Background: Previous literature showed contradictory evidence on the subject of predictors of chemotherapy-induced Palmar Plantar Erythrodysesthesia (PPE). While there is evidence to suggest that dose and schedule of the drugs play a large role, the fact that many still go on to develop severe PPE following dose reduction would indicate that there are other factors involved. Since the incidence of PPE is more prevalent during the first three cycles of treatment this would also indicate that there are factors other than a cumulative effect. The contradictory evidence in the literature relates to biographical factors, performance status, co-morbidities and renal function. There is a lack of empirical evidence to support the theory that PPE is caused by damage to the microcapillaries due to everyday activities that cause friction or pressure to the hands or feet. Purpose: The aim of this exploratory study was to identify pre-treatment risk factors for the development of PPE prior to cycle four. Patients and methods: The study was made up of two phases, a retrospective phase and a prospective phase, using mixed strategies to collect data. Thus providing two independent samples to compare and validate or refute results. Phase I: A retrospective notes review of patients who had received Infusional 5FU or capecitabine containing regimes over a 1 year period (n=392). Phase II Prospective data collection from participants receiving capecitabine monotherapy (n = 125). Data was collected during semi-structured interviews, from participant's diaries, physical examination of the hands and feet and notes review. Data relating to activities that cause friction, pressure or heat were collected during this phase. Data from both samples were analysed independently using bivariate (chi-square and t-test) tests where each independent variable was analysed against PPE. The variables which achieved statistical significance were entered into a multivariate (binary logistic regression) model. The multivariate analysis employed a specific modelling algorithm using a relaxed alpha value applied to various entry methods to produce multiple models. The outcomes from these models were entered into a ROC curve test to establish which model was the best predictor of PPE. Results: Phase I The bivariate analysis demonstrated that those at most risk of developing PPE prior to cycle 4 of capecitabine monotherapy were males with non-metastatic colorectal cancer, who had either developed PPE with previous chemotherapy regimes or not had previous chemotherapy and who started their treatment during the winter months. When variables were combined in a multivariate logistic regression model, those that were associated with an increased risk of PPE were male, no metastatic spread, no inflammatory condition as co morbidity, smoked, did not drink, had weight loss prior to treatment, a low/normal pre treatment ALP level and started their treatment during the winter. Phase II: The bivariate analysis demonstrated that those at most risk of developing PPE prior to cycle 4 of capecitabine monotherapy were those with no metastatic disease, had an inflammatory condition as co morbidity, were receiving capecitabine as adjuvant treatment, had a good performance status (0-1) and had a tendency to have warm hands. When variables were combined in a multivariate logistic regression model, those that were associated with an increased risk of PPE were younger (< 65) had no metastatic disease, an inflammatory condition as co morbidity, drank alcohol regularly, had a good performance status, had not received previous radiotherapy, were overweight or obese, had a pre treatment creatinine clearance of 30-50mls/min and had a tendency to have warm hands. Conclusions: Similarly to the literature, contradictory findings were seen between the two samples within this study. There was only one variable that was associated with the development of PPE prior to cycle 4, which was the absence of metastatic disease. Limitations of retrospective data may explain variation in some variables which may have been underreported; however it is likely that it is not possible to identify specific factors that increase the risk of PPE. This is the first study to have collected and analysed data related to friction, pressure and heat causing activities. These activities have been suggested as increasing the risk of developing PPE and form the basis of patient education to avoid these activities. Data from this study indicates that only a tendency to have warm hands is associated with an increased risk of PPE. Whilst this finding would need validating in larger studies, it is a unique contribution to the body of knowledge of PPE. This finding indicates that avoidance of activities that cause friction and pressure has no evidence base. Patients may therefore be avoiding activities that add to their enjoyment which at this stressful time in their lives may add to any psychological distress. Despite limitations of this study, the importance of the findings presented here lie in its usefulness in shaping future research to investigate identified variables, where before no direction was available.

<p><strong>Bakgrund:</strong> Hand-fot syndrom är en form av perifer sensorisk neuropati orsakad av cytostatikabehandling. Syndromet kan ge biverkningar såsom smärta, obehag, domningar, svullnad och nedsatt balans. Utvärderade behandlingsmetoder saknas.</p><p><strong>Syfte:</strong> Undersöka hur tolv veckors sjukgymnastisk behandling med långvågsdiametri, interferens och balansträning påverkar biverkningar i fot/underben orsakad av cytostatikabehandling hos sju patienter med hand-fot syndrom.</p><p><strong>Metod:</strong> Gruppstudie, kvasiexperimentell resultatstudie. Sju patienter deltog. Variabler som mättes var, smärta, obehag, domningar och balans. Tre mätningar utfördes, före, efter samt åtta veckor efter interventionen. Självrapporterad skattning och fysisk mätning användes.</p><p><strong>Resultat: </strong>Gruppens smärta, obehag och domningar minskade vid samtliga mätningar. För smärta visade mätning efter intervention samt åtta veckor efter signifikans (p=0,027), (p=0,042). Obehag visade signifikans efter interventionen (p=0,018). Domningar visade ingen signifikans. Balans visade signifikans i: Skärpt Romberg, höger, blundande, åtta veckor efter interventionen (p=0,043). Skärpt Romberg, vänster, blundande, efter interventionen (p=0,027), åtta veckor efter interventionen (p=0,028). Stående på ett ben, höger, blundande, efter interventionen (p=0,042), åtta veckor efter interventionen (p=0,027). Inga mätningar visade försämringar.</p><p><strong>Slutsats: </strong>Restultaten visade att behandling med långvårdsdiametri, interferens och balansträning minskade smärta, obehag, domningar och delvis förbättrade balans vid hand-fot syndrom. Dock går det inte att påvisa vilken behandlingskomponent som påverkat mest. Ytterligare studier behövs för att ge resultat större giltighet.</p> / <p><strong>Background</strong>: Hand-foot syndrome is a form of perifier sensory neuropathy caused by chemotherapy. The syndrome can cause side effects such as pain, discomfort, numbness, swelling and impaired balance. Evaluated treatment is lacking.</p><p><strong>Purpose:</strong> Examine how twelve week physiotherapy treatment short-wave diathermy, interference and balance training affects side effects of the foot/lower leg caused by chemotherapy in seven patients with hand-foot syndrome.</p><p><strong>Method:</strong> Study group, quasi-experimental outcome study. Seven patients participated. Variables measured were, pain, discomfort, numbness, and balance. Three measurements were carried out, before, after, and eight weeks after the intervention. Self-reported estimates and the physical measurement were used. <strong></strong></p><p><strong>Results:</strong> The group's pain, discomfort and numbness decreased in all measurements. For pain measurement after the intervention and eight weeks after showed significance (p = 0,027),(p = 0,042). Discomfort showed significance after the intervention (p = 0,018). Numbness showed no significance. Balance showed significance in: Sharpened Romberg, left, eyes closed, eight weeks after intervention (p = 0,043). Sharpened Romberg, left, eyes closed, after the intervention (p = 0,027), eight weeks after intervention (p = 0,028). Standing on one leg, the right, eyes closed, after the intervention (p = 0,042), eight weeks after intervention(p = 0,027). No measurements showed deterioration.</p><p><strong>Conclusion:</strong> The results showed that treatment with short-wave diathermy, interference and balance training reduced pain, discomfort, numbness and partial improvements in balance in hand-foot syndrome. However, it is not possible to demonstrate which treatment component that affected the most. Further studies are needed to produce results more valid.</p>

Bakgrund: Hand-fot syndrom är en form av perifer sensorisk neuropati orsakad av cytostatikabehandling. Syndromet kan ge biverkningar såsom smärta, obehag, domningar, svullnad och nedsatt balans. Utvärderade behandlingsmetoder saknas. Syfte: Undersöka hur tolv veckors sjukgymnastisk behandling med långvågsdiametri, interferens och balansträning påverkar biverkningar i fot/underben orsakad av cytostatikabehandling hos sju patienter med hand-fot syndrom. Metod: Gruppstudie, kvasiexperimentell resultatstudie. Sju patienter deltog. Variabler som mättes var, smärta, obehag, domningar och balans. Tre mätningar utfördes, före, efter samt åtta veckor efter interventionen. Självrapporterad skattning och fysisk mätning användes. Resultat: Gruppens smärta, obehag och domningar minskade vid samtliga mätningar. För smärta visade mätning efter intervention samt åtta veckor efter signifikans (p=0,027), (p=0,042). Obehag visade signifikans efter interventionen (p=0,018). Domningar visade ingen signifikans. Balans visade signifikans i: Skärpt Romberg, höger, blundande, åtta veckor efter interventionen (p=0,043). Skärpt Romberg, vänster, blundande, efter interventionen (p=0,027), åtta veckor efter interventionen (p=0,028). Stående på ett ben, höger, blundande, efter interventionen (p=0,042), åtta veckor efter interventionen (p=0,027). Inga mätningar visade försämringar. Slutsats: Restultaten visade att behandling med långvårdsdiametri, interferens och balansträning minskade smärta, obehag, domningar och delvis förbättrade balans vid hand-fot syndrom. Dock går det inte att påvisa vilken behandlingskomponent som påverkat mest. Ytterligare studier behövs för att ge resultat större giltighet. / Background: Hand-foot syndrome is a form of perifier sensory neuropathy caused by chemotherapy. The syndrome can cause side effects such as pain, discomfort, numbness, swelling and impaired balance. Evaluated treatment is lacking. Purpose: Examine how twelve week physiotherapy treatment short-wave diathermy, interference and balance training affects side effects of the foot/lower leg caused by chemotherapy in seven patients with hand-foot syndrome. Method: Study group, quasi-experimental outcome study. Seven patients participated. Variables measured were, pain, discomfort, numbness, and balance. Three measurements were carried out, before, after, and eight weeks after the intervention. Self-reported estimates and the physical measurement were used. Results: The group's pain, discomfort and numbness decreased in all measurements. For pain measurement after the intervention and eight weeks after showed significance (p = 0,027),(p = 0,042). Discomfort showed significance after the intervention (p = 0,018). Numbness showed no significance. Balance showed significance in: Sharpened Romberg, left, eyes closed, eight weeks after intervention (p = 0,043). Sharpened Romberg, left, eyes closed, after the intervention (p = 0,027), eight weeks after intervention (p = 0,028). Standing on one leg, the right, eyes closed, after the intervention (p = 0,042), eight weeks after intervention(p = 0,027). No measurements showed deterioration. Conclusion: The results showed that treatment with short-wave diathermy, interference and balance training reduced pain, discomfort, numbness and partial improvements in balance in hand-foot syndrome. However, it is not possible to demonstrate which treatment component that affected the most. Further studies are needed to produce results more valid.

(thesis): Palmar-plantar erythrodysesthesia (PPE) frequently accompanies the therapy with a continuous 5-FU infusion or peroral capecitabine (5-FU prodrug). In the most severe cases this adverse effect leads to discontinuation of a needful therapy. Local 10 % uridine ointment is used to prevent and treat the said adverse event. Nevertheless, this method is not generally accepted as an effective one because it has never been proved in a randomized controlled clinical trial. Most probably, a direct effect of a cytostatic compound on the skin of hands and foots causes PPE. The toxicity of 5-FU is mediated primarily by its incorporation into RNA and by thymidylate synthase (TS) inhibition and subsequent DNA synthesis disruption. The importance of particular 5-FU toxicity mechanisms varies in different cell types. For choosing the best PPE local antidote it is necessary to find out which molecular mechanism applies in keratinocytes. We have chosen pyrimidine nucleosides as the most suitable compounds for the local PPE therapy because the uridine ointment is already being used in several oncology centers in the Central Europe. In order to find out the 5-FU toxicity mechanism, we further tested the effect of calciumfolinate (CF) which strengthens the TS inhibition by 5-FU. We studied also uracil and...

There is high variability in response to cancer chemotherapies among patients. Its sources are diverse: genetic, physiologic, comorbidities, concomitant medications, environment, compliance, etc. As the therapeutic window of anticancer drugs is usually narrow, such variability may have serious consequences: severe (even life-threatening) toxicities or lack of therapeutic effect. Therefore, various approaches to individually tailor treatments and dosing regimens have been developed: a priori (based on genetic information, body size, drug elimination functions, etc.) and a posteriori (that is using information of measurements of drug exposure and/or effects). Mixed-effects modelling of pharmacokinetics and pharmacodynamics (PK-PD), combined with Bayesian maximum a posteriori probability estimation of individual effects, is the method of choice for a posteriori adjustments of dosing regimens. In this thesis, a novel approach to adjust the doses on the basis of predictions, given by a model for ordered categorical observations of toxicity, was developed and investigated by computer simulations. More technical aspects concerning the estimation of individual parameters were analysed to determine the factors of good performance of the method. These works were based on the example of capecitabine-induced hand-and-foot syndrome in the treatment of colorectal cancer. Moreover, a review of pharmacodynamic models for discrete data (categorical, count, time-to-event) was performed. Finally, PK-PD analyses of hydroxyurea in the treatment of sickle cell anemia were performed and used to compare different dosing regimens and determine the optimal measures for monitoring the treatment

Il existe une grande variabilité dans la réponse aux chimiothérapies anticancéreuses. Ses sources sont diverses: génétiques, physiologiques, comorbidités, médicaments associés, etc. La marge thérapeutique de ces médicaments étant généralement étroite, une telle variabilité peut avoir de graves conséquences: toxicités graves ou absence d'effet thérapeutique. Plusieurs approches pour adapter individuellement les posologies ont été proposées: a priori (basées sur l'information génétique, la taille corporelle, les fonctions d'élimination, etc.) et a posteriori (sur les informations de mesures d'exposition au médicament et/ou effets). La modélisation à effets-mixtes de la pharmacocinétique et de la pharmacodynamie (PK-PD), combinée avec une estimation bayésienne des effets individuels, est la meilleure méthode pour individualiser des schémas posologiques a posteriori. Dans cette thèse, une nouvelle approche pour ajuster les doses sur la base des prédictions données par un modèle pour les observations catégorielles de toxicité a été développée et explorée par simulation. Les aspects plus techniques concernant l'estimation des paramètres individuels ont été analysés pour déterminer les facteurs de bonne performance de la méthode. Ces travaux étaient basés sur l'exemple du syndrome mains-pieds induit par la capécitabine dans le traitement du cancer colorectal. Une revue des modèles pharmacodynamiques de données discrètes (catégorielles, de comptage, de survie) a été effectuée. Enfin, des analyses PK-PD de l'hydroxyurée dans le traitement de la drépanocytose ont été réalisées pour comparer des différentes posologies et déterminer les modalités optimales de suivi du traitement / There is high variability in response to cancer chemotherapies among patients. Its sources are diverse: genetic, physiologic, comorbidities, concomitant medications, environment, compliance, etc. As the therapeutic window of anticancer drugs is usually narrow, such variability may have serious consequences: severe (even life-threatening) toxicities or lack of therapeutic effect. Therefore, various approaches to individually tailor treatments and dosing regimens have been developed: a priori (based on genetic information, body size, drug elimination functions, etc.) and a posteriori (that is using information of measurements of drug exposure and/or effects). Mixed-effects modelling of pharmacokinetics and pharmacodynamics (PK-PD), combined with Bayesian maximum a posteriori probability estimation of individual effects, is the method of choice for a posteriori adjustments of dosing regimens. In this thesis, a novel approach to adjust the doses on the basis of predictions, given by a model for ordered categorical observations of toxicity, was developed and investigated by computer simulations. More technical aspects concerning the estimation of individual parameters were analysed to determine the factors of good performance of the method. These works were based on the example of capecitabine-induced hand-and-foot syndrome in the treatment of colorectal cancer. Moreover, a review of pharmacodynamic models for discrete data (categorical, count, time-to-event) was performed. Finally, PK-PD analyses of hydroxyurea in the treatment of sickle cell anemia were performed and used to compare different dosing regimens and determine the optimal measures for monitoring the treatment