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Concurrent chemoradiation for locally advanced oropharyngeal cancer
American Journal of Otolaryngology–Head and Neck Medicine and Surgery 28 (2007) 3 – 8 www.elsevier.com/locate/amjoto
Original contributions
Concurrent chemoradiation for locally advanced oropharyngeal cancer Nam P. Nguyen, MDa,b,4, Paul Vos, PhDd, Herbert J. Smith, MDc, Phuc D. Nguyen, MDa,b, Alan Alfieri, PhDe, Ulf Karlsson, MD, PhDf, Suresh Dutta, MDg, Claire Lemanski, MDh, Ly M. Nguyen, BSi, Sabah Sallah, MDj a
Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA b Radiation Oncology, VA North Texas Health Care System, Dallas, TX, USA c Radiology, VA North Texas Health Care System, Dallas, TX, USA d Department of Biostatistics, East Carolina University, Greenville, NC, USA e Department of Radiation Oncology, Albert Einstein College of Medicine, New York, NY, USA f Department of Radiation Oncology, East Carolina University, Greenville, NC, USA g Department of Radiation Oncology, University of Southern California, Los Angeles, CA, USA h Department of Radiation Oncology, Centre Val D’Aurelle, Montpellier, France i School of Public Health, University of Michigan, Ann Arbor, MI, USA j Novo Nordisk, Division of Hematology/Oncology Research, Athens, Greece
Abstract
Purpose: The aim of this study was to assess the survival, pattern of failure, morbidity, and prognostic factors of concurrent chemoradiation for locally advanced oropharyngeal cancer. Materials and methods: A retrospective survey of patients who underwent chemotherapy and radiation for locally advanced oropharyngeal carcinoma at the Veteran Affairs North Texas Health Care System, Dallas, Tex. Results: Between December 1999 and September 2004, 48 patients with locally advanced oropharyngeal cancer underwent concurrent chemotherapy and radiation. At a median follow-up of 23 months, the 3- and 5-year survival for the whole group were, respectively, 52% and 41%. Seventeen patients (35%) developed recurrences. There were 12 (25%) locoregional failures (6 local failures alone and 6 local and regional failures). Distant metastases developed in 8 patients (5 alone, 3 associated with locoregional failures). Four patients (8%) developed second primaries. No difference was observed in survival between base of tongue and tonsillar carcinoma ( P = .32). The 5-year survival for T1-T2 and T3-T4 tumors was, respectively, 84% and 27% ( P = .01). No patient with T1-T2 tumors developed distant metastases ( P = .04). Forty-five patients (94%) developed toxicity grade 3 to 4 (40 mucositis and 26 hematological). The median weight loss was 18 lb (range, 0–47 lb). Eight patients (16%) developed aspiration pneumonia during and after treatment. Five patients (10%) died of aspiration (2 during and 3 post treatment). Four patients (8%) developed esophageal strictures requiring repeated dilatations post treatment. Two patients had radionecrosis (1 soft tissue and 1 bone) requiring hyperbaric oxygen. Eighteen patients (37%) had prolonged tube feedings ( N 3 months) after treatments because of severe dysphagia or aspiration. Conclusion: Concurrent chemoradiation provided good locoregional control for locally advanced oropharyngeal carcinoma. Patients with small tumors (T1-T2) had excellent survival. The poor prognosis associated with large tumors may be due to the risk of developing distant metastases. Acute and late toxicities remained significant. Aspiration pneumonia and severe dysphagia were the most prevalent complications of the combined modality approach. D 2007 Elsevier Inc. All rights reserved.
4 Corresponding author. Radiation Oncology Service (111), VA North Texas Health Care System, Dallas, TX 75216, USA. Tel.: +1 214 857 0142; fax: +1 214 857 0145. E-mail address: [email protected] (N.P. Nguyen). 0196-0709/$ – see front matter. D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjoto.2006.03.007
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N.P. Nguyen et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 28 (2007) 3–8
1. Introduction The oropharynx plays a central role in speech and swallowing [1]. Movement of the soft palate modifies the size and shape of the resonating cavities, thereby influencing vowel production. Closure of the soft palate also prevents food regurgitation through the nose. The base of tongue modulates production of vowels and consonants because of its obstruction of the vocal tract. Elevation of the base of tongue forces the bolus into the oropharynx. Tumors arising from the soft palate and base of tongue may impede speech and swallowing especially when they are locally advanced [2]. Management of locally advanced oropharyngeal tumor is also difficult because of the high recurrence rate. Surgery followed by radiation has been the standard of care [3]. However, resection of a large amount of normal tissue to achieve tumor-free margins induces severe speech and swallowing dysfunction that adversely affects patient quality of life [4]. Addition of postoperative radiation compounds the issues because of resulting xerostomia and scarring [5]. As an alternative, concurrent chemoradiation has been introduced for organ preservation and local control. Increased radiation and chemotherapy-induced cell killing from the combined modality may improve local control [6]. However, the radiosensitization effect of chemotherapy may also lead to increased acute toxicity and late complications of the normal tissue attendant with disease [7]. The radiation therapy fields usually cover a large area of head and neck to ensure that tumor bed and regional lymph nodes receive an adequate dose. High radiation dose to the oropharynx may produce irreversible damage to the critical structures necessary for normal deglutition—such as tongue, larynx, and pharyngeal muscles. To investigate these issues, we undertook a retrospective review of patients with locally advanced oropharyngeal cancer who underwent concurrent chemoradiation at Veterans Affairs North Texas Health Care System. 2. Patients and methods 2.1. Patient population Between December 1999 and September 2004, 48 patients with locally advanced oropharyngeal cancer (stage III and IV) underwent concurrent chemotherapy and radiation at Veterans Affairs North Texas Health Care System. Patients were included if they had T1-T4 primary tumor, N1-N3 metastatic neck nodes, Karnofsky performance status higher than 70%, and adequate end-organ function defined as an absolute neutrophil count of more than 1 500/mm3, platelets more than 100 000/mm3, serum creatinine lower than 1.5 normal, serum bilirubin below 35 lmol/L, and normal serum glutamic oxalacetic and pyruvic transaminase. All patients signed an informed consent. Before treatment, the patients underwent dental extraction, nutritional assessment, and placement of a gastrostomy tube for enteral feeding during treatment.
Forty-eight male patients were enrolled in the study and are summarized in Table 1 (patient characteristics). Their ages ranged from 46 to 77 years (median age, 59 years). There were 40 whites and 8 African Americans. The tumors were located at the base of tongue (26), tonsils (19), and soft palate (3). Eleven patients had stage III disease, and 37 had stage IV (27 IVA and 10 IVB). There were 4 T1, 10 T2, 17 T3, and 17 T4. The nodal stages were 13 N0, 4 N1, 22 N2, and 9 N3. The histology was squamous carcinoma. The tumor grades were well differentiated (3), moderately differentiated (23), poorly differentiated (10), and unspecified (12). 2.2. Chemoradiation After enrollment, the patients received 5-fluorouracil 1000 mg/m2 intravenously (continuous infusion on days 1–4 and 21–24) and cisplatin 100 mg/m2 intravenously on days 1 and 21 of radiation. Radiation therapy was delivered on a cobalt unit or a 6-mV linear accelerator using standard technique (2 lateral and 1 supraclavicular field, off cord at 3960–4000 cGy, 180–200 cGy per fraction). The dose to the gross tumor was 6600 to 7200 cGy; lymph nodes at risk for subclinical metastasis received 5000 to 5400 cGy. Patients were evaluated weekly during treatment or more frequently if clinically indicated. Toxicity during treatment was assessed according to the Radiation Therapy Oncology Group toxicity scale. Degree of weight loss and any treatment delays were recorded at the end of treatment.
Table 1 Patient characteristics Characteristics
No. of patients (%)
Patient no. Male Age: 46–77 years (median, 59 years) Race Whites Africans Americans Histology: squamous Grade 1 2 3 Not specified Sites Base of tongue Tonsils Soft palate Stage III 4A 4B T stage 1 2 3 4
48 (100) 48 (100)
Follow–up: 12 to 69 months (median, 24 months).
40 (83) 8 (17) 48 (100) 3 23 10 12
(6) (48) (21) (25)
26 (54) 19 (40) 3 (6) 11 (23) 27 (56) 10 (21) 4 10 17 17
(9) (21) (35) (35)
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After completion of treatment, patients were followed monthly with repeated endoscopy by the ear, nose, and throat service at each visit. Patients were instructed to continue with tube feeding until resolution of the acute mucositis enabled them to resume a normal diet. 2.3. Statistical analysis Statistical analysis was performed using the log-rank test. Differences with values of P b .05 were considered statistically significant. 3. Results 3.1. Tumor control and survival At a median follow-up of 23 months (range, 12–69 months), 17 patients (35%) developed recurrences. There were 12 local recurrences (25%). Of the local recurrences, 6 were isolated and 6 associated with neck recurrence. No patient developed isolated neck recurrences. Eight patients (17%) developed distant metastases (5 alone, 3 associated with local recurrences). The sites of metastases were lungs (6) and lungs and liver (2). Four patients (8%) had second primary tumors (2 lungs, 1 trachea, and 1 thyroid cancer). Median, 3-year, and 5-year actuarial survival for the whole group were, respectively, 36 months, 52%, and 41% (Fig. 1). There was no statistical difference in survival between patients with base of the tongue and tonsillar carcinoma ( P = .32). The median, 3-year, and 5-year actuarial survival for base of tongue and tonsillar carcinoma were 23 and 36 months, 43% and 67%, and 37% and 48%, respectively (Fig. 2). However, for the whole group, there was a statistically significant difference in survival between small and large tumors ( P = .01). The 3-year and 5-year actuarial survival for T1-T2 and T3-T4 tumors were,
Fig. 1. The 3- and 5-year actuarial survival for the whole group of patients were, respectively, 52% and 41%, based on the log-rank test.
Fig. 2. The 3- and 5-year actuarial survival of patients with base of the tongue and tonsillar carcinoma were 43% and 67% and 37% and 48%, respectively, based on the log-rank test ( P = .32).
respectively, 84% and 41% and 84% and 27% (Fig. 3). The distant metastases rate was, respectively, 0% (0/14) and 23% (8/34) for T1-T2 and T3-T4 ( P = .04). Corresponding numbers for local failures were, respectively, 14% (2/14) and 29% (10/34). This difference is not statistically significant ( P = .6). There was no correlation between survival and nodal stage. Median, 3-year, and 5-year actuarial survival for N0-N1 and N2-N3 were, respectively, 32 and 37 months, 43% and 56%, and 32 and 45% ( P = .8).
Fig. 3. The 3- and 5-year actuarial survival for T1-T2 and T3-T4 tumors were, respectively, 84% and 41% and 84% and 27%, based on the log-rank test ( P = .04).
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3.2. Toxicity 3.2.1. Acute toxicity Six patients received only 1 cycle of chemotherapy because of renal failure (3), severe weight loss (1), sepsis (1), and patient refusal (1). The dose of 5-fluorouracil was reduced by 25% in 1 patient because of severe mucositis. Radiation therapy was discontinued in 2 patients at 4860 cGy and 5000 cGy because of death secondary to sepsis (1) and patient refusal to continue treatment (1). Forty-five patients (94%) developed toxicity grade 3 to 4. There were 40 (84%) and 26 (54%) mucositis grade 3 to 4 and hematological toxicity, respectively. The median weight loss was 18 lb (range, 0–47 lb). Eight patients (16%) developed aspiration pneumonia during (5) and after (3) treatment. Five patients (10%) died of aspiration (2 during and 3 post treatment). One patient had urinary tract infection and sepsis. One patient developed acute viral hepatitis. 3.2.2. Late toxicity Four patients (8%) developed esophageal strictures after treatment requiring repeated dilatations. Two patients had radionecrosis (osteo- and soft tissue) requiring hyperbaric oxygen. Eighteen patients (37%) required prolonged tube feedings (N 3 months) because of severe dysphagia or aspiration. 4. Discussion The management of locally advanced oropharyngeal carcinoma remains a challenge. Surgery followed by postoperative radiation has been the standard treatment because of the high recurrence rate [3]. However, surgery of the oropharynx carries significant morbidity. Pauloski et al [4] demonstrated severe speech dysfunction after surgical resection. Conversational understandability was related to the volume of tongue and resected soft palate. Long-term swallowing difficulty was also noted after resection because of abnormal movement of the tongue base and pharyngeal wall [8]. Both speech and swallowing dysfunction were compounded by postoperative radiation because of xerostomia and scarring of the pharyngeal muscles [5]. Anxiety and depression were frequently observed because of the disfiguring effect of surgery [9]. However, despite the aggressive treatment, survival and functional outcome remained poor for advanced lesions [10]. In an attempt to improve the prognosis, concurrent chemoradiation has been introduced, anticipatory of the chemotherapy interactions as a tumor radiosensitizer. The high rate of radiation-induced apoptosis and DNA damage repair inhibition from the combined modality was hypothesized to increase tumor cell killing while allowing organ preservation [11]. Preliminary studies were encouraging because higher rates of local control were observed even for inoperable tumors [12]. However, the acute toxicity of chemotherapy and radiation was significant [13]. Mucositis
grade 3 to 4 occurred frequently, thereby preventing the patient from oral feeding and necessitating long-term dependence on gastrostomy tube feeding. Hematological toxicity was also significant, with neutropenia and anemia. Sepsis and death could result from the treatment. The combined modality also induced long-term damage to the digestive tract. Stasis of the bolus and, in severe cases, aspiration were observed after chemoradiation. Late grade 3 toxicity occurred in up to 24% of the patients with oropharyngeal carcinoma at 3 years after chemoradiation, consisting mainly of chronic dysphagia/aspiration and soft tissue necrosis [14]. Once chronic dysphagia occurred, swallowing rarely came back to normal [15]. Dysphagia had a profound impact on cancer survivors because of anxiety and depression [16]. Most chemoradiation studies have reported the survival of stage III and IV together. The influence of tumor and nodal stage on local control and survival remained relatively unknown. There has also been no analysis of the relationship of tumor anatomical site to survival rate. This prompted us to conduct this retrospective study. We observed a survival rate of 84% at 3 and 5 years for T1 and T2 tumors. This is in agreement with other chemoradiation studies with resectable tumors [14]. However, the 3- and 5-year survival decreased to 41% and 27%, respectively, for T3 and T4 lesions ( P = .01). There was no statistically significant difference in locoregional control between the 2 groups. There were no distant metastasis in the T1-T2 group. However, the distant metastasis rate for T3-T4 lesions was 23% ( P = .04). This difference may indeed account for the differences observed in survival between the 2 groups. Large tumors could be associated with a high rate of occult metastases, which manifested later as the patient achieved locoregional control and lived longer. Our high rate of distant metastases was also in agreement with other studies [10]. This observation may have an important clinical application. Patients with large tumors may benefit from adjuvant chemotherapy after concurrent chemoradiation to decrease the metastasis rate and to improve survival. We observed no statistically significant difference in survival between base of tongue and tonsillar carcinoma. However, because of the small number of patients in each group, no definite conclusions could be made at this time. The acute toxicity in our study was significant; almost all patients developed grade 3 – 4 mucositis and hematological toxicity. Our chemotherapy regimen was similar to the intergroup study, which also reported significant acute toxicity [17]. However, we observed a high rate of aspiration (16%). Of the 8 patients who aspirated, 5 died of aspiration pneumonia. Our patients suffered malnutrition because of the mucositis. Despite tube feedings, the median weight loss was 18 lb. The combination of poor nutrition and immunosuppression from the chemotherapy may have been contributing factors to aspiration pneumonia and death [18]. Aspiration during head and neck chemoradiation may
N.P. Nguyen et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 28 (2007) 3–8
be silent because of the absence of a cough reflex [19]. It may be underrecognized and underreported. We have advocated the use of modified barium swallow as a means to detect early aspiration during treatment [20,21]. The survival rate could be improved, as all patients who aspirated—including the 5 who died—had had complete response of their primary tumor to chemoradiation. After treatment, long-term gastrointestinal toxicity remained high. Thirty-seven percent of our patients became dependent on tube feedings for a prolonged period ( N 3 months). They had severe dysphagia or chronic aspiration. Modified barium swallow may be useful to determine the need for long-term tube feedings and for swallowing therapy. Patients in this study were also at risk for esophageal strictures (8%) that required repeated dilatations. This complication became more prevalent (up to 14%) as the number of long-term cancer-free survivors increased after chemoradiation [22]. Although there were no reported deaths from the esophageal dilatation, it added to the discomfort and altered patient quality of life. We postulate that these long-term gastrointestinal complications, that is, severe dysphagia and chronic aspiration, may result from excessive fibrogenesis after chemoradiation. Abnormalities of the bolus transit, stasis, and aspiration have been reported after chemoradiation [23]. Autocrine hyperstimulation of transforming growth factor b1, a peptide responsible for collagen formation and degradation, has been attributed to radiation-induced fibrosis and atrophy [24,25]. Because hyperactivation of transforming growth factor b from hydroxyl radicals produced by radiation may induce excessive fibrosis responsible for the dysphagia, we postulate that neutralization of these chemoradiation-induced radicals may reduce the occurrence of dysphagia after chemoradiation. In this approach, the thiol compound Amifostine had recently been recognized as a radioprotector in clinical studies. Buntzel et al [26], reported a significant reduction of dysphagia and fibrosis in 313 patients with head and neck cancer who received Amifostine during chemoradiation, as compared with 218 patients who did not have Amifostine. Further studies should be done to confirm this finding. The limitations of our study include the retrospective nature of the study, the small number of patients, and a relatively short follow-up. However, we would like to emphasize the feasibility of concurrent chemoradiation for locoregional control of unresectable tumors. 5. Conclusion Concurrent chemoradiation for oropharyngeal carcinoma provides excellent survival for patient with small tumors. Patients with large tumors are at risk for distant metastases. Adjuvant chemotherapy should be considered for these patients in future prospective studies. Acute and late toxicities remain significant for the combined modality. Patients undergoing chemoradiation are at risk for aspiration
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and severe dysphagia. As such, we advocate modified barium swallow as a useful tool to assess aspiration risk and for patient rehabilitation.
Acknowledgment The authors thank Brenda M. Lewis and Randy Steward for their efforts in the preparation of this article.
References [1] Lauciello FR, Vergo T, Schaff NG, et al. Prosthodontic and speech rehabilitation after partial and complete glossectomy. J Prosthet Dent 1980;43:204 - 11. [2] Pauloski BR, Rademaker AW, Logemann JA, et al. Pretreatment swallowing function in patients with head and neck cancer. Head Neck 2000;22:472 - 82. [3] Tupchong L, Scott CB, Blitzer PH, et al. Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03. Int J Radiat Oncol Biol Phys 1991;20:21 - 8. [4] Pauloski BR, Logemannn JA, Colangelo LA, et al. Surgical variables affecting speech in treated patients with oral and oropharyngeal cancer. Laryngoscope 1998;108:908 - 16. [5] Pauloski BR, Logemann JA. Impact of tongue base and posterior pharyngeal wall biomechanics on pharyngeal clearance in irradiated postsurgical oral and oropharyngeal cancer patients. Head Neck 2000; 22:120 - 31. [6] Nguyen NP, Sallah S. Combined chemotherapy and radiation in the treatment of locally advanced head and neck cancers. In Vivo 2000; 14:35 - 9. [7] Nguyen NP, Sallah S, Karlsson U, et al. Combined chemotherapy and radiation therapy for head and neck malignancies. Cancer 2002; 94:1131 - 41. [8] Pauloski BR, Rademaker AW, Logemann JA, et al. Surgical variables affecting swallowing in patients treated for oral/oropharyngeal cancer. Head Neck 2004;26:625 - 36. [9] Dropkin MJ. Body image and quality of life after head and neck cancer surgery. Cancer Pract 1999;7:309 - 13. [10] Denitis AS, Machtay M, Rosenthal DI, et al. Advanced oropharyngeal carcinoma treated with surgery and radiotherapy: oncologic outcome and functional assessment. Am J Otolaryngol 2001;22:329 - 35. [11] Lawrence TS, Blackstock AW, McGinn C. The mechanism of action of radiosensitization of conventional chemotherapeutic agents. Semin Radiat Oncol 2003;13:13 - 21. [12] Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concurrent chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 1999; 91:2081 - 6. [13] Olmi P, Crispino S, Fallai C, et al. Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy—a multicenter randomized trial. Int J Radiat Oncol Biol Phys 2003;55:78 - 92. [14] Machtay M, Rosenthal DI, Hershock D, et al. Organ preservation therapy using induction plus concurrent chemoradiation for advanced resectable oropharyngeal carcinoma: a University of Pennsylvania Phase II trial. J Clin Oncol 2002;20:3964 - 71. [15] Nguyen NP, Moltz CC, Frank C, et al. Severity and duration of chronic dysphagia following treatment for head and neck cancer. Anticancer Res 2005;25:2929 - 34. [16] Nguyen NP, Frank C, Moltz CC, et al. Impact of dysphagia on quality of life after treatment of head and neck cancer. Int J Radiat Oncol Biol Phys 2005;61:772 - 8.
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[17] Adelstein DJ, Adams GL, Wagner H, et al. An Intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiation in patients with unresectable squamous head and neck cancer. J Clin Oncol 2003;21:92 - 8. [18] Eisbruch A, Lyden T, Bradford CR, et al. Objective assessment of swallowing dysfunction and aspiration after radiation concurrent with chemotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2002;53:23 - 8. [19] Pauloski BR, Rademaker AW, Logemann JA, et al. Swallow function and perception of dysphagia in patients with head and neck cancer. Head Neck 2002;24:555 - 65. [20] Martin-Harris B, Logemann JA, McMahon S, et al. Clinical utility of the modified barium swallow. Dysphagia 2000;15:136 - 41. [21] Kotz T, Abraham S, Beitler JJ, et al. Pharyngeal dysfunction consequent to an organ sparing protocol. Arch Otolaryngol Head Neck Surg 1999;125:480 - 3.
[22] Maguire MD, Peyerson MB, Neal CR, et al. Toxic cure: hyperfractionated radiotherapy with concurrent cisplatin and fluorouracil for stage III and IVA head and neck cancer in the community. Int J Radiat Oncol Biol Phys 2004;58:598 - 704. [23] Kotz T, Abraham S, Beitler JJ, et al. Pharyngeal dysfunction consequent to an organ sparing protocol. Arch Otolaryngol Head Neck Surg 1999;125:480 - 3. [24] Nguyen NP, Antoine JE, Dutta S, et al. Current concept in radiation enteritis and implications for future clinical trials. Cancer 2002;95: 1153 - 63. [25] Heldin CH, Miyazono K, ten Didjke P. TGF-b signaling from cell membrane to nucleus through SMADS proteins. Nature 1997;390: 465 - 71. [26] Buntzel J, Glatzel M, Kuttner K, et al. Amifostine in simultaneous radio-chemotherapy of advanced head and neck cancer. Semin Radiat Oncol 2002;12:4 - 13.
Original contributions
Concurrent chemoradiation for locally advanced oropharyngeal cancer Nam P. Nguyen, MDa,b,4, Paul Vos, PhDd, Herbert J. Smith, MDc, Phuc D. Nguyen, MDa,b, Alan Alfieri, PhDe, Ulf Karlsson, MD, PhDf, Suresh Dutta, MDg, Claire Lemanski, MDh, Ly M. Nguyen, BSi, Sabah Sallah, MDj a
Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA b Radiation Oncology, VA North Texas Health Care System, Dallas, TX, USA c Radiology, VA North Texas Health Care System, Dallas, TX, USA d Department of Biostatistics, East Carolina University, Greenville, NC, USA e Department of Radiation Oncology, Albert Einstein College of Medicine, New York, NY, USA f Department of Radiation Oncology, East Carolina University, Greenville, NC, USA g Department of Radiation Oncology, University of Southern California, Los Angeles, CA, USA h Department of Radiation Oncology, Centre Val D’Aurelle, Montpellier, France i School of Public Health, University of Michigan, Ann Arbor, MI, USA j Novo Nordisk, Division of Hematology/Oncology Research, Athens, Greece
Abstract
Purpose: The aim of this study was to assess the survival, pattern of failure, morbidity, and prognostic factors of concurrent chemoradiation for locally advanced oropharyngeal cancer. Materials and methods: A retrospective survey of patients who underwent chemotherapy and radiation for locally advanced oropharyngeal carcinoma at the Veteran Affairs North Texas Health Care System, Dallas, Tex. Results: Between December 1999 and September 2004, 48 patients with locally advanced oropharyngeal cancer underwent concurrent chemotherapy and radiation. At a median follow-up of 23 months, the 3- and 5-year survival for the whole group were, respectively, 52% and 41%. Seventeen patients (35%) developed recurrences. There were 12 (25%) locoregional failures (6 local failures alone and 6 local and regional failures). Distant metastases developed in 8 patients (5 alone, 3 associated with locoregional failures). Four patients (8%) developed second primaries. No difference was observed in survival between base of tongue and tonsillar carcinoma ( P = .32). The 5-year survival for T1-T2 and T3-T4 tumors was, respectively, 84% and 27% ( P = .01). No patient with T1-T2 tumors developed distant metastases ( P = .04). Forty-five patients (94%) developed toxicity grade 3 to 4 (40 mucositis and 26 hematological). The median weight loss was 18 lb (range, 0–47 lb). Eight patients (16%) developed aspiration pneumonia during and after treatment. Five patients (10%) died of aspiration (2 during and 3 post treatment). Four patients (8%) developed esophageal strictures requiring repeated dilatations post treatment. Two patients had radionecrosis (1 soft tissue and 1 bone) requiring hyperbaric oxygen. Eighteen patients (37%) had prolonged tube feedings ( N 3 months) after treatments because of severe dysphagia or aspiration. Conclusion: Concurrent chemoradiation provided good locoregional control for locally advanced oropharyngeal carcinoma. Patients with small tumors (T1-T2) had excellent survival. The poor prognosis associated with large tumors may be due to the risk of developing distant metastases. Acute and late toxicities remained significant. Aspiration pneumonia and severe dysphagia were the most prevalent complications of the combined modality approach. D 2007 Elsevier Inc. All rights reserved.
4 Corresponding author. Radiation Oncology Service (111), VA North Texas Health Care System, Dallas, TX 75216, USA. Tel.: +1 214 857 0142; fax: +1 214 857 0145. E-mail address: [email protected] (N.P. Nguyen). 0196-0709/$ – see front matter. D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjoto.2006.03.007
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N.P. Nguyen et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 28 (2007) 3–8
1. Introduction The oropharynx plays a central role in speech and swallowing [1]. Movement of the soft palate modifies the size and shape of the resonating cavities, thereby influencing vowel production. Closure of the soft palate also prevents food regurgitation through the nose. The base of tongue modulates production of vowels and consonants because of its obstruction of the vocal tract. Elevation of the base of tongue forces the bolus into the oropharynx. Tumors arising from the soft palate and base of tongue may impede speech and swallowing especially when they are locally advanced [2]. Management of locally advanced oropharyngeal tumor is also difficult because of the high recurrence rate. Surgery followed by radiation has been the standard of care [3]. However, resection of a large amount of normal tissue to achieve tumor-free margins induces severe speech and swallowing dysfunction that adversely affects patient quality of life [4]. Addition of postoperative radiation compounds the issues because of resulting xerostomia and scarring [5]. As an alternative, concurrent chemoradiation has been introduced for organ preservation and local control. Increased radiation and chemotherapy-induced cell killing from the combined modality may improve local control [6]. However, the radiosensitization effect of chemotherapy may also lead to increased acute toxicity and late complications of the normal tissue attendant with disease [7]. The radiation therapy fields usually cover a large area of head and neck to ensure that tumor bed and regional lymph nodes receive an adequate dose. High radiation dose to the oropharynx may produce irreversible damage to the critical structures necessary for normal deglutition—such as tongue, larynx, and pharyngeal muscles. To investigate these issues, we undertook a retrospective review of patients with locally advanced oropharyngeal cancer who underwent concurrent chemoradiation at Veterans Affairs North Texas Health Care System. 2. Patients and methods 2.1. Patient population Between December 1999 and September 2004, 48 patients with locally advanced oropharyngeal cancer (stage III and IV) underwent concurrent chemotherapy and radiation at Veterans Affairs North Texas Health Care System. Patients were included if they had T1-T4 primary tumor, N1-N3 metastatic neck nodes, Karnofsky performance status higher than 70%, and adequate end-organ function defined as an absolute neutrophil count of more than 1 500/mm3, platelets more than 100 000/mm3, serum creatinine lower than 1.5 normal, serum bilirubin below 35 lmol/L, and normal serum glutamic oxalacetic and pyruvic transaminase. All patients signed an informed consent. Before treatment, the patients underwent dental extraction, nutritional assessment, and placement of a gastrostomy tube for enteral feeding during treatment.
Forty-eight male patients were enrolled in the study and are summarized in Table 1 (patient characteristics). Their ages ranged from 46 to 77 years (median age, 59 years). There were 40 whites and 8 African Americans. The tumors were located at the base of tongue (26), tonsils (19), and soft palate (3). Eleven patients had stage III disease, and 37 had stage IV (27 IVA and 10 IVB). There were 4 T1, 10 T2, 17 T3, and 17 T4. The nodal stages were 13 N0, 4 N1, 22 N2, and 9 N3. The histology was squamous carcinoma. The tumor grades were well differentiated (3), moderately differentiated (23), poorly differentiated (10), and unspecified (12). 2.2. Chemoradiation After enrollment, the patients received 5-fluorouracil 1000 mg/m2 intravenously (continuous infusion on days 1–4 and 21–24) and cisplatin 100 mg/m2 intravenously on days 1 and 21 of radiation. Radiation therapy was delivered on a cobalt unit or a 6-mV linear accelerator using standard technique (2 lateral and 1 supraclavicular field, off cord at 3960–4000 cGy, 180–200 cGy per fraction). The dose to the gross tumor was 6600 to 7200 cGy; lymph nodes at risk for subclinical metastasis received 5000 to 5400 cGy. Patients were evaluated weekly during treatment or more frequently if clinically indicated. Toxicity during treatment was assessed according to the Radiation Therapy Oncology Group toxicity scale. Degree of weight loss and any treatment delays were recorded at the end of treatment.
Table 1 Patient characteristics Characteristics
No. of patients (%)
Patient no. Male Age: 46–77 years (median, 59 years) Race Whites Africans Americans Histology: squamous Grade 1 2 3 Not specified Sites Base of tongue Tonsils Soft palate Stage III 4A 4B T stage 1 2 3 4
48 (100) 48 (100)
Follow–up: 12 to 69 months (median, 24 months).
40 (83) 8 (17) 48 (100) 3 23 10 12
(6) (48) (21) (25)
26 (54) 19 (40) 3 (6) 11 (23) 27 (56) 10 (21) 4 10 17 17
(9) (21) (35) (35)
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After completion of treatment, patients were followed monthly with repeated endoscopy by the ear, nose, and throat service at each visit. Patients were instructed to continue with tube feeding until resolution of the acute mucositis enabled them to resume a normal diet. 2.3. Statistical analysis Statistical analysis was performed using the log-rank test. Differences with values of P b .05 were considered statistically significant. 3. Results 3.1. Tumor control and survival At a median follow-up of 23 months (range, 12–69 months), 17 patients (35%) developed recurrences. There were 12 local recurrences (25%). Of the local recurrences, 6 were isolated and 6 associated with neck recurrence. No patient developed isolated neck recurrences. Eight patients (17%) developed distant metastases (5 alone, 3 associated with local recurrences). The sites of metastases were lungs (6) and lungs and liver (2). Four patients (8%) had second primary tumors (2 lungs, 1 trachea, and 1 thyroid cancer). Median, 3-year, and 5-year actuarial survival for the whole group were, respectively, 36 months, 52%, and 41% (Fig. 1). There was no statistical difference in survival between patients with base of the tongue and tonsillar carcinoma ( P = .32). The median, 3-year, and 5-year actuarial survival for base of tongue and tonsillar carcinoma were 23 and 36 months, 43% and 67%, and 37% and 48%, respectively (Fig. 2). However, for the whole group, there was a statistically significant difference in survival between small and large tumors ( P = .01). The 3-year and 5-year actuarial survival for T1-T2 and T3-T4 tumors were,
Fig. 1. The 3- and 5-year actuarial survival for the whole group of patients were, respectively, 52% and 41%, based on the log-rank test.
Fig. 2. The 3- and 5-year actuarial survival of patients with base of the tongue and tonsillar carcinoma were 43% and 67% and 37% and 48%, respectively, based on the log-rank test ( P = .32).
respectively, 84% and 41% and 84% and 27% (Fig. 3). The distant metastases rate was, respectively, 0% (0/14) and 23% (8/34) for T1-T2 and T3-T4 ( P = .04). Corresponding numbers for local failures were, respectively, 14% (2/14) and 29% (10/34). This difference is not statistically significant ( P = .6). There was no correlation between survival and nodal stage. Median, 3-year, and 5-year actuarial survival for N0-N1 and N2-N3 were, respectively, 32 and 37 months, 43% and 56%, and 32 and 45% ( P = .8).
Fig. 3. The 3- and 5-year actuarial survival for T1-T2 and T3-T4 tumors were, respectively, 84% and 41% and 84% and 27%, based on the log-rank test ( P = .04).
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3.2. Toxicity 3.2.1. Acute toxicity Six patients received only 1 cycle of chemotherapy because of renal failure (3), severe weight loss (1), sepsis (1), and patient refusal (1). The dose of 5-fluorouracil was reduced by 25% in 1 patient because of severe mucositis. Radiation therapy was discontinued in 2 patients at 4860 cGy and 5000 cGy because of death secondary to sepsis (1) and patient refusal to continue treatment (1). Forty-five patients (94%) developed toxicity grade 3 to 4. There were 40 (84%) and 26 (54%) mucositis grade 3 to 4 and hematological toxicity, respectively. The median weight loss was 18 lb (range, 0–47 lb). Eight patients (16%) developed aspiration pneumonia during (5) and after (3) treatment. Five patients (10%) died of aspiration (2 during and 3 post treatment). One patient had urinary tract infection and sepsis. One patient developed acute viral hepatitis. 3.2.2. Late toxicity Four patients (8%) developed esophageal strictures after treatment requiring repeated dilatations. Two patients had radionecrosis (osteo- and soft tissue) requiring hyperbaric oxygen. Eighteen patients (37%) required prolonged tube feedings (N 3 months) because of severe dysphagia or aspiration. 4. Discussion The management of locally advanced oropharyngeal carcinoma remains a challenge. Surgery followed by postoperative radiation has been the standard treatment because of the high recurrence rate [3]. However, surgery of the oropharynx carries significant morbidity. Pauloski et al [4] demonstrated severe speech dysfunction after surgical resection. Conversational understandability was related to the volume of tongue and resected soft palate. Long-term swallowing difficulty was also noted after resection because of abnormal movement of the tongue base and pharyngeal wall [8]. Both speech and swallowing dysfunction were compounded by postoperative radiation because of xerostomia and scarring of the pharyngeal muscles [5]. Anxiety and depression were frequently observed because of the disfiguring effect of surgery [9]. However, despite the aggressive treatment, survival and functional outcome remained poor for advanced lesions [10]. In an attempt to improve the prognosis, concurrent chemoradiation has been introduced, anticipatory of the chemotherapy interactions as a tumor radiosensitizer. The high rate of radiation-induced apoptosis and DNA damage repair inhibition from the combined modality was hypothesized to increase tumor cell killing while allowing organ preservation [11]. Preliminary studies were encouraging because higher rates of local control were observed even for inoperable tumors [12]. However, the acute toxicity of chemotherapy and radiation was significant [13]. Mucositis
grade 3 to 4 occurred frequently, thereby preventing the patient from oral feeding and necessitating long-term dependence on gastrostomy tube feeding. Hematological toxicity was also significant, with neutropenia and anemia. Sepsis and death could result from the treatment. The combined modality also induced long-term damage to the digestive tract. Stasis of the bolus and, in severe cases, aspiration were observed after chemoradiation. Late grade 3 toxicity occurred in up to 24% of the patients with oropharyngeal carcinoma at 3 years after chemoradiation, consisting mainly of chronic dysphagia/aspiration and soft tissue necrosis [14]. Once chronic dysphagia occurred, swallowing rarely came back to normal [15]. Dysphagia had a profound impact on cancer survivors because of anxiety and depression [16]. Most chemoradiation studies have reported the survival of stage III and IV together. The influence of tumor and nodal stage on local control and survival remained relatively unknown. There has also been no analysis of the relationship of tumor anatomical site to survival rate. This prompted us to conduct this retrospective study. We observed a survival rate of 84% at 3 and 5 years for T1 and T2 tumors. This is in agreement with other chemoradiation studies with resectable tumors [14]. However, the 3- and 5-year survival decreased to 41% and 27%, respectively, for T3 and T4 lesions ( P = .01). There was no statistically significant difference in locoregional control between the 2 groups. There were no distant metastasis in the T1-T2 group. However, the distant metastasis rate for T3-T4 lesions was 23% ( P = .04). This difference may indeed account for the differences observed in survival between the 2 groups. Large tumors could be associated with a high rate of occult metastases, which manifested later as the patient achieved locoregional control and lived longer. Our high rate of distant metastases was also in agreement with other studies [10]. This observation may have an important clinical application. Patients with large tumors may benefit from adjuvant chemotherapy after concurrent chemoradiation to decrease the metastasis rate and to improve survival. We observed no statistically significant difference in survival between base of tongue and tonsillar carcinoma. However, because of the small number of patients in each group, no definite conclusions could be made at this time. The acute toxicity in our study was significant; almost all patients developed grade 3 – 4 mucositis and hematological toxicity. Our chemotherapy regimen was similar to the intergroup study, which also reported significant acute toxicity [17]. However, we observed a high rate of aspiration (16%). Of the 8 patients who aspirated, 5 died of aspiration pneumonia. Our patients suffered malnutrition because of the mucositis. Despite tube feedings, the median weight loss was 18 lb. The combination of poor nutrition and immunosuppression from the chemotherapy may have been contributing factors to aspiration pneumonia and death [18]. Aspiration during head and neck chemoradiation may
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be silent because of the absence of a cough reflex [19]. It may be underrecognized and underreported. We have advocated the use of modified barium swallow as a means to detect early aspiration during treatment [20,21]. The survival rate could be improved, as all patients who aspirated—including the 5 who died—had had complete response of their primary tumor to chemoradiation. After treatment, long-term gastrointestinal toxicity remained high. Thirty-seven percent of our patients became dependent on tube feedings for a prolonged period ( N 3 months). They had severe dysphagia or chronic aspiration. Modified barium swallow may be useful to determine the need for long-term tube feedings and for swallowing therapy. Patients in this study were also at risk for esophageal strictures (8%) that required repeated dilatations. This complication became more prevalent (up to 14%) as the number of long-term cancer-free survivors increased after chemoradiation [22]. Although there were no reported deaths from the esophageal dilatation, it added to the discomfort and altered patient quality of life. We postulate that these long-term gastrointestinal complications, that is, severe dysphagia and chronic aspiration, may result from excessive fibrogenesis after chemoradiation. Abnormalities of the bolus transit, stasis, and aspiration have been reported after chemoradiation [23]. Autocrine hyperstimulation of transforming growth factor b1, a peptide responsible for collagen formation and degradation, has been attributed to radiation-induced fibrosis and atrophy [24,25]. Because hyperactivation of transforming growth factor b from hydroxyl radicals produced by radiation may induce excessive fibrosis responsible for the dysphagia, we postulate that neutralization of these chemoradiation-induced radicals may reduce the occurrence of dysphagia after chemoradiation. In this approach, the thiol compound Amifostine had recently been recognized as a radioprotector in clinical studies. Buntzel et al [26], reported a significant reduction of dysphagia and fibrosis in 313 patients with head and neck cancer who received Amifostine during chemoradiation, as compared with 218 patients who did not have Amifostine. Further studies should be done to confirm this finding. The limitations of our study include the retrospective nature of the study, the small number of patients, and a relatively short follow-up. However, we would like to emphasize the feasibility of concurrent chemoradiation for locoregional control of unresectable tumors. 5. Conclusion Concurrent chemoradiation for oropharyngeal carcinoma provides excellent survival for patient with small tumors. Patients with large tumors are at risk for distant metastases. Adjuvant chemotherapy should be considered for these patients in future prospective studies. Acute and late toxicities remain significant for the combined modality. Patients undergoing chemoradiation are at risk for aspiration
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and severe dysphagia. As such, we advocate modified barium swallow as a useful tool to assess aspiration risk and for patient rehabilitation.
Acknowledgment The authors thank Brenda M. Lewis and Randy Steward for their efforts in the preparation of this article.
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