Long-Term Outcome and Morbidity After Treatment with Accelerated Radiotherapy and Weekly Cisplatin for Locally Advanced Head-and-Neck Cancer: Results of a Multidisciplinary Late Morbidity Clinic

Long-Term Outcome and Morbidity After Treatment with Accelerated Radiotherapy and Weekly Cisplatin for Locally Advanced Head-and-Neck Cancer: Results of a Multidisciplinary Late Morbidity Clinic
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  the number of chemotherapy and radiotherapy cycles, number of radiation fractions, the chemotherapy drug dose and themidplane radiation dose at the central axis. However, the patients in IM group had a smaller radiation dose gradient across theentire treatment volume (p  0.001) and required unscheduled treatment break in 2/18 (11%) of patients as compared to 9/21(43%) of patients in NIM group (p  .04). Acute Toxicities (RTOG): IM group had lower grade 3 or 4 toxicities in most of theorgans studied: *(p  .05), Skin (50% vs 62%), Mucositis (61% vs 90%), Dysphagia (50% vs 67%), Pain (28% vs 67%)*,Weight Loss (0% vs 14%), and Voice Changes (22% vs 10%). Chronic Toxicities (RTOG): The IM group had lower grade 3or 4 toxicities: Skin (0% vs 24%)*, Dysphagia (22% vs 43%), Salivary glands (22% vs 38%), Mandible (0% vs 5%), and Larynx(6% vs 10%). SOMA Scale: The IM group had lower SOMA scores; Skin and Subcutaneous tissue (0.30 vs 0.51), Mucosa (0.48vs 0.62), Salivary gland (2.50 vs 2.72), Mandible (0 vs 0.18) and Larynx (0.32 vs 0.43). Descriptive Analysis: There were fourpostcricoid stictures, 1 laryngeal stenosis, 1 laryngeal necrosis and 1 mandibular fracture    in NIM group. None of this occurredin IM group. Swallowing Measures: Patients in IM group were able to maintain better oral intake more than or equal to 50%of their nutrition, had lower pharyngeal residue and better Orophyaryngeal swallow ef  fi ciency. Patients in IM group were ableto swallow multiple bolus types in higher percentage and signi fi cantly more at the 3 and 5 ml volumes (p  .01). SpeechMeasures: The individual consonant speech sounds were consistently more understandable in the IM group. The difference    incorrect articulation of all consonants approaches signi fi cance in favor of the IM group. Quality of Life: The change in dif  fi cultyin swallowing was statistically signi fi cantly different between groups with more patients in the NIM group getting worse. Onmany of the other performance outcomes and functions/symptoms evaluated. There was a trend for more patients in the NIMgroup to be more symptomatic. Conclusion:  Use of IMRT resulted in reduced treatment-related interruptions, decreased acute and chronic toxicities, and betterspeech and swallowing functions. Techniques to improve radiation dose conformality around the target tissues while decreasingthe radiation dose to the normal tissues should be an integral part of aggressive combined modality therapy. 148  A Prospective Study on Tumor Hypoxia Kinetics to Implement Hypoxic Imaging-guided IMRT K.S. Chao, W.R. Bosch, S. Mutic, J.S. Lewis, F. Dehdashti, M.A. Mintun, J.F. Dempsey, C.A. Perez, J.A. Purdy, M.J. Welch  Radiology, Washington University, St. Louis, St. Louis, MO Purpose:  Local/regional tumor control for locally advanced cancers with radiation therapy has been unsatisfactory. This is inpart associated with the phenomenon of tumor hypoxia. Assessing hypoxia in human tumors has been dif  fi cult due to the lack of clinically non-invasive and reproducible methods. A recently developed positron emission tomography (PET) imaging-basedhypoxia measurement technique employing a Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) tracer is of greatinterest. Intensity modulated radiation therapy (IMRT) allows selective targeting of tumor and sparing of normal tissues. In thisstudy we examined the feasibility of combining these novel technologies to develop hypoxia imaging guided IMRT, and tounderstand the kinetics of tumor hypoxia during a course of fractionated RT. Materials and Methods:  Sixteen patients with carcinoma of the head and neck area were prospectively enrolled in a study toinvestigate the kinetics of tumor hypoxia during a course of fractionated radiation therapy (RT). A CT and PET imagingco-registration system was integrated into the thermoplastic immobilization head mask using four CT and PET compatible fi ducial markers to assist image fusion on a Voxel-Q treatment planning computer. Before the initiation of the clinical trial, we fi rst performed a quality assurance phantom study to assess the spatial accuracy of target volume mapping after multi-modalityimage co-registration. The gross tumor volume (GTV) was delineated based on physical and radiological  fi ndings. Delineationof ATSM-avid or hypoxic tumor volume (hGTV) and the generation of hypoxia imaging-guided IMRT treatment plans werepreviously reported. The Cu-ATSM PET scan was performed at different time points during a course of RT (before RT, at 20Gy, and at 40 Gy) to study the evolution of tumor hypoxia. Results:  The quality assurance study on the accuracy of target volume mapping showed that the spatial  fi delity and imagingdistortion after CT and PET image co-registration were within 2 mm. Using  fi ducial markers to assist CT/PET imaging fusionin patients, a heterogeneous distribution of 60Cu-ATSM within the GTV illustrated the success of 60Cu-ATSM PET to selectan ATSM-avid or hypoxic tumor sub-volume (hGTV). We further demonstrate the feasibility of Cu-ATSM-guided IMRT byshowing that the radiation dose to the hGTV could be escalated without compromising normal tissue (parotid glands and spinalcord) sparing. The results of tumor hypoxia evolution during RT will also be presented. Conclusion:  We demonstrated the feasibility of a novel Cu-ATSM-guided IMRT approach through co-registering hypoxia60Cu-ATSM PET to the corresponding CT images for IMRT planning. Information on tumor hypoxic kinetics will expand ourunderstanding of target volume uncertainty before implementing this novel therapeutic approach to patients with locallyadvanced tumor. Acknowledgments:  This study is supported in part by NIH grant R01 CA-89198, DOE grant DE-FG02-87ER60512, and anAlvin J. Siteman Cancer Center grant. 149  ARCON: Experience in 215 Patients with Advanced Head and Neck Cancer J.H. Kaanders 1 , L.A. Pop 1 , H.A. Marres 2 , I. Bruaset 3 , F.J. van den Hoogen 2 , M.A. Merkx 3 , A.J. van der Kogel 1 1  Radiation Oncology, University Medical Center St Radboud, Nijmegen, Netherlands,  2 Otorhinolaryngology, University Medical Center St Radboud, Nijmegen, Netherlands,  3 Oral and Maxillofacial Surgery, University Medical Center St  Radboud, Nijmegen, Netherlands Purpose:  Hypoxia and tumor cell repopulation are radiation resistance mechanisms with proven clinical relevance in head and neck carcinomas. Randomized clinical trials have demonstrated the effectiveness of accelerated radiotherapy to counterbalance tumorrepopulation.Anextsteptofurtherimprovetreatmentoutcomeisbycombinationofacceleratedradiotherapywithhypoxiamodi fi ers.Studies in mouse tumors showed signi fi cant sensitization when accelerated radiotherapy was administered together with carbogenbreathing and nicotinamide to reduce chronic and acute hypoxia (ARCON). An enhancement ratio of 1.9 relative to conventionallyfractionated radiotherapy alone was obtained with doses and fractionation schedules close to those used clinically.83Proceedings of the 43rd Annual ASTRO Meeting  The aim of this phase II study was to assess the feasibility, toxicity and potential effectiveness of ARCON for advanced headand neck cancer. Patients and Methods:  Two-hundred-and- fi fteen patients with advanced head and neck carcinomas were enrolled in the studybetween October 1993 and October 2000. There were 166 men and 49 women and the median age was 58 years (range 28-87).The primary tumor site was larynx in 100, hypopharynx in 50, oropharynx in 52 and oral cavity in 13 cases. Eight patients hadstage II disease, 71 stage III and 136 stage IV.The total radiation dose was 68 Gy for oral cavity and oropharynx tumors and 64 Gy for larynx and hypopharynx tumors.Treatments were given on weekdays with fractions of 2 Gy. The overall treatment time was limited to 36-38 days by givingtwo fractions per day during the last one and a half week of the treatment. The interval between fractions was at least 6 h.Carbogen breathing commenced 4 min before irradiations and continued throughout. Nicotinamide (60-80 mg/kg) wasadministered orally 1 – 1.5 h before irradiations. Results:  Median follow-up of surviving patients was 31 months at the time of analysis. Twenty-six patients (12%) were unableto breathe carbogen during the entire course of the treatment because of discomfort with the breathing procedure orhyperventilation. Apart from this, carbogen breathing produced no particular side-effects. In the initial phase of the study thenicotinamide dose was 80 mg/kg which produced severe nausea and vomiting necessitating discontinuation of the drug in 31%of the patients. During the study the nicotinamide dose was reduced to 60 mg/kg and prophylactic anti-emetic treatment wasinitiated resulting in a reduction of the discontinuation rate to 10%.Con fl uent mucositis was observed in 91% of the patients with a median duration of 6 weeks (range 1-16 weeks). Seventy-fourpatients (34%) required temporary tube feeding. Moist desquamation of skin was observed in 57% of the patients with a medianduration of 2 weeks (range 1-11 weeks). Healing of early mucosal and skin reactions was complete in all patients.RTOG/EORTC grade 4 late complications occurred in 10 patients (5%) including super fi cial mucosal necrosis in 3, necrosisof the laryngeal cartilage in 3 and osteoradionecrosis in 4.The 3-year actuarial loco-regional control, disease-free survival and overall survival rates for the whole group were 69%, 63%and 60%. The actuarial 3-year control rates at the primary tumor site were 80% for larynx, 69% for hypopharynx and 76% fororal cavity/oropharynx tumors. The regional control rates were 95%, 72% and 81% for the respective tumor sites. For T3 andT4 larynx carcinomas (N  79) the local control rate was 80% at 3 years. Conclusion:  The multifactorial approach of ARCON yields high local and regional control rates in advanced head and neck carcinomas with acceptable early and late morbidity. Compliance with carbogen breathing and nicotinamide is satisfactory. Thelocal control rate of 80% in T3 and T4 larynx carcinomas offers excellent possibilities for organ preservation. 150  A Phase II Trial of Subcutaneous Amifostine and Radiation Therapy in Patients with Head and NeckCancer (WR-B060) P. Anne  1 , W. Curran 1 , M. Machtay 2 , D. Rosenthal 2 , D. Brizel 3 , D. Irwin 4 , P. Chougule 5 , N. Estopinal 6 , A. Berson 7 , W.Morrison 8 1  Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA,  2  Radiation Oncology, University of Pennsylvania, Philadelphia, PA,  3  Radiation Oncology, Duke University Medical Center, Durham, NC,  4  RadiationOncology, Alta Bates Comprehensive Cancer, Berkley, CA,  5  Radiation Oncology, Rhode Island Hospital, Providence, RI, 6   Radiation Oncology, Comprehensive Cancer Institute of Huntsville, Huntsville, AL,  7   Radiation Oncology, St. Vincent  ’ s Hospital, New York, NY,  8   Radiation Oncology, MD Anderson Cancer Center, Houston, TX  Amifostine is an organic thiophosphate that protects normal tissues from the cytotoxic effects of radiation therapy (RT). Resultsof a Phase III trial of RT    amifostine in head and neck cancer patients showed that pretreatment with intravenous (IV)amifostine signi fi cantly reduced the incidence of   Grade 2 acute/late xerostomia (Brizel, J Clin Oncol 18:3339-3345,2000).Objectives of this Phase II trial were to verify that subcutaneous (SC) amifostine, as suggested by pharmacokinetic andpreclinical data, protects against RT-induced xerostomia and ameliorates side effects known to occur with IV amifostine. Theseside effects include nausea, vomiting and hypotension. Patients received amifostine as two 250 mg SC injections (2.5 mL total)60 minutes prior to RT (1.8-2.0 Gy/day for 25-35 fractions). Xerostomia was graded according to RTOG criteria. 55 patientswere enrolled, with 54 evaluable for xerostomia. Results are shown below, along with similar results from the Phase III trial.Acute xerostomia was observed in this trial at a comparable rate as in the amifostine arm in the Phase III trial. There were noreports of Grade 3 hypotension or Grade 3 nausea/vomiting following SC amifostine (3% and 7%, respectively with IV). Grade3 generalized cutaneous toxicity occurred in 13% of patients (3% with IV). Cutaneous reactions such as localized skin reactionswere the most signi fi cant side effect. In summary, these data suggest that SC amifostine provides comparable protective effectsagainst RT-induced acute xerostomia, and reduces the amifostine-related side effects of nausea, vomiting and hypotension. Thecutaneous reactions reported in this trial are being investigated in further programs using prophylactic measures. Phase II Phase IIISC Amifostine IV Amifostine  RT RT p valueN 54 148 153  Grade 2 acute xerostomiaIncidenceAll patients 56% 51% 78%   0.0001Patients receiving  60 Gy RT 49% 51% 78%   0.0001Median time to onset 40 days 45 days 30 days 0.0001Median cumulative RT dose to onset 58 Gy 60 Gy 42 Gy 0.0001 84 I. J. Radiation Oncology  ●  Biology  ●  Physics Volume 51, Number 3, Supplement 1, 2001
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