Prostatepedia

Conversations With Prostate Cancer Experts


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PET/CT Imaging + Radiation?

 

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Dr. Michael Zelefsky, a radiation oncologist, is Professor of Radiation Oncology, Chief of the Brachytherapy Service, and Co-Leader of the Genitourinary Disease Management Team at Memorial Sloan Kettering Cancer Center in New York City.

Prostatepedia recently spoke with him about how advances in imaging have impacted radiation therapy. Subscribe to read the entire conversation.

Do you think molecular imaging will be incorporated soon?

Dr. Zelefsky: There’s a lot of excitement with PET/CT imaging. PET imaging fused with MRI is also emerging now. This has been used effectively for various disease sites, not only prostate cancer. For prostate cancers specifically, newer PET tracers such as PET C-11 Choline and exciting developments in PSMA tracers will be used. These provide us unique opportunities to see where micrometastatic disease could be lodged. That information is critical for the radiation oncologist to pinpoint the disease. There are also exciting developments using some of these tracers as a form of therapy. Tracers such as PSMA are linked to lutetium-177 and tracers can be integrated with radiation planning as well. We are on the verge of seeing these new developments; these changes will soon be integrated with radiation.

Is there anything else you think patients should know about imaging’s role in radiation therapy?

Dr. Zelefsky: With new advances in imaging and by working in close collaboration with diagnostic radiology, we are getting much more accurate information concerning where microscopic disease is located and the critical zones within the prostate where tumors are lodged. We use imaging to consider re-biopsying patients where there may be a discrepancy between what looks like earlier states of disease, but the MRI shows there is greater volume of disease than what was anticipated. We need to know this information in order to plan the radiation well. We need to consider opportunities to intensify the dose to the DIL in the prostate and whether there is nodal disease and where exactly the nodal disease could be within the pelvis. Imaging plays a huge role in our follow-up with patients, allowing us to detect recurrences earlier than ever before. This is vital information for patients because earlier detection of recurrences allow for salvage therapies much sooner and treating such patients at earlier time points is often associated with more successful outcomes.

In the future, imaging will help us consider focal ablative therapies where the paradigm is shifting in earlier cancer s. Simply put, we could just focus on the DIL and spare the rest of the prostate if we can be sure that there is no significant disease in other parts of the gland. There have been a number of efforts to use focal therapy with advanced imaging to small subunits of the prostate. So new imaging possibilities are opening up new directions and opportunities in the treatment of prostate cancer.

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Imaging + Radiation Therapy

Dr. Michael Zelefsky, a radiation oncologist, is Professor of Radiation Oncology, Chief of the Brachytherapy Service, and Co-Leader of the Genitourinary Disease Management Team at Memorial Sloan Kettering Cancer Center in New York City.

Prostatepedia recently spoke with him about how advances in imaging have impacted radiation therapy. Subscribe to read the entire conversation.

What role does imaging now play in radiation therapy?

Dr. Zelefsky: Radiation therapy has been linked to imaging for many years. In the late 1970s and early 1980s with the advent of the CAT scan, those images were used in the treatment planning process to provide greater accuracy for targeting the radiation. Over the ensuing 20-30 years, there have been significant advances in imaging, from CAT scanning to MRI, and from multiparametric MRI to molecular imaging. These advances in diagnostic imaging continue to be linked to radiation treatment. We use multiparametric MRI imaging to target radiation to the prostate with exquisite precision. Just as importantly, we use these technologies to understand the geometry and anatomy of the surrounding normal tissues. For the prostate, that could mean the bladder, rectum, bowels, and even specific anatomic regions like the bladder neck and the neurovascular bundles that control erectile function.

Advances in imaging have allowed us to visualize these normal tissue structures, and this information is incorporated into treatment planning, giving us a way to deliver the radiation with a precision we’ve never had before.

What sorts of changes do you think are on the horizon as we develop better imaging techniques?

Dr. Zelefsky: We have successfully moved from CT-based imaging to MR-based imaging. Now, we commonly use MRI and fuse those images with the CAT scan. At Memorial Sloan Kettering, we have moved to the next step, which is pure MRI-based planning. This means we don’t need the intermediary step of a CT scan anymore. We can plan directly off the MRI, and we map everything out from these sets of specific We’ve also moved beyond MRI to what we call multiparametric MRI. We look at different sequences and formats of the MRI, including dynamic contrast enhanced imaging, and diffusion-weighted imaging to give us further information about the location of the disease within the prostate, which is called the dominant intraprostatic lesion (DIL). This dominant intraprostatic lesion is an important area to target because recurrences after radiation stem from regrowth of disease from that initial site of disease in the prostate.

Radiation oncologists are recognizing that there may be opportunities to intensify the focus of the radiation to the DIL to improve the tumor control rates with radiation. We have moved from CT-based to MR-based radiation therapy to pure MRI-based planning, and now we incorporate important information from multiparametric imaging. In the future, we’ll also incorporate molecular imaging, which comes from advanced nuclear medicine studies.

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D’Amico On Surgery Versus Radiation

Dr. Anthony D’Amico is Professor of Radiation Oncology at Harvard Medical School and Chief of the Division of Genitourinary Radiation Oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts.

Photo by Sam Ogden.
Anthony D'Amico, M.D., Ph.D.

Dr. Anthony D’Amico is Professor of Radiation Oncology at Harvard Medical School and Chief of the Division of Genitourinary Radiation Oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts.

Prostatepedia spoke with him about advances in radiation oncology for prostate cancer.

Are there any further thoughts on how radiation compares to surgery?

Dr. D’Amico: The ProtecT trial was published in the New England Journal of Medicine a couple of months ago. ProtecT is the first and only randomized study comparing surgery with radiation plus short-course hormones.

What I found very exciting about their results is that for 10 years we don’t see a difference in metastatic prostate cancer between the two major modalities of either radiation or surgery. It’s the first evidence that men with Gleason 6 or 7 prostate cancer truly have a choice between radiation therapy with short-course hormones or surgery. ProtecT is a randomized, 1,500-patient study. This is level-one evidence. ProtecT also shows that the quality of life men experience following these two treatments is very different. Two recent papers also show that even with advances in robotic prostatectomy and in radiation, the side effect profiles of those treatments have not really changed relative to one another. The absolute rates of toxicity have decreased, but you still have more urinary incontinence and erectile dysfunction with surgery and more bowel issues with radiation.

How do we rank surgery versus radiation, knowing as we do that cancer control is truly equivalent? Patients can choose their treatment based on the side effect profile alone and not worry that they may die of prostate cancer if they make the wrong choice.

So the choice of surgery versus radiation comes down to personal preference?

Dr. D’Amico: Correct. Just like in breast cancer: lumpectomy and radiation versus mastectomy? Women have a choice. Men with a Gleason 6 or 7 prostate cancer have a choice.

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Prostate Cancer Treatment Advances

Pp_July_2017_V2_N12_ThumbIn July, Prostatepedia is talking about advances in urology, radiation therapy, oncology and immunotherapy for prostate cancer.

Not a member? Join us to read the conversations.

Dr. Oliver Sartor, one of the leading researchers in advanced prostate cancer today, has the following to say about this month’s conversations.

Three of the biggest areas in prostate cancer right now are: 1) the use of the checkpoint inhibitor PD-1 to treat men with mismatch DNA repair defects, 2) the use of either PARP inhibitors or platinums to treat mismatch DNA repair defects, and 3) better imaging techniques.

Within the next year or two, we’ll be able to define a subset of patients who will benefit from the PD-1 inhibitors that Dr. Charles Drake discusses in his conversation on immunology. I anticipate that PD-1 inhibitors may be meaningful for around 10% of men.

The FDA recently approved Keytruda (pembrolizumab) for those with mismatch DNA repair mutations, which applies to a subset of prostate cancer patients. This story will be meaningful to watch as testing for these mutations becomes more prevalent.

As Dr. Daniel Petrylak alludes to, there are now a variety of rapidly moving clinical trials looking at the combination of three DNA repair defects—BRCA1, BRCA2, and ATM. Data to support the use of PARP inhibitors in men with this combination of repair defects is rapidly evolving. This practice remains unproven in prostate cancer, though, despite promising preliminary data published by Dr. Joaquin de Mateo in the New England Journal of Medicine in 2016. [See Prostatepedia June 2016 for a conversation with Dr. Mateo about his work.]

But I do want to make sure that Prostatepedia readers are aware that if you have metastatic prostate cancer and a DNA repair defect—like BRCA1, BRCA2, and ATM—there is some reasonable preliminary data to support using carboplatin. We have a manuscript at press right now that shows that if you have an inherited BRCA2 mutation, there is better activity if a carboplatin plus a taxane are administered as opposed to just giving you a taxane alone. Thus carboplatin appears to be an option for men with certain DNA repair alterations.

Advances in imaging are also discussed in several of the conversations that follow. PSMA imaging is moving quickly. Axumin (fluciclovine F18) is the new imaging technique on the block with FDA approval. I think that in using these newer imaging techniques we will be able to define oligometastatic disease groups more and more efficiently. The consequences will be less therapy that just sets patients up to fail and, hopefully, more therapy that, if targeted to those lesions, will have a meaningful effect.

Stay tuned: the prostate cancer field is evolving really fast right now. I believe some men with advanced disease will potentially have molecularly targeted therapies available to them within the next several years.

Subscribe to read our July conversations on advances in treatment.

 


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Join A Trial: Combining Xofigo + Provenge

Male, ManDr. Emmanuel Antonarakis is an Associate Professor of Oncology and Urology at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center.

Prostatepedia spoke with him recently about his clinical trial combining Provenge (sipuleucel-T) with Xofigo (radium-223).

What is the thinking behind your clinical trial?

Dr. Emmanuel Antonarakis: There is a lot of interest in combining immune therapies with other drugs to make immunotherapy work better.

The FDA approved Provenge (sipuleucel-T) in 2010. We’ve been using that drug for the last seven years. We’ve seen that patient survival improves by approximately three to four months on Provenge (sipuleucel-T) compared to a placebo.

However, we don’t typically see PSA levels dropping, tumors shrinking, or symptoms improving. While we recognize that Provenge (sipuleucel-T) is an immunotherapy that does have some activity in prostate cancer, the effects are fairly marginal.

We, and others, have been trying to increase its effectiveness by combining it with other medications. In this particular trial, we’re combining Provenge (sipuleucel-T) with a radiopharmaceutical drug called Xofigo (radium-223).

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Why? We think radiation therapy can boost immunotherapy for several reasons.

One reason is that in patients who receive external beam radiotherapy, or conventional radiotherapy, healing tumor cells can release proteins called antigens from inside the cancer. Those antigens released into the circulation by radiotherapy can stimulate the immune cells that recognize and fight prostate cancer.

The second reason is that there is some preliminary evidence that these liquid radiotherapies—or radiopharmaceutical drugs that are injected into the veins, bind to the bone and then give off radiation particles at the bone—might also increase the number of antigens.

An antigen is a substance foreign to the body that elicits an immune response. These antigens are released as part of the cancer cell into the circulation and are then recognized by a stimulated immune system.

The hypothesis is that if you combine Xofigo (radium-223) with Provenge (sipuleucel-T), you would see higher immune responses against the tumor than if you used Provenge (sipuleucel-T) by itself.

What should patients expect?

Dr. Antonarakis: We’re selecting hormone-resistant prostate cancer patients with one or more bone metastases. In other words, their cancer has progressed after standard hormone therapy, but they don’t have any bone pain. Bone metastases have to be present, you have to have hormone-resistant disease, but you can’t have bone pain.

Patients will be randomized to one of two groups. Group 1 will receive Provenge (sipuleucel-T) by itself, according to the FDA dose schedule of three doses two weeks apart.

Group 2 will receive a combination of Xofigo (radium-223) plus Provenge (sipuleucel-T). The Xofigo (radium-223) will be given first according to the FDA dose schedule of intravenous injection every four weeks for six doses.

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After the second out of six doses of Xofigo (radium-223), they will then receive the Provenge (sipuleucel-T).

After Provenge (sipuleucel-T), they will receive the third through sixth doses of Xofigo (radium-223). In other words, we give Provenge (sipuleucel-T) in between the second and third Xofigo (radium-223) doses.

Why in the middle?

Dr. Antonarakis: We are guessing when the immune system will be most stimulated by the Xofigo (radium-223). We hypothesize—and this is only a guess—that it will take at least two doses of Xofigo (radium-223) to release enough tumor antigens into the circulation to simulate the antitumor immune cells. We wanted to continue to give at least four additional doses of Xofigo (radium-223) after the immune system has been stimulated to see if we can maintain a prolonged immune stimulation period.

In a perfect world, we would have multiple different sequences, but that would require a much larger trial with at least four different study arms. We thought that was too complicated.

You said you were looking for patients with one or two bone metastases. Are you excluding those with more?

Dr. Antonarakis: Patients have to have a minimum of one bone metastasis, but there is no maximum. If a patient has a hundred bone metastases, he is eligible.

Patients cannot have liver or lung metastases larger than one centimeter in diameter.

Why?

Xofigo (radium-223) does not get into the liver or the lung. It only targets the bone. And we have never seen liver or lung metastases shrink with Provenge (sipuleucel-T) by itself. We wanted to exclude patients who wouldn’t benefit from Xofigo (radium-223), so we decided to exclude liver or lung metastases more than one centimeter.

We also exclude patients with lymph node metastases more than three centimeters. We allow small liver or lung metastases less than one centimeter and modest lymph node metastases less than three centimeters.

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Is the trial being conducted only in Baltimore, Maryland?

Dr. Antonarakis: The trial is being conducted at four sites across the United States: John Hopkins University in Baltimore, Maryland is the lead site. The other sites are Tulane University in Louisiana; Duke University in North Carolina; and Cedars-Sinai Cancer Center in Los Angeles, California.

For more information, contact Dr. Emmanuel Antonarakis by emailing eantona1@jhmi.edu or calling 410-955-8964.


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Clinical Trial: Statins Before Surgery

Dr. Hyung Kim is a urologic oncologist at Cedars-Sinai in Los Angeles.

Prostatepedia spoke with him recently about a clinical trial he’s running that looks at the effects of cholesterol-lowering therapy before radical prostatectomy.

What do we know currently about the connection between cholesterol, statins, and prostate cancer?

Dr. Kim: A lot of our data comes from epidemiology studies in which statins were used to lower cholesterol to improve cardiovascular health. In many of these studies, the observation was made that patients with prostate cancer who were on statins were less likely to die of their cancers

The other line of evidence comes from basic science research. People like Dr. Michael Freeman have done preclinical laboratory studies showing that lowering cholesterol levels in mice can slow down the growth of prostate cancer.

We have epidemiology data. We have preclinical data. The missing piece is prospective data in patients to help establish a firm cause/effect relationship between lowering cholesterol and favorable prostate cancer outcomes.

The epidemiology data is interesting because the link between statin use and the incidence of prostate cancer is weak, but there is a stronger link between statin use and the likelihood of dying from prostate cancer.

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This suggests the possibility that statin use targets the lethal form of prostate cancer. It also suggests that statin use may not lower the likelihood of developing prostate cancer. However, if you develop prostate cancer, perhaps statin use will improve your likelihood of surviving the disease.

Mouse studies are controlled experiments where you do see a clear cause/effect relationship. You lower the cholesterol level in the mice and the tumors you implant in them grow more slowly. We have some idea of the basic mechanism behind this observation, but does this cause-and-effect relationship carry over to patients? Does that cause/effect relationship explain the epidemiology data that we see?

Those are the unknowns. This is why we’re conducting our trial.

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Download February 2017 Prostatepedia.

Read more about this trial and about the link between cholesterol, statins, and prostate cancer.

 


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Hypofractionated Radiation For Prostate

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Prostatepedia talks with Dr. W. Robert Lee, of Duke University Medical Center about hypofractionated radiation therapy. (Read the interview.)

Hypofractionation is a form of external radiation therapy that uses fewer, larger doses per fraction. Historically, the conventional radiation dose for most solid tumors is 1.8 to 2 Gray per day. (Gray is just the scientific term to measure the dose.) That conventional dose comes out of the French school of radiotherapy that dominated radiotherapy in the 1940s and 1950s and made its way over to the United States. Most patients treated with external radiation therapy for prostate cancer in 2016 are treated five days a week for eight or nine weeks.

 
There is some evidence that fewer, larger doses may, in fact, be better. Some studies have been designed to prove that hypofractionation is better, but the results of several studies have failed to demonstrate that theory. Other studies have been designed to determine if hypofractionation is “no worse than” conventional fractionation; these are known as noninferiority studies. Noninferiority studies are used to show that we can accomplish the same objective with a shorter, more convenient treatment.

 
I’ve just published a paper in the Journal of Clinical Oncology (April 2016) showing that you can accomplish the same thing with hypofractionation in five and a half weeks versus eight and a half weeks. There is another study from the United Kingdom, which was published in June 2016, which shows that you can accomplish the same thing in a four-week schedule that you can with an eight-and-a-half.week schedule. The results from all of these noninferiority studies are consistent: they show that you can accomplish the same objective in four or five weeks versus eight or nine weeks.

 
Another hypofractionation approach is stereotactic body radiation therapy (SBRT), which is an example of extreme hypofractionation. You get four to five treatments over a period of one to two weeks rather then four to five weeks. This is an emerging approach. We’ve been doing SBRT at Duke University since 2009 and I think it is safe, but it has yet to be compared to more traditional treatment in a rigorous manner. To repeat, we don’t have rigorous comparisons of SBRT to other definitive radiotherapy options, but they’re forthcoming.

Is a shorter course better for patients just for financial reasons, or is it also just more convenient?

Shorter courses are unambiguously more convenient for patients; in 25 years of practice I have never had a patient request longer courses of treatment.

Do patients usually travel to a radiation therapy center?

Yes. I tell men that, “We’re working on it, but we still haven’t figured out a way to bring the machine to you. You have to come to the machine.” There are significant economic advantages with shorter courses as well. In our current healthcare system, value is increasingly important. If you can accomplish the same thing with fewer resources, less time, and more patient convenience, then that is something you should do.