- Email: [email protected]
A randomized phase II trial of amifostine for head and neck irradiation in lymphoma
A Randomized Phase II Trial of Amifostine for Head and Neck Irradiation in Lymphoma Andrea K. Ng, Gayle Hickey, Sigui Li, Donna Neuberg, and Peter M. Mauch Acute and long-term oral complications occur in patients receiving mantle radiation therapy or irradiation to the head and neck region for Hodgkin’s disease or non-Hodgkin’s lymphoma. While considerable data are available on the effect of radiation therapy on the oral function and quality of life of patients with squamous cell carcinoma of the head and neck, such information is lacking for similarly irradiated lymphoma patients. In this article we discuss the rationale and study design of an ongoing, randomized phase II study evaluating the role of amifostine (Ethyol; Medimmune Inc, Gaithersburg, MD) as a radiation protectant in patients receiving head and neck irradiation for lymphoma. Further investigation in this lymphoma population is needed to improve our understanding of the extent of the problem and its impact on patients’ daily living and functioning. Importantly, fine-tuning the treatment and management approaches to minimize morbidity while maximizing the survival and quality of life of patients are crucial next steps. Semin Oncol 31(suppl 18):20-24 © 2004 Elsevier Inc. All rights reserved.
cute and long-term oral complications, including mucositis, dysphagia, xerostomia, radiation-induced caries, and taste alteration, are known to occur in patients who received mantle radiation therapy (RT) or irradiation to the head and neck region for Hodgkin’s disease or non-Hodgkin’s lymphoma.1-3 The time-course of the oral dysfunction, its effect on patients’ quality of life (QOL), and other potential contributing factors, however, are not as well-documented. While considerable retrospective4-11 and prospective12-17 data are available on the effect of RT on the oral function and QOL of patients with squamous cell carcinoma of the head and neck, such information is lacking for similarly irradiated lymphoma patients. More work in the lymphoma population is needed to improve our understanding of the extent of the problem and its impact on patients’ daily living and functioning.
A
tients with head and neck malignancies.17-20 Eisbruch et al20 at the University of Michigan prospectively measured salivary flow rates in 88 patients with head and neck carcinoma (HNC) who were irradiated with conformal techniques. Parotid gland dose thresholds, above which the flow rates became significantly reduced, were calculated. The authors reported respective mean dose thresholds of 24 and 26 Gy for unstimulated and stimulated salivary flow rates, and also noted partial volume thresholds of 67%, 45%, and 24% gland volume in patients receiving greater than 15, 30, and 45 Gy, respectively. The same group subsequently showed that the submandibular gland dose, oral cavity dose, and baseline dry mouth significantly predicted for xerostomia using a self-reported xerostomia-specific questionnaire.19
Salivary Function in Relation to Radiation Dose and Volume
Amifostine as a Radioprotective Agent
Reduced salivary flow rate is related to radiation dose and the amount of salivary gland tissue in the irradiated field in pa-
Amifostine (Ethyol; Medimmune Inc, Gaithersburg, MD), a cytoprotective agent that reduces damage induced by radiation or alkylating agents by scavenging free radicals, has been extensively studied in patients receiving head and neck irradiation.21 However, data on amifostine as a radioprotector for oral complications are largely limited to patients with squamous cell HNC. In the multi-institutional phase III study of Brizel et al,22 315 patients with HNC receiving RT with or without intravenous (IV) amifostine received daily pre-RT.22 The total dose of RT in this
Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. Supported by MedImmune, Inc. Dr Ng has received honoraria from MedImmune Inc. Address reprint requests to Andrea K. Ng, MD, MPH, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, 75 Francis St, ASB1-L2, Boston, MA 02115; E-mail: [email protected]
20
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.12.007
Amifostine for HNC irradiation in lymphoma study ranged from 50 to 70 Gy. Patients in the amifostine arm had significantly reduced acute and chronic xerostomia, as well as superior salivary production at 1 year posttreatment. Using a Patient Benefit Questionnaire addressing various oral symptoms, patients on the amifostine arm had significantly more favorable Patient Benefit Questionnaire scores up to 11 months post-treatment.23 A smaller, randomized study by Rudat et al24 showed the protective effect of IV amifostine on dental health in patients with squamous cell carcinoma of the head and neck. For patients receiving concurrent carboplatin (Paraplatin; Bristol Myers Squibb, New York, NY) and RT for HNC, Buntzel et al25 reported in their phase III study that IV amifostine significantly decreased acute mucositis, dysphagia and dermatitis, acute and late xerostomia and taste loss, and late fibrotic reaction and post-therapeutic pain.25 The effectiveness of IV amifostine in preventing radiochemotherapy-induced mucositis, xerostomia and dysphagia up to 18 months post-treatment was similarly shown in another randomized study.26 In that study by Antonadou et al,26 patients in the amifostine arm also had a significantly shorter treatment duration. The main observed side effects of IV amifostine include transient hypotension (less than 1% to 13.6%), nausea/vomiting (4.5% to 5%), and venous catheter-related complications (5%).22,25 Because the administration of IV amifostine as a radioprotector requires daily vein catheterization, this might be difficult in patients with limited venous access. In addition, patients need to be closely monitored during and after the infusion for acute hypotension and severe nausea and vomiting. The entire administration procedure requires extensive nursing support, may take up to an hour each day, and can be of considerable burden to a busy radiation oncology department. To evaluate a simpler way to administer amifostine, a randomized phase II study was conducted addressing the feasibility and efficacy of subcutaneous (SC) administration of amifostine.27 In that study, Koukourakis et al accrued 60 patients with thoracic, 40 patients with HNC, and 40 patients with pelvic malignancies undergoing RT, and randomized them to either 500 mg of amifostine administered SC before each radiation treatment or RT alone. They reported that amifostine, given by this more convenient route, continued to confer a significant benefit in reducing mucositis, skin reaction, and bladder toxicity when compared with RT alone. In another phase II trial limited to patients with squamous cell HNC, 55 patients received SC amifostine daily before each radiation fraction.28 The percentage of patients who experienced acute mucositis was comparable to historical controls treated with IV amifostine. With SC amifostine, the incidence of hypotension appears to be negligible. In the study by Koukourakis et al,27 grade 2 vomiting was observed in 3% of the patients, 15.7% of patients had severe asthenia occurring between the fourth and 15th day of amifostine injection, and 9% developed an allergic reaction, which subsided after discontinuation of the amifostine. In the study by Anne et al,28 cutaneous toxicity
21 occurred in 13% of patients, mainly because of localized skin reactions at the site of injection.
Head and Neck Irradiation in Lymphoma Patients A significant proportion of patients with Hodgkin’s disease and non-Hodgkin’s lymphoma present with disease in the neck, or head and neck region, and require RT to the area. Limited data are available in this patient population on the radiation dose-effect relationship, on the influence of the treatment on patients’ QOL, and on the efficacy of amifostine as a radioprotector. Compared with patients with squamous cell carcinoma of the head and neck, the sociodemographic profile of patients with lymphoma can be quite different. For example, they tend to be younger at diagnosis, and the gender distribution tends to be more even, as opposed to the male predominance observed in HNC patients. They are also less likely to have a significant history of tobacco or alcohol use, may have better baseline oral health, and potentially possess a different level of compliance with health maintenance. Treatment for lymphoma is also considerably different, in terms of types of chemotherapy, sequencing of chemoradiation therapy, radiation treatment field, and radiation dose and fractionation scheme. Given their distinctive baseline characteristics and level of treatment exposure, this patient population’s potential benefit from amifostine needs to be studied separately. A longitudinal documentation of QOL with or without amifostine, using multi-dimensional, validated, and site-specific as well as general QOL instruments will also be important. Finally, the prognosis for patients with Hodgkin’s disease and certain types of nonHodgkin’s lymphoma is generally favorable, and along with having potentially less comorbid illnesses than HNC patients, patients with lymphoma may enjoy a longer life expectancy. Therefore, the study of late effects and QOL is especially relevant in these patients. Because of the relatively lower doses used for lymphoma, most of the acute effects of mucositis, pharyngitis, dry mouth, and taste changes subside within several weeks after treatment, mainly in the younger population. However, in older patients, despite the typically lower lymphoma doses, the impact of the radiation treatment on oral health and functioning may persist over a prolonged period of time. Such age-related effects have also been reported in patients with HNC.10 The chronic problems of permanent xerostomia and teeth loss, which are especially pronounced in the older population, can have substantial effect on patients’ physical, emotional, and social functioning. For these patients, clinicians are often faced with the difficult decision of selecting an optimal radiation dose and field to minimize toxicity while preserving therapeutic efficacy. Both a formal documentation of oral dysfunction in relationship to treatment exposure, and identification of strategies to limit oral toxicities, either through treatment modification or use of cyto-
A.K. Ng et al
22 toxic protective agents, are especially important in the older age group.
An Ongoing Trial Evaluating the Role of Amifostine in Lymphoma Patients At the Brigham and Women’s Hospital and Dana-Farber Cancer Institute (Boston, MA), we recently initiated a phase II randomized trial evaluating the role of amifostine as a radiation protectant in patients receiving head and neck irradiation for lymphoma. The primary objectives of the study are: (1) to evaluate the efficacy of amifostine in reducing acute and chronic radiation-induced oral toxicity in these patients; (2) to determine the general and site-specific health-related QOL; and (3) to determine whether the administration of amifostine affects the disease response rates. Secondary objectives are: (1) to identify treatment- and patient-related factors that affect QOL and oral function; and (2) to evaluate the toxicities of SC amifostine in patients with lymphoma receiving RT to the head and neck region. The main treatment-related factors that will be evaluated are radiation parameters including radiation dose to and volume of salivary glands irradiated.
Eligibility Criteria Patients age 40 or older with histologically confirmed Hodgkin’s disease or non-Hodgkin’s lymphoma receiving RT to the head and neck region as part of treatment, including Waldeyer’s ring, cervical and supraclavicular nodal chain, parotid, or a full mantle field, are eligible for the study. The decision to exclude younger patients from the study was based on our following clinical observation: young patients tend to regain full salivary gland function within 1 to 2 months after treatment, while older patients appear to be more susceptible to long-term xerostomia and dental problems. Patients with prior history of head and neck malignancies, or who have received prior RT to the head and neck region are also excluded. The decision to also exclude patients with stage I Hodgkin’s lymphoma receiving RT alone was because of our concern of a potential lymphoma-protective effect of amifostine in patients with a highly curable disease receiving RT as the sole modality of treatment.
Study Procedure The study design is a randomized phase II trial, carried out through the Department of Radiation Oncology. An observation arm, in which patients receive no amifostine, is included because of the scarcity of published data that formally documents the rate of occurrence of acute and chronic xerostomia in this patient population. Patients who are randomized to the amifostine arm will receive prochlorperazine (Compazine; GlaxoSmithKline, UK) 10 mg, or another antiemetic if prochlorperazine fails to control nausea, administered orally 1 to 2 hours before SC injection of amifostine. Amifostine will be administered at a flat dose of 500 mg diluted in 2.9 mL of
normal saline. The solution will be injected SC in two sites (1.45 mL each), alternating daily among sites including upper arm, thigh, or abdominal area. The injection will be administered daily 30 to 60 minutes before each radiation treatment. Blood pressure will be measured before injection, both 5 and 15 minutes after injection, and immediately after RT each day. Amifostine will be discontinued in patients with evidence of allergic reaction manifested as generalized cutaneous rash. The administration will be given by one of the study physicians or registered nurses. Amifostine is administered daily for the duration of RT, and administered on days when a fraction of RT is given. There is no maximum number of doses of amifostine. However, in RT for lymphoma, the typical radiation dose range is 30 to 45 Gy, and the number of fractions typically ranges from 15 to 25. Therefore, it will be unlikely that patients will require more than 30 doses of amifostine.
Radiation Planning All patients will undergo 3-dimensional radiation planning. The following volumes will be contoured at the time of planning: parotid glands, submandibular glands, and the oral cavity (encompassing the buccal mucosa, tongue, base of tongue, floor of mouth, and soft and hard palates). The oral cavity volume will serve as a surrogate of the volume of the minor salivary glands. The minimum, maximum, and mean radiation dose to each of the above contoured volumes, as well as to the combined volume, designated as “total salivary gland,” will be determined. The respective dose volume histograms will also be generated. Patient position, immobilization technique, field design, beam arrangement, and radiation dose and fractionation will be at the discretion of the treating radiation oncologist depending on the disease presentation. In general, for patients’ initial cervical nodal involvement to be treated with a full mantle or modified mantle field, the superior border of the radiation field should be at the level of the external auditory meatus to ensure adequate coverage of the cervical chain. For involved-field RT to the unilateral cervical nodal chain, if there is initial involvement of the cervical node only, the medial border of the field can be set at the ipsilateral pedicles, the superior border at the level of the external auditory meatus, and the inferior border at the bottom of the clavicle. A small lung block can be added 1.5 cm below the clavicle. If there is involvement of the supraclavicular region, however, the medial border of the field needs to be set at the contralateral pedicles. For treatment of the parotid, the wedge pair technique should be used with an approximately 60° hinge angle and 30° wedges. For the Waldeyer’s ring field, the nasopharynx should be covered superiorly and the submental nodes included inferiorly.
Toxicity Assessment Radiation-induced toxicities will be graded according to the European Organization for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group Acute and Late Radiation Morbidity Scoring Criteria for relevant organ
Amifostine for HNC irradiation in lymphoma tissues. Toxicity scores will be obtained pre-radiation treatment, weekly during radiation treatment, and at 1, 3, 6, 12, 18, and 24 months post-treatment. To monitor amifostineassociated toxicity, patients will be assessed based on the Eastern Cooperative Oncology Group Common Toxicity Criteria based on nausea, vomiting, hypotension, local skin reaction, and allergy adverse events for each administration.
Quality of Life Assessment The validated 35-item EORTC-Quality of Life Questionnaire (QLQ)-H&N questionnaire, along with the EORTC-QLQC30 that measures general QOL, will be included in the study design.29-33 These self-administered questionnaires will be given pre-radiation treatment, and at 1, 3, 6, 12, 18, and 24 months post-treatment.
Disease Assessment The main purpose of response assessment in this study is to determine whether amifostine adversely affects treatment efficacy. Therefore, it may not be appropriate to assess response in patients receiving combined chemoradiation therapy, because the amifostine is administered only during the RT phase of treatment. Response assessment will therefore be limited to patients receiving RT and amifostine without chemotherapy, which we estimate will comprise approximately 50% of the study population. Tumor response will be assessed based on the International Workshop on Response Criteria for Non-Hodgkin’s Lymphoma.34 The disease status after completion of RT will be assessed relative to the disease status at presentation before initiation of treatment. A complete response is defined as no measurable disease both radiographically and by physical examination; lymph nodes previously greater than 1.5 cm must regress to ⱕ1.5 cm, and lymph nodes that were previously 1.1 to 1.5 cm must decrease to ⱕ1 cm. complete response/unconfirmed is defined as regression of lymph node mass greater than 75% along with a negative physical examination. Partial response is defined as ⱖ50% reduction in lymph node mass. Stable disease is defined as less than a partial response, but not progressive disease. Progressive disease is defined as ⱖ50% increase in nodal mass, or appearance of new sites of disease during or at the end of therapy. We further add that nuclear imaging post-treatment, if performed, should be negative for patients with either a complete response or complete response/unconfirmed. However, if nuclear imaging were to be included as part of the response assessment, a pretreatment nuclear medicine study must be available to demonstrate tumor avidity. Relapsed disease is scored by the appearance of any new lesions or increase by ⱖ50% in the size of previously involved sites after the end of therapy. Response assessment will be based on physical examination, computed tomography scans and/or nuclear medicine scans performed within the first 5 months posttreatment.
Biostatistical Analysis In this trial, 110 eligible patients will be randomized equally to each of the two arms (55 patients/arm); approximately 5%
23 are expected to be ineligible. In addition, the analysis will be based on patients who complete all doses of amifostine. We estimate that 10% of the study subjects will be either lost or not assessed during or at the end of RT. Thus, accrual should a total 129 patients to achieve a desired sample size. For the experimental arm, a proportion of patients who experience grade 2 (or worse) xerostomia of 0.4 (or less) will be interpreted as evidence of treatment activity. This study will have an 83% power against the null hypothesis of 0.60 (based on a clinical estimate, and because o the lack of published data on the rate of xerostomia for this patient population) using a one-sided 0.025-alpha level exact binomial test. Therefore, the treatment regimen can be considered promising if, at most, 25 of the 55 eligible patients experience grade 2 (or worse) xerostomia. The 95% exact binomial confidence interval for the true but unknown rate of xerostomia (assuming that 25 of 55 patients experience this toxicity) is 32% to 59%. Although the study was powered for comparison at the end of RT, longitudinal models will be used to assess how the incidence of toxicities is changing over time. The power calculations for the QOL assessment will be based on the “dry-mouth” item from the EORTC-QLQ-H&N questionnaire because amifostine is expected to have the most direct impact on this item. Responses will be linearly transformed to obtain a score from 0 to 100 based on the scoring procedure detailed in the EORTC QLQ-C30 scoring manual. The possible scores for this single item are: 0 (not at all); 33.33 (a little); 66.67 (quite a bit); and 100.00 (very much). A higher score for this item indicates a higher level of symptoms. A change from baseline score of at least 33.33 will be interpreted as a worsening of the dry mouth symptom. The maximum 95% confidence interval width for the true worsening dry mouth symptom rate (ie, rate of patients with a change of baseline score of at least 33.33) is 28% (eg, 35% to 63%). To determine which treatment- and patient-related factors affect QOL, we will examine a multiple linear regression model that includes the covariates treatment and oral function. Strategies for adding additional covariates will be based on a combination of scientific judgment (eg, including variables for which there is strong scientific basis for an effect regardless of statistical significance of the estimated regression coefficient), along with statistical approaches such as stepwise regression. A similar approach will be used to determine which treatment and patient-related factors (ie, age, gender, history of tobacco use, history of alcohol use, and baseline dental health) affect oral function. However, a logistic regression model will be used for this endpoint.
Future Directions Future directions include moving onto a phase III study that may help definitively establish the role of amifostine in these patients, and to evaluate strategies of targeted RT in conjunction with a radioprotectant in patients with lymphoma of the head and neck region. Effective treatments for various forms of lymphoma have been successfully developed over the years. The next important steps are to fine-tune the treatment
A.K. Ng et al
24 and management approaches to minimize morbidity while maximizing the survival and QOL of patients.
20.
References 1. Bucher JA, Fleming TJ, Fuller LM, et al: Preliminary observations on the effect of mantle field radiotherapy on salivary flow rates in patients with Hodgkin’s disease. J Dent Res 67:518-521, 1988 2. Keene HJ, Fleming TJ, Toth BB: Cariogenic microflora in patients with Hodgkin’s disease before and after mantle field radiotherapy. Oral Surg Oral Med Oral Pathol 78:577-582, 1994 3. Herrin HK: The oral implications of Hodgkin’s disease. Gen Dent 47: 572-575, 1999 4. Allal AS, Dulguerov P, Bieri S, et al: Assessment of quality of life in patients treated with accelerated radiotherapy for laryngeal and hypopharyngeal carcinomas. Head Neck 22:288-293, 2000 5. Epstein JB, Emerton S, Kolbinson DA, et al: Quality of life and oral function following radiotherapy for head and neck cancer. Head Neck 21:1-11, 1999 6. Weymuller EA Jr, Yueh B, Deleyiannis FW, et al: Quality of life in head and neck cancer. Laryngoscope 110:4-7, 2000 7. Ringash J, Redelmeier DA, O’Sullivan B, et al: Quality of life and utility in irradiated laryngeal cancer patients. Int J Radiat Oncol Biol Phys 47:875-881, 2000 8. Ringash J, Bezjak A: A structured review of quality of life instruments for head and neck cancer patients. Head Neck 23:201-213, 2001 9. Epstein JB, Robertson M, Emerton S, et al: Quality of life and oral function in patients treated with radiation therapy for head and neck cancer. Head Neck 23:389-398, 2001 10. Hammerlid E, Silander E, Hornestam L, et al: Health-related quality of life three years after diagnosis of head and neck cancer–A longitudinal study. Head Neck 23:113-125, 2001 11. Hammerlid E, Taft C: Health-related quality of life in long-term head and neck cancer survivors: A comparison with general population norms. Br J Cancer 84:149-156, 2001 12. Janda M, Johnson D, Woelfl H, et al: Measurement of quality of life in head and neck cancer patients utilizing the quality of life radiation therapy questionnaire. Strahlenther Onkol 178:153-158, 2002 13. de Graeff A, de Leeuw RJ, Ros WJ, et al: A prospective study on quality of life of laryngeal cancer patients treated with radiotherapy. Head Neck 21:291-296, 1999 14. Gritz ER, Carmack CL, de Moor C, et al: First year after head and neck cancer: Quality of life. J Clin Oncol 17:352-360, 1999 15. de Graeff A, de Leeuw JR, Ros WJ, et al: Long-term quality of life of patients with head and neck cancer. Laryngoscope 110:98-106, 2000 16. Ohrn KE, Sjoden PO, Wahlin YB, et al: Oral health and quality of life among patients with head and neck cancer or haematological malignancies. Support Care Cancer 9:528-538, 2001 17. Henson BS, Inglehart MR, Eisbruch A, et al: Preserved salivary output and xerostomia-related quality of life in head and neck cancer patients receiving parotid-sparing radiotherapy. Oral Oncol 37:84-93, 2001 18. Liu RP, Fleming TJ, Toth BB, et al: Salivary flow rates in patients with head and neck cancer 0.5 to 25 years after radiotherapy. Oral Surg Oral Med Oral Pathol 70:724-729, 1990 19. Eisbruch A, Kim HM, Terrell JE, et al: Xerostomia and its predictors
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following parotid-sparing irradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys 50:695-704, 2001 Eisbruch A, Dawson LA, Kim HM, et al: Conformal and intensity modulated irradiation of head and neck cancer: the potential for improved target irradiation, salivary gland function, and quality of life. Acta Otorhinolaryngol Belg 53:271-275, 1999 Wasserman TH, Brizel DM: The role of amifostine as a radioprotector. Oncology (Huntingt) 15:1349-1354, 2001; discussion 15:1357-1360, 2001 Brizel DM, Wasserman TH, Henke M, et al: Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 18:3339-3345, 2000 Wasserman T, Mackowiak JI, Brizel DM, et al: Effect of amifostine on patient assessed clinical benefit in irradiated head and neck cancer. Int J Radiat Oncol Biol Phys 48:1035-1039, 2000 Rudat V, Meyer J, Momm F, et al: Protective effect of amifostine on dental health after radiotherapy of the head and neck. Int J Radiat Oncol Biol Phys 48:1339-1343, 2000 Buntzel J, Glatzel M, Kuttner K, et al: Amifostine in simultaneous radiochemotherapy of advanced head and neck cancer. Semin Radiat Oncol 12:4-13, 2002 Antonadou D, Pepelassi M, Synodinou M, et al: Prophylactic use of amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in head-and-neck cancer. Int J Radiat Oncol Biol Phys 52:739747, 2002 Koukourakis MI, Kyrias G, Kakolyris S, et al: Subcutaneous administration of amifostine during fractionated radiotherapy: A randomized phase II study. J Clin Oncol 18:2226-2233, 2000 Anne PR, Curran WJ Jr: A phase II trial of subcutaneous amifostine and radiation therapy in patients with head and neck cancer. Semin Radiat Oncol 12:18-19, 2002 Bjordal K, Hammerlid E, Ahlner-Elmqvist M, et al: Quality of life in head and neck cancer patients: Validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-H&N35. J Clin Oncol 17:1008-1019, 1999 Bjordal K, de Graeff A, Fayers PM, et al: A 12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC QLQ-H&N35) in head and neck patients. EORTC Quality of Life Group. Eur J Cancer 36:1796-1807, 2000 Hammerlid E, Bjordal K, Ahlner-Elmqvist M, et al: A prospective study of quality of life in head and neck cancer patients. Part I: At diagnosis. Laryngoscope 111:669-680, 2001 Bjordal K, Ahlner-Elmqvist M, Hammerlid E, et al: A prospective study of quality of life in head and neck cancer patients. Part II: Longitudinal data. Laryngoscope 111:1440-1452, 2001 Sherman AC, Simonton S, Adams DC, et al: Assessing quality of life in patients with head and neck cancer: Cross-validation of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Head and Neck module (QLQ-H&N35). Arch Otolaryngol Head Neck Surg 126:459-467, 2000 Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17: 1244-1253, 1999
cute and long-term oral complications, including mucositis, dysphagia, xerostomia, radiation-induced caries, and taste alteration, are known to occur in patients who received mantle radiation therapy (RT) or irradiation to the head and neck region for Hodgkin’s disease or non-Hodgkin’s lymphoma.1-3 The time-course of the oral dysfunction, its effect on patients’ quality of life (QOL), and other potential contributing factors, however, are not as well-documented. While considerable retrospective4-11 and prospective12-17 data are available on the effect of RT on the oral function and QOL of patients with squamous cell carcinoma of the head and neck, such information is lacking for similarly irradiated lymphoma patients. More work in the lymphoma population is needed to improve our understanding of the extent of the problem and its impact on patients’ daily living and functioning.
A
tients with head and neck malignancies.17-20 Eisbruch et al20 at the University of Michigan prospectively measured salivary flow rates in 88 patients with head and neck carcinoma (HNC) who were irradiated with conformal techniques. Parotid gland dose thresholds, above which the flow rates became significantly reduced, were calculated. The authors reported respective mean dose thresholds of 24 and 26 Gy for unstimulated and stimulated salivary flow rates, and also noted partial volume thresholds of 67%, 45%, and 24% gland volume in patients receiving greater than 15, 30, and 45 Gy, respectively. The same group subsequently showed that the submandibular gland dose, oral cavity dose, and baseline dry mouth significantly predicted for xerostomia using a self-reported xerostomia-specific questionnaire.19
Salivary Function in Relation to Radiation Dose and Volume
Amifostine as a Radioprotective Agent
Reduced salivary flow rate is related to radiation dose and the amount of salivary gland tissue in the irradiated field in pa-
Amifostine (Ethyol; Medimmune Inc, Gaithersburg, MD), a cytoprotective agent that reduces damage induced by radiation or alkylating agents by scavenging free radicals, has been extensively studied in patients receiving head and neck irradiation.21 However, data on amifostine as a radioprotector for oral complications are largely limited to patients with squamous cell HNC. In the multi-institutional phase III study of Brizel et al,22 315 patients with HNC receiving RT with or without intravenous (IV) amifostine received daily pre-RT.22 The total dose of RT in this
Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. Supported by MedImmune, Inc. Dr Ng has received honoraria from MedImmune Inc. Address reprint requests to Andrea K. Ng, MD, MPH, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, 75 Francis St, ASB1-L2, Boston, MA 02115; E-mail: [email protected]
20
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.12.007
Amifostine for HNC irradiation in lymphoma study ranged from 50 to 70 Gy. Patients in the amifostine arm had significantly reduced acute and chronic xerostomia, as well as superior salivary production at 1 year posttreatment. Using a Patient Benefit Questionnaire addressing various oral symptoms, patients on the amifostine arm had significantly more favorable Patient Benefit Questionnaire scores up to 11 months post-treatment.23 A smaller, randomized study by Rudat et al24 showed the protective effect of IV amifostine on dental health in patients with squamous cell carcinoma of the head and neck. For patients receiving concurrent carboplatin (Paraplatin; Bristol Myers Squibb, New York, NY) and RT for HNC, Buntzel et al25 reported in their phase III study that IV amifostine significantly decreased acute mucositis, dysphagia and dermatitis, acute and late xerostomia and taste loss, and late fibrotic reaction and post-therapeutic pain.25 The effectiveness of IV amifostine in preventing radiochemotherapy-induced mucositis, xerostomia and dysphagia up to 18 months post-treatment was similarly shown in another randomized study.26 In that study by Antonadou et al,26 patients in the amifostine arm also had a significantly shorter treatment duration. The main observed side effects of IV amifostine include transient hypotension (less than 1% to 13.6%), nausea/vomiting (4.5% to 5%), and venous catheter-related complications (5%).22,25 Because the administration of IV amifostine as a radioprotector requires daily vein catheterization, this might be difficult in patients with limited venous access. In addition, patients need to be closely monitored during and after the infusion for acute hypotension and severe nausea and vomiting. The entire administration procedure requires extensive nursing support, may take up to an hour each day, and can be of considerable burden to a busy radiation oncology department. To evaluate a simpler way to administer amifostine, a randomized phase II study was conducted addressing the feasibility and efficacy of subcutaneous (SC) administration of amifostine.27 In that study, Koukourakis et al accrued 60 patients with thoracic, 40 patients with HNC, and 40 patients with pelvic malignancies undergoing RT, and randomized them to either 500 mg of amifostine administered SC before each radiation treatment or RT alone. They reported that amifostine, given by this more convenient route, continued to confer a significant benefit in reducing mucositis, skin reaction, and bladder toxicity when compared with RT alone. In another phase II trial limited to patients with squamous cell HNC, 55 patients received SC amifostine daily before each radiation fraction.28 The percentage of patients who experienced acute mucositis was comparable to historical controls treated with IV amifostine. With SC amifostine, the incidence of hypotension appears to be negligible. In the study by Koukourakis et al,27 grade 2 vomiting was observed in 3% of the patients, 15.7% of patients had severe asthenia occurring between the fourth and 15th day of amifostine injection, and 9% developed an allergic reaction, which subsided after discontinuation of the amifostine. In the study by Anne et al,28 cutaneous toxicity
21 occurred in 13% of patients, mainly because of localized skin reactions at the site of injection.
Head and Neck Irradiation in Lymphoma Patients A significant proportion of patients with Hodgkin’s disease and non-Hodgkin’s lymphoma present with disease in the neck, or head and neck region, and require RT to the area. Limited data are available in this patient population on the radiation dose-effect relationship, on the influence of the treatment on patients’ QOL, and on the efficacy of amifostine as a radioprotector. Compared with patients with squamous cell carcinoma of the head and neck, the sociodemographic profile of patients with lymphoma can be quite different. For example, they tend to be younger at diagnosis, and the gender distribution tends to be more even, as opposed to the male predominance observed in HNC patients. They are also less likely to have a significant history of tobacco or alcohol use, may have better baseline oral health, and potentially possess a different level of compliance with health maintenance. Treatment for lymphoma is also considerably different, in terms of types of chemotherapy, sequencing of chemoradiation therapy, radiation treatment field, and radiation dose and fractionation scheme. Given their distinctive baseline characteristics and level of treatment exposure, this patient population’s potential benefit from amifostine needs to be studied separately. A longitudinal documentation of QOL with or without amifostine, using multi-dimensional, validated, and site-specific as well as general QOL instruments will also be important. Finally, the prognosis for patients with Hodgkin’s disease and certain types of nonHodgkin’s lymphoma is generally favorable, and along with having potentially less comorbid illnesses than HNC patients, patients with lymphoma may enjoy a longer life expectancy. Therefore, the study of late effects and QOL is especially relevant in these patients. Because of the relatively lower doses used for lymphoma, most of the acute effects of mucositis, pharyngitis, dry mouth, and taste changes subside within several weeks after treatment, mainly in the younger population. However, in older patients, despite the typically lower lymphoma doses, the impact of the radiation treatment on oral health and functioning may persist over a prolonged period of time. Such age-related effects have also been reported in patients with HNC.10 The chronic problems of permanent xerostomia and teeth loss, which are especially pronounced in the older population, can have substantial effect on patients’ physical, emotional, and social functioning. For these patients, clinicians are often faced with the difficult decision of selecting an optimal radiation dose and field to minimize toxicity while preserving therapeutic efficacy. Both a formal documentation of oral dysfunction in relationship to treatment exposure, and identification of strategies to limit oral toxicities, either through treatment modification or use of cyto-
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22 toxic protective agents, are especially important in the older age group.
An Ongoing Trial Evaluating the Role of Amifostine in Lymphoma Patients At the Brigham and Women’s Hospital and Dana-Farber Cancer Institute (Boston, MA), we recently initiated a phase II randomized trial evaluating the role of amifostine as a radiation protectant in patients receiving head and neck irradiation for lymphoma. The primary objectives of the study are: (1) to evaluate the efficacy of amifostine in reducing acute and chronic radiation-induced oral toxicity in these patients; (2) to determine the general and site-specific health-related QOL; and (3) to determine whether the administration of amifostine affects the disease response rates. Secondary objectives are: (1) to identify treatment- and patient-related factors that affect QOL and oral function; and (2) to evaluate the toxicities of SC amifostine in patients with lymphoma receiving RT to the head and neck region. The main treatment-related factors that will be evaluated are radiation parameters including radiation dose to and volume of salivary glands irradiated.
Eligibility Criteria Patients age 40 or older with histologically confirmed Hodgkin’s disease or non-Hodgkin’s lymphoma receiving RT to the head and neck region as part of treatment, including Waldeyer’s ring, cervical and supraclavicular nodal chain, parotid, or a full mantle field, are eligible for the study. The decision to exclude younger patients from the study was based on our following clinical observation: young patients tend to regain full salivary gland function within 1 to 2 months after treatment, while older patients appear to be more susceptible to long-term xerostomia and dental problems. Patients with prior history of head and neck malignancies, or who have received prior RT to the head and neck region are also excluded. The decision to also exclude patients with stage I Hodgkin’s lymphoma receiving RT alone was because of our concern of a potential lymphoma-protective effect of amifostine in patients with a highly curable disease receiving RT as the sole modality of treatment.
Study Procedure The study design is a randomized phase II trial, carried out through the Department of Radiation Oncology. An observation arm, in which patients receive no amifostine, is included because of the scarcity of published data that formally documents the rate of occurrence of acute and chronic xerostomia in this patient population. Patients who are randomized to the amifostine arm will receive prochlorperazine (Compazine; GlaxoSmithKline, UK) 10 mg, or another antiemetic if prochlorperazine fails to control nausea, administered orally 1 to 2 hours before SC injection of amifostine. Amifostine will be administered at a flat dose of 500 mg diluted in 2.9 mL of
normal saline. The solution will be injected SC in two sites (1.45 mL each), alternating daily among sites including upper arm, thigh, or abdominal area. The injection will be administered daily 30 to 60 minutes before each radiation treatment. Blood pressure will be measured before injection, both 5 and 15 minutes after injection, and immediately after RT each day. Amifostine will be discontinued in patients with evidence of allergic reaction manifested as generalized cutaneous rash. The administration will be given by one of the study physicians or registered nurses. Amifostine is administered daily for the duration of RT, and administered on days when a fraction of RT is given. There is no maximum number of doses of amifostine. However, in RT for lymphoma, the typical radiation dose range is 30 to 45 Gy, and the number of fractions typically ranges from 15 to 25. Therefore, it will be unlikely that patients will require more than 30 doses of amifostine.
Radiation Planning All patients will undergo 3-dimensional radiation planning. The following volumes will be contoured at the time of planning: parotid glands, submandibular glands, and the oral cavity (encompassing the buccal mucosa, tongue, base of tongue, floor of mouth, and soft and hard palates). The oral cavity volume will serve as a surrogate of the volume of the minor salivary glands. The minimum, maximum, and mean radiation dose to each of the above contoured volumes, as well as to the combined volume, designated as “total salivary gland,” will be determined. The respective dose volume histograms will also be generated. Patient position, immobilization technique, field design, beam arrangement, and radiation dose and fractionation will be at the discretion of the treating radiation oncologist depending on the disease presentation. In general, for patients’ initial cervical nodal involvement to be treated with a full mantle or modified mantle field, the superior border of the radiation field should be at the level of the external auditory meatus to ensure adequate coverage of the cervical chain. For involved-field RT to the unilateral cervical nodal chain, if there is initial involvement of the cervical node only, the medial border of the field can be set at the ipsilateral pedicles, the superior border at the level of the external auditory meatus, and the inferior border at the bottom of the clavicle. A small lung block can be added 1.5 cm below the clavicle. If there is involvement of the supraclavicular region, however, the medial border of the field needs to be set at the contralateral pedicles. For treatment of the parotid, the wedge pair technique should be used with an approximately 60° hinge angle and 30° wedges. For the Waldeyer’s ring field, the nasopharynx should be covered superiorly and the submental nodes included inferiorly.
Toxicity Assessment Radiation-induced toxicities will be graded according to the European Organization for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group Acute and Late Radiation Morbidity Scoring Criteria for relevant organ
Amifostine for HNC irradiation in lymphoma tissues. Toxicity scores will be obtained pre-radiation treatment, weekly during radiation treatment, and at 1, 3, 6, 12, 18, and 24 months post-treatment. To monitor amifostineassociated toxicity, patients will be assessed based on the Eastern Cooperative Oncology Group Common Toxicity Criteria based on nausea, vomiting, hypotension, local skin reaction, and allergy adverse events for each administration.
Quality of Life Assessment The validated 35-item EORTC-Quality of Life Questionnaire (QLQ)-H&N questionnaire, along with the EORTC-QLQC30 that measures general QOL, will be included in the study design.29-33 These self-administered questionnaires will be given pre-radiation treatment, and at 1, 3, 6, 12, 18, and 24 months post-treatment.
Disease Assessment The main purpose of response assessment in this study is to determine whether amifostine adversely affects treatment efficacy. Therefore, it may not be appropriate to assess response in patients receiving combined chemoradiation therapy, because the amifostine is administered only during the RT phase of treatment. Response assessment will therefore be limited to patients receiving RT and amifostine without chemotherapy, which we estimate will comprise approximately 50% of the study population. Tumor response will be assessed based on the International Workshop on Response Criteria for Non-Hodgkin’s Lymphoma.34 The disease status after completion of RT will be assessed relative to the disease status at presentation before initiation of treatment. A complete response is defined as no measurable disease both radiographically and by physical examination; lymph nodes previously greater than 1.5 cm must regress to ⱕ1.5 cm, and lymph nodes that were previously 1.1 to 1.5 cm must decrease to ⱕ1 cm. complete response/unconfirmed is defined as regression of lymph node mass greater than 75% along with a negative physical examination. Partial response is defined as ⱖ50% reduction in lymph node mass. Stable disease is defined as less than a partial response, but not progressive disease. Progressive disease is defined as ⱖ50% increase in nodal mass, or appearance of new sites of disease during or at the end of therapy. We further add that nuclear imaging post-treatment, if performed, should be negative for patients with either a complete response or complete response/unconfirmed. However, if nuclear imaging were to be included as part of the response assessment, a pretreatment nuclear medicine study must be available to demonstrate tumor avidity. Relapsed disease is scored by the appearance of any new lesions or increase by ⱖ50% in the size of previously involved sites after the end of therapy. Response assessment will be based on physical examination, computed tomography scans and/or nuclear medicine scans performed within the first 5 months posttreatment.
Biostatistical Analysis In this trial, 110 eligible patients will be randomized equally to each of the two arms (55 patients/arm); approximately 5%
23 are expected to be ineligible. In addition, the analysis will be based on patients who complete all doses of amifostine. We estimate that 10% of the study subjects will be either lost or not assessed during or at the end of RT. Thus, accrual should a total 129 patients to achieve a desired sample size. For the experimental arm, a proportion of patients who experience grade 2 (or worse) xerostomia of 0.4 (or less) will be interpreted as evidence of treatment activity. This study will have an 83% power against the null hypothesis of 0.60 (based on a clinical estimate, and because o the lack of published data on the rate of xerostomia for this patient population) using a one-sided 0.025-alpha level exact binomial test. Therefore, the treatment regimen can be considered promising if, at most, 25 of the 55 eligible patients experience grade 2 (or worse) xerostomia. The 95% exact binomial confidence interval for the true but unknown rate of xerostomia (assuming that 25 of 55 patients experience this toxicity) is 32% to 59%. Although the study was powered for comparison at the end of RT, longitudinal models will be used to assess how the incidence of toxicities is changing over time. The power calculations for the QOL assessment will be based on the “dry-mouth” item from the EORTC-QLQ-H&N questionnaire because amifostine is expected to have the most direct impact on this item. Responses will be linearly transformed to obtain a score from 0 to 100 based on the scoring procedure detailed in the EORTC QLQ-C30 scoring manual. The possible scores for this single item are: 0 (not at all); 33.33 (a little); 66.67 (quite a bit); and 100.00 (very much). A higher score for this item indicates a higher level of symptoms. A change from baseline score of at least 33.33 will be interpreted as a worsening of the dry mouth symptom. The maximum 95% confidence interval width for the true worsening dry mouth symptom rate (ie, rate of patients with a change of baseline score of at least 33.33) is 28% (eg, 35% to 63%). To determine which treatment- and patient-related factors affect QOL, we will examine a multiple linear regression model that includes the covariates treatment and oral function. Strategies for adding additional covariates will be based on a combination of scientific judgment (eg, including variables for which there is strong scientific basis for an effect regardless of statistical significance of the estimated regression coefficient), along with statistical approaches such as stepwise regression. A similar approach will be used to determine which treatment and patient-related factors (ie, age, gender, history of tobacco use, history of alcohol use, and baseline dental health) affect oral function. However, a logistic regression model will be used for this endpoint.
Future Directions Future directions include moving onto a phase III study that may help definitively establish the role of amifostine in these patients, and to evaluate strategies of targeted RT in conjunction with a radioprotectant in patients with lymphoma of the head and neck region. Effective treatments for various forms of lymphoma have been successfully developed over the years. The next important steps are to fine-tune the treatment
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24 and management approaches to minimize morbidity while maximizing the survival and QOL of patients.
20.
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