at the Curie Institut (Paris) between 1958 and 1974; 90 patients had T1–T2 cancer [30]. Sixty-two patients were evaluable at 2 years; the remainder died less than 2 years from RT and were continuously locally controlled. Local control was achieved in 32 patients (52 %) of 62 patients. Eleven (2.5 %) of 434 patients had fatal complications. Of 114 patients alive and disease-free at 3 years, 12 (11 %) had major non-fatal complications. Nakajima et al. reported on 103 patients with T1–T2 SCCs of the pyriform sinus and posterior pharyngeal wall who were treated with primary RT at the Osaka Medical Center between 2000 and 2008 [19]. The median follow-up on living patients was 41 months. The 3-year local control rates for those with SCC of the pyriform sinus were: lateral
Eur Arch Otorhinolaryngol
wall (15 patients), 87 %; and medial wall (76 patients), 82 %, respectively. Six patients developed CGrade 3 late complications. Yoshimura et al. reported on 77 patients with T1–T2 N0 hypopharyngeal SCC treated with primary RT between 1988 and 2007 at the Tokyo Medical and Dental University [21]. Fifty (65 %) of 77 patients had pyriform sinus cancers. The median follow-up was 33 months. The 5-year rate of local control with voice preservation was 76 %. Seven patients (9 %) had CGrade 3 complications; 6 of 7 occurred after salvage surgery. Blanchard et al. reported on 249 patients with SCC of the pyriform sinus treated with primary RT between 1990 and 2006 at the Institut Gustave Roussy (Villejuif, France) [18]. Adjuvant chemotherapy was administered to 153 patients (61 %) and 50 patients (20 %) had a neck dissection prior to RT. The median follow-up was 6.5 years. The 5-year local control rate in those with T1–T2 cancers (107 patients) was 85 %. Moderate to severe late complications were observed in 50 (20 %) of 249 patients.
Conclusion T1–T2 SCC of the pyriform may be treated with either primary RT or partial laryngopharyngectomy. Our bias is to treat patients with primary RT because it likely is associated with fewer severe complications and a substantial proportion of patients, if operated, would require postoperative RT because of neck disease. Patients are treated with altered fractionation using either hyperfractionation (7440 cGy in 62 fractions over 31 treatment days) or simultaneous integrated boost (7000 cGy/35 fractions over 30 treatment days). The former is preferred unless logistical considerations dictate otherwise. Patients with positive nodes receive concomitant weekly cisplatin 30 mg/M2. Patients undergo PET-CT scan 3 months following RT and those with residual regional disease undergo a planned neck dissection. Alternatively, the decision to add a neck dissection is based on a contrast-enhanced CT obtained 4 weeks after completion of RT [4, 31]. Acknowledgments
This study received no financial support.
Conflict of interest
None.
References 1. Joo YH, Lee YS, Cho KJ, Park JO, Nam IC, Kim CS et al (2013) Characteristics and prognostic implications of high-risk HPVassociated hypopharyngeal cancers. PLoS One 8(11):e78718 2. Li XZ, Jin T, Cai XL, Pan XL (2011) Preservation of laryngeal functions in surgical treatment of pyriform sinus carcinoma. Acta Otolaryngol 131(3):316–322
3. Gupta T, Chopra S, Agarwal JP, Laskar SG, D’Cruz AK, Shrivastava SK et al (2009) Squamous cell carcinoma of the hypopharynx: single-institution outcome analysis of a large cohort of patients treated with primary non-surgical approaches. Acta Oncol 48(4):541–548 4. Liauw SL, Mancuso AA, Amdur RJ, Morris CG, Villaret DB, Werning JW et al (2006) Postradiotherapy neck dissection for lymph node-positive head and neck cancer: the use of computed tomography to manage the neck. J Clin Oncol 24(9):1421–1427 5. van Mierlo IJ, Levendag PC, Eijkenboom WM, Jansen PP, Meeuwis CA, van Assendelft PJ et al (1995) Radiation therapy for cancer of the piriform sinus. A failure analysis. Am J Clin Oncol 18(6):502–509 6. Krengli M, Pastore G, Invernizzi A, Pisani P, Negri G (1993) Exclusive radiotherapy of pyriform sinus carcinomas. Retrospective analysis of 90 cases. Radiol Med 85(4):472–475 7. Dubois JB, Guerrier B, Di Ruggiero JM, Pourquier H (1986) Cancer of the piriform sinus: treatment by radiation therapy alone and with surgery. Radiology 160(3):831–836 8. Steiner W, Ambrosch P, Hess CF, Kron M (2001) Organ preservation by transoral laser microsurgery in piriform sinus carcinoma. Otolaryngol Head Neck Surg 124(1):58–67 9. Chevalier D, Watelet JB, Darras JA, Piquet JJ (1997) Supraglottic hemilaryngopharyngectomy plus radiation for the treatment of early lateral margin and pyriform sinus carcinoma. Head Neck 19(1):1–5 10. Spector JG, Sessions DG, Emami B, Simpson J, Haughey B, Harvey J et al (1995) Squamous cell carcinoma of the pyriform sinus: a nonrandomized comparison of therapeutic modalities and long-term results. Laryngoscope. 105(4 Pt 1):397–406 11. Laccourreye H, Lacau St Guily J, Brasnu D, Fabre A, Menard M (1987) Supracricoid hemilaryngopharyngectomy. Analysis of 240 cases. Ann Otol Rhinol Laryngol 96(2 Pt 1):217–221 12. Vandenbrouck C, Eschwege F, De la Rochefordiere A, Sicot H, Mamelle G, Le Ridant AM et al (1987) Squamous cell carcinoma of the pyriform sinus: retrospective study of 351 cases treated at the Institut Gustave-Roussy. Head Neck Surg. 10(1):4–13 13. Ogura JH, Marks JE, Freeman RB (1980) Results of conservation surgery for cancers of the supraglottis and pyriform sinus. Laryngoscope. 90(4):591–600 14. Marks JE, Kurnik B, Powers WE, Ogura JH (1978) Carcinoma of the pyriform sinus. An analysis of treatment results and patterns of failure. Cancer 41(3):1008–1015 15. Iwai H, Koike Y, Nagahara K (1975) Subtotal pharyngolaryngectomy conservation surgery for carcinoma of sinus pyriformis extending toward the larynx. Arch Otorhinolaryngol. 209(4):271–276 16. Holsinger FC, Motamed M, Garcia D, Brasnu D, Menard M, Laccourreye O (2006) Resection of selected invasive squamous cell carcinoma of the pyriform sinus by means of the lateral pharyngotomy approach: the partial lateral pharyngectomy. Head Neck 28(8):705–711 17. Krstevska V. Early stage squamous cell carcinoma of the pyriform sinus: a review of treatment options. Indian J Cancer. 2012;49(2):236-44 18. Blanchard P, Tao Y, Veresezan O, Lusinchi A, Le Ridant AM, Janot F et al (2012) Definitive radiotherapy for squamous cell carcinoma of the pyriform sinus. Radiother Oncol 105(2):232–237 19. Nakajima A, Nishiyama K, Morimoto M, Nakamura S, Suzuki O, Kawaguchi Y et al (2012) Definitive radiotherapy for T1–2 hypopharyngeal cancer: a single-institution experience. Int J Radiat Oncol Biol Phys 82(2):e129–e135 20. Lim YC, Jeong HM, Shin HA, Choi EC (2011) Larynx-preserving partial pharyngectomy via lateral pharyngotomy for the treatment of small (T(1 * 2)) hypopharyngeal squamous cell carcinoma. Clin Exp Otorhinolaryngol 4(1):44–48
123
Eur Arch Otorhinolaryngol 21. Yoshimura R, Kagami Y, Ito Y, Asai M, Mayahara H, Sumi M et al (2010) Outcomes in patients with early-stage hypopharyngeal cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 77(4):1017–1023 22. Nakamura K, Shioyama Y, Kawashima M, Saito Y, Nakamura N, Nakata K et al (2006) Multi-institutional analysis of early squamous cell carcinoma of the hypopharynx treated with radical radiotherapy. Int J Radiat Oncol Biol Phys 65(4):1045–1050 23. Joo YH, Cho KJ, Park JO, Nam IC, Kim MS (2012) Role of larynx-preserving partial hypopharyngectomy with and without postoperative radiotherapy for squamous cell carcinoma of the hypopharynx. Oral Oncol 48(2):168–172 24. Rabbani A, Amdur RJ, Mancuso AA, Werning JW, Kirwan J, Morris CG et al (2008) Definitive radiotherapy for T1–T2 squamous cell carcinoma of pyriform sinus. Int J Radiat Oncol Biol Phys 72(2):351–355 25. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (eds) (2011) American Joint Committee on Cancer. Cancer Staging Manual. Springer, Chicago, IL 26. Mendenhall WM, Riggs CE, Vaysberg M, Amdur RJ, Werning JW (2010) Altered fractionation and adjuvant chemotherapy for head and neck squamous cell carcinoma. Head Neck 32(7):939–945
123
27. Taylor JM, Mendenhall WM, Lavey RS (1992) Dose, time, and fraction size issues for late effects in head and neck cancers. Int J Radiat Oncol Biol Phys 22(1):3–11 28. Plouin-Gaudon I, Lengele B, Desuter G, Rombaux P, Ledeghen S, Gregoire V et al (2004) Conservation laryngeal surgery for selected pyriform sinus cancer. Eur J Surg Oncol 30(10):1123–1130 29. Makeieff M, Mercante G, Jouzdani E, Garrel R, Crampette L, Guerrier B (2004) Supraglottic hemipharyngolaryngectomy for the treatment of T1 and T2 carcinomas of laryngeal margin and piriform sinus. Head Neck 26(8):701–705 30. Bataini P, Brugere J, Bernier J, Jaulerry CH, Picot C, Ghossein NA (1982) Results of radical radiotherapeutic treatment of carcinoma of the pyriform sinus: experience of the Institut Curie. Int J Radiat Oncol Biol Phys 8(8):1277–1286 31. Yeung AR, Liauw SL, Amdur RJ, Mancuso AA, Hinerman RW, Morris CG et al (2008) Lymph node-positive head and neck cancer treated with definitive radiotherapy: can treatment response determine the extent of neck dissection? Cancer 112(5):1076–1082
HEAD AND NECK
Primary radiotherapy for squamous cell carcinoma of the pyriform sinus William M. Mendenhall1 • Robert J. Amdur1 • Christopher G. Morris1 Jessica Kirwan1 • Peter T. Dziegielewski2 • John W. Werning2
•
Received: 20 February 2015 / Accepted: 18 May 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract The objective of this study is to report the longterm outcomes of primary radiotherapy (RT) for patients with T1–T2 squamous cell carcinomas (SCC) of the pyriform sinus. Between November 1964 and March 2008, 135 patients with T1–T2 pyriform sinus SCC were treated with primary RT at the University of Florida. Adjuvant chemotherapy was employed in 21 patients (16 %) and 62 patients (46 %) underwent a planned neck dissection. Median follow-up was 3.5 years (range 0.2–24.7 years); median follow-up on living patients was 8.3 years (range 3.8–24.0 years). The 5-year outcomes were as follows: local control, 85 %; regional control, 81 %; local–regional control, 71 %; distant metastasis-free survival, 76 %; cause-specific survival, 62 %; and overall survival, 38 %. The 5-year local control rate was 88 % for T1 cancers and 84 % for those with T2 SCCs (p = 0.5429). Sixteen patients (12 %) experienced severe late complications. Primary RT results in a high probability of cure with a relatively modest risk of severe late complications for patients with T1–T2 SCCs of the pyriform sinus. Keywords Primary radiotherapy Head and neck Pyriform sinus Adjuvant chemotherapy Neck dissection
& William M. Mendenhall [email protected] 1
2
Radiation Oncology, University of Florida College of Medicine, 2000 SW Archer Rd., PO Box 100385, Gainesville, FL 32610-0385, USA Otolaryngology, University of Florida College of Medicine, Gainesville, FL, USA
Introduction Squamous cell carcinomas (SCC) of the pyriform sinus are relatively uncommon and frequently found in patients with a long history of tobacco and/or ethanol abuse. A small proportion of patients may have SCCs that are positive for high-risk human papilloma virus (HR-HPV) and have an improved prognosis compared with those who are HRHPV negative [1]. As has been observed with patients who present HR-HPV-positive oropharyngeal SCCs, they tend to be younger and are more likely to be non-smokers [1]. Patients usually present with local-regionally advanced disease and have a poor prognosis and a low probability of laryngeal preservation [2]. A small subset of patients present with T1–T2 SCCs and may be suitable for larynx preservation strategies with either partial laryngopharyngectomy alone or combined with adjuvant radiotherapy (RT) or primary RT alone or combined with adjuvant chemotherapy and/or planned neck dissection [3–19]. Comparing the relative advantages and disadvantages of these two strategies is difficult because T1–T2 cancers are uncommon and because they are often grouped with other hypopharyngeal sites and/or T stages when outcomes are reported [2, 4, 14, 19–23]. The aim of this paper is to update our experience in the treatment of patients with T1– T2 SCCs of the pyriform sinus with primary RT at the University of Florida [24].
Materials and methods Between November 1964 and March 2008, 135 patients with previously untreated T1–T2 N0–N3 M0 SCCs of the pyriform sinus were treated with primary RT at the University of Florida. Patients were staged according to the
123
Eur Arch Otorhinolaryngol
American Joint Committee on Cancer (AJCC) staging system, version 7 [25]. Patients with T2 cancers usually had low volume primary tumors (\6.5 cc) and fully mobile vocal cords. Those with more advanced lesions were usually treated with surgery and are not included in this series. A small subset of patients treated with planned split-course RT between 1969 and 1974 was excluded. The median follow-up was 3.5 years (range, 0.2–24.7 years); the median follow-up on living patients was 8.3 years (range, 3.8–24.0 years). The characteristics of the patent population are depicted in Table 1. The median age was 63 years (range, 43–83 years). One hundred twenty-three patients were treated with conventional RT techniques and 12 patients received intensity-modulated RT (IMRT). Fractionation schedules included the following: once-daily fractionation, 55 patients (41 %); twice-daily fractionation, 67 patients (49 %); and concomitant boost technique, 13 patients (10 %). The median dose in those treated once daily was 6960 cGy (range 5650–7500 cGy). Patients treated twice daily usually received 7440 cGy in 62 fractions. The concomitant boost technique consisted of 7200 cGy in 42 fractions over 30 treatment days [26]. All patients were treated with planned continuous-course RT. Adjuvant chemotherapy was administered to 21 patients (16 %). Induction chemotherapy usually consisted of 2–3 Table 1 Patient population Parameter
No. of patients
Percent
T stage T1
28
21
T2
107
79
N0
28
21
N1
22
16
N2A
11
8
N2B
36
27
N2C
15
11
N3
23
17
N stage
Overall stage I
8
6
II
18
13
III
23
17
IVA
62
46
IVB
24
18
Negative
93
69
Positive
31
23
No data
11
8
Apex involvement
123
cycles of fluorouracil and cisplatin and was administered in 4 patients (3 %). The use of induction chemotherapy was discontinued in approximately 1997. Concomitant chemotherapy, which has often been employed for node positive patients since 1997, usually consisted of weekly cisplatin 30 mg/and was received by 17 patients (13 %). A temporary nasogastric feeding tube was required during RT in 10 patients (7 %); 28 patients (21 %) required a temporary gastrostomy. Planned neck dissection was performed after RT on 62 patients (46 %) and was unilateral in 60 patients (44 %) and bilateral in 2 patients (2 %). Since approximately 1995, the addition of a planned neck dissection has been reserved for node positive patients with an incomplete response to RT based on a 4-week post-RT computed tomography (CT) scan and/or a 3-month post-RT positron emission tomography (PET)-CT scan. Pathologic evidence of residual SCC was detected in 32 of 62 patients (51 %) after RT (Table 2). Planned neck dissection was usually not performed prior to RT. Complications were coded as severe if they required hospitalization, necessitated surgical intervention, or resulted in death [27]. Additionally, patients who required a permanent tracheotomy and/or gastrostomy were coded as having a severe complication. SAS and JMP software were used for statistical analysis (SAS Institute, Cary, NC). The Kaplan–Meier product limit method provided estimates of freedom from selected endpoints. The log-rank test statistic assessed level of statistical significance between strata of selected prognostic factors.
Results Figure 1 depicts event-free survival rates. Time to recurrence Of 135 patients, 53 patients (39 %) developed a local, regional, and/or distant recurrence following treatment. Of the 53 patients with a recurrence, the time to recurrence was within 2 years in 47 patients (89 %), within 3 years in 52 patients (98 %), and within 5 years in 52 patients (98 %). Local control The local control rates at 5 years were as follows: T1, 88 %; T2, 84 %; and overall, 85 % (p = 0.5429). The 5-year ultimate local control rates, including patients successfully salvaged after a local recurrence, were as follows: T1, 92 %; T2, 92 %, and overall, 92 % (p = 0.9401).
Eur Arch Otorhinolaryngol Table 2 Literature review Series/institution
Number of patients
Treatment
Local control interval
Severe complications (%)
Holsinger et al. University of Paris V [16]
30
PLP ± PORT
79.6 % (5 years)
13
Plouin-Gaudin et al. Saint-Luc University [28]
34
PLP ± PORT
90 % (NS)
35
Makeieff et al. Hopital Gui de Chauliac [29]
87
PLP ± PORT
81 % (NS)
8
Chevalier et al. Lille University [9]
48a
PLP ± PORT
98 % (NS)
4
Steiner et al. University of Goettingen [8]
129
PLP ± PORT
82 % for I–II; 69 % for III–IV (5 years)
7
Bataini et al. Curie Institut [30]
62
RT
52 %
11
Nakajima et al. Osaka Medical Center [19]
91
RT
Lateral wall 87 %; Medial wall 82 % (3 years)
6b
Yoshimura et al. Tokyo Medical and Dental University [21]
77c
RT
76 % (5 years)
9
Blanchard et al. Institut Gustave Roussy [18]
107
RT
85 % (5 years)
20d
Mendenhall et al. Present Series
135
RT
85 % (5 years)
12
PLP: partial laryngopharyngectomy, PORT: postoperative radiotherapy, RT: radiotherapy, NS: not stated a
Includes 17 patients with aryepiglottic fold cancers
b
Includes 12 patients with posterior pharyngeal wall cancers (total 103 patients)
c
Includes 12 postcricoid and 15 pharyngeal wall cancers
d
Complications in 249 patients including 107 with T1–T2 cancers
71 % (p \ 0.0001). Seventeen patients had a local recurrence including 4 patients who also had a regional failure. Twelve patients underwent attempted surgical salvage, which was successful in 8 patients. Twenty-two patients had a regional failure, including 4 patients who also had a local recurrence. Eight patients underwent attempted surgical salvage, which was successful in 1 patient. The 5-year ultimate local–regional control rates were as follows: I–II, 92 %; III, 82 %; IVA, 85 %; IVB, 37 %; and overall, 78 % (p \ 0.0001). Distant metastasis-free survival rate Fig. 1 Event-free survival rates at 5 years
Regional control The 5-year regional control rates were as follows: N0, 92 %; N1, 95 %; N2A, 100 %; N2B, 90 %; N2C, 61 %; N3, 39 %; and overall, 81 % (p \ 0.0001). The 5-year ultimate regional control rates were as follows: N0, 92 %; N1, 95 %; N2A, 100 %; N2B, 90 %; N2C, 67 %; N3, 39 %; and overall, 82 % (p \ 0.0001).
The 5-year distant metastasis-free survival rates were as follows: I–II, 96 %; III, 90 %; IVA, 69 %; IVB, 59 %; and overall, 76 % (p = 0.0043). Cause-specific survival The 5-year cause-specific survival rates were as follows: I–II, 86 %; III, 75 %; IVA, 61 %; IVB, 22 %; and overall, 62 % (p \ 0.0001). Overall survival
Local–regional control The 5-year local–regional control rates were as follows: I–II, 87 %; III, 68 %; IVA, 81 %; IVB, 24 %; and overall,
The 5-year overall survival rates were as follows: I–II, 62 %; III, 48 %; IVA, 35 %; IVB, 13 %; and overall, 38 % (p = 0.0005).
123
Eur Arch Otorhinolaryngol
Complications Four patients (3 %) were hospitalized during or shortly after completing RT. Seventeen patients underwent either a salvage neck dissection (5 patients), a salvage partial pharyngectomy (1 patient), or a total laryngectomy combined with a partial or total pharyngectomy alone or combined with a neck dissection (11 patients). Severe postoperative complications occurred in 5 patients (29 %) and included pharyngocutaneous fistula (3 patients), wound breakdown and fatal carotid rupture (1 patient), and fatal myocardial infarction (1 patient). Severe late complications occurred in 16 patients (12 %) and included temporary tracheostomy for laryngeal edema (1 patient), permanent tracheostomy (2 patients), permanent gastrostomy (9 patients), permanent gastrostomy and tracheotomy (2 patients), and laryngopharyngectomy for necrosis (2 patients).
Discussion There are a variety of problems comparing the outcomes of retrospective studies reporting on the efficacy of partial laryngopharyngectomy versus primary RT. Some reporting the outcomes of partial laryngectomy employ a pathologic staging system that results in stage migration, which may lead to artificial improvement in outcomes within a tumor stage. One of the most significant problems is selection bias. Patients with more advanced neck disease are more likely to experience a regional and/or distant recurrence and have a lower probability of survival. For these reasons, the most useful outcomes to compare are local control and severe complications. Holsinger et al. reported on 30 patients who underwent a partial laryngopharyngectomy at the University of Paris V for T1 (16 patients) or T2 (14 patients) pyriform sinus SCC [16]. Preoperative chemotherapy was given to 8 patients and 22 patients received postoperative RT. Three patients (10 %) died postoperatively and one additional patient (3.3 %) experienced a severe complication. The 5-year local control rate was 79.6 %. Plouin-Glaudin et al. reported on 34 patients with SCC of the pyriform sinus who underwent a partial laryngopharyngectomy with or without postoperative RT between 1986 and 2001 at Saint-Luc University Hospital (Brussels, Belgium) [28]. Thirty-one patients had previously untreated T1–T2 cancers; 4 patients were operated for surgical salvage after failing RT. Three patients (8.8 %) died postoperatively and were excluded from the analysis of local–regional control. Nine additional patients (26 %) experienced postoperative infection and fistulae; 2 required
123
surgical intervention. The median follow-up was 45.2 months. Local control was obtained in 90 % of patients; 80 % had local control with larynx preservation. The local–regional control rate at 5 years was 86 %. Makeieff et al. reported on 87 patients with T1 (14 patients) and T2 (73 patients) SCC of the pyriform sinus and laryngeal margin who underwent a supraglottic hemipharyngo-laryngectomy between 1981 and 1998 at the Hopital Gui de Chauliac (Montpellier, France) [29]. Postoperative RT was administered to 80 patients. Two patients (2.3 %) died postoperatively. Five patients (5.7 %) developed complications after completion of postoperative RT including tracheotomy (3 patients) and necrosis (2 patients). Local control was achieved in 81 %. Chevalier et al. reported on 48 patients with SCC of the pyriform sinus (31 patients) and aryepiglottic fold (17 patients) treated with a supraglottic hemilaryngopharyngectomy between 1979 and 1994 at the Lille University Medical Center (Lille, France) [9]. Two patients (4 %) died postoperatively. Postoperative RT was administered to 43 patients (88 %). Local control was obtained in 47 patients (98 %). Steiner et al. reported on 129 patients who underwent transoral CO2 microsurgery for SCC of the pyriform sinus between 1981 and 1996 at the University of Goettingen [8]. Patients were pathologically staged, likely resulting in stage migration. The distribution of pT stage was: pT1, 24 patients; pT2, 74 patients; pT3, 17 patients; and pT4, 14 patients. Postoperative RT was administered to 58 % of patients. The median follow-up was 44 months. Major postoperative complications included bleeding (5 patients; 3.9 %) and laryngeal edema requiring surgery (1 patient; 0.8 %). Late complications were observed in 3 patients (2.3 %) who required a permanent gastronomy for aspiration (2 patients) and stenosis (1 patient). The 5-year local control rates were 82 % for patients with stage I–II SCCs and 69 % for those with III–IV cancers. Bataini et al. reported on 434 patients with SCCs of the pyriform sinus treated with primary RT at the Curie Institut (Paris) between 1958 and 1974; 90 patients had T1–T2 cancer [30]. Sixty-two patients were evaluable at 2 years; the remainder died less than 2 years from RT and were continuously locally controlled. Local control was achieved in 32 patients (52 %) of 62 patients. Eleven (2.5 %) of 434 patients had fatal complications. Of 114 patients alive and disease-free at 3 years, 12 (11 %) had major non-fatal complications. Nakajima et al. reported on 103 patients with T1–T2 SCCs of the pyriform sinus and posterior pharyngeal wall who were treated with primary RT at the Osaka Medical Center between 2000 and 2008 [19]. The median follow-up on living patients was 41 months. The 3-year local control rates for those with SCC of the pyriform sinus were: lateral
Eur Arch Otorhinolaryngol
wall (15 patients), 87 %; and medial wall (76 patients), 82 %, respectively. Six patients developed CGrade 3 late complications. Yoshimura et al. reported on 77 patients with T1–T2 N0 hypopharyngeal SCC treated with primary RT between 1988 and 2007 at the Tokyo Medical and Dental University [21]. Fifty (65 %) of 77 patients had pyriform sinus cancers. The median follow-up was 33 months. The 5-year rate of local control with voice preservation was 76 %. Seven patients (9 %) had CGrade 3 complications; 6 of 7 occurred after salvage surgery. Blanchard et al. reported on 249 patients with SCC of the pyriform sinus treated with primary RT between 1990 and 2006 at the Institut Gustave Roussy (Villejuif, France) [18]. Adjuvant chemotherapy was administered to 153 patients (61 %) and 50 patients (20 %) had a neck dissection prior to RT. The median follow-up was 6.5 years. The 5-year local control rate in those with T1–T2 cancers (107 patients) was 85 %. Moderate to severe late complications were observed in 50 (20 %) of 249 patients.
Conclusion T1–T2 SCC of the pyriform may be treated with either primary RT or partial laryngopharyngectomy. Our bias is to treat patients with primary RT because it likely is associated with fewer severe complications and a substantial proportion of patients, if operated, would require postoperative RT because of neck disease. Patients are treated with altered fractionation using either hyperfractionation (7440 cGy in 62 fractions over 31 treatment days) or simultaneous integrated boost (7000 cGy/35 fractions over 30 treatment days). The former is preferred unless logistical considerations dictate otherwise. Patients with positive nodes receive concomitant weekly cisplatin 30 mg/M2. Patients undergo PET-CT scan 3 months following RT and those with residual regional disease undergo a planned neck dissection. Alternatively, the decision to add a neck dissection is based on a contrast-enhanced CT obtained 4 weeks after completion of RT [4, 31]. Acknowledgments
This study received no financial support.
Conflict of interest
None.
References 1. Joo YH, Lee YS, Cho KJ, Park JO, Nam IC, Kim CS et al (2013) Characteristics and prognostic implications of high-risk HPVassociated hypopharyngeal cancers. PLoS One 8(11):e78718 2. Li XZ, Jin T, Cai XL, Pan XL (2011) Preservation of laryngeal functions in surgical treatment of pyriform sinus carcinoma. Acta Otolaryngol 131(3):316–322
3. Gupta T, Chopra S, Agarwal JP, Laskar SG, D’Cruz AK, Shrivastava SK et al (2009) Squamous cell carcinoma of the hypopharynx: single-institution outcome analysis of a large cohort of patients treated with primary non-surgical approaches. Acta Oncol 48(4):541–548 4. Liauw SL, Mancuso AA, Amdur RJ, Morris CG, Villaret DB, Werning JW et al (2006) Postradiotherapy neck dissection for lymph node-positive head and neck cancer: the use of computed tomography to manage the neck. J Clin Oncol 24(9):1421–1427 5. van Mierlo IJ, Levendag PC, Eijkenboom WM, Jansen PP, Meeuwis CA, van Assendelft PJ et al (1995) Radiation therapy for cancer of the piriform sinus. A failure analysis. Am J Clin Oncol 18(6):502–509 6. Krengli M, Pastore G, Invernizzi A, Pisani P, Negri G (1993) Exclusive radiotherapy of pyriform sinus carcinomas. Retrospective analysis of 90 cases. Radiol Med 85(4):472–475 7. Dubois JB, Guerrier B, Di Ruggiero JM, Pourquier H (1986) Cancer of the piriform sinus: treatment by radiation therapy alone and with surgery. Radiology 160(3):831–836 8. Steiner W, Ambrosch P, Hess CF, Kron M (2001) Organ preservation by transoral laser microsurgery in piriform sinus carcinoma. Otolaryngol Head Neck Surg 124(1):58–67 9. Chevalier D, Watelet JB, Darras JA, Piquet JJ (1997) Supraglottic hemilaryngopharyngectomy plus radiation for the treatment of early lateral margin and pyriform sinus carcinoma. Head Neck 19(1):1–5 10. Spector JG, Sessions DG, Emami B, Simpson J, Haughey B, Harvey J et al (1995) Squamous cell carcinoma of the pyriform sinus: a nonrandomized comparison of therapeutic modalities and long-term results. Laryngoscope. 105(4 Pt 1):397–406 11. Laccourreye H, Lacau St Guily J, Brasnu D, Fabre A, Menard M (1987) Supracricoid hemilaryngopharyngectomy. Analysis of 240 cases. Ann Otol Rhinol Laryngol 96(2 Pt 1):217–221 12. Vandenbrouck C, Eschwege F, De la Rochefordiere A, Sicot H, Mamelle G, Le Ridant AM et al (1987) Squamous cell carcinoma of the pyriform sinus: retrospective study of 351 cases treated at the Institut Gustave-Roussy. Head Neck Surg. 10(1):4–13 13. Ogura JH, Marks JE, Freeman RB (1980) Results of conservation surgery for cancers of the supraglottis and pyriform sinus. Laryngoscope. 90(4):591–600 14. Marks JE, Kurnik B, Powers WE, Ogura JH (1978) Carcinoma of the pyriform sinus. An analysis of treatment results and patterns of failure. Cancer 41(3):1008–1015 15. Iwai H, Koike Y, Nagahara K (1975) Subtotal pharyngolaryngectomy conservation surgery for carcinoma of sinus pyriformis extending toward the larynx. Arch Otorhinolaryngol. 209(4):271–276 16. Holsinger FC, Motamed M, Garcia D, Brasnu D, Menard M, Laccourreye O (2006) Resection of selected invasive squamous cell carcinoma of the pyriform sinus by means of the lateral pharyngotomy approach: the partial lateral pharyngectomy. Head Neck 28(8):705–711 17. Krstevska V. Early stage squamous cell carcinoma of the pyriform sinus: a review of treatment options. Indian J Cancer. 2012;49(2):236-44 18. Blanchard P, Tao Y, Veresezan O, Lusinchi A, Le Ridant AM, Janot F et al (2012) Definitive radiotherapy for squamous cell carcinoma of the pyriform sinus. Radiother Oncol 105(2):232–237 19. Nakajima A, Nishiyama K, Morimoto M, Nakamura S, Suzuki O, Kawaguchi Y et al (2012) Definitive radiotherapy for T1–2 hypopharyngeal cancer: a single-institution experience. Int J Radiat Oncol Biol Phys 82(2):e129–e135 20. Lim YC, Jeong HM, Shin HA, Choi EC (2011) Larynx-preserving partial pharyngectomy via lateral pharyngotomy for the treatment of small (T(1 * 2)) hypopharyngeal squamous cell carcinoma. Clin Exp Otorhinolaryngol 4(1):44–48
123
Eur Arch Otorhinolaryngol 21. Yoshimura R, Kagami Y, Ito Y, Asai M, Mayahara H, Sumi M et al (2010) Outcomes in patients with early-stage hypopharyngeal cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 77(4):1017–1023 22. Nakamura K, Shioyama Y, Kawashima M, Saito Y, Nakamura N, Nakata K et al (2006) Multi-institutional analysis of early squamous cell carcinoma of the hypopharynx treated with radical radiotherapy. Int J Radiat Oncol Biol Phys 65(4):1045–1050 23. Joo YH, Cho KJ, Park JO, Nam IC, Kim MS (2012) Role of larynx-preserving partial hypopharyngectomy with and without postoperative radiotherapy for squamous cell carcinoma of the hypopharynx. Oral Oncol 48(2):168–172 24. Rabbani A, Amdur RJ, Mancuso AA, Werning JW, Kirwan J, Morris CG et al (2008) Definitive radiotherapy for T1–T2 squamous cell carcinoma of pyriform sinus. Int J Radiat Oncol Biol Phys 72(2):351–355 25. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (eds) (2011) American Joint Committee on Cancer. Cancer Staging Manual. Springer, Chicago, IL 26. Mendenhall WM, Riggs CE, Vaysberg M, Amdur RJ, Werning JW (2010) Altered fractionation and adjuvant chemotherapy for head and neck squamous cell carcinoma. Head Neck 32(7):939–945
123
27. Taylor JM, Mendenhall WM, Lavey RS (1992) Dose, time, and fraction size issues for late effects in head and neck cancers. Int J Radiat Oncol Biol Phys 22(1):3–11 28. Plouin-Gaudon I, Lengele B, Desuter G, Rombaux P, Ledeghen S, Gregoire V et al (2004) Conservation laryngeal surgery for selected pyriform sinus cancer. Eur J Surg Oncol 30(10):1123–1130 29. Makeieff M, Mercante G, Jouzdani E, Garrel R, Crampette L, Guerrier B (2004) Supraglottic hemipharyngolaryngectomy for the treatment of T1 and T2 carcinomas of laryngeal margin and piriform sinus. Head Neck 26(8):701–705 30. Bataini P, Brugere J, Bernier J, Jaulerry CH, Picot C, Ghossein NA (1982) Results of radical radiotherapeutic treatment of carcinoma of the pyriform sinus: experience of the Institut Curie. Int J Radiat Oncol Biol Phys 8(8):1277–1286 31. Yeung AR, Liauw SL, Amdur RJ, Mancuso AA, Hinerman RW, Morris CG et al (2008) Lymph node-positive head and neck cancer treated with definitive radiotherapy: can treatment response determine the extent of neck dissection? Cancer 112(5):1076–1082
