Little evidence of inbreeding depression for birth mass, survival and growth in Antarctic fur seal pups.

Inbreeding depression, the loss of offspring fitness due to consanguineous mating, is generally detrimental for individual performance and population viability. We investigated inbreeding effects in a declining population of Antarctic fur seals (Arctocephalus gazella) at Bird Island, South Georgia. Here, localised warming has reduced the availability of the seal's staple diet, Antarctic krill, leading to a temporal increase in the strength of selection against inbred offspring, which are increasingly failing to recruit into the adult breeding population. However, it remains unclear whether selection operates before or after nutritional independence at weaning. We therefore used microsatellite data from 885 pups and their mothers, and SNP array data from 98 mother-offspring pairs, to quantify the effects of individual and maternal inbreeding on three important neonatal fitness traits: birth mass, survival and growth. We did not find any clear or consistent effects of offspring or maternal inbreeding on any of these traits. This suggests that selection filters inbred individuals out of the population as juveniles during the time window between weaning and recruitment. Our study brings into focus a poorly understood life-history stage and emphasises the importance of understanding the ecology and threats facing juvenile pinnipeds.

How do young men want to receive information about fertility? Young men's attitudes towards a fertility campaign targeting men in Copenhagen, Denmark.

STUDY QUESTION: What are young men's attitudes towards the Danish fertility campaign 'How's your sperm?' and how do they want to receive fertility information in the future? SUMMARY ANSWER: The young men found that the campaign had limited impact because it was not relevant to their current life situation and they believed general fertility awareness should be a mandatory part of education, while more targeted information would be helpful through web-based venues when it was more relevant to their lives (e.g. when ready to have children). WHAT IS KNOWN ALREADY: It is estimated that 16-26% of the Danish population who want children will experience infertility at some point in their lives. In Denmark, 25% of young healthy men have decreased sperm quality, and 20% of 50-year-old men are childless. Men play an important role in the fertility decision-making of couples, thus, it is important to target men and ensure that they have sufficient fertility knowledge. However, fertility awareness is limited among men and there have been few fertility awareness initiatives targeting men. In October 2018, the Municipality of Copenhagen launched the campaign 'How's your sperm?' as a tool to increase fertility knowledge among men. To identify potential barriers for the effect of fertility campaigns targeting men, evaluations of such campaigns are needed. STUDY DESIGN SIZE DURATION: This study was a cross-sectional, qualitative study of six focus groups including a total of 27 currently childless young men from the Capital Region of Copenhagen, Denmark. Data collection took place between April and October 2019. PARTICIPANTS/MATERIALS SETTING METHODS: The interviewed young men were currently childless and were all residents in the Capital Region of Copenhagen. They were between 23 and 32 years old with an average age of 26 years, and almost all were university students or had a university degree. The focus group discussions were audiotaped, anonymized and transcribed in full. Data were analyzed using qualitative content analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, the campaign had limited influence on the young men because they believed the campaign was not relevant to their current life situation. Furthermore, the young men were confused about the aim and message of the campaign, as they thought it encouraged them to have their sperm quality tested. The young men also criticized the campaign for making a link between sperm quality and masculinity. They recognized the importance of knowledge about reproductive health but they wanted access to accurate information about fertility and risk factors for infertility. According to the young men, future initiatives should prioritize clear communication of accurate, reliable and understandable fertility information in web-based venues. In addition, the young men suggested that general fertility information should be a mandatory part of the (sexual) education curriculum in primary and secondary schools. LIMITATIONS REASONS FOR CAUTIONS: Participants were young and highly educated; thus the findings cannot be generalized to all men of a similar age group or to men at older ages. WIDER IMPLICATIONS OF THE FINDINGS: Different strategies that are relevant to the lifespan are needed to increase fertility awareness in the male population. The young men's responses underscored that any fertility awareness strategy or campaign must convey respect for the individual's autonomy. The findings highlight that how information is communicated and the quality or type of information that is disseminated are both important in acceptability by target users. STUDY FUNDING/COMPETING INTERESTS: No funding was received for this study. No conflicts were declared for all authors. TRIAL REGISTRATION NUMBER: N/A.

Combined dual energy and iterative metal artefact reduction for PET/CT in head and neck cancer.

Metal artefacts in PET/CT images hamper diagnostic accuracy in head and neck cancer (HNC). The aim of this study is to characterise the clinical effects of metal artefacts on PET/CT in HNC and to inform decision-making concerning implementation of MAR techniques. We study a combined dual energy CT and inpainting-based metal artefact reduction (DECT-I-MAR) technique for PET/CT in three settings: (A) A dental phantom with a removable amalgam-filled tooth to evaluate the PET error in comparison to a known reference. (B) PET-positive patients with metallic implants to demonstrate the relationship between CT metal artefacts and PET error. (C) Metabolic tumour volumes delineated in PET-positive patients with metal implants to evaluate the clinical impact. In (A) DECT-I-MAR reduced the PET error significantly. In (B) we demonstrate an increasing PET error with increasing CT artefact severity in patients. In (C) it is shown that the presence of artefacts in the same axial slices as the tumour significantly decreases biomarker stability and increase delineation variability. This work shows the practical feasibility of DECT-I-MAR-based PET/CT imaging, and indicates a positive clinical impact of using the technique routinely for HNC patients. The impact of CT artefacts on PET is considerable, especially in workflows where quantitative PET biomarkers and tumour volumes are used. In such cases, and for patients with tumours in proximity of metals, we recommend that a MAR technique for PET/CT is employed.

PET/CT-guided treatment planning for paediatric cancer patients: a simulation study of proton and conventional photon therapy.

OBJECTIVE: To investigate the impact of including fluorine-18 fludeoxyglucose ((18)F-FDG) positron emission tomography (PET) scanning in the planning of paediatric radiotherapy (RT). METHODS: Target volumes were first delineated without and subsequently re-delineated with access to (18)F-FDG PET scan information, on duplicate CT sets. RT plans were generated for three-dimensional conformal photon RT (3DCRT) and intensity-modulated proton therapy (IMPT). The results were evaluated by comparison of target volumes, target dose coverage parameters, normal tissue complication probability (NTCP) and estimated risk of secondary cancer (SC). RESULTS: Considerable deviations between CT- and PET/CT-guided target volumes were seen in 3 out of the 11 patients studied. However, averaging over the whole cohort, CT or PET/CT guidance introduced no significant difference in the shape or size of the target volumes, target dose coverage, irradiated volumes, estimated NTCP or SC risk, neither for IMPT nor 3DCRT. CONCLUSION: Our results imply that the inclusion of PET/CT scans in the RT planning process could have considerable impact for individual patients. There were no general trends of increasing or decreasing irradiated volumes, suggesting that the long-term morbidity of RT in childhood would on average remain largely unaffected. ADVANCES IN KNOWLEDGE: (18)F-FDG PET-based RT planning does not systematically change NTCP or SC risk for paediatric cancer patients compared with CT only. 3 out of 11 patients had a distinct change of target volumes when PET-guided planning was introduced. Dice and mismatch metrics are not sufficient to assess the consequences of target volume differences in the context of RT.

The impact of involved node, involved field and mantle field radiotherapy on estimated radiation doses and risk of late effects for pediatric patients with Hodgkin lymphoma.

BACKGROUND: The use of radiotherapy (RT) is debated for pediatric patients with Hodgkin lymphoma (HL) due to the late effects of treatment. Radiation doses to the thyroid, heart, lungs, and breasts are compared with the extensive mantle field (MF), Involved Field RT(IFRT), Modified IFRT (mIFRT), and Involved Node RT (INRT) and the risk of radiation-induced cardiovascular disease, secondary cancers, and the corresponding Life Years Lost (LYL) is estimated with each technique. PROCEDURE: INRT, mIFRT, IFRT, and MF plans (20 and 30 Gy) were simulated for 10 supradiaphragmatic, clinical stage I­II classical HL patients <18 years old, total of 4 x 2 plans for each patient. The lifetime excess risks of cardiac morbidity, cardiac mortality, lung, breast, and thyroid cancer with each technique were estimated. The estimated excess risks attributable to RT were based on HL series with long-term follow-up, treating death from other causes as competing risks. The corresponding LYL were derived from the estimated excess risks. Statistical analyses were performed with repeated measures ANOVA. RESULTS: Both a reduction in field size and in prescribed radiation dose significantly lowered the estimated dose to the heart, lungs, breasts, and thyroid compared to past,extended fields, even for patients with mediastinal disease. This translated into a significantly reduced estimated risk of cardiovascular disease, secondary cancers, and LYL. CONCLUSIONS: Involved Node Radiotherapy should be considered for pediatric patients with Hodgkin lymphoma since it is estimated to substantially lower the risk of severe long-term complications.

Interobserver delineation variation in lung tumour stereotactic body radiotherapy.

OBJECTIVES: In radiotherapy, delineation uncertainties are important as they contribute to systematic errors and can lead to geographical miss of the target. For margin computation, standard deviations (SDs) of all uncertainties must be included as SDs. The aim of this study was to quantify the interobserver delineation variation for stereotactic body radiotherapy (SBRT) of peripheral lung tumours using a cross-sectional study design. METHODS: 22 consecutive patients with 26 tumours were included. Positron emission tomography/CT scans were acquired for planning of SBRT. Three oncologists and three radiologists independently delineated the gross tumour volume. The interobserver variation was calculated as a mean of multiple SDs of distances to a reference contour, and calculated for the transversal plane (SD(trans)) and craniocaudal (CC) direction (SD(cc)) separately. Concordance indexes and volume deviations were also calculated. RESULTS: Median tumour volume was 13.0 cm(3), ranging from 0.3 to 60.4 cm(3). The mean SD(trans) was 0.15 cm (SD 0.08 cm) and the overall mean SD(cc) was 0.26 cm (SD 0.15 cm). Tumours with pleural contact had a significantly larger SD(trans) than tumours surrounded by lung tissue. CONCLUSIONS: The interobserver delineation variation was very small in this systematic cross-sectional analysis, although significantly larger in the CC direction than in the transversal plane, stressing that anisotropic margins should be applied. This study is the first to make a systematic cross-sectional analysis of delineation variation for peripheral lung tumours referred for SBRT, establishing the evidence that interobserver variation is very small for these tumours.

Methods for estimating the site of origin of locoregional recurrence in head and neck squamous cell carcinoma.

PURPOSE: Methods to estimate the likely origin of recurrences after radiation therapy for head and neck squamous cell carcinoma are compared. METHODS AND MATERIALS: A total of 25 patients meeting the following inclusion criteria were randomly selected: curatively intended intensity-modulated radiotherapy planned on a positron emission tomography-computed tomography (PET/CT) scan during the period 2005-2009; squamous cell carcinoma in the oral cavity, pharynx or larynx; complete clinical response followed by locoregional recurrence; and a CT scan at recurrence before any salvage therapy. Exclusion criteria were previous cancer in the area, surgery prior to radiotherapy, or a synchronous cancer. Three methods of estimating focal points of recurrence origin and two volume overlap methods assigning the recurrences to the most central target volumes encompassing at least 50% or 95% of the recurrence volumes were tested. Treatment planning and recurrence scans were rigid and deformable co-registered in order to transfer focal points to the treatment planning scan. Double determinations of all volumes, points, and co-registrations were made. RESULTS: The volume overlap methods assigned the recurrences to significantly more peripheral target volumes than focal methods (p < 0.0001 for all comparisons of 95% overlap vs. focal methods, p < 0.028 for all comparisons of 50% overlap vs. focal methods). Repeated registrations of the same point had higher reproducibility with deformable registration than with rigid registration (median distance 0.31 vs. 0.35 cm, p = 0.015). No significant differences were observed among the focal methods. CONCLUSION: Significant differences between methods were found which may affect strategies to improve radiotherapy based on pattern of failure analyses.

Preoperative PET/CT in early-stage breast cancer.

BACKGROUND: The aim of this study was to assess the diagnostic and therapeutic impact of preoperative positron emission tomography and computed tomography (PET/CT) in the initial staging of patients with early-stage breast cancer. PATIENTS AND METHODS: A total of 103 consecutive patients with newly diagnosed operable breast cancer with tumors ≥2 cm were independently examined preoperatively with conventional assessment (mammography, breast/axillary ultrasound, chest X-ray and blood samples) and PET/CT with no prior knowledge of the other. RESULTS: PET/CT identified a primary tumor in all but three patients (97%). PET/CT solely detected distant metastases (ovary, bones and lung) in 6 patients and new primary cancers (ovary, lung) in another two patients, as well as 12 cases of extra-axillary lymph node involvement. In 15 patients (15%), extra-axillary malignancy was detected by PET/CT only, leading to an upgrade of initial staging in 14% (14/103) and ultimately a modification of planned treatment in 8% (8/103) of patients. CONCLUSIONS: PET/CT is a valuable tool to provide information on extra-axillary lymph node involvement, distant metastases and other occult primary cancers. Preoperative (18)F-fluorodeoxyglucose-PET/CT has a substantial impact on initial staging and on clinical management in patients with early-stage breast cancer with tumors ≥2 cm.

Does the use of diagnostic PET/CT cause stage migration in patients with primary advanced ovarian cancer?

OBJECTIVE: To investigate if the use of diagnostic FDG-PET/CT leads to stage migration in patients with advanced ovarian cancer and to evaluate the prognostic significance of FDG-PET/CT. METHODS: From September 2004 to August 2007, 201 patients with a Risk of Malignancy Index (RMI) >150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within 2 weeks prior to standard surgery/debulking of a pelvic tumor. On 15 August, 2009 overall survival and prognostic variables were analysed in 66 ovarian cancer patients (64 stage III and 2 stage IV). RESULTS: Median follow-up was 30.2 months; median age was 62.5 years (range 35-85 years); 97% (64/66) had a performance status

Prediction of suboptimal primary cytoreduction in primary ovarian cancer with combined positron emission tomography/computed tomography--a prospective study.

OBJECTIVE: To prospectively identify combined PET/CT predictors of incomplete/suboptimal primary cytoreduction in advanced ovarian cancer. METHODS: From September 2004 to March 2007, 179 patients with a Risk of Malignancy Index (RMI) >150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within 2 weeks prior to standard surgery/debulking of a pelvic tumor. Ten PET/CT features were identified and evaluated as predictors of cytoreduction in 54 patients with advanced ovarian cancer. RESULTS: Complete cytoreduction (no macroscopic residual disease) was achieved in 35% and optimal cytoreduction (<1 cm residual disease) was achieved in 56%. Using univariate analysis, predictors of incomplete cytoreduction were large bowel mesentery implants (LBMI) (P<0.003), pleural effusion (P<0.009), ascites (P<0.009) and peritoneal carcinosis (P<0.01). LBMI (P<0.03) and ascites (P<0.05) were also predictors of suboptimal cytoreduction. Using multivariate analysis, LBMI was the only independent predictor of incomplete cytoreduction (P=0.004) and no predictor of suboptimal cytoreduction was found. CONCLUSION: PET/CT predictors of cytoreduction were found. But they should not be used to withhold patients form primary cytoreductive surgery. We suggest PET/CT as a supplementary image modality prior to surgery in primary OC patients whenever accurate and comprehensive preoperative evaluation of primary tumor and metastases is desired.

Contrast-enhanced FDG-PET/CT vs. SPIO-enhanced MRI vs. FDG-PET vs. CT in patients with liver metastases from colorectal cancer: a prospective study with intraoperative confirmation.

BACKGROUND: The choice of imaging before liver surgery is debated regarding the use of magnetic resonance (MR) imaging, computed tomography (CT), and positron emission tomography (PET). No studies have compared contrast-enhanced PET/CT with superparamagnetic iron oxide (SPIO)-enhanced MR imaging. PURPOSE: To compare PET/CT with superparamagnetic iron oxide (SPIO)-enhanced MR imaging, PET, and CT in the detection of liver metastases (LM) and extrahepatic tumor from colorectal cancer (CRC). MATERIAL AND METHODS: Thirty-five patients with suspected LM underwent PET/CT with a contrast-enhanced CT protocol and SPIO-enhanced MR imaging. Readers independently analyzed images from MR imaging, PET/CT, and the CT part and PET part of the PET/CT study. Imaging findings were compared with surgical and histological findings. RESULTS: Lesion-by-lesion sensitivity and accuracy for liver lesions was 54% and 77% for PET alone, 66% and 83% for PET/CT, 82% and 82% for SPIO-enhanced MR imaging, and 89% and 77% for CT alone, respectively. CT and SPIO-enhanced MR imaging were less specific but significantly more sensitive than PET (P<0.0001). For extrahepatic tumor, sensitivity and specificity was 83% and 96% for PET/CT and 58% and 87% for CT, respectively. CONCLUSION: CT and SPIO-enhanced MR imaging are more sensitive but less specific than PET in the detection of LM. PET/CT can detect more patients with extrahepatic tumor than CT alone.

A prospective study of PET/CT in initial staging of small-cell lung cancer: comparison with CT, bone scintigraphy and bone marrow analysis.

BACKGROUND: Small-cell lung cancer (SCLC) accounts for 15%-20% of all lung cancer cases. Accurate and fast staging is mandatory when choosing treatment, but current staging procedures are time consuming and lack sensitivity. PATIENTS AND METHODS: A prospective study was designed to examine the role of combined positron emission tomography/computed tomography (PET/CT) compared with standard staging (CT, bone scintigraphy and immunocytochemical assessment of bone marrow biopsy) of patients with SCLC. Thirty-four consecutive patients were included. Twenty-nine patients received initial PET/CT. RESULTS: PET/CT caused change of stage in 5/29 (17%). Excluding patients with unconfirmed findings or pleural effusion, the sensitivity for accurate staging of patients with extensive disease was the following: for standard staging 79%, PET 93% and PET/CT 93%. Specificity was 100%, 83% and 100%, respectively. CONCLUSION: The results from this first study on PET/CT in SCLC indicates that PET/CT can simplify and perhaps even improve the accuracy of the current staging procedure in SCLC. A larger clinical trial, preferably with consequent histological confirmation in case of discordance, however, is warranted.

PET/CT with intravenous contrast can be used for PET attenuation correction in cancer patients.

PURPOSE: If the CT scan of a combined PET/CT study is performed as a full diagnostic quality CT scan including intravenous (IV) contrast agent, the quality of the joint PET/CT procedure is improved and a separate diagnostic CT scan can be avoided. CT with IV contrast can be used for PET attenuation correction, but this may result in a bias in the attenuation factors. The clinical significance of this bias has not been established. Our aim was to perform a prospective clinical study where each patient had CT performed with and without IV contrast agent to establish whether PET/CT with IV contrast can be used for PET attenuation without reducing the clinical value of the PET scan. METHODS: A uniform phantom study was used to document that the PET acquisition itself is not significantly influenced by the presence of IV contrast medium. Then, 19 patients referred to PET/CT with IV contrast underwent CT scans without, and then with contrast agent, followed by an 18F-fluorodeoxyglucose whole-body PET scan. The CT examinations were performed with identical parameters on a GE Discovery LS scanner. The PET data were reconstructed with attenuation correction based on the two CT data sets. A global comparison of standard uptake value (SUV) was performed, and SUVs in tumour, in non-tumour tissue and in the subclavian vein were calculated. Clinical evaluation of the number and location of lesions on all PET/CT scans was performed twice, blinded and in a different random order, by two independent nuclear medicine specialists. RESULTS: In all patients, the measured global SUV of PET images based on CT with IV contrast agent was higher than the global activity using non-contrast correction. The overall increase in the mean SUV (for two different conversion tables tested) was 4.5+/-2.3% and 1.6+/-0.5%, respectively. In 11/19 patients, focal uptake was identified corresponding to malignant tumours. Eight out of 11 tumours showed an increased SUVmax (2.9+/-3.1%) on the PET images reconstructed using IV contrast. The clinical evaluation performed by the two specialists comparing contrast and non-contrast CT attenuated PET images showed weighted kappa values of 0.92 (doctor A) and 0.82 (doctor B). No contrast-introduced artefacts were found. CONCLUSION: This study demonstrates that CT scans with IV contrast agent can be used for attenuation correction of the PET data in combined modality PET/CT scanning, without changing the clinical diagnostic interpretation.

Cementless porous-coated total knee arthroplasty: 10-year results in a consecutive series.

We report the results of 114 AGC 2000 porous-coated, cementless total knee arthroplasties (TKA) performed consecutively in 102 patients during the period 1984-1986. After 10 years, 58 TKAs in 52 patients were evaluated with patient assessment, Hospital for Special Surgery knee score, weight-bearing radiographs done under fluoroscopic control, and survivorship analysis. All dropouts within the first 9 years were patients dying with a functioning TKA except 1 revision secondary to a supracondylar fracture after 8.5 years. Of the patients, 53 (92%) were satisfied or very satisfied with their TKA, and 55 (95%) of the knees were rated good or excellent. There was no pain in 53 knees, and the median knee flexion was 110 degrees. Six radiolucencies >1 mm were found beneath parts of the tibial component, and 5 radiolucencies were seen beneath the femoral component. None had progressed compared with the 5-year follow-up, and in all cases trabeculae could be seen reaching the prosthetic component. No migrations had occurred since the 5-year follow-up. No obvious joint space reduction was seen. Osteolysis presenting as an isolated cyst was found in 1 knee in the lateral tibial condyle and was not progressive. Two tibial components had been revised because of aseptic loosening and 1 because of septic loosening, all within the first 3 years. No femoral or patellar components were revised. The cumulative prosthesis survival rate after 10 to 11 years was 97%. When pain and radiographic loosening also were considered, the success rate was 87%. Cementless insertion of a nonmodular, porous-coated TKA resulted in a long-term durable bone-prosthesis interface. The flat-on-flat articulation did not result in catastrophic polyethylene wear or osteolysis within the first 10 years.

[Intraoral cancer in the county of Copenhagen]. / Intraoral cancer i Københavns Amt.

A retrospective study of patients treated for intra-oral squamous cell carcinoma in Copenhagen county is reported. The material included 156 patients, 66 females and 90 males. Age at diagnosis varied between 35 and 95 years with a mean of 65 years. Mean age of females/males was 70/62 years. Twelve therapeutic modalities were performed; surgery, radiotherapy, chemotherapy and different combinations of these. Five year disease specific survival related to tumours' T-classification was 84% for T1, 35% for T2, 20% for T3 and 27% for T4. A statistically significant relation between the tumours' T-classification and the disease specific survival was noted (p < 0.00001). Five year disease specific survival related to N-classification was 62% for N0, 30% for N1, 25% for N2 and 0% for N3. Crude five year survival was 37% overall, 61% for patients in stage I, 32% for patients in stage II, 16% for patients in stage III and 17% for patients in stage IV. The results are similar to those achieved in other centres. Since no significant improvement has been noted in patient survival during the last five to six decades and since the therapeutic morbidity has not always been acceptable to the patients, other therapeutic principles, such as the so called minimal invasive therapy should be considered in future treatment of intra-oral cancer.

A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85.

PURPOSE: A multicenter randomized and balanced double-blind trial with the objective of assessing the efficacy and tolerance of nimorazole given as a hypoxic radiosensitizer in conjunction with primary radiotherapy of invasive carcinoma of the supraglottic larynx and pharynx. PATIENTS AND TREATMENT: Between January 1986 and September 1990, 422 patients (414 eligible) with pharynx and supraglottic larynx carcinoma were double-blind randomized to receive the hypoxic cell radiosensitizer nimorazole, or placebo, in association with conventional primary radiotherapy (62-68 Gy, 2 Gy per fraction, five fractions per week). The median observation time was 112 months. RESULTS: Univariate analysis showed that the outcome (5-year actuarial loco-regional tumor control) was significantly related to T-classification (T1-T2 48% versus T3-T4 36%, P = 0.0008), neck-nodes (N- 53% versus N+ 33%), pre-irradiation hemoglobin (Hb) concentration (high 46% versus low 37%, P = 0.02) and sex (females 51% versus males 38%, P = 0.03). Overall the nimorazole group showed a significantly better loco-regional control rate than the placebo group (49 versus 33%, P = 0.002). A similar significant benefit of nimorazole was observed for the end-points of final loco-regional control (including surgical salvage) and cancer-related deaths (52 versus 41%, P = 0.002). This trend was also found in the overall survival but to a lesser, non-significant extent (26 versus 16%, 10-year actuarial values, P = 0.32). Cox multivariate regression analysis showed the most important prognostic parameters for loco-regional control to be positive neck nodes (relative risk 1.84 (1.38-2.45)), T3-T4 tumor (relative risk 1.65 (1.25-2.17)) and nimorazole (relative risk 0.69 (0.52-0.90)). The same parameters were also significantly related to the probability of dying from cancer. The compliance to radiotherapy was good and 98% of the patients received the planned dose. Late radiation-related morbidity was observed in 10% of the patients, irrespective of nimorazole treatment. Drug-related side-effects were minor and tolerable with transient nausea and vomiting being the most frequent complications. CONCLUSION: Nimorazole significantly improves the effect of radiotherapeutic management of supraglottic and pharynx tumors and can be given without major side-effects.

Neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the head and neck: a randomized phase III study.

BACKGROUND AND PURPOSE: In 1986 a prospective, randomized, multi-centre trial for evaluation of neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in the treatment of advanced squamous cell carcinoma of the head and neck was initiated. As survival in this group of patients is poor the purpose was to find a possible survival benefit of the chemotherapy in addition to radiotherapy compared to radiotherapy only. METHODS: Four-hundred sixty-one patients from Denmark, Norway and Sweden with tumors in oral cavity, oropharynx, hypopharynx and larynx were randomized to receive either standard treatment (radiotherapy or radiotherapy followed by surgery) or neoadjuvant chemotherapy followed by standard treatment. Chemotherapy included three courses of cisplatin 100 mg/m2 i.v. infusion on day 1 followed by 5-fluorouracil 1000 mg/m2 per day continuous i.v. infusion for 120 hours. Radiotherapy 64-70 Gy in 2 Gy per fraction, 5 times/week, was given to patients in both treatment arms. RESULTS: Response rate was 71% for patients randomized to chemotherapy-radiotherapy and 66% for patients randomized to standard treatment (not statistically significant). Residual tumors were excised if possible. After surgery 62% of the patients randomized to chemotherapy-radiotherapy and 60% of the patients in the standard treatment group were clinically tumor free. CONCLUSIONS: No statistically significant benefit in survival was observed for patients treated with neoadjuvant chemotherapy followed by radiotherapy. Nor was there any impact of chemotherapy on the number of patients achieving loco-regional tumor control after primary treatment.

Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation.

PURPOSE: Accelerated repopulation of tumor cells during radiotherapy has been suggested as an important cause of treatment failure in squamous cell carcinoma of the head and neck. Due to tumor heterogeneity, not all tumors may benefit from accelerated radiotherapy at the expense of a lower total dose. This analysis evaluates the impact of histological differentiation on loco-regional control in relation to treatment duration. PATIENTS AND METHODS: A total of 501 patients with advanced supraglottic and pharyngeal squamous cell carcinoma with known histopathological grading were treated with planned split-course (191 patients) or continuous radiotherapy (310 patients) in two consecutive randomized controlled trials. Irradiation was given 2 Gy per fraction, 5 fractions per week to a dose of 66-68 Gy in 9.5 or 6.5 weeks, respectively. RESULTS: Overall, split-course and continuous treatment resulted in a 5-year loco-regional control of 30% and 41% (P = 0.007), respectively. However, the detrimental effects of split-course were only found in moderately and well-differentiated tumors, where the 5-year tumor controls were 38% and 21% after continuous and split-course treatment, respectively (P = 0.001). In contrast, in poorly differentiated tumors loco-regional control was obtained in 44% of the cases for continuous and 40% for split-course treatment (P = 0.63). CONCLUSIONS: It is suggested that the ability to accelerate repopulation may be lost by dedifferentiation, and that prolongation of the overall treatment time only lead to reduced loco-regional control in well to moderately differentiated tumors.