Outcome of preoperative radiotherapy in the treatment of cervical cancer with focus on protein expression and dosimetry

Abstract: Treatment with preoperative intracavitary radiotherapy (ICRT) is used in cervical cancer with the intention to reduce the tumour burden and sterilize microscopic disease in the paracervical tissues. Preoperative ICRT is, however, a controversial treatment regime since it is unclear if addition of ICRT to surgery improves treatment outcome compared to surgery alone. This question constitutes the basis of this thesis. In relation to this issue we have studied clinical, dosimetric and molecular key factors with focus on DNA damage repair signalling molecules of possible importance for radiotherapy sensitivity. One possible way to investigate the potential benefit of preoperative ICRT is to analyze whether complete tumour remission in the surgical specimen after preoperative ICRT is correlated to treatment outcome or not. In paper I we analyzed treatment results after preoperative ICRT in patients with cervical cancer stage IB-IIA. We found a strong correlation between pathologic complete remission (pCR) and survival with a 5-year survival of 95% in patients with pCR compared to 46% in patients with residual tumour (non-pCR) (p<0.0001). These results indicate that the use of preoperative ICRT may contribute to treatment outcome compared to surgery alone. DNA double strand breaks (DNA DSBs) and their repair has in tumour cell lines been linked to radiosensitivity. In paper II we therefore analyzed the expression of proteins related to the DNA-PK repair pathway; DNA-PKcs, Ku70, Ku86, p53, p21 and Mdm-2 in pre-treatment tumour tissue with the aim to find predictive markers for radiotherapy response. Our hypothesis was that high DNA repair capacity in the primary tumour, reflected by a high frequency of cells positive for DNA-PK proteins, would correlate with non-pCR cases. However, we did not find that any of the analyzed proteins were predictive for radiotherapy response. Our hypothesis in paper III was that residual tumours that survived radiotherapy would display a higher frequency of DNA-PK positive cells reflecting a higher capacity to DNA DSB repair compared to their corresponding primary tumours. The expression of DNA-PKcs, Ku70, Ku86, p53, p21 and Mdm-2 proteins was compared in pre- and post-treatment tumour tissue. We found that residual tumours showed an increased frequency of tumour cells positive for DNA-PK complex proteins compared to the frequency in the primary tumour. This result may be interpreted as that radiation causes a selection pressure allowing tumour cells with high DNA-PK expression to survive RT. Biological effective dose (BED) can be used to predict the influence on outcome of different treatment schedules for individual patients. In paper IV we evaluated BED with respect to survival, local control and late toxicity in patients treated either with radiotherapy and surgery or with radiotherapy alone. We found a correlation between BED and treatment outcome for patients treated with radiotherapy alone but not for patients treated with radiotherapy and surgery. No correlations were found between BED and late toxicity from bladder and rectum. In conclusion this thesis illustrates that treatment with preoperative intracavitary radiotherapy may be beneficial for patients with cervical cancer stage IB-IIA. We found that the expression of the DNA-PK complex proteins in primary tumour cannot predict RT response. We did, however, find that the frequency of the DNA-PK complex proteins is higher in residual tumour after ICRT than in corresponding primary tumour. BED cannot be used as a predictive factor for the outcome in patients treated with pre-and postoperative radiotherapy or for the late side effects but does correlate with local control of the tumour and survival in patients treated with RT alone.