- [Show abstract] [Hide abstract] ABSTRACT: Introduction: Trismus is a treatment-related late side effect in patients treated for cancer in the head and neck region (HNC). The condition can have a considerable negative impact on nutrition, dental hygiene, ability to speak and quality of life. We have previously studied trismus within the frame of a randomized phase 3 study of HNC patients treated with mainly three-dimensional (3D) conformal radiotherapy (CRT) and found a strong association to mean radiation dose to the mastication muscles, especially the ipsilateral masseter muscle (iMAS). In the present study we have investigated trismus prevalence and risk factors in a more recent cohort of patients, treated with todays’ more updated radiation techniques. Material and methods: Maximal interincisal distance (MID) was measured on 139 consecutive patients. Trismus was defined as MID ≤35 mm. Patient-, disease- and treatment-specific data were retrospectively recorded. Differences between groups were analyzed and mean absorbed dose to mastication structures was evaluated. Dosimetric comparisons were made between this study and our previous results. Results: The prevalence of trismus was 24% at a median of 16 months after completion of radiotherapy. In bivariate analysis treatment technique (3DCRT vs. intensity modulated radiotherapy or helical tomotherapy), tumor site (oropharynx vs. other sites) and mean radiation doses to the ipsilateral lateral pterygoid muscle, the paired masseter muscles and the iMAS were significantly associated with MID ≤35 mm. In multivariable analysis only mean radiation dose to the iMAS was significantly associated to MID ≤35 mm. Conclusion: Mean radiation dose to the ipsilateral masseter muscle is an important risk factor for trismus development. Dose reduction to this structure during radiotherapy should have a potential to diminish the prevalence of trismus in this patient group.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Low-dose rate brachytherapy (LDR-BT) has been used in Sweden for more than a decade for treatment of low-risk prostate cancer. This study presents the outcome for patients treated with LDR-BT at a single institution with focus on the association between dose and biochemical failure-free survival (BFFS). Methods: In total 195 patients were treated with LDR-BT between 2004 and 2008. The patients were followed systematically for side effects for at least one year. PSA levels were followed regularly from three months and for at least five years. Outcome was analyzed in relation to clinical variables at baseline and to radiotherapy data. Results: Kaplan-Meier estimated BFFS at five years was 95.7%. Dose to the prostate in terms of D90% was significantly associated with BFFS [HR 0.90 (95%CI 0.83-0.96), p = 0.002]. Conclusion: Out data confirmed that absorbed dose is a predictive factor for BFFS for low-risk patients without androgen deprivation therapy. With our treatment routines and dosimetry, a D90% in the range of 170-180 Gy gives excellent outcomes with acceptable toxicity for patients with low-risk prostate cancer.
- [Show abstract] [Hide abstract] ABSTRACT: Objectives/hypothesis: We investigated whether exposing a wound-healing-sensitive cell line to human wound fluid (HWF) could prime the cells to increase their tumor-forming ability in nude mice and, if so, whether this ability can be inhibited by pharmacological substances. Study design: Experimental animal model. Methods: Take rate was measured in BALB/c nude mice after pretreatment of the cells with HWF using human serum and fetal bovine serum as controls. Inhibition of signal transducer and activator of transcription 3 (STAT3) with S3I-201 tocilizumab, and of interleukin 6 receptor (IL6R) with tocilizumab was performed. Results: Preincubation with HWF resulted in a significant increase in take rate compared to controls. The increase in take rate could be decreased by both STAT3 and IL6R inhibition. Conclusions: The results indicate that head and neck squamous cell cancer cells might be stimulated to increase their tumor-forming ability both close to a surgical wound and at more distant locations, as a consequence of the wound-healing response. The work also suggests new treatment modalities aimed at decreasing these stimulatory effects. Level of evidence: NA Laryngoscope, 2016.
- [Show abstract] [Hide abstract] ABSTRACT: Conclusion Neck dissection after radiotherapy increased the risk of aspiration as a late effect in a sub-sample of patients treated for head and neck cancer in the ARTSCAN study. Patients treated with accelerated fractionation (AF) developed aspiration, with or without coughing, more frequently than patients treated with conventional fractionation (CF). Objectives A long-term follow-up study was conducted to determine the frequency of aspiration as a late effect in patients with head and neck cancer treated with AF or CF. Method One-hundred and eight patients were recruited from two centres of the Swedish multi-centre study, ARTSCAN, where AF and CF were compared. Patients with positive lymph nodes were treated with neck dissection after completing radiotherapy. The follow-up was performed at a median of 65 months after initiation of radiotherapy and included an ENT and a videofluoroscopic examination. Results Aspiration was found in 51/108 (47%) and silent aspiration in 34/96 (35%) patients. Neck dissection (n = 47 patients) was significantly associated with both aspiration and silent aspiration. Aspiration was more common among patients treated with AF (34/61; 56%) compared to CF (17/47; 36%; p = 0.053). Silent aspiration was also more common after AF (24/54; 44%) than after CF (10/42; 24%; p = 0.052).
- [Show abstract] [Hide abstract] ABSTRACT: Background and purpose: Health related quality of life (HRQoL) was assessed in the randomised, prospective ARTSCAN study comparing conventional radiotherapy (CF) with accelerated radiotherapy (AF) for head and neck cancer. Material and methods: 750 patients with squamous cell carcinoma (of any grade and stage) in the oral cavity, oro-, or hypopharynx or larynx (except T1-2, N0 glottic carcinoma) without distant metastases were randomised to either conventional fractionation (2Gy/day, 5days/week in 49days, total dose 68Gy) or accelerated fractionation (1.1+2.0Gy/day, 5days/week in 35days, total dose 68Gy). HRQoL was assessed with EORTC QLQ-C30, QLQ-H&N35 and HADS at baseline, at end of radiotherapy (eRT) and at 3 and 6months and 1, 2 and 5years after start of treatment. Results: The AF group reported HRQoL was significantly lower at eRT and at 3months for most symptoms, scales and functions. Few significant differences were noted between the groups at 6months and 5years. Scores related to functional oral intake never reached baseline. Conclusion: In comparison to CF, AF has a stronger adverse effect on HRQoL in the acute phase.
- [Show abstract] [Hide abstract] ABSTRACT: Purpose: The aim of this study was to determine whether PET scans after radiotherapy (RT), visually interpreted as equivocal regarding metabolic neck node response can be used to accurately categorize patients as responders or nonresponders using a Likert scale and/or maximum standardized uptake value (SUVmax). Other aims were to determine the performance of different methods for assessing post-RT PET scans (visual inspection, a Likert scale and SUVmax) and to establish whether any method is superior in predicting regional control (RC) and overall survival (OS). Methods: In 105 patients with neck node-positive head and neck cancer, the neck node response was evaluated by FDG PET/CT 6 weeks after RT. The scans were clinically assessed by visual inspection and, for the purposes of this analysis, re-evaluated using the Deauville criteria, a five-point Likert scale previously used in lymphoma studies. In addition, SUVmax was determined. Results: All assessment methods were able to significantly predict RC but not OS. The methods were also able to significantly predict remission of tumour after completion of RT. Of the 105 PET scans, 19 were judged as equivocal on visual inspection. The Likert scale was preferable to SUVmax for grouping patients as responders or nonresponders. Conclusion: All methods (visual inspection, SUVmax and the Likert scale) identified responders and nonresponders and predicted RC. A Likert scale is a promising tool to reduce to a minimum the problem of PET scans judged as equivocal. Consensus regarding qualitative assessment would facilitate PET reporting in clinical practice.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Elective treatment of lymph nodes in oropharyngeal cancer (OPC) has impact on both regional recurrences (RR) and risk of late side effects. This study was performed to quantify the dose-dependent impact on RR and overall survival (OS) in a prospectively collected cohort of OPC from the ARTSCAN study with emphasis on elective treatment. Methods: ARTSCAN is a previously published prospective, randomized, multicentre study of altered radiotherapy (RT) fractionation in head and neck cancer. In ARTSCAN the elective treatment volume for node positive OPC varied significantly between centres due to local treatment principles. All patients with OPC in complete response after primary treatment were eligible for the present case-control study. Cases were patients with RR during five years follow-up. Patients with no recurrence were eligible as controls. Four controls per case were matched according to T- and N-stage. Mean (D mean) and median (D 50%) dose for the lymph node level (LNL) of RR in the cases and the corresponding LNL in the controls were analysed with conditional logistic regression. OS was estimated with the Kaplan-Meier method and evaluated by multivariate Cox regression analysis. Results: There was a dose-dependent risk reduction for D 50% in the interval that represented elective treatment (40-50 Gy) (OR = 0.18, p < 0.05) and a trend in the same dose interval for D mean (OR = 0.19, p = 0.07). OS rates at five years were 0.39 (0.24-0.65) for cases and 0.70 (0.62-0.81) for controls (p < 0.001). The Kaplan-Meier and the Cox regression analysis for cases categorised by delivered dose showed an inverse relationship between dose and survival. The cases with RR in a LNL outside planning target volume (PTV) (D mean < 40 Gy) had an OS rate comparable to that of all patients, and those with RR in a LNL in PTVelective (D mean 40-60 Gy) or PTVtumour (D mean >60 Gy) did significantly worse (p < 0.05). The same inverse relationship was also shown for a small subset of patient with known HPV-status, defined by over expression of p16 (p < 0.05). Conclusions: There was a significant risk reduction for RR of elective treatment. However the OS for patients with RR outside target volumes was not affected, with similar results for patients with HPV-positive OPC. This could be an argument for a prospective randomized study on limited elective target volumes in OPC.
- [Show abstract] [Hide abstract] ABSTRACT: Background: The purpose of this study was to evaluate if a positron emission tomography (PET) scan, 6 weeks post radiotherapy (RT), adequately selects patients in whom a neck node dissection can be omitted. Primary endpoints were isolated neck recurrences and overall survival (OS). Methods: 105 patients, mainly with oropharyngeal human papilloma virus (HPV) positive tumors, with a positive PET scan before treatment, were evaluated regarding the neck response 6 weeks post RT. The PET results determined the management of the neck: observation vs. neck dissection. Results: Median follow-up was 25 months. Positive predictive value (PPV) and negative predictive value (NPV) were 56% and 94%, respectively. Four isolated neck recurrences occurred. The 2 year OS rate was 86.3%. Conclusion: PET scans performed 6 weeks after RT have a high NPV and can obviate neck dissections but the PPV is insufficient. A later scheduled scan is recommended. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
- [Show abstract] [Hide abstract] ABSTRACT: Background. Well-specified and unambiguous treatment protocols are essential both for current practice and for the future development of radiation therapy. In order to provide assistance for writing good protocols, irrespective of treatment intention and complexity, up-to-date guidelines are highly desirable. Methods. We have analysed the radiotherapy work-flow, including clinical and physical aspects, such as preparatory imaging, treatment planning, delivery and evaluation, with the aim to outline a consistent framework covering the entire radiotherapy process. Results. Based on the analysis, a recipe-style template for specifying the description of the radiotherapy process has been designed. The template is written in a general format, which allows for modified phrasing, and should be customised for the specific clinical situation and diagnosis, as well as facility resources. Conclusions. The template can be used as a tool to ensure a consistent and comprehensive description of the radiotherapy section of clinical guidelines, care programmes and clinical trial protocols.
- [Show abstract] [Hide abstract] ABSTRACT: Objectives Cetuximab is an epidermal growth factor receptor (EGFR)-targeting drug that has shown effects in head and neck squamous cell carcinoma (HNSCC). The effects are, however, small and have mainly been proven in a subset of patients, and the cost-effectiveness has been questioned. For this reason, we need to know more about the basic mechanisms controlling the effect of EGFR signalling on tumour growth. Materials and methods We investigated the effect of the EGFR ligand transforming growth factor alpha (TGF-α) and cetuximab, alone and in combination, on HNSCC cell lines, measuring proliferation and the activity of intracellular signalling pathways. Results In line with previous reports we found the majority of the cell lines to be growth-inhibited by TGF-α. Surprisingly, two of the cell lines, which were more thoroughly investigated, were either growth-inhibited or stimulated by both cetuximab and TGF-α, depending on the presence or absence of the other substance. We also present data indicating the existence of two different receptor activities emanating from the EGFR protein. Conclusion We therefore show that TGF-α can have both growth-stimulating and growth-inhibiting effects in the same cell line and that EGFR-targeting drugs can be similarly double-edged. The implication for such drugs is that the micro-environment within a tumour, and possibly within portions of a tumour, may influence the growth-inhibiting effect of the drug. There may also be important implications for our understanding of EGFR signalling and its influence on growth and development.
- [Show abstract] [Hide abstract] ABSTRACT: Several studies on the use of erythropoietin (Epo) to treat anaemia in patients undergoing cancer treatment have shown adverse effects on tumour control and survival. Experimental studies indicate that this could be linked to an interaction with wound healing processes and not an effect on tumour cells per se. We have previously shown that erythropoietin in combination with surgical trauma stimulates tumour growth. In the present study, we investigated the effect of surgery and Epo on gene expression. Human tumours from oral squamous cell cancer were xenotransplanted to nude mice treated with Epo. The tumours were then transected in a standardised procedure to mimic surgical trauma and the change in gene expression of the tumours was investigated by microarray analysis. qRT-PCR was used to measure the levels of mRNAs of pro-apoptotic genes. The frequency of apoptosis in the tumours was assessed using immunohistochemistry for caspase-3. There was little change in the expression of genes involved in tumour growth and angiogenesis but a significant down-regulation of the expression of genes involved in apoptosis. This effect on apoptosis was confirmed by a general decrease in the expression of mRNA for selected pro-apoptotic genes. Epo-treated tumours had a significantly lower frequency of apoptosis as measured by immunohistochemistry for caspase 3. Our results suggest that the increased tumour growth during erythropoietin treatment might be due to inhibition of apoptosis, an effect that becomes significant during tissue damage such as surgery. This further suggests that the decreased survival during erythropoietin treatment might be due to inhibition of apoptosis.
- [Show abstract] [Hide abstract] ABSTRACT: Background Weight loss is a common problem in patients with Squamous Cell Carcinoma of the Head and Neck (SCCHN) treated with radiotherapy (RT). The aims of the present study were to determine if treated volume (TV), as a measure of the radiation dose burden, can predict weight loss in patients with oropharyngeal cancer and to analyze weight loss and body mass index (BMI) in the same patient group in relation to 5-year overall survival. Methods The ARTSCAN trial is a prospective, randomized, multicenter trial in patients with SCCHN. Nutritional data from the ARTSCAN trial were analyzed retrospectively using univariate and multivariate statistical methods based on information on percentage weight loss from the start of RT up to five months after the termination of RT (study cohort 1, n = 232) and information on patients’ BMI at the start of RT (study cohort 2, n = 203). TV was defined as the volume of the patient receiving at least 95% of the prescribed dose. TV64.6 Gy encompasses macroscopic tumor and TV43.7 Gy elective lymph nodes of the neck. Results TV64.6 Gy and TV43.7 Gy were both significantly correlated with higher weight loss up to five months after the termination of RT in study cohort 1 (p < 0.001 for both). BMI at the start of RT was shown to be a prognostic factor for 5-year overall survival in study cohort 2 but weight loss was not. The hazard ratios and 95% confidence intervals were 3.78 (1.46–9.75) and 2.57 (1.43–4.62) in patients with underweight and normal weight, respectively. Conclusions TV can predict weight loss during RT in patients with oropharyngeal cancer regardless of clinical stage. A high BMI (>25 kg/m2) at the start of RT is positively associated with survival in patients with oropharyngeal cancer.
- [Show abstract] [Hide abstract] ABSTRACT: Aim of the study: To analyse late morbidity and mortality in pre and post-menopausal breast cancer patients treated with postmastectomy radiotherapy, with emphasis on side-effects from the heart, cerebrovascular and respiratory systems. Methods: Long term follow-up of two randomised, clinical trials with 1100 patients was carried out. Pre-menopausal women were allocated to radiotherapy (RT), RT+oral cyclophosphamide (RT+C) or cyclophosphamide only (C). Post-menopausal women were allocated to RT, RT+Tamoxifen for one year (RT+Tam) or tamoxifen only (Tam). Information on admission to hospital, mortality and causes of death was obtained from national registers. Results: After 25 years, adding RT to cyclophosphamide in pre-menopausal women raised the mortality from heart disease from zero to 0.8% (p=0.04). In post-menopausal women, adding RT to Tam raised the mortality from heart disease from 10.5% to 18.4% (p=0.005). In post-menopausal women mortality due to cerebrovascular disease increased from 3.4% to 8.7% by adding RT to Tam (p=0.015). The differences were not evident until in the second decade of follow-up. In spite of differences in specific causes of death, there were no significant differences between the treatment arms concerning morbidity or overall mortality. Conclusion: Postmastectomy radiotherapy to the chest wall and loco-regional lymph nodes including the parasternal lymph nodes as delivered in the end of the seventies did not reduce overall mortality, but gave a significantly increased risk of death from heart and cerebrovascular disease, which appeared during the second decade after radiotherapy.
- [Show abstract] [Hide abstract] ABSTRACT: Conclusion: PET-CT scans seem to be sufficient to rule out residual tumour at the primary site. Patients with positive or equivocal PET findings should be scheduled for endoscopy with biopsy or a second PET-CT scan. Objectives: Assessment of remission at the primary site, in patients treated with organ preservation therapy with curative intent, is important to identify residual tumours requiring treatment with salvage surgery. The aim of this study was to evaluate the diagnostic accuracy of fluorodeoxyglucose positron emission tomography (FDG-PET) after radiotherapy with or without chemotherapy in assessing primary site response in patients with head and neck cancer. Methods: A total of 82 patients, with a positive baseline PET-CT scan before start of treatment, were evaluated with a PET-CT scan 6-7 weeks post-radiotherapy and with a clinical examination/endoscopy with or without biopsy 1-2 weeks later. The majority of patients had p16-positive oropharyngeal tumours. Results: Post-treatment, 77% of the patients had no visible hypermetabolism. If equivocal PET scans are regarded as positive, the sensitivity, specificity, negative (NPV) and positive predictive value (PPV) and accuracy were 100%, 78%, 100%, 6% and 78%, respectively. Eight patients suffered from relapses involving the primary site during the 9-month follow-up.
- [Show abstract] [Hide abstract] ABSTRACT: Background and purpose The purpose of this study was to investigate the correlation between the haematological toxicity observed in patients treated with craniospinal irradiation, and the dose distribution in normal tissue, specifically the occurrence of large volumes exposed to low dose. Materials and methods Twenty adult male patients were included in this study; eight treated with helical tomotherapy (HT), and twelve with three-dimensional conformal radiation therapy. The relative volume of red bone marrow and body that was exposed to low dose (i.e. the so-called dose bath) was evaluated and correlated with nadir blood values during treatment, i.e. the severity of anaemia, leukopaenia, and thrombocytopaenia. The correlation was tested for different dose levels representing the dose bath using the Pearson product-moment correlation method. Results We found a significant correlation between the volume of red bone marrow exposed to low dose and the severity of thrombocytopaenia during treatment. Furthermore, for the HT patients, a significant correlation was found between the relative volume of the body exposed to low dose and the severity of anaemia and leukopenia. Conclusions The severity of haematological toxicity correlated with the fraction of red bone marrow or body that was exposed to low dose.
- [Show abstract] [Hide abstract] ABSTRACT: Persistent severe swallowing dysfunction with aspiration is a common and sometimes overlooked sequelae after treatment for squamous cell carcinoma of the head and neck (SCCHN) and may impact food intake and nutritional status. More knowledge is needed to increase the understanding of severe swallowing dysfunction as a risk factor for persistent nutritional deteriorations in SCCHN survivors. The purpose of the study was to investigate weight loss and body mass index (BMI) in relation to pharyngeal swallowing function in a long-term perspective in patients after SCCHN treatment. Data from 101 patients were available for the analyses. Swallowing function was assessed by videofluoroscopy at a mean of 71.6 months after the start of radiotherapy (RT). Percent weight change (calculated with weight at the start of RT as the reference) and BMI at follow-up were the primary nutritional measures. Aspiration was present in 48 of 101 patients (48 %). Patients with aspiration had a significantly higher mean weight loss and a lower BMI (-10.9 % and 23.1, respectively) at follow-up compared with patients without aspiration (-2.8 % and 26.0, respectively). Patients with aspiration were unable to gain weight after 23 months. Only ten of 101 patients (10 %) were underweight at follow-up. Swallowing dysfunction with aspiration was related to long-term weight loss and reduced BMI. Few patients were underweight despite the high prevalence of swallowing dysfunction.
- [Show abstract] [Hide abstract] ABSTRACT: Unlabelled: Trismus, a well-known sequelae after treatment of head and neck cancer, decreases a patient's oral function and quality of life. The main objectives of this study were to: 1) investigate the long-term prevalence of radiation-induced trismus in patients treated for head and neck cancer according to two different fractionation schedules; and 2) model a dose-response relationship for trismus. Material and methods: Patients were recruited from the Swedish ARTSCAN trial, a prospective randomised multicentre study comparing conventional and accelerated fractionation. A total of 124 patients agreed to a clinical ENT examination 21-127 months (median 66 months) after beginning radiation therapy. Trismus-related scores were assessed using the EORTC H&N35 Quality of Life questionnaire. The TheraBite(®) range of motion scale was used to measure maximal interincisal distance. The dose-response relationship for structures important for mastication and the temporomandibular joints was investigated by normal tissue complication probability modelling. Results: No significant differences in patient-reported trismus or maximal interincisal distance were found between the two trial arms. Patient-reported moderate to high scores regarding trismus increased from 3% at the start of radiation therapy to 25% at the long-term follow-up. Maximal interincisal distance correlated significantly with patient-reported scores of trismus. The best dose-response fit to the endpoint data was found for the dose to the ipsilateral masseter. Conclusions: Trismus is a persistent complication after radiotherapy with 3D-conformal radiation therapy. We found no difference between the severity and prevalence of trismus between conventional and accelerated fractionation, but a significant correlation between the absorbed dose to the mastication structures and opening of the mouth. Further prospective studies may determine whether a reduced dose to structures important for mastication using intensity-modulated radiation therapy will reduce problems with trismus.
Umeå, Västerbotten, Sweden
- Department of Radiation Sciences
Lund, Skåne, Sweden
- • Department of Otolaryngology
- • Department of Oncology