Several scientific and technological advancements in radiation oncology have resulted in dramatic improvements in dose conformity and delivery to the target volumes using external beam radiation therapy (EBRT). However, radiation therapy acts as a double-edged sword leading to drastic side-effects, one of them being secondary malignant neoplasms in cancer survivors. The latency time for the occurrence of second cancers is around $10$-$20$ years. Therefore, it is very important to evaluate the risks associated with various types of clinically relevant radiation treatment protocols, to minimize the second cancer risks to critical structures without impairing treatment to the primary tumor volume. A widely used biologically motivated model (known as the initiation-inactivation-proliferation model) with heterogeneous dose volume distributions of Hodgkin's lymphoma survivors is used to evaluate the excess relative risks (ERR). There has been a paradigm shift in radiation therapy from purely photon therapy to other particle therapies in cancer treatments. The extension of the model to include the dependence of linear energy transfer (LET) on the radio-biological parameters and mutation rate for charged particle therapy is discussed. Due to the increase in the use of combined modality regimens to treat several cancers, it is extremely important to evaluate the second cancer risks associated with these anti-cancer therapies. The extension of the model to include chemotherapy induced effects is also discussed. There have been several clinical studies on early and late relapses of cancerous tumors. A tumor control probability (TCP) model with recurrence dynamics in conjunction with the second cancer model is developed in order to enable design of efficient radiation regimens to increase the tumor control probability and relapse time, and at the same time decrease secondary cancer risks. Evolutionary dynamics has played an important role in modeling cancer progression of primary cancers. Spatial models of evolutionary dynamics are considered to be more appropriate to understand cancer progression for obvious reasons. In this context, a spatial evolutionary framework on lattices and unstructured meshes is developed to investigate the effect of cellular motility on the fixation probability. In the later part of this work, this model is extended to incorporate random fitness distributions into the lattices to explore the dynamics of invasion probability in the presence and absence of migration.

<p>The Swedish Cancer Register was used to determine the relative survival rate in colon and rectal cancer and to estimate the occurrence of second cancers related to radiation therapy for rectal cancer. The Swedish Hospital Discharge Register and hospital records were used to estimate the rate of late adverse effects due to radiation therapy for rectal cancer. The whole Swedish population was the source of the survival studies. Patients participating in the Uppsala Trial and the Swedish Rectal Cancer Trial on radiation therapy for rectal cancer constituted the subjects of the studies on late adverse effects and second cancers.</p><p>The main results of the survival analysis revealed a significant improvement in the 5-year relative survival rate for both colon and rectal cancer. During the time period 1960-1999, the survival improved from 39.6% to 57.2% in colon cancer and from 36.1% to 57.6% in rectal cancer.</p><p>Patients irradiated for rectal cancer, in addition to surgery, were at increased risk for a second cancer compared to those treated by surgery alone. This risk increase was mainly found for cancers developing in organs within or adjacent to the irradiated target (relative risk (RR) 2.04; 95% confidence interval (CI) 1.10–3.79). Furthermore, the most important late adverse effects of radiation therapy seem to be those on the gastrointestinal tract, in the form of small bowel obstruction (RR 1.88; 95%CI 1.10–3.20) and abdominal pain (RR 1.92; 95% CI 1.14–3.23). Overall, the benefit of radiation therapy was greater than its drawbacks, as a large reduction in local recurrences and better survival was noted in patients treated preoperatively with irradiation for rectal cancer.</p><p>In conclusion, significant improvements in the survival of patients with colon and rectal cancers have occurred in the last decades, especially in patients with rectal cancer. These improvements probably are related to advances in surgical and adjuvant treatment. The radiation therapy has several drawbacks, however, including an increased risk of second cancers and of bowel obstruction. This emphasises the need to further improve the radiation technique and to select only those patients for radiation therapy who are most likely to benefit from it.</p>

The Swedish Cancer Register was used to determine the relative survival rate in colon and rectal cancer and to estimate the occurrence of second cancers related to radiation therapy for rectal cancer. The Swedish Hospital Discharge Register and hospital records were used to estimate the rate of late adverse effects due to radiation therapy for rectal cancer. The whole Swedish population was the source of the survival studies. Patients participating in the Uppsala Trial and the Swedish Rectal Cancer Trial on radiation therapy for rectal cancer constituted the subjects of the studies on late adverse effects and second cancers. The main results of the survival analysis revealed a significant improvement in the 5-year relative survival rate for both colon and rectal cancer. During the time period 1960-1999, the survival improved from 39.6% to 57.2% in colon cancer and from 36.1% to 57.6% in rectal cancer. Patients irradiated for rectal cancer, in addition to surgery, were at increased risk for a second cancer compared to those treated by surgery alone. This risk increase was mainly found for cancers developing in organs within or adjacent to the irradiated target (relative risk (RR) 2.04; 95% confidence interval (CI) 1.10–3.79). Furthermore, the most important late adverse effects of radiation therapy seem to be those on the gastrointestinal tract, in the form of small bowel obstruction (RR 1.88; 95%CI 1.10–3.20) and abdominal pain (RR 1.92; 95% CI 1.14–3.23). Overall, the benefit of radiation therapy was greater than its drawbacks, as a large reduction in local recurrences and better survival was noted in patients treated preoperatively with irradiation for rectal cancer. In conclusion, significant improvements in the survival of patients with colon and rectal cancers have occurred in the last decades, especially in patients with rectal cancer. These improvements probably are related to advances in surgical and adjuvant treatment. The radiation therapy has several drawbacks, however, including an increased risk of second cancers and of bowel obstruction. This emphasises the need to further improve the radiation technique and to select only those patients for radiation therapy who are most likely to benefit from it.

Merkel cell carcinoma (MCC) is a rare neuroendocrine malignancy of the skin that is highly aggressive and often metastasizes early. MCC is diagnosed based on histopathological findings and is most commonly treated with surgical resection, which may be accompanied by chemotherapy and/or radiation. This report describes a 55-year-old male with history of recurrent malignant melanoma of the right pinna and subsequent excision. Three years following the excision of melanoma, he presents with a lesion to the right forehead as well as a right-sided neck mass that were found to be metastatic Merkel cell carcinoma. Although there have been reports describing the development of second cancers following the treatment of MCC, the development of MCC after the treatment of other malignancies has not been well-described. Merkel cell carcinoma remains a highly aggressive and frequently metastatic malignancy that should not be overlooked, especially when developed after the diagnosis and treatment of other primary cutaneous malignancies such as melanoma.

Depuis deux décennies, les nombreux développements des techniques de radiothérapie par modulation d’intensité (RCMI) ont permis de mieux conformer la dose au volume cible et ainsi, d’augmenter les taux de réussite des traitements des cancers. Ces techniques ont souvent l’avantage de réduire la dose aux organes à risque proches de la zone traitée, mais elles ont l’inconvénient d’apporter un niveau de dose périphérique plus important que les techniques basiques sans modulation d’intensité. Dans ce contexte, l’augmentation du taux de survie des patients qui en résulte, accroît également la probabilité de manifestation d’effets iatrogènes dus aux doses périphériques (tels que les cancers secondaires). Aujourd’hui, la dose périphérique n’est pas considérée lors de la planification du traitement et il n’existe aucun outil numérique fiable pour sa prédiction. Il devient cependant indispensable de prendre en compte le dépôt de dose périphérique lors de la planification du traitement, notamment dans les cas pédiatriques. Cette étude doctorale a permis la réalisation de plusieurs étapes du développement d’un outil numérique, précis et rapide, de prédiction de la dose hors-champ fondé sur le code Monte Carlo PENELOPE. Dans cet objectif, nous avons démontré la capacité du code PENELOPE à estimer la dose périphérique en comparant ses résultats avec des mesures de référence réalisées à partir de deux configurations expérimentales (métrologique et pré-clinique). Ces travaux expérimentaux ont notamment permis la mise en place d’un protocole d’utilisation des dosimètres OSL pour la mesure des faibles doses. En parallèle, nous avons pu mettre en évidence la convergence lente et rédhibitoire du calcul en vue d’une utilisation clinique. Par conséquent nous avons réalisé un travail d’accélération du code en implémentant une nouvelle technique de réduction de variance appelée transport pseudo-déterministe spécifiquement dédiée à l’amélioration de la convergence dans des zones lointaines du faisceau principal. Ces travaux ont permis d’améliorer l’efficacité des estimations dans les deux configurations de validation définies (gain d’un facteur 20) pour atteindre des temps de calcul raisonnables pour une application clinique. Des travaux d’optimisation du code restent à entreprendre de façon à améliorer encore la convergence de l’outil pour ensuite en envisager une utilisation clinique. / Over the last two decades, many technical developments have been achieved on intensity modulated radiotherapy (IMRT) and allow a better conformation of the dose to the tumor and consequently increase the success of cancer treatments. These techniques often reduce the dose to organs at risk close to the target volume; nevertheless they increase peripheral dose levels. In this situation, the rising of the survival rate also increases the probability of secondary effects expression caused by peripheral dose deposition (second cancers for instance). Nowadays, the peripheral dose is not taken into account during the treatment planification and no reliable prediction tool exists. However it becomes crucial to consider the peripheral dose during the planification, especially for pediatric cases. Many steps of the development of an accurate and fast Monte Carlo out-of-field dose prediction tool based on the PENELOPE code have been achieved during this PhD work. To this end, we demonstrated the ability of the PENELOPE code to estimate the peripheral dose by comparing its results with reference measurements performed on two experimental configurations (metrological and pre-clinical). During this experimental work, we defined a protocol for low doses measurement with OSL dosimeters. In parallel, we highlighted the slow convergence of the code for clinical use. Consequently, we accelerated the code by implementing a new variance reduction technique called pseudo-deterministic transport which is specifically with the objective of improving calculations in areas far away from the beam. This step improved the efficiency of the peripheral doses estimation in both validation configurations (by a factor of 20) in order to reach reasonable computing times for clinical application. Optimization works must be realized in order improve the convergence of our tool and consider a final clinical use.