Can you hear me all right? Yes? All right, great. So thank you everyone for inviting me to present on the role of radiation therapy in vulvar cancer. As we all know, vulvar cancer is relatively uncommon, representing 4% of gynecological malignancies. There's several challenges. In addition to being relatively uncommon, it's predominantly presents in a more elderly population and often can be quite advanced at presentation. Often therapy has to be individualized based on patient circumstances, and as we had also seen even the previous case. And as a result of all those factors, management is often guided based on either large retrospective studies or phase two studies rather than large randomized control studies. So for today, today's objectives of my presentation would be first of all, a brief overview about the factors influencing management of vulvar cancer, the indications of radiotherapy and the rationale. And just for the purposes, I've divided them up in the adjuvant setting where it should be divided. We consider it management of the nodes separate to the primary, as well as in the upfront setting where surgery is not possible. And if time permits some expected outcomes based on our experience. So as we all know, there's some very established factors that influence the management, such as disease extent, the size of the primary tumor and laterality, as well as depth of invasion. These generally determine whether a patient is operable as well as the type of surgical procedure and surgical staging that they undertake. And issues such as margins and nodal status influence the risk of local and local regional recurrence and subsequently the overall survival. However, particularly in vulvar cancer where sometimes surgery and radiation is difficult to be tolerated, other factors really need to be taken into consideration such as the age, performance status, overall fitness, as well as local expertise and experience and available resources from a practical point of view. So starting with early stage or resectable vulval cancer, we all know that surgery would be the mainstay of treatment as well as staging in terms of whether it's a central nodes or a groin dissection. For early stage vulval cancer, the surgery of vulvectomy with nodal assessment guided by the size and the depth of invasion as well as whether or not one gets a unilateral or bilateral node assessment is really guided by the factors I've stated prior to that. So for the well-accepted indications for adjuvant radiotherapy, first of all to the lymph nodes would be generally at least two nodes or more than one node. So two or more nodes of pathologically involved lymph nodes or alternatively a grossly positive node with another risk factor such as extra capsular extension or LVSI. Now, with regards to the primary, the generally radiotherapy will be discussed or considered for close or positive resection margins where reexcision is not feasible. If lymph nodes are negative and a clear resection margin, no adjuvant radiotherapy is indicated. With regards to the rationale of adjuvant radiotherapy, we'll all probably be very familiar with a landmark study, GOG study by Holmesley et al. Back in 1986, where 114 patients following a valvectomy and bilateral groin dissection were randomized if they were not positive between radiotherapy to the bilateral groins and pelvis versus an ipsilateral pelvic node dissection. The midline, for those who received radiotherapy, the midline was shielded to reduce toxicity and the aim was to compare survival and morbidity of these patients. As we all know that there was a clear advantage seen in the radiotherapy up where the addition of adjuvant radiotherapy to the pelvis and groin improved local control and survival, which was statistically significant at two years as well as it reduced groin recurrence rates significantly. Not surprisingly, recurrence on other sites was similar. So overall, if patients were to require adjuvant radiotherapy for nodes, the policy would generally be to deliver at least 45 grade to regions here harboring subclinical disease, which will include the next echelon of nodes in the ipsilateral pelvis, the subcutaneous ridge, and would consider the contralateral uninvolved groin depending on the adequacy of nodal dissection. And of course, the actual area of postoperative tumor bed would receive more than 54 grade in general. The next question would be, can radiotherapy replace surgical lymphadenectomy? Now, subsequent to the previous study I mentioned, the FDA in 1988 looked at comparing bilateral inguinal irradiation versus inguinal plasphemal dissection with patients with clinically negative inguinal nodes undergoing a valvectomy. Now, the outcomes were significantly inferior in the radiotherapy alone arm, and the authors concluded that radiation of the intact groins was inferior to dissection in patients with clinically negative nodes. However, this study was heavily criticized where for three reasons, mainly that those who received radiotherapy alone only at treatment of the inguinal nodes, whereas the surgical arm had dissection of inguinal and pelvic lymph nodes. The evaluation of the lymph node status was determined clinically rather than based on imaging. And also the fact that the radiation technique was heavily criticized as the prescription of the radiation was prescribed to three centimeters, which would mean that many patients would actually be severely underdosed. And this is certainly the case for larger patients. And certainly that will be the case in the Australian population. As you can see, generally it's at least about five centimeters or more for a very obese patient, which would be severely underdosed. So for those reasons, the GOG88 was criticized. Now, moving on to adjuvant radiotherapy to the actual primary site. Now, many of us would be aware of a very known paper and what they even call the HEAPS criteria, which was published in the gynecology oncology in 1990, which showed that local recurrences were associated with surgical margins. And generally patients who had positive margins or eight millimeters pathologically or one centimeter clinically, as they say there's some shrinkage once the formula is fixed, and LVSI contributed to local recurrence. However, as we discussed previously and alluded that this absolute eight millimeter margin has been recently has been actually challenged and the actual indications of radiotherapy based on margins varies with local practice. But generally, if margins are close, re-resection is generally indicated. Speaking of the studies that have been done looking at margin status, there were two studies that I'm gonna discuss, one by Bedell et al that was aiming to re-evaluate whether re-excision or adjuvant radiotherapy was required for stage one vulval cancers with narrow margins defined as those with less than eight millimeters. The authors found that whether they had radiation or re-excision, it had not much of a statistically significant difference in terms of relapse-free survival or overall survival. Subsequently, a European group also looked at this question. Once again, looking at patients with at least five-year follow-up, looking at whether or not local recurrence was related to margins. What the authors found was that local recurrence was more related to whether there was a presence of VIN or lichen sclerosis more than the actual margin distance and found that when they had looked at the multivariate analysis of their survival, the cutoff was three millimeters. Nonetheless, in terms of at least subsequently, another study has looked at this question once again, looking at Neville Hecker's group in Sydney, where in the Royal Hospital of Whitman in Australian study, looking at 345 patients who were carefully followed up between 1987 to 2017 with a follow-up of at least five years and stratified, found all those patients with margins of less than eight millimeters and stratified them according to margins which are positive, less than five or between five and eight millimeters. And they did find that there was a significant difference between those who had, in terms of local recurrence, comparing eight millimeters, margins of more than eight millimeters or less than eight millimeters. So therefore, based on the study they've mentioned, another one looking at the radiation dose, first of all, Akila from the Dana-Farber Institute reported in 2013, looking at 205 patients with early stage vulval cancer, post-surgical excision. And once again, close or positive margins was found to be a risk factor for recurrence with the highest risk of patients less or equal to five millimeters. Patients who had adjuvant radiotherapy for narrow margins significantly reduced their risk of local recurrence and they have recommended adjuvant radiotherapy doses of more than 50 gray, as they found that, at least retrospectively, that anything less than that was associated with higher risk of vulval relapse. So now, with regards to more advanced or rather unresectable vulval cancer, a definitive radiotherapy could be considered upfront if definitive surgery may compromise function, particularly for T3 or T4 lesions. Even for smaller lesions who are periclitoral or periurethral, in our practice, that would be what we would be considering or if a function would be compromised, for example, if a primary lesion was encroaching the anal sphincter. Another group of patients that could be considered is even if the primary was fairly small, but was found to have extensive normal disease either clinically or radiologically. And needless to say, the management of these patients should be individualized and often require multidisciplinary management and certainly should be discussed at the local tumor board. Looking at the data in supporting preoperative or definitive radiotherapy, it first started in 1998 where there was a GOG phase two study looking at patients with T3 or T4 lesions requiring exentorative surgery. Out of 74 patients, they underwent radiotherapy with concurrent radiosensitizing chemo. They used the 5-FU and cisplatin for chemotherapy regimen, for which 46.5% had clinical complete CR with three patients needing gastrointestinal or dual diversions. This was a particularly toxic regimen, although even though they did have quite good results, but this led to other similar studies involving unrespectable disease and notes in disease becoming respectable following radiotherapy. So as I mentioned, there were several studies, but one I'd like to draw your attention to is what the 2012 phase two study, which actually supports our practice, which we do here in Melbourne, Australia, which looked in this study, the phase two study of T3, T4 lesions using radiotherapy followed by surgical resection or biopsy of residual tumor. This time, instead of 5-FU, we used cisplatin, which is a similar regimen, which is used for the treatment of cervical cancer, was used as a radiosensitizer and 64% of patients had a complete CR and of which 78 of those patients had complete pathologic response when they had a surgical biopsy, which was extremely encouraging. So generally for either definitive or preoperative radiotherapy, this would involve external beam treatment to at least 45 gray of all areas of subclinical disease and gross disease would be boosted to a higher dose, preferably something closer to 60 gray equivalent. However, the real issue with vulva cancer is that the skin tolerance is generally at about 55 gray. So even with very modern external beam techniques and radiotherapy techniques, such as IMRT or VMAT, which allow dose painting, it's quite difficult to tolerate just to large areas more than 60 gray. So areas, ways around that would be the rationale of radiosensitizing chemotherapy, which allows a modest dose escalation with non-competing toxicities. And also depending on the area and if local expertise are available, select patients can be boosted with interstitial brachytherapy with extremely good outcomes. In terms of the role of imaging for vulva cancer patients, generally for early stage or cases that are suitable for centenode biopsy, obviously imaging generally is, the negative predictive value is too low to replace surgical staging, but it may be useful to exclude bulky suspicious nodes within the pelvis or any intercurrent distant metastasis. However, certainly for locally advanced vulva cancer, in our practice, we certainly would, either it's a large primary, generally, if it's more than two centimeters, we would image with either at least a CT test at the pelvis or a PET if available. If extensive local therapy is being planned, an MRI would certainly be of benefit, either to assist if there's involvement of the anal sphincter or to assist surgical planning or radiotherapy boost if brachytherapy is being considered. It's also useful in radiotherapy planning as well as response to therapy. A very common question is whether or not radiation works for gross nodes. Well, there's certainly been some reports from individual institutions rather than randomized control studies. And this particular study published in the Ghanai Oncology in 2018 showed that patients with gross inguinal adenopathy with a median size of two and a half centimeters did have an excellent response with overall survival rate of more than 50%. And the CR rate was fairly high of more than 70%. So I'm just thinking, how are we going for time here? So I just want to, just an example of a particular patient that I've recently seen. There was, it was with locally advanced vulval cancer. This Mrs. Casey, who was a 72 year old renal transplant recipient with, who was immunocompromised. Fairly good performance status, but not completely zero, not excellent. However, she had, she presented with this in the clinic, at least a five centimeter tumor, which was posteriorly located, fairly exophytic and an examination. It clearly, it crossed the midline and extended to the mid vagina encroaching the anal sphincter clinically. She underwent an MRI and a PET scan on MRI. Sorry, I did not have the images to share with you, but it did confirm the primary tumor, but was particularly abutting and encroaching the rectum as well as, sorry, the anus. And based on the tumor board discussion, she was referred for upfront chemo radiotherapy with the aim of an early assessment for suitability of surgery. She did not have concurrent chemotherapy on the basis of her renal function and had radiotherapy alone. So this is a picture of her after nearly 57, more than 57 gray. So this regimen gives us a biologically equivalent dose of close to 60 gray. We just gave it in a short course and she had a radiotherapy to the vulva and the bilateral groins. And I'm pleased to say that it significantly reduced. Clinically, we could tell that at four weeks following completion of radiotherapy and at three months, she healed quite well with just a tiny area of suspicious, that was suspicious. She was actually being worked up for potentially a limited surgery. However, the biopsy of the area in the clinic was actually negative and consistent with inflammation alone. And after she was carefully counseled, she actually declined surgery and we did a restaging PET scan at six months following completion. And I'm pleased to state that she had a complete metabolic response with no nodal or distant metastasis either. So looking at our outcomes in our experience in Peter Mac, Victoria, Australia, generally the referral patterns on patients are generally referred in the adjuvant setting for nodal status, for nodal positive disease. We had 88 patients altogether, sorry, 259 patients treated with curative intent. Sorry, 259 patients treated with curative intent. Adjuvantly for nodal positive disease, 88 patients. And post-operatively for positive margin, 17. Definitive chemoradiotherapy, 77. And for recurrence and for salvage chemoradiation with no prior radiotherapy, 182. With a minimum follow-up of three years, 64% are alive without recurrence. And out of the 92, 44 died from tumor. Out of those patients who were treated definitively, majority of them had chemotherapy, of which 65, sorry, 60% of them are alive without recurrence. Toxicity rates were pretty acceptable with the worst toxicity. Most of them having grade one and two toxicity in the vagina, skin, and lymphedema. But the maximum or the worst toxicity documented was two patients with grade two toxicity, which is basically cyanosis of the upper third of the vagina. And grade two skin being telangiectasia, but in grade three of these were two patients had severe induration and one patient had severe lymphedema. Out of the, they had nearly 40% of patients had relapsed, but majority of them are multisite within the pelvis. One relapsed in the primary alone, one successfully salvaged and three declined and died of their disease. With regards to note positive cases, we reviewed 53 of our cases between 2000 and 2012, where 23 were treated with definitive chemotherapy and 30 treated in the adjuvant setting. Overall, we had pretty decent local control of 70% and 17% of patients died of uncontrolled local regional disease only. At three years, 11 failed at the primary site of which three were successfully salvaged. And three failed in both in the primary and pelvis and died of disease. And four suffered from pelvic relapse without disease in the primary. And so overall, I think what overall radiotherapy does, at least for locally advanced cases, does offer some local control with or without surgery. So in summary, just putting it all together, what I've discussed, what we'd say is that in the management of our cancer, radiation does certainly play a role. I'm certainly considerate for locally advanced unresectable T3, T4 tumors, either preoperatively with the aim of reassessing for a limited resection or in the definitive setting. Although there isn't any randomized control trials comparing radiotherapy alone versus human radiation, certainly it is very tolerable and it does offer some form of modest dose escalation with a high number of complete responses. With the, in the post-operative setting for operable cancers, the absolute indications would usually be for two or more lymph nodes or one with extra capsule extension. There are areas of gray where depending on the adequacy of the nodal dissection, if it's one lymph node and that's generally discussed at the tumor ward level for the post-op radiation of the primary, certainly for positive margins or narrow margins if surgical excision is not possible. Thank you.

radiation therapy

vulvar cancer

management

individualized therapy

surgical treatment

adjuvant radiotherapy