I don't mind if people ask questions during the presentation, but Anuja, would you prefer questions at the end? Yeah, I think we went to do the questions at the end, this way you can do your whole talk and it's easier. Okay. I want to applaud Solomon and the team for presenting this case. Vulvar cancer, I think is very, very difficult to treat. I've been involved with trainees for many, several decades now, and it's a very challenging disease site for radiation oncologists. There's not a tremendous amount of data, but I'd like to go through some of it. So the things that I'll particularly focus on are margin status. What do we do with the number of lymph nodes, concurrent chemotherapy, and recurrent disease? So here's the current staging system. This was published by Dr. Allaway three years ago, and as Solomon indicated, this case is stage 3B with a fairly large tumor, six centimeters in size. Of note, if she was node negative, she'd be stage two. There's a pretty strong influence in stage three, depending upon nodal size. So what I'd like to emphasize is the size of the nodes impacts prognosis. Stage 4A is disease fixed to the pelvic bone or ulcerated regional lymph nodes, and stage 4B is distant metastases, including pelvic lymph nodes. Perhaps we'll discuss that. Here are the survival curves as published in Dr. Allaway's paper. Stage 3B is the pink line indicating that at five years, you have about a 50% survival, which is reasonable. The other point that I'd like to make is vulvar cancer, whether treated with surgery or radiotherapy, those patients don't do well. If you look at the original groin study with long follow-up, even those patients with fairly small lesions, their survival rate was relatively poor. So how do we do radiotherapy optimally for vulvar cancer? So these are guidelines published by a group in Europe. What they indicated is that adjuvant radiotherapy should start as soon as possible, preferably within six weeks. There is no consensus for the threshold or margin distance between which adjuvant radiotherapy should be advised. So there's new data, there's important data, and I'll go through some of that. Post-op radiotherapy of the groin is recommended for cases with more than one lymph node or presence of extra capsular lymph node involvement, or ECE. This is, I think, controversial, and I'll go through that too. Adjuvant radiotherapy for the groin should include an upper limit at the level of the bifurcation of the common iliac artery. There's expert opinion only on that. I don't think there's much data. Based on evidence from other cancers, they typically recommend sensitizing chemotherapy. I fully agree with that. Here's another report from MD Anderson, Dr. Gingren's institutions, and it's basically focusing on how to do vulvar radiotherapy correctly. This was a Sear Medicare study. They had 306 patients, 69% received radiotherapy, the median age was 78, and three delivery metrics were associated with improved outcomes. Completion of greater than 20 fractions, treatment duration less than eight weeks, and less than one week of treatment break. Patients who achieved these three metrics demonstrated better outcomes, and only 51% of patients who received radiotherapy achieved all benchmarks. Again, radiotherapy, it's difficult to do technically, I think. It's also difficult to get our patients through treatment. Let's discuss margin status. This is a very strange world because what we previously believed, I don't know if it's true anymore, so I'd like to take you through it. There's a high local recurrence rate in vulvar cancer. We know that. The margin status has been postulated that differentiated VIN and lichen sclerosis may also play a role. Surgical margins should be one centimeter. These are guidelines from the National Comprehensive Cancer Center Network published a few years ago. Recent studies question the traditional eight millimeter margin and smaller margins may be acceptable. For close margins, observation may be reasonable. Reexcision should be considered for a positive margin. Radiotherapy is another alternative. Survival differences between surgery and radiotherapy are not clear. Positive margins that involve the urethra, anus, or vagina may not be resectable without significantly impacting quality of life. Reexcision may not be beneficial in patients with METs to inguinal lymph nodes that require chemo after surgery or chemoradiotherapy. Here are the guidelines as published in NCCN. It gets a little complicated to discuss this, so I won't go through it, but Susan, I trust these slides will be available for people later. Yes. Great. Thank you. So here's the paper that informed our practice for decades. This is the HEAPS paper published out of UCLA. Dr. Barak was the senior author. They had 135 patients. 91 patients had a margin greater than eight millimeters and none had a local recurrence. 44 had a margin less than eight millimeters and nearly half had a local recurrence giving a highly statistically significant P-value. And they stated that surgical margin is the most powerful predictor of local recurrence in vulvar cancer. Then the Dutch who have provided a lot of data in vulvar cancer generated this important paper five years ago. It was a study from two centers, 287 patients, local recurrence rate at 10 years was 42%. So note this. These are some of the best centers in the world and they had a fairly high local recurrence rate if you follow your patients long enough. Pathologic tumor-free margin distance did not influence the risk on local recurrence. It didn't matter what the margin distance was. Multivariate analysis showed a higher local recurrence rate in patients with DVIN and lichen sclerosis in the margin and patients with DVIN in the margin and a stage two or higher tumor. Shown here are the recurrence rates. The curve on the left in blue is DVIN in the margin. In the green, DVIN adjacent to tumor. In this panel, the highest recurrence rate, which is nearly 80% at close to five years is DVIN and lichen sclerosis. And again, here's another study out of Europe. This is the Franco-Gein group. This is 112 patients, a multi-center trial and margin distance, whether it was less than three millimeters, three to eight or greater than eight did not statistically impact survival. So what do we do in practice? Well, many centers pick a number arbitrarily. I've talked with Dr. Maki Oonk from the Netherlands, as she indicated a couple of years ago that they choose three millimeters and we try to adhere to about the same. So what about lymph node status? This is a fun topic. There's data on either side. I'd like to show that. So again, here's the treatment schema from the NCCN, and I won't take the time to go through this, but you can download the slides if you want to. So what's the case for no radiotherapy in lymph node positive disease? So as you can note from this AgoCare study, this multi-center trial out of Germany, the PFS rates were low as well as the OS rates. Radiotherapy did not impact those patients with a single positive node, but patients with multiple positive nodes appeared to benefit from adjuvant radiotherapy. This is the GOG study, the Holmesley trial, nearly 40 years old. They had 114 patients. Patients were randomized to radiotherapy to the groin and pelvis or to surgery. The patients that had radiotherapy did better. On an update published by Charles Kunos, those patients that had a single positive lymph node did not seem to have a difference in their proportion surviving, whereas those that did seem to benefit from the radiotherapy. So in this case, what's the survival benefit in adjuvant radiotherapy in node positive vulvar cancer? This was a SEER study. This is on the pro side. This is showing the benefit, and that is a survival benefit persisted in women with just one and two or more lymph nodes, and they concluded that all lymph node positive patients should receive adjuvant radiotherapy, including those with a single positive lymph node. Another study indicating the benefits of radiotherapy in a single positive lymph node, this was an NCDB study out of the United States. They had 2,800 node positive vulvar cancer patients on multivariate analysis. There was a survival advantage for patients with one positive lymph node with a hazard ratio of 0.8 and within those with two or more positive lymph nodes with a hazard ratio of 0.59. Chemotherapy yielded an incremental improvement in survival with two or more positive lymph nodes, but in this case, not for the single positive lymph node. And then furthermore, the Franco-Gein group have published that in a trial of 176 women with at least a single positive lymph node, they showed no significant differences for overall survival rates in patients with one extracapsular versus one intracapsular lymph node mets or with two nodes. For intracapsular mets, LBSI was an independent negative prognostic factor for relapse-free survival and adjuvant radiotherapy was a positive independent factor associated with relapse-free survival. So they concluded that irrespective of the number of affected lymph nodes, radiotherapy should be considered, especially in the cases of LBSI. And here are their survival curves, helping to support those comments and those data. So what about chemoradiotherapy? There's quite a bit of data on this subject. I won't go through it extensively, however, I do want to talk about this study, which was just published in the JCO by Dr. Horowitz et al. This is a GOG study. This builds on several decades of work by the GOG and they've incrementally increased the dose. The dose to this study was 64 gray. They did a couple things different in this study. They used IMRT and they also added a second drug. They added gemcitabine in addition to the standard of cisplatin. It's hard to read, but the majority of patients had stage 2 or 3, however, some 23% did have stage 4 disease. They didn't have HPV serotyping or tumor status on many of their patients, but of those that they did, 34% did have it or 18 and two were HPV negative. So the vast majority were HPV positive. Here is the PFS and OS curves indicating that at about five years, 60% of patients were surviving. Pretty good, pretty good results. And in fact, the highest pathologic complete response rates that I've seen for patients with unresectable vulvar cancer. So in the 52 patients treated with gemcitabine, cisplatin and IMRT, 73% had a complete pathologic response. A total of 80% completed therapy as prescribed. 85% experienced a grade three or higher toxicity, which is pretty significant. I don't know if gemcitabine is adding much here. It is toxic treatment and I would suggest caution until we can figure this out. The GOG did do this successfully and they did achieve a high pathologic complete response. Dr. Fleming indicated in the relevant section of the manuscript that IMRT is appropriate for use in women with locally vulvar cancer. A randomized trial would be needed to confirm the benefits of the addition of gemcitabine, but this could be considered in patients with good performance status. I completely agree with Dr. Fleming. I'd also like to comment that those of us that are young, we trained in the 3D era. Treating these patients with three-dimensional conformal radiotherapy was far more difficult. It was harder with match lines, et cetera. IMRT has made things better. It's also made things more tolerable for our patients. So I think we get a lower dose to organs at risk. So what about recurrent disease and other considerations? And again, here's the NCCN schema. In the interest of time, I won't go through that. So what are some of the best practices for radiotherapy? Well, I want to applaud Solomon and his team. I think they are providing fantastic care for the patients in Uganda. So what about dose prescription? Well, primary vulvar cancer doses typically should be 60 to 70 gray. Post-op, negative margins, 45 to 50 gray. Post-op, closer positive margins, 54 to 60 gray. And then for patients with involved lymph nodes that are positive, post-excision, typically 50 to 55. Those patients with excised nodes with ECE, 54 to 64. And then gross residual lymph node disease, again, 60 to 70 gray. So what is the impact of adjuvant chemotherapy for patients with radiation and node-positive disease? There's not a lot of data here. However, this is an NCDB study indicating that chemotherapy showed a pretty marked benefit in terms of survival compared to those patients that didn't. We have to be very wary in studies like this from the NCDB and SEER because it's very likely that the patients that are gonna get additional therapy are patients with a higher performance status and hence may do better. So again, non-randomized data, but a pretty large signal here. And here's a second study showing the same thing. Again, NCDB, medium doses, 60 gray, and five-year overall survival was higher for those patients that received chemoradiotherapy compared to those that received radiotherapy. So how much morbidity do we inflict? Well, it can be very toxic. It's very hard acutely to get patients through treatment, but there can be serious late effects too, including in some cases, lymphedema. However, this report from Dr. Barakat, this has been published, but I haven't seen this, excuse me, this has been presented. I have not seen this published, but in this leg study from the GOG, they didn't see a difference in lymphedema in patients who received radiotherapy. Now, the majority of these patients were cervical or endometrial cancer. There is more data on the influence of lower lymphedema after vulvar cancer. Here's a meta-analysis looking at 27 studies and 2,500 women the incidence of lymphedema was 29% overall and 17% in the seven prospective cohort studies. Lymphedema increased five-fold in those patients that received an inguinal femoral lymph node dissection compared to sentinel lymph node procedure. Radiation was a risk factor in one study. All right, so what's the impact of HPV? Patients who are HPV positive do far better than patients that are HPV negative. There's many studies showing this. This is a study by Dr. Jessica McAlpine from British Columbia. And here is a meta-analysis showing the same thing with a hazard ratio of 0.6, indicating a statistically significant benefit for those patients that are HPV positive. So here's a very nice report out of MD Anderson, Dr. Zhengren's institution, can radiotherapy sterilize gross inguinal lymph node disease? They had a small number of patients, 33, median groin tumor diameter was 2.5 centimeters, 48% had positive pelvic lymph nodes, the median dose was 60 gray. The three-year actuarial groin recurrence rate was 17%. So they're providing sterilization at 83%. That's pretty remarkable, very nice data. I do wanna show a few highlights from our contouring paper that was published nearly a decade ago. We worked very hard on this publication, a large number of us. There's only a few salient points that I'd like to show here. The consensus contour is the contour in red. So what we had is we had about 15 different investigators, contour, which you can see in the various different colors, and then the consensus conferences in red. So we published that you don't need to provide a skin bridge always between the groin and the vulva. And in addition, where the tumor does not abut the skin, your PTV or your CTV does not need to include the skin. I would suggest using OSLDs or TLDs to confirm your skin dose in every case. Another point that we indicated is that you don't need to bring your CTV deep to the inguinal vessels, which is important. And then similarly, in cases where there's vaginal extension your CTV should include contouring up the vagina or with approximately a three centimeter margin if you don't have good imaging. Good imaging in this case would be an MRI because CT does not allow you to easily discriminate the tumor. So here's a paper indicating that in some advanced cases, surgery may not be beneficial. And in this NCDB study, again, non-randomized, the patients that received higher doses, 55 gray and concurrent chemo, they had a comparable survival compared to patients who had pre-op chemoradiotherapy followed by surgery. So Solomon and the team showed this. They achieved very nice sparing to OARs. The bladder had a pretty high dose and again, MRI could perhaps help one in reducing dose to that OAR. Again, I think the team did great things, but I'd like to discuss these strengths or these points that Solomon brought up. What is the strength of evidence of split course radiotherapy versus single phase radiotherapy? It's mostly expert opinion. Split course, there are published data, the GOG did this in their initial paper, but have since abandoned it. Not because the data was poor or there was randomized evidence not in support of it, but simply that in the case of first principles, it's not something we routinely do in radiotherapy. So if we do a split course, that may trigger accelerated repopulation, may allow the tumor to kick into growth. It may permit or may require us to give a higher dose. And so hence, in most places that I'm aware of, we do not favor split course. So I don't do split course, but nevertheless, many of our patients do receive a break. That break should be kept to a minimum as shown in that one report out of MD Anderson. So I do favor a single phase course in radiotherapy, but I have to admit, I don't think there's anything in particular wrong with doing a split course. It'd be nice to have more data on this subject. What's the optimal concurrent chemotherapy regimen? We extrapolate a lot in this case from cervix cancer. I like very much what Solomon and the team did, the weekly cisplatin 40 milligrams per meter squared. I think we have a fair amount of data for that. There probably will never be, or there may never be randomized trials. It will be very interesting to see if immunotherapy has a role in vulvar cancer and whether that will be dependent upon the HPV status. What is the role for brachytherapy to the primary plus or minus vagina? The vagina is a very excellent site to do brachytherapy. The vulva, I think, significantly more challenging. In centers that have a lot of expertise with brachytherapy, I would encourage this, but again, I think there's a lot of technical points here that are very challenging. And so unless you have a great deal of experience, I wouldn't lean into it initially. What is the role of neoadjuvant or adjuvant chemotherapy? So again, we extrapolate largely from cervix cancer because we have a lot more data. I would say, unless if you have access to radiotherapy, there's essentially no role for neoadjuvant chemotherapy alone or adjuvant chemotherapy. Why do I say that? Dr. Gingren just presented at ASCO a report from the RTOG indicating that there is no benefit for adjuvant chemotherapy in node positive disease. This parallels the Outback trial in intact or unresected cervix cancer, which showed no benefit for adjuvant chemotherapy in cervix cancer. So I would not recommend adjuvant chemotherapy. What is the role for HPV test and treatment and follow-up? Great question. I think we know that HPV positive patients do better. HPV negative patients may be fairly radio resistant. One can consider giving a higher dose. I've never seen data indicating the benefit of that, but I think it's something that bears consideration. What are the best practices for skincare during and post radiotherapy? One needs to provide significant attention to the skin. It's a very painful site for people to receive radiotherapy. Moisturizing creams throughout, I think are important. Antifungal creams, if there's any hint of a yeast infection, sitz baths are important. And then continuing that care shortly thereafter. With that, I'll close. I wanna thank Solomon and the team and be happy to address questions from my valued colleagues. Thank you very much. Thank you, Dr. Gaffney. And thank you for an amazing discussion. And I am going to open this up for questions and answers. And I'm actually gonna start with a question actually from some of my colleagues around the world who are treating vulvar cancer. But just first of all, my disclaimer, and I've said this a hundred times, vulvar-

vulvar cancer

radiotherapy

chemotherapy

HPV status

treatment outcomes

patient care