this presentation really focusing on very advanced disease. I can imagine but I'm not sure if there is a need for better explanation of the more basic principles of radiotherapy or background of radiotherapy for locally advanced cervical cancer. I have additional slides but based on this question I just want to start with focusing on this very advanced disease. I start with the focus on stage IVa. This is just a summary statement of the role of radiotherapy in locally advanced cervical cancer. The combination of external beam radiotherapy with concurrent cisplatinum, usually weekly cisplatinum chemotherapy followed by practice therapy is the standard treatment for locally advanced cervical cancer. I think we have more and more evidence about the role of image-guided practice therapy and of combined intracavitary and interstitial practice therapy with which it is possible to achieve higher doses in the cancer and lower doses in the surrounding normal healthy organs. That is of course of benefit, especially in more advanced disease. Practice therapy we know that is associated with higher survival compared to external beam radiotherapy techniques when you attempt to give a higher dose by external beam technique. Practice therapy gives an intrinsic high radiation dose and that has an advantage. The ongoing trials at the moment they investigate the benefit of adjuvant or neoadjuvant systemic therapy and in all these studies, also for very advanced disease, the standard treatment still is as stated above the combination of external beam radiotherapy cisplatinum followed by brachytherapy. This is just one slide to summarize and I can talk a whole hour about this. When we focus now on stage IVa disease, I summarized a few interesting publications that really illustrate this specific problem. When we look at the data accumulated in prospective GOG studies, there were 51 patients and that already indicates it's quite a rare situation. Of these 51 patients, the patients that they had more data on, there were 44 patients with bladder involvement and four with rectal involvement and that is also as according to other literature you will see in a moment, the majority presents with bladder invasion and very rare it is rectal invasion. When compared to patients with stage IIIb disease, they usually have a poorer performance and larger tumor size and more frequent bilateral parametric involvement but also bilateral hydronephrosis and we know that that's poor prognostic factors. In addition, these patients at higher stages, higher T-stages, also have higher chance of pelvic but also periortic nodal involvement which affects prognosis. In this case of these studies, there were also pelvic nodal metastasis has a significant effect or close significant effect on progression-free and overall survival. Here you see from this study results the survival curves of the patients treated with and without brachytherapy also near significant but given the numbers it's a clear indication, a clear message. The patients who did not receive brachytherapy received higher dose external beam radiotherapy and in these protocols part of the patients received concurrent cisplatinum and part of the patients did not receive, it was radiation alone and in these results you do not see a clear effect of combined cisplatinum as additive effect but we know from other studies that there is an effect, a benefit. But it is good to see that you can also achieve this with radiation alone. When we look at the topic of physical vaginal fistula in stage 4a, this is a study in which they attempted to find prognostic factors for physical or rectovaginal fistula and they found 30 patients with stage 4a. Again, the majority had extension towards the bladder and only a minority to the rectum. The majority had an attempt for curative treatment with five-year overall survival rate of 40% which is in line with the GOG data I just showed you and you can see this in the curve on the left. These patients, 22% developed a fistula and the five-year fistula free survival was 64%. In this small number of patients they tried to find prognostic, pretreatment prognostic factors but were not able to find them. But this is a paper that I think very well summarizes the relevant risks in this disease and this specific problem. Then there is an important, I think a relevant publication from the Institut Gustave Roussy in France where they also over a longer period of time summarized their data specifically for bladder invasion also with an attempt to look into prognostic factors related to bladder invasion. They had 71 patients in this long period. Part of them were treated with low dose rates brachytherapy and part of them approximately half with PDR brachytherapy image guided and 21 of the 71 patients also had periortic nodal involvement so were actually stage 4B but local T stage 4A and here you see the clinical outcomes and local control is still reasonably good in patients with 4A disease and again overall survival here in red is in line with the previous results about 40% at five years. In their analysis there were 63 patients without fistula at diagnosis and 15 developed vesicofaginal fistula during follow-up and there were eight patients who had a vesicofaginal fistula, which would be an F at diagnosis and of the eight, in two patients the fistula resolved after treatment. Importantly, this vesicofaginal fistula occurred in 19% of patients without local relapse and in 40% with local relapse. It's always important if there is in the follow-up then a fistula to also be aware of the chance that it is related to local recurrence. So they performed a multivariate analysis of risk factors and I will show an image in the next slide. They also looked at specific findings on pretreatment MRI and they found that necrosis in the anterior portion of the tumour towards the bladder on the baseline MRI, so prior to the start of radiotherapy, was associated with an increased risk of vesicofaginal fistula formation and also the height of the involvement or the extent of the involvement of the anterior bladder wall or posterior bladder wall was also prognostic. Here you see an image of that publication where you see on the top level a patient where you see necrosis in the tumour in the anterior part of the tumour and in red it's indicated the height of bladder involvement and here you see six weeks after brachytherapy you clearly see that there is an increased zone of necrosis and there is an area of fistulation and on the lower pane you see another example where there is bladder involvement again here which is also confirmed by cystoscopy but there is no necrosis and here you see the complete resolvement of the tumour, complete remission of the tumour six weeks after brachytherapy and a nice healing of the bladder wall. So these are two examples with a nice image. So just I have from a case of myself just two images also to illustrate the role of image-guided brachytherapy. Here you see also a patient with bladder involvement at the level of also of the ostium of the ureter on the left side and here you see also the stent going into the bladder and you see the residual tumour at time of brachytherapy which is still quite extensive and you can see here the additional positioning of freehand needle in the anterior vaginal wall and on the sagittal axial plane you can also see apart from the standard typical intracavitary position here the intrauterine tube which goes all the way up into the uterus and the ovoids or ring is situated just at the level of the cervix and here you see the additional interstitial needles from the applicator and here also from the freehand needles in the vaginal wall and here you see the typical dose distribution that you can achieve with image-guided brachytherapy and the combination of in this case very important interstitial brachytherapy because with interstitial brachytherapy you can achieve this asymmetric loading guided to the residual tumour at time of brachytherapy. So this is just an example. I have just two slides also for the discussion which I think is relevant in this situation. Often at diagnosis there are several factors you have to take into account and I will come back to that a little later where you have to decide is this still a curative treatment, is this a curative intent or for different reasons is curation not feasible, is it a more palliative intent and it's good to know that recently there was an important publication in Yama Oncology from the National Cancer Database in the United States looking into patients with metastatic cervical cancer and comparing patients that received in part of their primary treatment also radiation or not and here you can see in the Kaplan-Meier curve that the patients that received radiation in addition to the chemotherapy have an improved overall survival and they also looked into detail and the conclusion is when also brachytherapy, so local treatment was part of the overall treatment plan, the results in terms of median overall survival were the highest. But it's important to remember of course in such an analysis, this is retrospective, there is of course a certain amount of bias because patients should be fit enough to undergo this treatment and that is not easy to account for in such an analysis. And the majority of the patients in this situation received upfront chemoradiation, brachytherapy and chemotherapy. So coming slowly towards the summary, when asking the questions what are the indications or contraindications for radiotherapy, I think it's important to discuss that these are quite relative. It is important again to make the distinction or try to make the distinction if the intent is curative or palliative. If it is localized disease, in principle we have seen the results in the literature that there is a fair chance of overall survival, 40% at 5 years. But of course this is also partly selection because you have to take prognosis into account, especially patients with paraortic nodal metastasis, nodal disease, have a high chance of subsequent systemic relapse and poor overall survival chances. There are more in the order of 20%. When considering such a treatment, we have to know the performance status and comorbidities of the patient because they also affect the chances or feasibility of such a treatment. So you have to take medical factors into account, but also important the social emotional condition of the patient because it is quite an intensive and prolonged treatment and the patient, but also the family, has to be able to cope also with these aspects of the whole treatment. For brachytherapy there are some specific considerations that can depend a little bit on anatomical consideration of patient factors, but in the majority of cases brachytherapy is feasible. But I think it's also important to know in your team, so that is my question for you at the end, so what are the local possibilities, what are the technical availabilities because it depends a lot if you have interstitial brachytherapy available, if you have image guidance, if you can use ultrasound in some way. So that also depends in the consideration what the intent is of the treatment and what the order of treatment is. For example, in very extensive tumours you can still consider the role of neoadjuvant or palliative chemotherapy and then followed by a higher dose treatment with radiotherapy. But in principle, and that is part of the background literature, it is not standard and also not for a disease. Standard is start primary chemoradiation, but limited access can also play a role in the timing. So to continue when we consider palliation, there are two options basically. Sometimes you need fast symptom relief and that's usually in the very poor prognostic and then you consider hypofractionated external beam. The other part is when you consider to achieve as long as possible local tumour regression and symptom control and that is usually achieved with a higher dose of fractionated radiotherapy and if possible combined with brachytherapy, then you achieve the best result. And then of course there is discussion about the role of palliative chemotherapy and the sequencing of the chemotherapy and the radiotherapy. And the advantage of starting with the chemotherapy if you decide it is a more palliative situation is that you can take the response on chemotherapy into account when deciding what the optimal radiotherapy schedule would be for such a patient. So in good responders, you could really go for full curative treatments or an attempt for a high dose including brachytherapy. So my take home message is that chemoradiation and brachytherapy is the standard for locally advanced cervical cancer including stage IVa, but of course there are some local considerations and it can be because of availability of radiotherapy and technical considerations and these also have to be taken into account in this decision making and I am aware that in some situations it is the best situation local to start with chemotherapy for instance because of availability. In stage IVa disease is relatively infrequent and the majority present with bladder involvement. Five year overall survival around 40% after curative radiotherapy and about 20 to 25% develop a fistula and we just discussed risk factors. Contraindications are relative and these contraindications can make you also consider alternative ways of delivering radiation or chemotherapy and I just want to stress the importance of the multidisciplinary team in both assessment evaluation of such a patient which can be complex and also the treatment decision making. So that was the first part of and I think the principal part of my didactic realm. I have more but I think we can better do that in a separate didactic on the background if that is appreciated. I think so, yeah. We won't have time.

radiotherapy

locally advanced cervical cancer

brachytherapy

prognostic factors

adjuvant systemic therapy

multidisciplinary team