Hearing loss due to concurrent daily low-dose cisplatin chemoradiation for locally advanced head and neck cancer.

BACKGROUND AND PURPOSE: Cisplatin-based chemo-irradiation (CRT) is increasingly used for head and neck squamous cell carcinoma (HNSCC). We aimed to assess hearing deterioration due to low-dose cisplatin chemoradiation and to compare the observed hearing loss with hearing loss in our previously described high-dose cisplatin CRT cohort. MATERIALS AND METHODS: A prospective analysis of hearing thresholds at low and (ultra)-high frequencies obtained before and after treatment in 60 patients. Patients received low-dose cisplatin (6mg/m(2), daily infusions, 20-25 days) with concomitant accelerated radiotherapy (70Gy). RESULTS: Audiometry up to 16kHz was performed before therapy and 31 days (median) post-treatment. The total incidence of ototoxicity in CTCAEv3.0 was 31% in audiograms up to 8kHz, and 5% of ears tested qualified for HAs due to treatment. The mean hearing loss at speech frequencies was 2.6dB (SD 5.7) and 2.3dB (SD 9.2) at PTA 1-2-4kHz air-conduction and bone-conduction, respectively. The mean hearing loss at ultra-high frequencies (PTA AC 8-10-12.5kHz) was 9.0dB (SD 8.1). Low-dose cisplatin CRT caused less acute hearing loss (CTCAE 31%), compared to high-dose cisplatin CRT (CTCAE 78%). CONCLUSIONS: Low-dose cisplatin chemo-irradiation for HNSCC is a relatively safe treatment protocol with respect to ototoxicity.

Prognostic value of primary tumor volume after concurrent chemoradiation with daily low-dose cisplatin for advanced-stage head and neck carcinoma.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of tumor volume in head and neck squamous cell carcinoma treated with chemoradiation. METHODS: Forty-six patients were treated with radiotherapy and cisplatin (6 mg/m(2) IV x 20, daily). Baseline primary tumor volume was recorded from MRI scans. The prognostic impact of tumor volume and other factors for locoregional control, disease-free survival (DFS), and overall survival (OS) was tested. RESULTS: Mean tumor volume was 28 cm(3) (median 23 cm(3); range, 3-112). The locoregional control rate at 3 years was 81% for patients with tumor volumes or = median (p = .036). At multivariate analysis, it appeared that tumor volume remained an independent determinant of locoregional control and survival when adjusted for other factors. CONCLUSIONS: In advanced-stage head and neck squamous cell carcinoma treated with concurrent chemoradiation, primary tumor volume is associated with locoregional control and survival. Larger studies are needed to confirm whether incorporation of tumor volume in the staging system improves prediction of treatment outcome and can serve as a tool to guide treatment options.

Ototoxicity in a randomized phase III trial of intra-arterial compared with intravenous cisplatin chemoradiation in patients with locally advanced head and neck cancer.

PURPOSE: Cisplatin concomitantly administered with radiotherapy is increasingly used in locally advanced head and neck squamous cell carcinoma. We aimed to compare the incidence of hearing loss between patients treated with intra-arterial high-dose cisplatin chemoradiation with sodium thiosulfate (CRT-IA) and intravenous high-dose cisplatin chemoradiation without sodium thiosulfate (CRT-IV). PATIENTS AND METHODS: We conducted a prospective analysis of hearing thresholds at low and (ultra-) high frequencies obtained before, during, and after treatment in 158 patients. Patients were randomly assigned for either CRT-IA (150 mg/m(2), four courses) with sodium thiosulfate cisplatin neutralization or CRT-IV (100 mg/m(2), three courses) without rescue. All patients received concomitant radiation therapy (RT; 70 Gy). RESULTS: CRT-IA resulted in approximately 10% less hearing loss at frequencies vital for speech perception, compared with CRT-IV (P < .001). In CRT-IA, fewer ears qualified for hearing aids (36% v 49%; P = .03). However, in both treatment arms, the incidence expressed in National Cancer Institute Common Terminology Criteria of Adverse Events (version 3) did not deviate (P > .14). Age, cumulative cisplatin dose, cumulative RT dose, and the considered frequency area determine the degree of hearing loss (P < .001). Cisplatin induced increasing hearing loss of 24% to 60% with increasing frequencies. RT induced hearing loss at speech frequencies of 9% to 12%. CONCLUSION: Depending on the criteria used to assess hearing loss due to treatment, differences in ototoxicity between CRT-IA and CRT-IV were found in favor of CRT-IA. It is desirable to specify hearing loss criteria toward frequencies vital for speech perception, and to refine grading scales to reveal subtle and clinically relevant dissimilarities in ototoxicity between different treatment protocols.

Concurrent chemoradiation with daily low dose cisplatin for advanced stage head and neck carcinoma.

BACKGROUND AND PURPOSE: To evaluate treatment results of concurrent chemoradiation with daily low dose cisplatin. MATERIALS AND METHODS: 121 patients with advanced stage HNSCC were treated with RT (35 x 2 Gy) and cisplatin (6 mg/m(2) i.v. x20, daily before RT). After 47 patients, the treatment protocol (Standard Group) was changed: Daily i.v. prehydration and accelerated RT were given to the subsequent 74 patients (Hydr-Ac-RT Group). RESULTS: Mean follow-up was 29 months (range 7-62). More chemotherapy could be administered in the Hydr-Ac-RT Group (maximum no. of 20 cisplatin-infusions increased from 59% to 91% of patients, p=0.008), with less renal toxicity (p<0.001) and less hospital admissions (p<0.02). However, mucositis was more pronounced and tubefeeding more frequent in the Hydr-Ac-RT Group. The CR rate of the primary tumor increased from 74% (Standard Group) to 90% (Hydr-Ac-RT Group) (p=0.06), although this did not lead to an improvement in loco-regional control. CONCLUSIONS: Concurrent chemoradiation with daily low dose cisplatin is feasible and effective for selected patients with advanced HNSCC. Although the addition of accelerated RT resulted in more mucositis and tubefeeding, the introduction of prehydration led to better compliance to therapy with more chemotherapy administered and less hospital admissions.

Risk factors of ototoxicity after cisplatin-based chemo-irradiation in patients with locally advanced head-and-neck cancer: a multivariate analysis.

PURPOSE: Cisplatin chemo-irradiation is increasingly used in locally advanced squamous cell carcinoma of the head and neck. The objective of this study is to determine risk factors of ototoxicity due to intra-arterial high-dose cisplatin chemoradiation. METHODS AND MATERIALS: A prospective analysis of hearing thresholds at low and (ultra) high frequencies obtained before, during, and after treatment in 146 patients. Treatment consisted of intra-arterial infusion of high-dose cisplatin (150 mg/m(2), four courses) with sodium thiosulfate rescue and concurrent radiation therapy (70 Gy). Patient and chemoradiation variables were studied in a multivariate analysis. RESULTS: After treatment, 23% of the ears were under consideration for hearing aids because of therapy. Twenty-two percent of the patients developed an increase in air-bone gap >10 dB during or after therapy. In the multivariate explanatory analysis, cumulative dose of cisplatin and radiation therapy, and young age displayed a causal relationship with increased sensorineural hearing loss during and after therapy (p < 0.001). In the multivariate prediction analysis, pretreatment hearing level of the concerning ear was identified as an independent predictive factor for hearing capability after therapy (p < 0.0001). CONCLUSIONS: Both cisplatin and radiation therapy were proven to induce sensorineural hearing loss, in this study with short-term follow-up. Of all patient and treatment variables studied, the patients pretreatment hearing level appeared to be the main predictive factor for hearing capability after high-dose intra-arterial cisplatin chemoradiation.

Relationship between clinical factors and the incidence of toxicity after intra-arterial chemoradiation for head and neck cancer.

BACKGROUND AND PURPOSE: Concomitant chemoradiation is more and more used for advanced head and neck cancer. It improves local control and survival compared to radiotherapy alone, but goes along with serious toxicity. This study was set up to determine the relationship between patient-, tumour- and treatment-related factors and acute/late toxicity after concomitant chemoradiation. PATIENTS AND METHODS: One hundred and twenty-five consecutive patients with newly diagnosed inoperable stage III and IV head and neck cancer were enrolled for intra-arterial chemoradiation. There were 28 women (22%) and 97 men (78%) and the mean age was 55 years (range 30-80). One hundred and nine patients had stage IV disease (87%), 16 patients (13%) had stage III disease. Statistical analyses were performed to identify an association between factors and acute/late toxicity. RESULTS: There were eight treatment-related deaths (6%). Severe acute toxicity (grade 3-4), mainly mucositis and dysphagia as categorized by the RTOG toxicity criteria, was recorded in 51% of the patients. Leucopenia (grade 3-4) occurred in 39% and aspiration pneumonia in 20% of patients. Tracheotomy was necessary in 15 (12%) patients. Neurological complications during treatment occurred in 3 (2%) patients. Severe late toxicity occurred in 34% of the patients. The most important of these were pneumonia (14%), osteoradionecrosis (9%) and swallowing problems with permanent percutaneous gastrostomy (20%). Statistical analysis did show a significant association between site and severe acute mucositis (p = 0.007), site and osteoradionecrosis (p = 0.014) and age and xerostomia (p = 0.004). CONCLUSIONS: Chemoradiation is frequently associated with serious toxicity. Oral cavity tumours and older age are related to acute mucositis/osteoradionecrosis and xerostomia, respectively.

Health-related quality of life in survivors of locally advanced breast cancer: an international randomised controlled phase III trial.

BACKGROUND: Dose-intensive chemotherapy has generated much interest in the treatment of patients with locally advanced breast cancer because it might offer a survival benefit. We aimed to compare the effects of such an approach with those of standard chemotherapy on health-related quality of life (HRQOL). METHODS: 224 patients with locally advanced breast cancer were randomly assigned to 75 mg/m(2) cyclophosphamide given orally on days 1-14, and 60 mg/m(2) epirubicin and 500 mg/m(2) fluorouracil both given intravenously on days 1 and 8, for six cycles every 28 days (6 months' treatment; standard treatment) and 224 patients to 830 mg/m(2) cyclophosphamide and 120 mg/m(2) epirubicin both given intravenously on day 1, and 5 microg/kg filgrastim per day given subcutaneously on days 2-13, for six cycles every 14 days (3 months' treatment; dose-intensive treatment). HRQOL was assessed by use of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Baseline assessments were done before randomisation; then once a month for the first 3 months; and at months 6, 9, 12, 18, 26, 34, 42, 48, and 54. The primary endpoint was progression-free survival; secondary endpoints were HRQOL, response, safety, overall response, and health economics. Analyses were by intention to treat. FINDINGS: Previously reported data showed that groups did not differ in progression-free survival. Patients assigned shorter, intensified treatment had a significantly lower overall HRQOL score during the first 3 months than did those assigned standard treatment (mean score at 3 months 41.8 [SD 1.78] vs 49.6 [1.64], p=0.0015). However, scores returned to near baseline, with no difference between groups, at 12 months (62.6 [1.97] vs 65.6 [2.04], p=0.3007). Over the remaining 2 years, the groups showed few significant differences in HRQOL. INTERPRETATION: Dose-intensive treatment only has a temporary effect on HRQOL, thus enabling more research on intensive treatment for patients with locally advanced breast cancer.

Pretreatment probability model for predicting outcome after intraarterial chemoradiation for advanced head and neck carcinoma.

BACKGROUND: Concurrent chemoradiation is being used increasingly to treat patients with advanced-stage head and neck carcinoma. In the current study, a clinical nomogram was developed to predict local control and overall survival rates for individual patients who will undergo chemoradiation. METHODS: Ninety-two consecutive patients with UICC TNM Stage III/IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and supraglottic larynx were treated with selective-targeted chemoradiation (acronym: RADPLAT). All living patients had a minimum follow-up of 2 years. In addition to general factors, the following parameters were analyzed in a multivariable analysis: primary tumor volume, lymph node tumor volume, total tumor volume, lowest involved neck level, comorbidity, pretreatment hemoglobin level, pretreatment weight loss, and unilateral/bilateral intraarterial infusion. Relevant factors for local control and survival were analyzed using the Cox proportional hazards model. RESULTS: At 5 years, the local control and overall survival rates for the whole group were 60% and 38%, respectively. Primary tumor volume (hazard ratio [HR], 1.03; P = 0.01) and unilateral infusion (HR, 5.05; P = 0.004) were found to influence local control significantly. Using tumor volume as a continuous variable, an adjusted risk ratio of 1.026 was found, indicating that each 1-cm(3) increase in volume was associated with a 2.6% decrease in probability of local control. Primary tumor volume (HR, 1.01; P = 0.003), comorbidity (American Society of Anesthesiologists [ASA] physical status 1 vs. > 1; HR, 2.47; P = 0.01), lowest involved neck level (HR, 3.45; P = 0.007), and pretreatment weight loss > 10% (HR, 2.04; P = 0.02) were found to be significant predictors of worse overall survival. Variables from the multivariable analysis were used to develop a nomogram capable of predicting local control and overall survival. CONCLUSIONS: Tumor volume was found to play a significant role in predicting local control and overall survival in patients with advanced-stage head and neck carcinoma who were treated with targeted chemoradiation. The nomograms may be useful for pretreatment selection of patients with advanced-stage head and neck carcinoma.

The effect of food on the pharmacokinetics of S-1 after single oral administration to patients with solid tumors.

PURPOSE: The purpose is to determine the effect of food on the bioavailability of S-1, an oral formulation of the 5-fluorouracil (5FU) prodrug Ftorafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), a dihydropyrimidine dehydrogenase inhibitor, and oxonic acid (an inhibitor of 5FU phosphoribosylation in normal gut mucosa) in a molar ratio of 1:0.4:1. EXPERIMENTAL DESIGN: Eighteen patients received a single dose of S-1 of 35 mg/m(2) with (535-885 kcal) or without food in a crossover study design: in arm A without breakfast on day -7 and with breakfast on day 0 and in arm B the reversed sequence. Blood samples were taken before and after S-1 administration. This food effect was evaluated according to the Food and Drug Administration guidelines using log-transformed data. RESULTS: Pharmacokinetic parameters for 5FU without breakfast were as follows: Tmax, 107 min; Cmax, 1.60 microm; area under the plasma concentration-time curve (AUC) 441 microm x min; and T(1/2), 104 min. Fasting decreased Tmax of FT, 5FU, CDHP, and oxonic acid significantly (P < 0.006) and increased the Cmax (P < 0.013). The food/fast ratio for the AUC of FT was not different, which for 5FU was 0.84 (P = 0.041), for CDHP was 0.89 (P = 0.191), for oxonic acid was 0.48 (P < 0.0005), and for cyanuric acid, the breakdown product of oxonic acid, was 5.1 (P = 0.019). Accumulation of uracil, indicative for dihydropyrimidine dehydrogenase inhibition, was not affected, as well as the T(1/2) of FT, 5FU, CDHP, and oxonic acid. Evaluation of the log-transformed data demonstrated that the 90% confidence interval for the food/fast ratio for the Cmax and AUC of FT, 5FU, CDHP, and uracil were within 70-143% and 80-125%, respectively, indicating no food effect. Only for oxonic acid and cyanuric acid were these values outside this interval. CONCLUSIONS: Food intake affected only the pharmacokinetics of the S-1 constituent oxonic acid but not of FT, CDHP, and 5FU. Because oxonic acid is included to protect against gastrointestinal toxicity, this observation might affect the gastrointestinal toxicity and thus the efficacy of S-1.

High-dose superselective intra-arterial cisplatin and concomitant radiation (RADPLAT) for advanced head and neck cancer.

BACKGROUND: The purpose of this study was to study the effect of intensive targeted chemoradiation in a group of patients with head and neck cancer with stage IV inoperable disease. METHODS: We examined 79 patients with inoperable stage IV head and neck cancer receiving intra-arterial infusion of high-dose cisplatin (150 mg/m(2)) on days 2, 9, 16, and 23 concomitant with delivery of external beam radiotherapy (total dose, 70 Gy; 2 Gy, 35 fractions; 1 fraction/day for 7 weeks). Sodium thiosulfate was administered intravenously to provide effective cisplatin neutralization. RESULTS: Four patients were not assessable. Complete local tumor response was achieved in 72 patients (91%) and a partial response in three patients. The complete response rate of neck node metastases was 90%. The 1- and 2-year locoregional control rates were 82% and 69%, respectively. The median overall survival time was 2.2 years, with a 3-year overall survival probability of 43%. Acute toxicities were as follows: grade III/IV hematologic toxicity (22%/16%), grade III/IV nephrotoxicity (0%), grade III mucositis (43%), grade III skin reactions (24%), grade III toxicity of the upper gastrointestinal tract (57%), grade III nausea (20%), and grade III subjective hearing loss (10%). Grade V toxicity (treatment-related deaths) was 3.8%. Six (18%) of 33 patients with complete remission needed tube feeding 2 years after treatment without intercurrent salvage surgery. CONCLUSIONS: Supradose superselective intra-arterial cisplatin and concomitant radiation is an effective organ-preserving therapy in an unfavorable group of patients. Our series confirms encouraging results reported previously. This regimen is justified in unresectable patients despite the substantial toxicity.

Major and minor salivary glands tumours.

Malignant salivary gland tumours are rare. The most common tumour site is the parotid. Aetiologic factors are not clear. Nutrition may be a risk factor, as well as irradiation or an histologically benign tumour occurred at a young age. Painless swelling of a salivary gland should always be considered as suspicious, especially if no sign of inflammation is present. Signs and symptoms related to major salivary gland tumours differ from those concerning minor salivary gland tumours, as they depend on the different location of the salivary gland. Surgical excision represents the standard option in the treatment of resectable tumours of both major and minor salivary glands. Neutron radiation may be a treatment option for inoperable locoregional disease. Surgery, irradiation or re-irradiation are treatment options for local relapse, whereas radical neck dissection is indicated for regional relapses. Metastastic disease may be either treated with radiotherapy or palliative chemotherapy, depending on the site of metastases.

Health-related quality-of-life assessments and patient-physician communication: a randomized controlled trial.

CONTEXT: There has been increasing interest in the use of health-related quality-of-life (HRQL) assessments in daily clinical practice, yet few empirical studies have been conducted to evaluate the usefulness of such assessments. OBJECTIVE: To evaluate the efficacy of standardized HRQL assessments in facilitating patient-physician communication and increasing physicians' awareness of their patients' HRQL-related problems. DESIGN: Prospective, randomized crossover trial. SETTING: Outpatient clinic of a cancer hospital in the Netherlands. PARTICIPANTS: Ten physicians and 214 patients (76% women; mean age, 57 years) undergoing palliative chemotherapy who were invited to participate between June 1996 and June 1998. INTERVENTION: At 3 successive outpatient visits, patients completed an HRQL questionnaire (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30). The responses were computer scored and transformed into a graphic summary. Physicians and patients received a copy of the summary before the consultation. MAIN OUTCOME MEASURES: Audiotapes of the consultations were content analyzed to evaluate patient-physician communication. Physicians' awareness of their patients' health problems was assessed by comparing physicians' and patients' ratings on the Dartmouth Primary Care Cooperative Information Functional Health Assessment (COOP) and the World Organisation Project of National Colleges and Academics (WONCA) charts. RESULTS: The HRQL-related issues were discussed significantly more frequently in the intervention than in the control group (mean [SD] communication composite scores: 4.5 [2.3] vs 3.7 [1.9], respectively (P =.01). Physicians in the intervention group identified a greater percentage of patients with moderate-to-severe health problems in several HRQL domains than did those in the control group. All physicians and 87% of the patients believed that the intervention facilitated communication and expressed interest in its continued use. CONCLUSION: Incorporating standardized HRQL assessments in daily clinical oncology practice facilitates the discussion of HRQL issues and can heighten physicians' awareness of their patients' HRQL.

Quality-of-life assessment after supradose selective intra-arterial cisplatin and concomitant radiation (RADPLAT) for inoperable stage IV head and neck squamous cell carcinoma.

OBJECTIVE: To evaluate quality-of-life (QOL) aspects of an organ preservation intra-arterial chemotherapy and concomitant radiation protocol, RADPLAT. DESIGN: Nonrandomized phase 2B feasibility trial. PATIENTS: Fifty consecutive patients with inoperable stage IV head and neck cancer. INTERVENTION: Supradose selective intra-arterial cisplatin and concomitant standard radiation (RADPLAT). MEASURES: Assessment with structured questionnaires before treatment and at 3, 6, and 12 months. RESULTS: Twenty-six patients were available for QOL assessment at 1 year (the "1-year QOL" group), as 16 patients died, 5 needed salvage surgery, and 3 were not available for interview (the "failure" group). Twelve-month results were mainly based on the first group. The functional well-being and head and neck scales showed a statistically significant improvement over time (P<.001). After 12 months, 21 patients (81%) returned to an oral diet, while 5 patients still needed tube feeding. For 23 patients (88%), the quality and strength of the voice was more or less normal. Of the 18 patients who were employed before their treatment, 10 were able to return to their job within 12 months. Xerostomia was reported by 17 patients (65%). Further detailed analysis showed statistically significant differences in pretreatment scores between the 1-year QOL group and the failure group, ie, physical well-being, functional well-being, and the head and neck scales (P<.05). Differences in these groups with respect to sex, age, tumor site, or stage could not be found. CONCLUSION: Given that only patients with locally (anatomic or functional) inoperable stage IV disease were treated, the results are promising, underlining the feasibility of the RADPLAT protocol.

Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis.

We determined the mechanisms of resistance of human CCRF-CEM leukemia cells to methotrexate (MTX) vs. those to six novel antifolates: the polyglutamatable thymidylate synthase (TS) inhibitors ZD1694, multitargeted antifolate, pemetrexed, ALIMTA (MTA) and GW1843U89, the non-polyglutamatable inhibitors of TS, ZD9331, and dihydrofolate reductase, PT523, as well as DDATHF, a polyglutamatable glycinamide ribonucleotide transformylase inhibitor. CEM cells were made resistant to these drugs by clinically relevant intermittent 24 hr exposures to 5-10 microM of MTX, ZD1694, GW1843U89, MTA and DDATHF, by intermittent 72 hr exposures to 5 microM of ZD9331 and by continuous exposure to stepwise increasing concentrations of ZD9331, GW1843U89 and PT523. Development of resistance required only 3 cycles of intermittent drug exposure to ZD1694 and MTA, but 5 cycles for MTX, DDATHF and GW1843U89 and 8 cycles for ZD9331. The predominant mechanism of resistance to ZD1694, MTA, MTX and DDATHF was impaired polyglutamylation due to approximately 10-fold decreased folylpolyglutamate synthetase activity. Resistance to intermittent exposures to GW1843U89 and ZD9331 was associated with a 2-fold decreased transport via the reduced folate carrier (RFC). The CEM cell lines resistant to intermittent exposures to MTX, ZD1694, MTA, DDATHF, GW1843U89 and ZD9331 displayed a depletion (up to 4-fold) of total intracellular reduced folate pools. Resistance to continuous exposure to ZD9331 was caused by a 14-fold increase in TS activity. CEM/GW70, selected by continuous exposure to GW1843U89 was 50-fold resistant to GW1843U89, whereas continuous exposure to PT523 generated CEM/PT523 cells that were highly resistant (1550-fold) to PT523. Both CEM/GW70 and CEM/PT523 displayed cross-resistance to several antifolates that depend on the RFC for cellular uptake, including MTX (95- and 530-fold). CEM/GW70 cells were characterized by a 12-fold decreased transport of [3H]MTX. Interestingly, however, CEM/GW70 cells displayed an enhanced transport of folic acid, consistent with the expression of a structurally altered RFC resulting in a 2.6-fold increase of intracellular folate pools. CEM/PT523 cells displayed a markedly impaired (100-fold) transport of [3H]MTX along with 12-fold decreased total folate pools. In conclusion, multifunctional mechanisms of resistance in CEM cells have a differential impact on cellular folate homeostasis: decreased polyglutamylation and transport defects lead to folate depletion, whereas a structurally altered RFC protein can provoke expanded intracellular folate pools.