Matteo Sepulcri: Dear colleagues, Mr. Chairman, thank you for the invitation. It's a pleasure for me to be here. And in our lecture, we will discuss the rationale of radiotherapy in prostate cancer. The radiotherapy treatment for prostate cancer, and the role of PET/CT in different settings.

First of all, radiation therapy kills neoplastic cells by leaving damage to the DNA. Lethal damage can be hit with the double-strand break and is defined as the alpha component. And we can also have sub-lethal damage with a single-strange break, called also a beta component.

Prostate cancer has a low alpha/beta ratio, and its benefits of high total dose and high-dose per fraction.

So, first of all, the radical setting of prostate cancer radiotherapy can be an effective treatment in the radical one with the disease classified as T1/T3, N0/N1, M0. Also in the post-operative setting, radiotherapy plays an important role in the case of immediate radiotherapy after surgery with an adjuvant aim, or at the raising of PSA. So it will be a delayed treatment, also called salvage radiotherapy.

Furthermore, in the oligometastatic disease up to three metastases, radiotherapy can be useful, and of course in the palliative setting, but this last we will not be discussing in our lecture.

About radical radiotherapy, and particularly for low-risk prostate cancer, this study compared 10-year outcomes after active monitoring, surgery, or radiotherapy for localized prostate cancer.

Each arm, the study has three arms with about 500 patients per arm. Most of all, they are low-risk prostate cancer, and this study confirms that radiotherapy can be an effective treatment compared with surgery.

But if for low-risk prostate cancer, we have a very good control rate. It's not the same for more aggressive disease. Recently the World Health Organization upgraded the prostate cancer classification, and we have the major difference in Gleason 7. In fact, Gleason 7 (3+4) will be classified as grade II according to WHO classification and Gleason 7 IV plus III will be classified as grade III. And then you can see the differences in outcome between the two entities. In summary, there are lower control rates for grade III or more.

On the other hand, in the last decades, many studies concerning dose escalation were conducted, and you can see for all classes of risk, low, intermediate, and high-risk, dose-escalation allows better oncological control.

Finally, a meta-analysis by Viani highlights the potential of dose escalation in prostate cancer, in primary prostate cancer, with better oncological control. This is more significant for high-risk disease, and the authors suggest that the Biological Effective Dose should be higher than 90 grays. This is a problem for organs at risk of toxicity.

Also, the latest NCCN guidelines suggest to use regimens with a total equivalent dose up to 80 grays with the standard, or with the hypofractionation schemes.

But how can we make the dose-escalation without increase organ at risk of toxicities? The first possibility is to change our radiotherapy strategy, our radiotherapy technique, going from 3D conformal radiotherapy to intensity-modulated radiotherapy. That allows dose-escalation on the prostate with maintaining the toxicity at the rectum and bladder the same. So intensity-modulated radiotherapy allows a safe dose escalation.

The other possibility is image-guided radiotherapy that means that with an online daily control by imaging, we can reduce the margin from clean-cut target volume to the planned target volume. And this allows us to spare the organs that risk toxicity and at the same time to escalate the dose to the target.

Where does the recurrence after definitive treatment with radiotherapy occur? These two studies, films show that local recurrence mainly occurs in the same site of the primary and in the region with high tumor burden suggest that a boost dose could be useful to control the tumor.

So as investigated by the FLAME study and that trial is a single-blind randomized Phase III trial to investigate the benefit of a focal boost within the prostate. The control arm, the patient in the control arm, received 77 grays on the prostate gland while in the experimental arm, it was an addiction of a booster up to 95 grays based on MRI findings.

The study closed two years ago, so the oncological outcomes, it's healthy to have oncological control rates, but recently have been published the results about toxicity. And as you can see, the blue line that represents the standard arm and the red dot line that represents the experimental arm, are substantially the same, and so the authors concluded that the focal boost within the prostate gland does not increase genitourinary and gastrointestinal toxicity.

Now we go to the first teaching case, clinical case, regarding radical radiotherapy. A 79-year-old man with cardiac comorbidities had a PSA of 6.4 ng/ml underwent biopsy with a diagnosis of adenocarcinoma of cT2, classified cT2 Gleason Score 7 (4+3), so grade III according to the WHO classification. And then went to a choline PET/CT for staging.

This is the PET scan that reveals an uptake only in the prostate gland. So the patient underwent to radical radiotherapy with a dose prescription of 70 grays in 28 fractions for a total equivalent dose of 80 grays, 2.5 grays per fraction in a moderate hypo-fractionated scheme. The technique was IMRT with two co-planar arcs, and regarding image guidance, we used the intraprostatic fiducial markers.

And Simultaneous Integrated Boost on PET choline uptake was also planned. And in this video, you can see the two plains above the standard plain and below the plain with the boost dose on the PET uptake. And you can see the isotope dose of the planning that is similar and also in the dose-volume histograms, the toxicity regarding bladder and rectum are comparable.

So the patient completed radiotherapy in March 2016 and the acute GU toxicity resolves in about 15 days and then the PSA values start falling down until 0.35 ng/ml reach in the last May.

So, first the questions for a nuclear medicine physician in the radical setting. How can PET/CT help the radiation oncologist? How to evaluate PET/CT findings? And which is the best radiotracer in this setting?

Laura Evangelista: Okay, I will try to give some answers to this question to the radiation oncologist. Before starting with the indication for choline and PET and PSMA just to divide the different indications for the initial staging of prostate cancer with PET. Because we have to differentiate for a patient with localized prostate cancer, it means that the presence of prostate cancer only gland. And patient with locally advanced prostate cancer, because a patient with localized prostate cancer can be cured with definite radiotherapy planning. And for this case are available some papers with the PSMA and choline PET/CT. Why a patient with locally advanced prostate cancer, it means with cancer in the prostate gland and also the involvement of local lymph nodes, they can benefit from definitive radiotherapy treatment, but including the extended field. And for these types of settings, we have now at disposal only papers with the PET/CT with choline and no data with the PSMA.

So by analyzing this data in particular for choline PET, we can see that a lot of data are favorable for the use of choline PET in this setting. Because by including choline PET for the definition of the planning treatment, we cannot increase the normal tissue complication probabilities to the rectum and bladder. And according to Pinkawa et al, the treatment planning with the simultaneous integrated booster allows an individual adapted dose escalation. So we can plan more accurately the radiotherapy planning by using choline PET.

And Pinkawa et al 2010 reported that also patients that were already pre-treated with neurology and prevention therapy can be treated by choline-guided radiotherapy planning.

And the main advantages of the treatment planning with the fluorocholine PET is to allow dose escalation to the macroscopic intraprostatic lesion without increasing toxicity. Because as reported by Pinkawa et al 2012, patients that were treated by included the simultaneous integrated boost guided by choline PET have a reduction in the genitourinary and gastrointestinal toxicity after two months, and 90 months from the end of radiotherapy treatment. But the simultaneous integrated boost based on choline PET can also have a reduction in toxicity after a few days from the radiotherapy treatment for gastrointestinal toxicity and sexual dysfunction. Before we can surely have some impact on the quality of life of the patient.

But if some papers are favorable for the use of choline PET for radiotherapy planning, some other papers do not completely agree with the use of this type of technique. Because, for example, Park and Bundschuh et al reported that automated threshold PET and histology volumes does not align perfectly, and in fact, as reported by Bundschuh in 2013, he said that unfortunately, the specificity of the choline uptake inside the prostate cancer is not so high. Therefore we can have a false-positive finding, for example, for benign conditions like in case of benign hyperplasia or another type of benign condition.

However, Chang et al reported that probably by using a particular type of threshold of the SUV, we can have a good correlation between choline PET and pathology, and therefore probably by using this cutoff we are able to guide to radiotherapy planning also in the primary tumor.

And about the PSMA-PET and radiotherapy planning in the primary tumor, we have at disposal a few papers, and the majority of cases, the papers are correlated with the change of the TNM staging by including PSMA-PET in the primary tumor. And as you can see in the majority of cases, the change in TNM staging was reported in particular for patients with a non-aggressive disease. It means for patients with high Gleason score and high PSA level and gallium-PSMA is also able to give some information about radiation treatment planning because it is able to identify the dominant intraprostatic lesion. In fact, as you can see in this plot, the gross tumor volume evaluated by PSMA-PET was similar to the gross tumor volume evaluated by magnetic resonance imaging. And for probably it can be used for guiding radiotherapy planning.

But in summary, for primary cancer, for both choline and PSMA, we have unfortunately not a wonderful sensitivity and specificity for the primary tumor because the value is ranging between 72% and 87% for the sensitivity, and 62% and 84% for the specificity in the choline. While for PSMA, the sensitivity is about 70%, and the specificity is about 84%.

But for choline, we have some data about the safety for organs at risk, not available for PSMA. And finally as originally reported by Dr. Sepulcri, the most important thing is also to know the tumor burden, and probably PSMA and choline PET can have in this definition because we have to remember that poorly differentiated prostate cancer cells are known to be more radioresistant and therefore probably the uptake of choline and PSA in the primary tumor can guide to the boost, so that can have probably a good effect on the outcome of the patient. Another point is the rule of fluoroethylcholine-PET in radiotherapy planning cases of locally advanced disease. It means in patient that there is not only the primary tumor in the prostate, but there's also the lymph node involvement. We have just a few papers about this topic and the only with choline and just to illustrate one published in 2011 that they reported the rule of fluoroethylcholine-PET that is helpful in dose escalation in prostate cancer allowing boost doses higher than 60 grays to metastatic lymph nodal region if PET/CT-planned planned modulated and image-guided radiotherapy is used.

Therefore, we are able by using choline PET not only to make the boost and the primary tumor, but we can make the boost only in the metastatic lymph node lesion. So in summary, the use of choline PET prior to radiotherapy may be useful in high-risk prostate cancer to detect lymph node metastases which may be included in the conventional irradiation field influencing conventional pathological tumor volume but we have also to remember that by including choline PET in the primary evaluation of the disease, we can also change the management of dose, choose between combined treatment in case of expansion of disease in other type of lymph node versus a single treatment, for example, radiotherapy or androgen deprivation therapy separately.

One of the most important things is androgen deprivation therapy before or after the radiotherapy planning. It means that if we want to plan a choline PET/CT in patients, what can they do to a definitive or radiotherapy treatment. We can already administer androgen deprivation therapy or is it better to wait? The response is better to wait because neoadjuvant hormonal treatment is known to decrease choline uptake prostate cancer. Therefore, the main problem is that we can't significantly understand the metabolic tumor volume and therefore the planning for radiotherapy treatment is not so careful as we awaited. 

Matteo Sepulcri: Now we present our study regarding the prognostic value of fluorocholine PET/CT in response to radical radiotherapy for localized prostate cancer. To our knowledge, this is the first study that evaluated the prognostic role of PET-CT in the treatment of primary prostate cancer tumors. So we enrolled 40 patients with intermediate or high-risk prostate cancer. All of them underwent to 18 fluorocholine PET-CT for staging and then to radical radiotherapy with a total dose ranging from 76 to 280 grays. The biochemical recurrence is defined as a rising of PSA above two ng/mL in respect to the NADIR, according to the Phoenix criteria. With the same quantitative analysis, we considered the SUVmax for the index lesion and in the presence of multifocality we considered the sum of SUVmean, the sum of metabolic tumor volume and the sum of TLA, total lesion activity, that is the product between SUVmean and metabolic tumor volume. We also considered a tumor background ratio. Coming to the results, on the left we have the patient characteristics and we recorded nine relapses on 40 patients.

For the intraprostatic dominant lesion SUVmax, as you can see, was found to correlate with the relapse while the tumor background ratio did not correlate probably due to the influence of androgen deprivation therapy before the PET scan. In cases instead of multifocality disease, sum metabolic tumor volume, sum-TLA, and sum of SUVmean were found to be related with relapse. So in conclusion of our study, high values of fluorocholine SUVs in prostate cancer of patients who are candidates to radiotherapy results from predictive of poor outcome after two years of follow up. And also the SUV values could be useful to identify those patients who could benefit a boosted radiotherapy dose to the IDL determined by fluorocholine PET/CT, without increasing toxicity to the organs at risk.

So we move on to the second teaching case regarding post-operative setting. Sixty-six-year-old patient with atrial fibrillation underwent biopsy and then a radical prostatectomy with a diagnosis of adenocarcinoma, pT3a, pN0, Gleason score 8, so grade 4 according to WHO classification. After three months, the PSA after surgery was 0.02 ng/mL. And then we decided to deliver neoadjuvant radiotherapy on the prostate fossae with the total load of 66 grays with standard fractionation.

This is the radiotherapy plan. You can see that we radiate only the prostate bladder and the yellow line represents the cranial border of the radiotherapy field. Keep it in mind for the prosecution of the clinical case. But why we perform adjuvant radiotherapy in these patients. These are the three main randomized clinical trials regarding adjuvant radiotherapy. And all three trials demonstrate an improved biochemical progression-free with adjuvant radiotherapy. The only trial was the SWOG trial that had the long followup that showed also an improved overall survival.

If we don't perform adjuvant radiotherapy the other option is to wait by monitoring the PSA value and perform a salvage treatment when the PSA rises up. It's very important the timing of salvage radiotherapy because for every growth of 0.1 nanograms of PSA, we had the 2.6 percentage loss of relapse-free survival. But it is a cutoff value for starting salvage radiotherapy. This study shows how a lower rate of biochemical recurrence and distant metastases, if salvage treatment starts at the lower PSA, in particular, lower than 0.5 ng/mL.

The answer where we had the question between adjuvant or salvage treatment will be provided by these ongoing randomized trials. So coming back to the case during the followup patients are means with non-evidence evidence of disease for about two years. And then the PSA starts rising from August 2017 with the value of 0.62 nanograms per milliliter. In January 2018, PSA reaches 1.24 nanograms per milliliter. We performed PET choline CT that was negative. So we decided to attend and grow in the PSA and when PSA reached 1.72 nanograms per milliliter, we performed another choline PET that reveals a pathological uptake on the right iliac node. This is the scans before radiotherapy. And with the first PET/CT that is negative and the second that reveals a pathological uptake in the iliac node. So in this time for the patient, there are two therapeutic options. The androgen deprivation therapy or stereotactic body radiation therapy on the positive node. We performed the second one and this is the plan of stereotactic therapy based on the uptake of choline. And as you can see is out of the previous radiation field.

Stereotactic body radiation therapy makes use of a high dose per fraction with the ablative aim. It consists of a low number of fractions with small treatment volumes and it needs the maximum precision in order to limit the toxicity. Recently has been published this important study, this is the STOMA trial. It is a prospective, randomized, multicenter Phase II Trial comparing surveillance versus metastasis-directed therapy for oligometastatic prostate cancer. The primary endpoint of the study was ADT free survival. And as you can see in the graph, the two lines split in favor of the MDT, the metastasis-directed therapy. So the author concluded that a metastasis-directed therapy for patients with oligorecurrent PCa is safe and improves androgen deprivation therapy free survival when compared with surveillance. So the questions for nuclear medicine physicians in the post-operative setting regarding the recurrence are the same and completes that.

Laura Evangelista: Again, if we want to evaluate the rule of PET in recurrent prostate cancer, we can recognize different settings. The first one is localized recurrence. It means patients with a recurrence only in the prostate gland or in prostate fossae. In the case of the prostate gland that we can plan re-irradiation radiotherapy and we have at disposal one article with choline. In case of recurrence in prostate fossae after radical prostatectomy, we can plan salvage radiotherapy in treatment. In this case, we have at disposal one article with choline and then we can also define the patient with oligometastatic disease where we can plan the salvage radiotherapy in planning and for this case, we have disposal data for choline and also PSMA.

And for local and lymph node recurrence we can plan again the salvage radiotherapy in planning by using an extended field. And again we have disposal data both for choline and also for PSMA. And by analyzing the data about choline, these studies report the obtaining of choline for the planning of the radiotherapy planning recurrence in the lymph node and also prostate gland. And the main results of this study were relative to prognosis, it means that by performing choline-based radiotherapy, we can improve the overall survival of the patient and also the biochemical-free survival. In particular, the overall survival after three years was about 90% while the biochemical-free survival was about 80% after one year. And we can also improve the toxicity. It means that in choline-based radiotherapy, recurrent prostate cancer can have a significant good impact for the control of acute toxicity and late toxicity, both gastrointestinal toxicity and the genitourinary toxicity.

While if we consider the PSMA-based radiotherapy in recurrent prostate cancer, the data now available in 2052 patients and then in all papers, the main endpoint is the evaluation of the PSA response during follow up after radiotherapy planning guided by PSMA. And as you can see, it was reduced in 72% of patients but pay attention because by reading carefully this article the author-date for low PSA values salvage radiotherapy of the prostate fossa should not be omitted in case of PSMA-negativity because we have the problem of the localization of the recurrence in the prostate fossa. But the problem of the omission of the prostate fossa with the RT is a very important topic. In fact, this is a survey that was made by involving 12 radiation oncologists that was asked if they would consider the omission of prostate fossa radiotherapy treatment in high-risk patients after completely resected prostate cancer with persisting PSA values.

And as you can see in most radiation oncologists were in favor of prostate fossa radiation therapy in case of PSMA positive lesions within the pelvis. Conversely, a high disagreement existed in the case of extrapelvic PSMA positive lymph node lesions as only finding in PET. Therefore, it is very important to give correct information because we can change not only the plan of a radiotherapy treatment but also the type of radiotherapy treatment. And again, we have to remember that we have the problem of the detection of the recurrence in prostatic fossae, both with the choline and PSMA because both, in particular, PSMA 11 as the fluorocholine are eliminated by the urinal excretion. So we can have a high accumulation of the traces that are inside the blood. And in order to improve the detection rate that we can insert a specific type of protocol acquisition.

In fact, by including the early acquisition we can improve the detection rate of about 70% by using choline PET. And we can improve the 25% by including the early acquisition of the PSMA PET/CT. While for the recurrence in lymph node limited lesion-based sensitivity of choline PET for detecting the lymph node recurrence as well as its inability to identify micrometastases has been reported due to its partial volume effect. But the ever-increasing experience with the PSMA-PET has demonstrated the improved performance for the detection of metastatic lymph nodes in recurrent prostate cancer patients. Therefore, probably PSMA for the detection of lymph node recurrence will be better than choline in particular for guiding to salvage radiotherapy planning. And it is very important to recognize the lymph node involvement because we can change the approach, the radiation therapy approach.

In fact, the conventional extended field is normally performed by irradiation of the former prostate bed with enlargement of irradiation field to the pelvic lymphatics in order to include all pelvic lymph nodes with or without a boost to PET-positive lymph nodes. But we can choose between involved the field and involved the nodal by including choline-PET in the early staging in patients because the involvement of the field means the irradiation of the former prostate bed and PET-positive lymph nodes and the corresponding lymphatic drainage vessels, for example, the iliac lymph nodes. And the involvement of the nodal technique means irradiation of the former prostate bed and the radiation of PET-positive lymph nodes only. It means only the lymph node that is positive at choline-PET. And by resuming the data about the change of treatment RT plans according to choline PET/CT, we have a disposal data for 2009 patients and the change of radiotherapy planning was reporting 23 to 27%. Conversely, the change of treatment plan according to PSMA PET was reported in 499 patients and it was [inaudible] about 37%.

Therefore, probably the impact of PSMA for the change of radiotherapy planning seems higher but also the number of patients is higher with the PSMA compared to choline.

Matteo Sepulcri: So let's move to the last clinical setting. The oligometastatic disease with the last teaching case. Seventy-seven-year-old patient with arterial blood hypertension had PSA of 8.3 nanograms per milliliter and the director exploration positive, underwent the biopsy with cT2 tumor, Gleason score 8 in eight cores on 12 and underwent the PET-CT scan for staging. As you can see the PET-CT reveals an uptake not only in the prostate gland but also in the right iliac bone. So this is considered a metastatic patient at the diagnosis. And the therapeutic options for this patient are androgen deprivation therapy that remains the standard of care, radiation on the primary tumor and bone metastasis plus androgen deprivation therapy or radical prostatectomy with radiation therapy on bone and long course androgen deprivation therapy.

We decided for the second one. And so radiation therapy on the primary and on bone metastasis. In this setting, we have less evidence principally retrospective data like SEER database with many patients in this study. Local treatment is radical prostatectomy, intensity-modulated radiotherapy or 3D conformal radiotherapy versus observation in metastatic prostate cancer. As you can see, the lines differ regarding survival probability between the radical prostatectomy and the IMRT versus 3DCRT and no local treatment.

A prospective study, no randomized study considered 77 patients metastatic castration-resistant prostate cancer patients. All of them, almost all of them are under androgen deprivation therapy and all of them underwent prostate radiotherapy and other also palliative radiotherapy was done. So the cures regarding overall survival and biochemical-free survival differ between who received treatment in the prostate gland. But these results, this benefit is for patients with good performance status and limited bone disease. So we have a selection bias in the study. This is the radiation planning for the patient. Underwent to 27 grays in three fraction with therapeutic radiotherapy for the bone metastasis and 70 grays in 28 fraction for on prostate gland. We only follow up after one year, follow up on PSA remains undetectable and we decided to restage the patient with the choline PET/CT. And as you can see the pre-radiotherapy and post-radiotherapy there were no more uptake neither in the prostate gland, neither in the bone.

So the last question for the nuclear medicine physician regarding the oligometastatic setting at metastatic patient after diagnosis.

Laura Evangelista: Okay. Like for the radiotherapy planning also for choline and PSMA, we have a few data about the role of these traces for oligometastatic disease. Therefore, we are invited to provide more evidence on this topic. However, if we consider this study, we can see that choline PSMA PET can be useful for guiding RT in patients with oligometastatic disease because it's as if it was provided by an improvement in progression-free survival particular profession with the castrate sensitive disease as compared to patients with the castrate resistant disease. It means that probably if we identify patients with the castrate-sensitive disease and with the oligometastatic disease and we plan a salvage radiation treatment we can improve its outcomes, so its survival. And also the safety was better by using the RT planning with the PSMA because as you can see only grade one genitourinary, gastrointestinal toxicity was reported and only one patient was reported the grade two toxicity but no grade three toxicity was reported.

And regarding the rule of choline PET for the evaluation of response to radiation treatment, there is a paucity of data about this topic until now. If we wanted to choose the correct interval time between the last radiotherapy treatment and the new PET/CT scan, we normally use the interval time of FDG PET. It means about three, four months. However, the optimum time point requires further study. Therefore, the problem may also [inaudible] in this case we are able to do to get there. And by considering this study by Sharla et al, we can see that radiotherapy resulted in a minor overall reduction in tumor choline uptake. This could signify the sterilization of the prostate.

It means that by considering the baseline SUV and the post-radiotherapy could be there was a reduction of about 52% and probably the authors that say that the load reduction was due also to post-radiation therapy inflammation while the tumor to background ratio was about 52% higher than the SUVmax because the authors state that the probably the reduction tumor and tumor to background after radiotherapy treatment was higher than that of SUV supporting the notion that the tumor to tissue in radiotherapy field of view may show an increase in uptake due to radiotherapy relative inflammation.

So we wanted to close our presentation by giving you some take-home messages in radical setting, choline PET and PSMA PET/CT can help for the identification of dominant intralesional disease that is very important for providing the booster radiotherapy planning. Therefore for the radiation oncologists, this information can be useful in order to improve the response to radiotherapy treatment in particular for patients with aggressive disease or a patient with the AI tumor volume. In post-operative setting, choline PET and PSMA PET can change the RT planning up to 37%. This value is particularly evident for PSMA PET/CT. While in an oligometastatic setting, the rule of both choline and PSMA should be defined for probably we can try to work together because of oligometastatic disease and now it is a very hot topic, not totally for prostate cancer, but also for the other type of cancer. Therefore, we have to try to work in this type of setting. Thank you very much for your kind attention.