Analysis of PET parameters as prognosticators of survival and tumor extent in Oropharyngeal Cancer treated with surgery and postoperative radiotherapy.

BACKGROUND: Positron-emission tomography (PET) is widely used to detect malignancies, but consensus on its prognostic value in oropharyngeal cancer has not been established. The purpose of this study was to analyze the PET parameters associated with tumor extent and survival in resectable oropharyngeal cancer. METHODS: The PET parameters in oropharyngeal cancer patients with regional node metastasis who underwent surgery and postoperative radiotherapy between January 2005 and January 2019 were analyzed. We calculated the SUVmax, tumor-to-liver ratio (TLR), metabolic tumor volume (MTV, volume over SUV 2.5), and total lesion glycolysis (TLG, MTV x mean SUV) of the primary lesion and metastatic nodes. Histologic findings, patient survival, and recurrence were reviewed in the medical records. RESULTS: Fifty patients were included, and the PET parameters were extracted for 50 primary lesions and 104 nodal lesions. In the survival analysis, MTV and TLG of the primary lesions showed significant differences in overall survival (OS) and recurrence-free survival (RFS). In the multiple regression analysis, TLG of the primary lesion was associated with the depth of invasion (DOI). MTV of the nodes was a significant factor affecting extranodal extension (ENE). CONCLUSIONS: PET parameters could be related with OS, RFS, DOI of the primary tumor, and ENE. PET would be expected to be a useful diagnostic tool as a prognosticator of survival and pathologic findings in oropharyngeal cancer.

Characterization and radiosensitivity of HPV-related oropharyngeal squamous cell carcinoma patient-derived xenografts.

Background: Oropharyngeal squamous cell carcinomas (OPSCC) are rising rapidly in incidence due to Human Papillomavirus (HPV) and/or tobacco smoking. Prognosis is better for patients with HPV-positive disease, but may also be influenced by tobacco smoking and other factors. There is a need to individualize treatment to minimize morbidity and improve prognosis. Patient-derived xenografts (PDX) is an emerging pre-clinical research model that may more accurately reflect the human disease, and is an attractive platform to study disease biology and develop treatments and biomarkers. In this study we describe the establishment of PDX models, compare PDX tumors to the human original, and assess the suitability of this model for radiotherapy research and biomarker development. Material and methods: Tumor biopsies from 34 patients with previously untreated OPSCC were implanted in immunodeficient mice, giving rise to 12 squamous cell carcinoma PDX models (7 HPV+, 5 HPV-). Primary and PDX tumors were characterized extensively, examining histology, immunohistochemistry, cancer gene sequencing and gene expression analysis. Radiosensitivity was assessed in vivo in a growth delay assay. Results: Established PDX models maintained histological and immunohistochemical characteristics as well as HPV-status of the primary tumor. Important cancer driver gene mutations, e.g., in TP53, PIK3CA and others, were preserved. Gene expression related to cancer stem cell markers and gene expression subtype were preserved, while gene expression related to hypoxia and immune response differed. Radiosensitivity studies showed high concordance with clinical observations. Conclusion: PDX from OPSCC preserves important molecular characteristics of the human primary tumor. Radiosensitivity were in accordance with clinically observed treatment response. The PDX model is a clinically relevant surrogate model of head and neck cancer. Perspectives include increased understanding of disease biology, which could lead to development of novel treatments and biomarkers.

Tumor volume as a prognostic marker in p16-positive and p16-negative oropharyngeal cancer patients treated with definitive intensity-modulated radiotherapy.

PURPOSE: To investigate the impact of primary gross tumor volume (pGTV) and nodal gross tumor volume (nGTV) in oropharyngeal squamous cell carcinoma (OPSCC) and the difference in their role between human papillomavirus (HPV)-positive and HPV-negative patients. METHODS: The patient cohort consists of 91 OPSCC patients treated with definitive radiochemotherapy or radiotherapy using intensity-modulated radiotherapy (IMRT). All patients had a minimum follow-up of 31 months. Volume measurements were made from computer tomography (CT) scans and HPV status was assessed by p16 immunohistochemistry. The end points were as follows: overall survival (OS), disease-free survival (DFS) and locoregional control (LRC). RESULTS: pGTV was a significant independent prognostic factor for overall survival (OS; p = 0.020) in p16-negative patients. nGTV of p16-negative tumors had significant prognostic value in all end points in multivariate analyses. High-stage (III-IVc) p16-negative tumors were only associated with significantly poorer OS (p = 0.046) but not with poorer LRC or DFS when compared with the low-stage (I-II) tumors. nGTV of p16-positive tumors was an independent prognostic factor for DFS (p = 0.005) and LRC (p = 0.007) in multivariate analyses. CONCLUSION: pGTV may serve as an independent prognostic factor in p16-negative patients and nGTV may serve as an independent prognostic factor both in p16-positive and p16-negative patients treated with radiochemotherapy or radiotherapy using IMRT. Tumor volume may have an impact on selecting patients for de-escalation protocols in the future, both in p16-positive and p16-negative patients.

Photobiomodulation therapy: management of mucosal necrosis of the oropharynx in previously treated head and neck cancer patients.

Necrosis of the oral mucosa following head and neck cancer radiation therapy presents considerable clinical management challenges. We report three cases of symptomatic persisting oral ulcerations where the addition of photobiomodulation therapy resulted in a rapid resolution of the oral lesions and in patient symptoms. These cases suggest that photobiomodulation may represent an adjunct to care of these difficult to manage complications in oncology.

Assessment of indomethacin oral spray for the treatment of oropharyngeal mucositis-induced pain during anticancer therapy.

PURPOSE: The efficacy and safety of indomethacin (IM) oral spray (OS) as a pain control therapy for oropharyngeal mucositis due to anticancer chemo- and radiotherapy were assessed in patients with head and neck carcinomas and haematological tumours. METHOD: We observed 35 patients (male/female, 20/15; 53 ± 17 years) with oropharyngeal mucositis who were treated with IM-OS preparation for pain relief at University of Tsukuba Hospital, Japan. Analgesic effects were assessed using the six-grade face scale for pain in 28 patients at the start of IM oral spray treatment. Systemic exposure was assessed by determining urinary excretions of IM in seven patients. RESULTS: Pain relief was achieved in 26 (93%) patients at 25 (5-60) min after applying the IM-OS preparation (15.6 ± 3.4 µg/kg) and analgesic effects were maintained for 120 (10-360) min. The pain was significantly decreased after using the spray (3.6 ± 0.7 vs. 2.4 ± 0.9, p < 0.01). Moreover, urinary IM excretion rates after applying the IM spray preparation were 1.8 ± 0.8% of the IM oral spray dose (130.5 ± 77.7 µg/kg/day), which was markedly lower than that following oral administration of IM (60%). No adverse events were observed following application of the spray. CONCLUSIONS: The present IM spray is an effective and safe preparation for pain relief and can be used as an alternative therapeutic option for oropharyngeal mucositis in cancer patients.

Radiotherapeutic treatment of a fighter pilot with nasopharyngeal carcinoma.

BACKGROUND: Radiotherapy is the standard and most effective treatment for nasopharyngeal carcinoma (NPC) in its early stages. However, its application in fighter pilots returning to flying duties with NPC has not been previously reported, presumably due to post-radiotherapeutic complications. CASE REPORT: A 36-yr-old male fighter pilot had a painless mass in the left neck for 5 mo. Pathological diagnosis demonstrated nonkeratinizing squamous cell carcinoma in the left nasopharynx which had metastasized to lymph nodes in the left side of the neck. He was diagnosed and staged with NPC (T1N2M0) before treatment with radiotherapy and adjuvant chemotherapy. The patient suffered from catarrhal otitis media and xerostomia after 3 mo of radiotherapy, but these symptoms resolved. After a total of 8 mo of radiotherapy, he was in remission with no evidence of tumor recurrence or metastasis. He had normal Eustachian tube, hearing, and vestibular function before and after hypobaric chamber testing and passed all flight-related physical examinations. Consequently, he was granted a medical waiver and returned to flying status in two-seat fighter aircraft, flying for 53 h in a 12-mo period. After passing all flight-related tests again, he was then allowed to fly in single-seat aircraft. At the time of submission of this article, he has flown for 147 h and remained on flying status for 26 mo. He will be monitored annually for long-term effects of radiotherapy and/or disease recurrence. CONCLUSIONS: Fighter pilots with NPC may be safely considered for medical waiver with appropriate monitoring after successful treatment.

Influence of remoteness of residence on timeliness of diagnosis and treatment of oral cavity and oropharynx cancer: A retrospective cohort study.

INTRODUCTION: Geographic disparities in head and neck cancer (HNC) outcomes in Australia may be mediated by timeliness of diagnosis and treatment. This retrospective cohort study examines geographic variations in survival and time intervals leading up to treatment for HNC at two tertiary referral centres in New South Wales. METHODS: Eligible patients were NSW residents aged ≥18 years, diagnosed with primary oropharynx or oral cavity squamous cell carcinoma (SCC) between 01 July 2008 and 30 June 2013, and treated with curative intent. Main outcomes were times from diagnosis to treatment and from surgery to post-operative radiotherapy and overall survival. Differences based on remoteness of residence (regional/remote or metropolitan) were assessed. RESULTS: A total of 224 patients were eligible. Median time from symptom onset to treatment was longer for regional/remote patients with oropharynx SCC (4.7 vs. 3.8 months, P = 0.044) and oral cavity SCC (6.4 vs. 3.3 months, P = 0.003). Median time from diagnosis to treatment was longer for regional/remote patients with oropharyngeal SCC (47 days vs. 36 days, P = 0.003). Time from surgery to adjuvant radiotherapy was longer among regional/remote patients with oral cavity SCC (66 vs. 42 days, P = 0.001). Overall survival did not differ based on remoteness. CONCLUSION: Regional/remote HNC patients experienced longer times to diagnosis and treatment, and regardless of remoteness of residence, fewer than half of patients were treated within guideline recommended timeframes. Despite this non-adherence to guidelines, there were no differences in survival outcomes among this cohort. However, the impact of not meeting guidelines on patient outcomes other than survival warrants further investigation.

Treatment outcomes in oropharynx cancer patients who did not complete planned curative radiotherapy.

PURPOSE: To evaluate outcomes in oropharyngeal cancer (OPC) patients who did not complete their planned curative radiation therapy (RT). METHODS: OPC Patients who received less than planned curative RT dose between 2002 and 2016 were identified for analysis. HPV status was assessed. Radiation dose was normalized for fractionation variations using biological effective doses assuming tumor α/ß = 10 Gy [BED10]. Outcomes were compared using BED10. Multivariable and univariable analysis identified OS predictors. RESULTS: From a total of 80 patients who did not complete therapy, 64 patients were eligible for analysis. RT incompletion was due to: RT side effects (n = 23), patients' decision (n = 21), disease progression or metastases (n = 3), and other causes (n = 7). Median BED10 (Gy) was 56.2 for the HPV-positive and 58 for the HPV-negative. Three-year OS was 74% vs 13% (p < 0.001) for the HPV-positive (n = 29) and HPV-negative (n = 24), respectively. HPV-positive patients who received BED10 ≥55 had higher OS than those received BED10 <55 (94% vs 47%, p = 0.002) while no difference in OS by BED10 ≥55 vs <55 for the HPV-negative (12 vs 13%, p = NS). HPV-positive status was associated with a higher OS (HR 12.5, 95% CI, 4.54 to 33.3, p < 0.001). A total of 37 patients were available to estimate TD50 for local control assessment. TD50 (BED10) was estimated at 60.5 Gy for HPV-negative patients compared to 27.2 Gy for HPV-positive patients. CONCLUSION: Overall, in patients with incomplete treatment, HPV-positive OPC patients demonstrated a better OS compared to HPV-negative patients. HPV-positive patients who received BED10 ≥55 have higher rates of OS.

Priorities of human papillomavirus-associated oropharyngeal cancer patients at diagnosis and after treatment.

INTRODUCTION: Little is known regarding how human papillomavirus-positive oropharyngeal cancer (HPV-OPC) patient goals change with treatment. This study evaluates whether patient ranking of non-oncologic priorities relative to cure and survival shift after treatment as compared to priorities at diagnosis. MATERIALS AND METHODS: This is a prospective study of HPV-OPC patient survey responses at diagnosis and after treatment. The relative importance of 12 treatment-related priorities was ranked on an ordinal scale (1 as highest). Median rank (MR) was compared using Wilcoxon matched-pairs signed-rank tests. Prevalence of high concern for 11 treatment-related issues was compared using paired t-test. The effect of patient characteristics on change in priority rank and concern was evaluated using linear regression. RESULTS: Among 37 patients, patient priorities were generally unchanged after treatment compared with at diagnosis, with cure and survival persistently ranked top priority. Having a moist mouth uniquely rose in importance after treatment. Patient characteristics largely did not affect change in priority rank. Concerns decreased after treatment, except concern regarding recurrence. DISCUSSION: Treatment-related priorities are largely similar at diagnosis and after treatment regardless of patient characteristics. The treatment experience does not result in a shift of priorities from cure and survival to non-oncologic domains over cure and survival. The rise in importance of moist mouth implies that xerostomia may have been underappreciated as a sequelae of treatment. A decrease in most treatment-related concerns is encouraging, whereas the persistence of specific areas of concern may inform patient counseling.

Target volume definition for head and neck intensity modulated radiotherapy: pre-clinical evaluation of PARSPORT trial guidelines.

AIMS: There is considerable controversy surrounding target volume definition for parotid-sparing intensity modulated radiotherapy (IMRT) for head and neck cancer. The aim of this study was to evaluate the dosimetric and radiobiological predictors of outcome anticipated by application of the detailed target volume definition guidelines agreed for the UK multicentre randomised controlled trial of parotid-sparing IMRT (PARSPORT). MATERIALS AND METHODS: Five patients eligible for the study were delineated using the trial guidelines. Following the protocol, plans were produced to treat these volumes with three-dimensional radiotherapy (control arm) and IMRT aimed to spare dose to the contralateral parotid gland (experimental arm). Dosimetric comparisons were made between plans, and normal tissue complication probability (NTCP) modelling for salivary glands was carried out. RESULTS: Doses delivered to the planning target volumes (PTV) were similar with each technique, although IMRT produced more homogeneous irradiation of the PTV. Mean doses to the contralateral parotid gland were 22.4+/-1.7 Gy with the IMRT plans vs 60.0+/-7.2 Gy with three-dimensional radiotherapy, P=0.0003. Calculated contralateral parotid gland NTCP values for grade 2 xerostomia were 20-22% for IMRT and 98-100% for three-dimensional radiotherapy (P<0.0001). CONCLUSION: Pre-clinical evaluation of the PARSPORT trial target volume definition guidelines provides theoretical support for a significant reduction in xerostomia rates. These data await confirmation from the clinical trial results.

Comparison of conventional fractionation (five fractions per week) and altered fractionation (six fractions per week) in stage I and II squamous cell carcinoma of oropharynx: An institutional study.

BACKGROUND: The radiotherapy (RT) dose and fractionation schedule for head and neck cancers for locoregional control and acceptable organ toxicity are still debatable. Accelerated RT includes administration of six fractions per week with the same dose per fraction. AIM: Comparison of conventional versus accelerated RT in terms of locoregional control, and acute and late radiation toxicity in squamous cell carcinoma oropharynx (stage I and II). SETTINGS AND DESIGN: Prospective, double arm, phase 2, randomized study. MATERIALS AND METHODS: Sixty patients of squamous cell carcinoma oropharynx (stage I and II) were randomized in two arms (accelerated fractionation, arm 1 and conventional fractionation, arm 2). All patients received RT dose of 66 Gray (Gy) in 33 fractions (#). The patients in arm 1 received six fractions per week with 2 Gy/# (Monday-Saturday) and in arm 2, five fractions per week with 2 Gy/# (Monday-Friday). No chemotherapy was administered. During and after the treatment, locoregional control, and acute and late radiation toxicity were assessed. RESULTS: At 1-year follow-up, 76% patients in arm 1 and 64% patients in arm 2 had complete response. The recurrence rate at the end of 1 year in arm 1 was 12% and it was 20% in arm 2.The acute Grade 2 and 3 toxicities were higher in the accelerated arm and no significant difference in late toxicities was found. SPSS version 4.0 was used for statistical analysis. CONCLUSION: Accelerated fractionation provides better locoregional control with higher but acceptable acute and equal late radiation toxicity in squamous cell carcinoma oropharynx.

Definitive Intensity-modulated Radiation Therapy in Elderly Patients with Locally Advanced Oropharyngeal Cancer.

BACKGROUND: To evaluate the treatment tolerance and clinical outcomes in patients aged 70 years and older with locally advanced oropharyngeal cancer treated by definitive intensity-modulated radiation therapy (IMRT). PATIENTS AND METHODS: We retrospectively analyzed 15 consecutive elderly patients, with histologically-proven squamous cell carcinoma of the oropharynx, staged T3-4 with or without involved lymph nodes at diagnosis, who received definitive sequential IMRT (70 Gy; 2 Gy/fraction). Adult Comorbidity Evaluation-27 (ACE-27) score was calculated and its influence on treatment tolerance and clinical outcomes was analyzed. RESULTS: A total of 15 patients were included with a median age of 77 years (range=70-88 years). At baseline, 8 patients (53.3%) had an ACE-27 score of 1, and the remainder (n=7, 46.7%) had a comorbidity index of 0. All patients completed programmed IMRT treatment, without any reduction of total dose. Oral pain and mucositis were the most common acute side-effects, classified as grade 3 in 6 patients (40%) only. Xerostomia was reported in 13 patients (86.7%), without severe manifestation. There was no hematological toxicity. ACE-27 score was not related to higher severe acute toxicity. No patients experienced grade 3 or more late toxicity. Five-year overall survival and disease-free survival rates were 63.6% (95% confidence interval=32.7-83.3%) and 55% (95% confidence interval=24.4-77.6%), respectively. Comorbidity score did not influence survival outcomes, both overall survival (p=0.46) and disease-free survival (p=0.55). CONCLUSION: Treatment tolerance, as well as survival outcomes were good in elderly oropharyngeal cancer patients treated with definitive sequential IMRT. Due to age and comorbidity, no dose or volume reduction for IMRT should be considered in this setting of patients. A prospective randomized trial with a large sample size should be conducted to confirm our results.

Randomized clinical trial on 7-days-a-week post-operative radiotherapy vs concurrent post-operative radiochemotherapy in locally advanced cancer of the oral cavity/oropharynx: a report on acute normal tissue reactions.

OBJECTIVE: The purpose of the study was to evaluate acute normal tissue reactions and treatment compliance in a randomized clinical trial on 7-days-a-week post-operative radiotherapy (p-CAIR) vs post-operative concurrent radiochemotherapy (p-RTCT) in locally advanced cancer of the oral cavity/oropharynx. The sample analyzed at present represents approximately 30% of the intended future trial size. METHODS: The patients were randomly assigned to receive 63 Gy in 1.8-Gy fractions 7 days a week (n = 44) or 63 Gy in 1.8-Gy fractions 5 days a week with concurrent cisplatin 80-100 mg per square metre of body surface area on Days 1, 22 and 43 of the course of radiotherapy (n = 40). Acute mucosal reactions were scored using the modified Dische system. RESULTS: 15 (17.9%) patients, including 5 patients in p-CAIR and 10 patients in p-RTCT, did not comply with the assigned radiation treatment, mostly because of rapid tumour progression or deteriorating general performance. In p-RTCT, 22 (55%) patients received less than the intended three courses of chemotherapy mostly owing to haematological toxicity. The average maximum mucosal severity score was 14.2 in p-CAIR compared with 13.4 in p-RTCT; the difference was not statistically significant (p = 0.31). CONCLUSION: The schedules compared (p-CAIR and p-RTCT) did not differ considerably with respect to acute mucosal reactions. Haematological toxicity in p-RTCT was elevated compared with p-CAIR. Both schedules were considered tolerable with respect to acute toxicity, which justifies further recruitment to the trial. ADVANCES IN KNOWLEDGE: The results show that early mucosal reactions are comparable in both trial arms but haematological toxicity is more pronounced during radiochemotherapy.

Experience with microvascular free flaps in preoperatively irradiated tissue of the oral cavity and oropharynx in 303 patients.

This study examined free flap reconstruction of surgical defects of the oral cavity and oropharynx after preoperative radiochemotherapy. Included in this analysis are 303 prospectively followed patients who underwent a multimodal treatment regime for advanced oral and oropharyngeal carcinoma. All patients received preoperative radiochemotherapy (Mitomycin C, 5-FU, 50 Gy), ablative surgery, and primary free flap reconstruction. Patient characteristics, surgical parameters like duration of surgery and ischaemia, size of defect, type of transplant, and clinical outcome parameters like duration of intensive care and hospitalization, type of complications, necessity and type of revision surgery were statistically evaluated. Overall flap success rate was 93.1%. Sixty seven patients required revision and 21 flaps (6.9%) were lost. Overall complication rate was 22.1%. Mean duration of intensive care (DOIC) and duration of overall postoperative hospitalization (DOH) were 11.0+/-9.6 days and 35.9+/-26.3 days, respectively. Flap success and flap related complications after 50 Gy focal radiation dosage were found in a comparable range as in published series of reconstructions in uncompromised tissue.

Management of oropharyngeal and tracheobronchial secretions in patients with neurologic disease.

BACKGROUND: Neurologic disorders may impair the normal clearance of secretions. Effective palliation requires the management of excessive oral, pharyngeal and/or tracheobronchial secretions. This requires an understanding of underlying mechanisms and familiarity with the many available medical and surgical treatment options. OBJECTIVES: The authors intend to review the relevant anatomy and physiology along with the available medical, surgical and physical therapies available to treat this commonly encountered problem. DESIGN: A review of current management and the supporting literature. CONCLUSIONS: Clinicians have many effective therapeutic options to choose from when managing the excessive oral, pharyngeal and/or tracheobronchial secretions caused by neurologic disorders. Treatment choices that are predicated upon pathophysiologic causes and patient status are the most likely to succeed.

Thermal tomography imaging in photonic traditional Chinese medicine information therapy with holistic effect for health whole nursing.

A photonic traditional Chinese medicine (TCM) information therapy was developed that has applications in whole health nursing including the prevention and treatment of ischemic cardiovascular and cerebrovascular diseases as well as the conditioning of the subhealth state. This therapy utilizes the beam of a 630 nm LED light to irradiate the oropharynx, while simultaneously employing two beams of 650 nm LED light to irradiate corresponding acupuncture points resulting in a synergistic outcome. This method was named "1 + 2 phototherapy." The principle mechanism of the therapy is a series of photon induced biological effects that are triggered by stimulating the photosensitive tissues of the oropharynx. This tissue includes the oral mucosa, capillaries, lymph nodes, saliva glands, nerves, and Jingluo and is stimulated by light beams of certain photon energy and imitative acupuncture information. Thermal tomography imaging shows that the average temperature of the upper-body was improved significantly after oropharyngeal irradiation under irradiation of "Futu point": the heat radiation of the spine, as well as chest, shoulders, arms, and clavicle, increased under irradiation of "Hoku," whereas the overall average temperature was below the temperature before irradiation. The experiment indicates that this therapy can promote blood circulation, regulate varied physiological parameters, and have holistic effects in whole health nursing.

Salvage irradiation by brachytherapy of velotonsillar squamous cell carcinoma in a previously irradiated field: results in 73 cases.

PURPOSE: The salvage brachytherapy performed in patients presenting velotonsillar carcinoma in a previously irradiated field is evaluated in terms of local control, complications and survival. METHODS AND MATERIALS: Between 1976 and 1990, 73 patients presenting with velotonsillar squamous cell carcinoma in a previously irradiated area were treated at Center Alexis Vautrin with brachytherapy along using an 192Ir implant (afterloading technique) with curative intent. According to the UICC 1987 TNM classification, there were 45 T1 N0, 20 T2 N0, one T3 NO, one T3 N2 and six Tx Nx. RESULTS: The 5-year actuarial local control for T1 N0 and T2 N0 are 80% and 67% respectively. The regional relapse rate was 10% in both groups. Grade 2 complications occurred in 13% of patients and these were neither related to the volume treated nor the dose rate. There were no Grade 3 or 4 complications. The 5-year specific survival is 64%, with a plateau after the 5th year, but the 5-year overall survival is only 30%. Fourty-two percent of the patients in this series died from another carcinoma. All but two of these were related to continued alcohol and tobacco intoxication. CONCLUSION: We conclude that brachytherapy alone (60 Gy) is optimal treatment for patients presenting with velontonsillar carcinoma in a previously irradiated field. The greatest challenge is the screening of these patients and the prevention of subsequent head and neck cancers. Recognizing the fact that these patients are at high risk for subsequent malignancies of upper aerodigestive tract, lung and esophagus, close surveillance is necessary for: (a) early diagnosis and prompt treatment; and (b) development of prevention strategies of field cancerization.

Acute radiation reactions in oral and pharyngeal mucosa: tolerable levels in altered fractionation schedules.

PURPOSE: To investigate whether a predictive estimate can be obtained for a 'tolerance level' of acute oral and pharyngeal mucosal reactions in patients receiving head and neck radiotherapy, using an objective set of dose and time data. MATERIALS AND METHODS: Several dozen radiotherapy schedules for treating head and neck cancer have been reviewed, together with published estimates of whether they were tolerated or (in a number of schedules) not. Those closest to the borderline were given detailed analysis. Total doses and biologically effective doses (BED or ERD) were calculated for a range of starting times of cellular repopulation and rates of daily proliferation. Starting times of proliferation from 5 to 10 days and daily cellular doubling rates of 1-3 days were considered. The standard published form of BED with its linear overall time factor was used: BED=nd(1 + d/(alpha/beta) - Ln2(T - T(k))/alpha T(p) (see text for parameters). RESULTS: A clear progression from acceptable to intolerable mucosal reactions was found, which correlated with total biologically effective dose (BED in our published modeling), for all the head and neck cancer radiotherapy schedules available for study, when ranked into categories of 'intolerable' or 'tolerable'. A review of published mechanisms for mucosal reactions suggested that practical schedules used for treatment caused stimulated compensatory proliferation to start at about 7 days. The starting time of compensatory proliferation had little predictive value in our listing, so we chose the starting time of 7 days. Very short and very long daily doubling rates also had little reliability, so we suggest choosing a doubling time of 2.5 days as a datum. With these parameters a 'tolerance zone of uncertainty' could be identified which predicted acute-reaction acceptability or not of a schedule within a range of about 2-10 Gy in total BED. If concurrent chemoradiotherapy is used, our provisional suggestion is that this zone should be reduced by up to roughly 3-5 Gy10 in BED, with a request for further evidence. CONCLUSIONS: It is suggested that total BED should be used, as specified above. Parameters of alpha=0.35 Gy-(1), alpha/beta=10 Gy, Tk=7 days and Tp=2.5 days are suggested. The 'acute/ tolerance zone' then turns out to be 59-61 Gy10 for radiation-only treatments. Further information about the decrement caused by concurrent head-and-neck cancer chemoradiotherapy, possibly 3-5 Gy10, is required.

Acute reaction parameters for human oropharyngeal mucosa.

The purpose of this study was to determine the influence of changes in dose rate over the range 0.8-240 Gy/h on acute oropharyngeal mucosal reactions in human subjects, and to estimate the values of the important parameters that influence these reactions. Sixty-one patients requiring radiotherapy to palliate incurable head and neck cancer were treated on a telecaesium unit, using opposing lateral portals to total midline doses, varying between 30 and 42 Gy in 10 daily fractions over 2 weeks, at dose rates of 0.8, 1.8, 3.0 and 240 Gy/h according to a central composite study design. The severity and time course of reactions were charted at least twice weekly for each patient, using the EORTC/RTOG acute mucosal reaction grading system. Duration of reaction at each grade was observed to provide a more sensitive reflection of effect than the proportion of patients reaching any particular reaction grade. Analysis of duration by direct and indirect methods suggest alpha/beta ratios in the range 7-10 Gy and half-time (t1/2) values in the range 0.27-0.5 h, if mono-exponential repair kinetics are assumed. The t1/2 values are short and raise the question as to whether the repair kinetics of this tissue are well described by a mono-exponential function. Further prospective studies involving multiple daily fraction treatment regimes delivered at high dose rate, in which interfraction interval is deliberately varied, are needed to find out whether the parameters derived from this project are applicable to fractionated treatment courses at high dose rate.