We have a very special guest among us. We're very lucky to have Dr. Lisa Diller come and talk to us about the long-term outcomes of survivors from Wilm's tumors and neuroblastoma patients. This is a very important topic given that over the last couple of decades we've made substantial strides in improvement of survival of these patients. Now we're leaning towards focusing more on improving the quality of life and preventing secondary cancers in this patient population. Uh, Doctor Diller is originally from New York and has been, spent most of her academic, uh, career here in, um, Boston shows both her, uh, training and, uh, academic, uh, lifespan here with a, a faint, um, I'm sorry, a short uh exception in UCSD for her medical school. She's the associate chief of the Division of Hematology and Oncology, and she's the director of the Pediatric Cancer survivorship, uh, Program in the David Perrini Quality of Life Clinic. So with this in mind, please. Uh, give me, um, let's welcome her to the podium and uh we are eager to listen to her talk. Thank you. Thank you very much. I'm very pleased to be here. Um, I just want to take a moment to dedicate this talk to Eileen Perrini. Um, Eileen Perrini, um, uh, had a son who, uh, passed away from, uh, Ewing sarcoma, and she and her husband dedicated the rest of their, uh, philanthropic careers raising money to support our survivorship program at the Dana-Farber, which is known as the David B. Perrini Jr. Quality of Life Clinic and the Perrini Family Survivor Center. And it's been my honor to spend much of my career on developing clinical program and doing research and survivorship, um, uh, very much with the support of the Parini family. So, um, Eileen passed away this month and I just want to recognize her today. And thank you, Doctor Schamberger, for inviting me to do this. Gonna talk today about Wilms tumor and neuroblastoma, give you a little bit of a brief overview of survivorship in general to set the stage, um, give you a couple of cases, and then, um, really pose to you some of the problems and survivors and, um, how modern therapies might be making those problems, uh, less prevalent and how other modern therapies might make, be making them more problematic. So, um, about 83% of children with malignancy will achieve a 5-year survival, which leaves us with a large population of patients who are long-term survivors of childhood cancer. In 2013, about over 400,000 estimated survivors of childhood cancer were identified in the United States. We expect that to be about half a million survivors going forward, and that means that about 1 in 750 children in the United States, or people in the United States, I should say young adults, is a childhood cancer survivor. But surviving cancer as a child is associated with increased late mortality. So when my patients survived 5 years, that doesn't mean that that's the end of the story. Um, here is a curve I want you to be sure to see that. This work? Yeah. Be sure to see that we're starting here at 70%. But here's the 5-year survival point here. So if you start at the 5-year survival point in a relatively young population, the mortality rate is actually quite low. Um, these patients are expected, normal people are expected to survive to, um, about age 35 or 40. But if you look at childhood cancer survivors, you do see a drop off of anywhere between 15 and 25%. Um, and that's of, of great concern, obviously. So what are the causes of death in those patients? Well, there's still, there continues to be, does this error work? Yeah, that's easier. Um, there continues to be, um, a, uh, a risk of recurrence, usually in the, uh, steep risk of recurrence in the 1st 5 years or 10 years since after diagnosis, which kind of levels out. External causes are uh causes like suicide, homicide, motor vehicle accidents, and that's about a steady rise just like you see in normal populations, not increased above uh non-cancer populations. But here is the rising concern with a very steep increase at 15 to 30 years after diagnosis of death from other health related causes, and that includes not only the occurrence of chronic disease as people age, but more importantly in this young population, death from late effects of cancer therapy. And if we look at standardized mortality ratios, the risk of developing, of having a death from a cause compared to what would be expected in a non-cancer population, the relative risk is anywhere between 7 and 15. Childhood cancer survivors are 15 times more likely than non-childhood cancer survivors to die of a second malignancy in the 30 years after treatment for childhood cancer. What about morbidity? There have been a number of papers, including this landmark paper from the New England Journal of Medicine, that shows about 2/3 of long-term survivors of childhood cancer have at least one chronic late condition and more than 1/3 of them have a severe or life-threatening condition. And what this tells us is that childhood cancer survivors kind of develop chronic conditions earlier in life than they should have. If you look at this sort of cumulative incidence curve of chronic conditions in childhood cancer survivors compared to their siblings, by age 50, about 20% of the siblings have developed a chronic condition. However, that 20% mark is hit in the survivors by age 20, so they sort of have premature aging in a sense, based upon the treatment that we've given them. What are these morbidities? There were second cancer, cardiac, pulmonary, endocrine, infertility, neurosensory, obesity, the list goes on and we'll look at those more specifically in the course of the next 40 minutes or so, um, uh, in specific about neuroblastoma and Wilms tumor survivors. So I'd like to focus on Wilms and neuroblastoma, um, diseases that Doctor Shamberger and I have been taking care of for many years, with a brief overview of trends in Wilms tumor treatment, um, and then a deeper look at Wilms tumor survivorship in, in terms of mortality, morbidity, and emerging questions. And then take a little break and then do the same thing for neuroblastoma. Let's back up to a case. Um, KD is a 29-year-old woman with a history of Wilms tumor. I started taking care of her when she was about 12. Uh, she initially presented here with hematuria and a right-sided renal mass and underwent a right nephrectomy. She was found to have favorable histology Wilms tumor with capsular and nodal involvement, and she received a chemotherapy regimen that was unique to the Dana-Farber and Boston Children's back in that era. Which included vincristine, actinomycin, and cyclophosphamide and unique because um cyclophosphamide, which is an alkalating agent, was not a standard nationally at the time. But what we were doing here was trying to, trying to avoid doxorubicin, which as you know, has significant cardiotoxicity. She received, received hemiabdominal right-sided radiation therapy and then at age 8, she had a small bowel obstruction requiring um lysis of adhesions by Doctor Fishman. I went back over her records last night. Um, and had a couple of other admissions for a small bowel obstruction which did not require surgical intervention. At age 22, uh, she presented with a neck mass and, uh, Doctor Shamberger did a total thyroidectomy. She had papillary thyroid carcinoma and received I 131 treatment. And at age 28, she was, uh, married and trying to have children, um, was, uh, having some trouble getting pregnant. Went in for an assisted reproductive therapy, um, uh, uh, evaluation, and at that time, imaging showed, uh, uterine masses that turned out to be, um, benign liomyomas and a S1 intradural extramedullary schwannoma, which she had resected, um, because of concern of, of the possibility of progression during eventual pregnancy. This is not an unusual case. This, I could have picked any one of a number of young adults who are dealing with multiple morbidities and multiple complications associated with their prior therapy. So what are the questions raised by this case? Well, what are the risks of treatment-related mortality and morbidity in survivors of childhood Wilms tumor? What are we doing about that and how should we care for and counsel survivors? I want to back up a little bit and talk about Wilm's treatment. Um, over the past 3, maybe even 4 decades, standards of care have emerged for Wilms tumor from an oncologic perspective. These are largely based on randomized clinical trials performed initially by the National Wilms Tumor Study Group and then by the Children's Oncology Group. We've sort of settled on that this is the treatment for Wilms tumor, nephrectomy and two-drug chemotherapy, that's vincrisin and actinomycin, neither of which are associated with significant late effects. However, advanced, advanced local disease or stage 3 disease or metastatic disease requires still radiation therapy and the addition of a third agent, doxorubicin. We usually don't use alkalating agents anymore except for relapse or in specific high-risk histologies like that cyclophosphamide that my patient got, that's probably contributing to her infertility. Recent, recent treatment trends in Wilms tumor included looking at low-stage Wilms tumor and seeing if we can get away with nephrectomy only, which I'm sure many of you are aware that for um very early-stage Wilms tumor with small tumors in young age and favorable histology, nephrectomy only has become a standard. How do we reduce total dose exposures? How do we get rid of alkyating agents in all patients and minimize doxorubicin and try to avoid radiation? That's where we're heading. And then using genetic markers so that we can not only stratify by stage, anatomic stage, but also by risk group. And trying to avoid radiation for patients with lung metastases by looking at chemotherapy responsiveness because of the late effects associated with lung radiation. And with all those strategies that we've put in place, Womb's tumor survivorship has really been excellent for many decades, from the initial advent of adjuvant chemotherapy back in the 70s till now, we've gone from about a 70 or so% 5 year disease free survival or overall survival, I should say, to over 90% overall survival. But what about beyond 5 years? There remains a late mortality risk. This, these data are from the National Wilms Tumor Study Group Long Term Survivor Study. Patients are 24 times more likely than the expected mortality to die in the 5 years after diagnosis of Wilms tumor, and that's, as you might expect, largely Wilms tumor associated mortality. But there remains an increased risk of death, um above what would be expected for these very young patients in the decades that follow. What are they dying of? This from the British Cancer Survivor Study, a large cohort study of patients in Britain. This is a very long, um, a very wide range of years in which the patients were treated from the mid-20th century up until about 1995, I believe. And the patients, the cumulative mortality at 50 years, here I'm There's my arrow point um rises up to about 20% above what would be expected down here and they're dying of second primary malignancies and cardiac disease. What are the chronic illnesses that they develop, not just mortality, but morbidity. Patients with Wilms tumor have an increased risk. This, these data are from the Childhood Cancer survivor Study, a large cohort study in the United States of childhood cancer survivors. They're much more likely than the sibling control group to have multiple chronic conditions or of, of all grades, of high grade, hypertension, congestive heart failure, renal failure. If we take a deeper dive looking at the second cancers that patients develop, you can see in the British Cancer Survivor Study a high risk and cumulative risk of developing a second cancer. In this group, they noted 71 2nd cancers versus 15 expected, and of note, a lot of those were GI cancers. The most common cancer seen was GI cancer. This is largely associated with radiation, and you can see that we have colon cancer, retroperitoneal cancers, liver cancers, and a variety of other, uh, uh, mostly carcinomas occurring in uh Wilms tumor survivors. We're seeing breast cancers, sarcomas, soft tissue sarcomas, and then leukemia and lymphoma, and thyroid disease. Why breast cancer? Patients with Wilms tumor, as you know, if they have lung metastases, get radiation to the chest, which includes the breast tissue. But even if they're just getting flank radiation, either unilateral or whole abdomen radiation, the breast buds which are outlined here in the cross-sectional imaging and shown here in port films, we do receive a low dose of radiation associated with an increased risk of breast cancer. And here's the overall cumulative incidence of breast cancer in the, uh, this is in the National Wilms Tumor Study Group showing that patients who receive chest radiation have about a 15% incidence of the cumulative risk of developing breast cancer compared with what would be expected of almost no breast cancer in the non-irradiated patient. But even the abdominal RT only patients develop breast cancer at a higher rate than would be expected. I want to um give a shout out to the group here for looking at uh one of the uh late effects of uh childhood cancer treatment that has been seen in the childhood cancer survivor study. In fact, the surgical group here is uh the most active surgical group in looking at the childhood cancer survivor study data. They've looked at, um, The effects of splenectomy on infection risk. Here's the effects of radiation and surgery or in patients who have abdominal or pelvic tumors versus non-abdominal or pelvic tumors developing a late intestinal obstruction requiring surgery. Um, and here's the, uh, cumulative incidence of needing surgery for, um, a late, uh, intestinal obstruction, uh, compared to a competing risk of developing a recurrence of second malignancy or death in patients who had abdominal or pelvic tumors versus non-abdominal or pelvic tumors where the risk is quite low. Um, Uh, the, uh, childhood cancer survivor study, just a little pitch to you guys, uh, uh, is a wealth of data on over 20,000 childhood cancer survivors in which their surgical data has been abstracted, uh, largely through the work of Dr. Weldon and Colleagues, um, and, uh, remains a public resource or uh academic resource for further work. If anybody's interested, please give me or Doctor Weldon a, a shout out to see what kind of analysis can be done in that, in that group. How about heart disease? Um, in the National Wilms Tumor Study follow-up group, the cumulative risk of congestive heart failure was, um, about 4% at 20 years after initial treatment with doxorubicin. Um, any patient who had a relapse had a much higher risk because we retreat with, um, uh, with doxorubicin, but probably more importantly because most of the relapse are lung relapses and we go on and radiate those lungs. So what are the risk factors for developing late congestive heart failure? They include gender. It appears in many studies across different diseases that doxorubicin sensitivity is higher in females than in males for unclear reasons. Cumulative dose of doxorubicin is a significant risk factor for developing congestive heart failure. Left abdominal radiation, as you might expect. And lung radiation, although not statistically significant in this series from the National Wilbs Tumor Study, is uh clearly a risk factor for developing late congestive heart failure and other heart disease in other survivor series. So what to do about this? Well, we need to continue to reduce therapy to reduce light toxicity, that's for sure. Have we been able to do that? Um, this is a recent look at the childhood cancer survivors study, um, abstracted data about exposures over time. Have we decade by decade, able to reduce exposure to radiotherapy and um Wilms tumor? Certainly. In the 1970s, almost 80% of children were receiving radiotherapy as part of their Wilms tumor therapy. Changes in therapy and awareness of late effects have reduced that to less than 50% and probably going down even more. And anthracyclin exposure the same. Um, Anthracyclins were a standard of care or remain a standard of care in Wilms tumor patients, but we've become more and more sensitive to knowing that total dose is an important factor for risk of heart disease and over time we've Been able to reduce our total dose exposures from close to 300 mg per meter squared down to safer doses considered to be less than 200 mg per meter squared. And I suspect this will go down as well as the use of cardio protectants will protect our children from development, development of congestive heart failure. So have these changes resulted in a decrease in late mortality? A recent study from the Childhood Cancer survivor Study performed by Greg Armstrong, one of my colleagues there, has actually looked at this and looked at combined late mortality and a variety of diseases based upon based upon decade. So for Wilms tumor survivors treated in the 70s, the risk of death of cardiac, pulmonary, and second cancer mortality was 2.2% in the eighties down to, this is a 15-year risk, was 2. 0.2%, down to 0.6% um for children treated in the 80s, down to 0.4% in children treated in the nineties and the predictive, the uh going into this model was what predicted these outcomes and it was clearly exposure to the amphacyclins and the radiation. So the combined cardiac, pulmonary, and second cancer mortality at 15 years from diagnosis has clearly been going down as we've been able to reduce exposure and at the same time maintain good cancer control. What do we do about this? Important is good survivorship care with attention to at-risk individuals. Exposure to radiation merits a consideration of second cancer screening for women who received chest radiation or who received flank radiation or abdominal radiation at a very young age. We consider mammography and breast MRI as standard. Early colonoscopy screening is part of our recommended childhood cancer survivor guidelines starting at age 35, um, and going forward from there. Exposure to anthracyclins is associated with clear guidelines for cardiac screening and certainly probably more important than screening in young adults is counseling about risk reduction, including no smoking, attention to other cardiac risk factors, management of diabetes, careful management and screening for diabetes, um, and diet. Attention to renal health and treatment of hypertension, these patients who generally only have one kidney, and early discussion of reproductive health given the technologies that can be used to preserve eggs or um uh and the risk of early menopause. Here are the breast cancer screening guidelines that are evolving in children who have survived, in women who have survived childhood cancer. There is a clear recommendation that children who, women who were treated as children with greater than 20 grade chest radiation undergo breast cancer surveillance, and that includes annual MRI and mammogram beginning at 25 years of age as long as it's at least 5 years, uh, 8 years from radiation. Most of the Wilms tumor patients will fall, fall into this range or even into this range where the recommendations are less clear about when mammography should be instituted, when or whether, whether mammography and breast MRI should be instituted. In general, we at um at the Dana-Farber uh adhere to this guideline here that uh women who receive relatively low dose chest radiation should actually go on and have breast cancer screening. The child cancer survivor study has an online cardiac risk calculator which uh you can uh look at by searching CCSS risk calculator in which you can plug in the total dose of anthocyclin, whether or not there's been chest radiation. And get an estimate as to whether or not the patient is at risk for developing congestive heart failure and what that risk is. In this example, I put in a woman who was less than 5 years of diagnosis, who received anthracyclins in a relatively low dose, but the patient's risk of developing congestive heart failure by age 50 is 13%. This is obviously a very concerning. statistic and one that we really need to address going forward uh as we think about what further, what future therapy should be like. Um, so this is our little break before we go on to neuroblastoma. This is me. Um, we have some, uh, visitors here, observers here from, um, Beijing Children's Hospital where I had the pleasure of giving a talk about survivorship there, uh, last June, and I want to acknowledge them for, um, their coming here and spending time with us and allowing me to visit them as well. I'll go on now to neuroblastoma survivorship. Let's go back to a case again. Um, LR is a 24-year-old with a history of stage 4 Wilms tumor diagnosed in 18 in 1989 at age 4. Now, in 1989, a child with stage 4 Wilms tumor at age 4 had about a 5 to 10% 5-year survival. These patients almost uniformly died when I started my Uh, career here as a fellow in 1988, um, at the Dana-Farber, we were very proud we had one long-term survivor of childhood, um, of high-risk, uh, neuroblastoma, and this was her and I, um, saw her in the survivorship clinic. She initially presented with proctosis and pancytopenia, fever, pain, and a large abdominal mass. She was treated with aggressive chemoradiotherapy, which included emergency radiation to her orbit, high dose platinum, anthracycline, cyclophosphamide. She received surgery, local radiation to the abdomen, and a TBI based transplant, which in the late 80s we were sort of beginning to use as a way to dose intensify therapy for patients with high-risk neuroblastoma. And she had been in continuous remission for 20 years. The complications of her therapy included hearing loss from her platinum-based therapy, hypothyroidism from her total body radiation, premature ovarian failure. She never went through puberty naturally, and insulin resistant and diabetes, which we'll come back to. So when I saw her in the survivor clinic, she presented with decreased appetite, weight loss, and vague abdominal pain. Laboratory studies um demonstrated a microcytic anemia and mild LFT elevation. Among, uh, as part of her workup, she had a PET scan. This is her PET scan. It showed multiple liver lesions and a colonic mass. She had metastatic colon cancer, and this was my introduction as a young investigator as to what we needed to deal with in survivorship. She had metastatic colon cancer and treatment was Um, minimal, and she passed away approximately 6 months later. So what are the major questions in neuroblastoma survivorship? Well, first of all, things aren't that bleak. We have a group of patients with low and intermediate risk stage neuroblastoma who we can treat more and more with more and more minimal therapy as we learn to classify them better. Um, and the questions are, do they, do our changes in therapy result in fewer late effects? More importantly, as 2/3 of our patients have high-risk disease, as more and more high-risk patients survive longer, what's the outcome for them? Can we identify screening and prevention strategies that reduce long-term morbidity? And what have we learned so far about the late effects of our newer therapies and our newer approaches, the cocktail that we use to treat these patients? So let's back up to low and intermediate risk disease. Low and intermediate risk disease babies with localized or um non-biologically aggressive disease, patients with localized disease that can be addressed surgically without adverse uh biologic features like NMC amplification. Those, those can usually be treated or historically then back at the beginning of my career, those were treated with very aggressive chemotherapy, surgery and radiation. No one could identify the patients who needed aggressive therapy versus those who didn't need aggressive therapy. And there was a sense that we were overtreating, especially using more radiation than we needed to use and higher dose chemotherapy than we needed to use in these patients that we now identify as low and intermediate risk, uh, neuroblastoma patients. So more recently, clinical trials worldwide support the concept of reduction of therapy trials in these patients, reducing exposure to alkalating agents and to radiation, minimizing the use of surgery. To do this, we needed to identify the patients with clinical and biologic factors likely to um be successfully treated with less aggressive therapy. And this included identifying patients who could be uh followed with observation only to minimize the use of radiation and surgery if possible, and to reduce chemotherapy total dosing. Um, this is a, I can't really see the whole title there, but this is a prospective study that was completed by the surgical group at the Children's oncology group looking at whether or not primary therapy for patients with localized small neuroblastomas that were picked up in very young infants could be followed without surgery at all. There were 87 patients enrolled. And of those, 81% avoided surgery completely. 16 patients underwent surgery, 10 had neuroblastoma. 2 had low grade adrenal cortical neoplasms, both of which were growing. And the reason for resection, they met the criteria in the study to go for resection. Two had extra lobar pulmonary sequestrations and there were no deaths. Um, I want you to notice that this is not 0, this is 60%, so the, this is the 81% avoiding surgery at all. Doctor Shamberger was a mover and shaker on this study and we're very happy to have patients come in now for whom we can recommend ultrasound surveillance only. How about the intermediate-risk patients, the patients who require chemotherapy, babies with non-biologically aggressive tumors but metastatic disease, children with larger tumors that are not resectable at diagnosis. What we did over the past 15 or 20 years really was reduce the amount of chemotherapy we exposed them to. We chose chemotherapy with a lower Risk of late toxicity, mostly because we limit the total dose. So we limit the total dose of carboplatin, etopicide, doxorubicin, and cyclophosphamide to the extent that using the data I presented earlier, we can have an expectation of no infertility, no cardiac disease, and minimal risk of hearing loss or renal disease from the platinum exposure. And that experiment has gone quite well. Patients have done exceedingly well. This is an overall survival curve comparing old strategy to new strategy, sort of higher dose chemotherapy, more aggressive chemotherapy to more modern chemotherapy, showing that our overall survivals are overlapping. Um, patients have done quite well with this, and the real question is who can get less chemotherapy? Can we go from 8 cycles to 4 cycles, 44 cycles to 2 cycles, 2 cycles to no cycles, and that's kinda where the oncology world is looking at how to reduce therapy in these patients. So as I said, the next steps in low and intermediate risk therapy is, can we expand the eligibility for observation only? Can patients who are a little bit older or have a little bit bigger tumors be observed only? Can we determine who can get fewer cycles of chemotherapy, determine the role of less aggressive surgeries? Do we need to have a surgery at all for some of these patients? Can they just be followed? Certainly US surgeons are are quite used to the concept that in neuroblastoma patients, a A true cancer operation is often not necessary, leaving positive margins or leaving even 50% of the tumor behind in order makes us wonder whether some of these patients need surgery at all, given that we can leave large amounts of tumor behind and still have disease be well controlled. And then improve the care for conditions associated with late toxicity. So even though there are low and intermediate risk patients who their neuroblastoma in a sense is not the issue, there are complexities associated with their neuroblastoma like oxyclonic myoclonus or symptomatic disease. Uh, involving massive liver involvement that, uh, cause the patient to, uh, have morbidity beyond, uh, the actual cancer associated morbidity, but either anatomic morbidity or neurologic morbidity. Focus the rest of my time talking about high-risk neuroblastoma. Um, high-risk neuroblastoma is for the first time a curable disease in a substantial percentage of patients. As I said earlier, um, when I started my career, high-risk neuroblastoma was probably the disease that we as pediatric fellows, uh, pediatric oncology fellows dreaded the most, the diagnosis. As we dreaded the most. There was really, we would tell patients, well, we'll give you chemotherapy and for as long as it lasts, it gets sort of we get responses and as long as they last, we'll keep giving it and we would give 1015, 20 cycles until the bone marrow didn't tolerate it at all and the survival rates were very, very poor. Late in the 80s, we started to experiment with dose intensification, with rescue with uh peripheral blood stem cells, um our first bone marrow and then peripheral blood stem cells. And we're able to sort of push out the survival curves, but we really weren't seeing a whole lot in the way of long-term survivors. The strategy now, um, that has become somewhat of a standard of care. Is induction chemotherapy with about 5 cycles of chemotherapy including high doses of cisplatin, causing hearing loss, doxorubicin associated with congestive heart failure, alkalating agents associated with infertility. Surgery of the primary tumor. We do peripheral blood stem cell transplants in in sequence, one after the other with peripheral blood stem cell rescue after each one. These are associated with, these are given with high dose alkalating agents. Radiation to the primary tumor and to metastatic sites. And biologic therapy with immunotherapy, cytokines, and isotretinoin, also known as retinoic acid or accutane. And this has resulted in gradual increases in overall survival in these patients to the point that we're at, we were at in the last published studies at about 50%. Um, event-free survival or overall survival, um, getting out to about 5 years. So I'm embarrassed and proud because that's a horrible mix of uh drugs and treatments that I just told you about to give to a 2 year old or a 4-year-old to put a family through. They're in the in and out of the hospital for 12 to 18 months in that therapy. However, um, here we are in a new era with long-term survivors. These are the treatment outcomes from a, um, paper that's um in preparation. Looking at high-risk neuroblastoma patients who completed our last randomized trial comparing single transplant versus double transplant as consolidation. The patients who received a double transplant and then went on to receive immunotherapy have an event-free survival of greater than 60%, approaching 70%, and an overall survival of close to 80%. And this is sort of over the course of now 3 decades since I started my fellowship, quite an accomplishment. An accomplishment that I say, I say accomplishment a bit sheepishly, uh, because of the, on the one hand, I'm a neuroblastoma clinical trialist and I'm quite proud of that. And on the other hand, I'm a survivorship doctor, and this is going to be what I would call a mess because these kids are just going to have a panoply of late effects. So what do we know about these patients? Um, not much yet. Um, there's a number of case series. Not particularly for the therapy I just outlined, but similar therapies from a variety of different centers. Many of these are just sort of cumulative, cumulative percentages of each of these many toxic toxicities that are seen in a variety of different groups, mostly large centers, single center series, kind of depends upon what you look for. If you don't do an echo, you don't see cardiac. Disease. They're sort of uncontrolled looks at a group of survivors of reports. Um, Laurie Cohen here at the Dana-Farber and Boston Children's looked at our patients, and I'll go a little bit more into detail, but we saw about what we saw. One of the accomplishments of that tandem transplant trial that I just showed you the results of is that it doesn't use total body radiation as one of the conditioning regimens during transplant, and we hope that will contribute to less toxicity, although we don't know that yet for sure. So what are the themes emerging in these survivors? Short stature and poor growth, and I think that will be seen even in the setting of not having total body radiation. The prevalence, depending upon if you look for it or not, is anywhere between 7 and 100%. It's evident, as I said, not only in those exposed to total body radiation, but those not exposed. It's not growth hormone responsive. This is not a growth hormone deficiency problem. We do worry that it's somewhat a nutritional compromise problem during therapy and a failure to have catch up growth. I know that the surgical approach to these patients can be often very extensive. Patients can have a poor absorption after. I can't lay that on, um, on this nutritional compromiser, but I think it is quite multifactorial. Many of our patients have hypothyroidism, um, which is likely exposure to therapeutic radiation. Some of the patients, many of the patients get diagnostic MIBG scans which is associated with uh the delivery of uh radioactive iodine and has been associated with the development of hypothyroidism. Many of them have abnormal glucose metabolism and they have delayed or abnormal pubertal development. So the endocrine burden is quite, uh, the endocrine disease burden is quite high. Um, Here's Dr. Cohen's, uh, work, uh, looking at late effects in our patient population here, noting the high incidence of endocrine and growth problems. Um, it was a retrospective chart review of 110 high-risk neuroblastoma survivors treated at Boston Children's and Dana-Farber between 1994 and 2007 and surviving at least one year after stem cell transplant. 80% of these, however, received total body radiation as part of a single or a tandem transplant regimen. And we observed a high prevalence of growth impairment, hearing loss, high BMI, increased hemoglobin A1C, and ovarian failure in the girls. This is a frequency plot of hemoglobin A1cs in these patients. Here's what the expected distribution would be in an age, in a like age population, and here's the distribution in our patients with a concerning group of patients developing high hemoglobin A1cs. What's the etiology of that? Not really clear. There is a report that abdominal radiotherapy is a determinant of metabolic syndrome in patients who've had Wilms tumor and neuroblastoma. That's intriguing in this regard. They looked at patients who had received a significant dose to the pancreas and were able to relate it to dose to the pancreas. And what they found is that in patients who did not receive abdominal radiation, The components of metabolic syndrome were, it were not generally seen or only one component was seen. Whereas the likelihood of having only one component seen if you developed, um, if you had exposure to abdominal radiation, the likelihood of having no or only one component seen was much lower and a much higher likelihood of having multiple components of the metabolic syndrome. So pancreatic damage may be an uh direct pancreatic damage may be an underlying cause of this um pre-diabetic or diabetic propensity that we've been seeing in our patients. What about second cancers? The um themes emerging for second neoplasms is that radiation-induced tumors are increasing over time. Um, we are seeing a fair number of early osteosarcoma and soft tissue sarcoma, even um with the rather low dose radiation that we deliver to um our patients. Osteosarcoma and soft tissue sarcoma, second tumors have a dose response curve. Other populations, and there's a concern here that we're seeing an emerging sec uh cancer predisposition syndrome of some sort of neuroblastoma followed by sarcoma, but we haven't really identified any underlying genetic underpinnings for that yet. I think that abdominal radiation will likely emerge as a culprit for abdominal cancers as we saw in the case that I presented, that we'll be seeing colon, hepatic, and renal cancers in these patients. They're just not old enough yet. Again, we'll be seeing emerging cancer predisposition syndromes and that not all solid tumors that we see in these patients are associated with radiation. So, again, suggesting that there's an underlying genetic uh uh disease. We do see myeloid leukemias in patients exposed to all kinds of chemotherapy, especially alkyating agents and um uh doxorubicin. However, um, we're only seeing that in the 1st 10 years after treatment and that kind of levels off over time, as has been observed in other populations besides neuroblastoma. And then benign growth seemed to be a significant problem in our patients, a problem for the parents because it makes them nervous, a problem for the surgeons because you're called to help us out with this, a problem for our radiologists because we don't know what to do about them. Those include focal nodular hyperplasia, which we see in over 10, maybe higher percent of neuroblastoma survivors, probably associated with chemotherapy and then osteochondromas which are benign, um but can sometimes be associated with uh symptomatic or growth impairment or growth deformities that need to be addressed surgically. So I start to ask, well, what happens to 5 year survivors, patients who were treated for neuroblastoma, who have survived 5 years, the parents say, are we out of the woods? Are we cured? We really didn't know very much about that in the modern era. So we went to the Children's oncology group Datasat and we looked at high risk patients who were treated between 2000 and 2009, kind of in the modern era, most of them without total body radiation. Most of them with transplant, most of them sort of with the schema that I outlined for you earlier. And of the patients that were in the data set, about 3000 patients, 708 were known to be alive at 5 years. The median age of diagnosis was as expected, about uh a little less than 3 years of age, and the median follow-up ranged from 5 years to 12.1 years with a follow-up of a median follow-up of 7.7 years. Of the 708, 459 had had no event in that 1st 5 years, so they've never relapsed. So I wanted to know kind of is, does it just go down? Did we just push the curve out or have we established a sort of really surviving population? So the overall survival at 10 years for those who survived 5 years was 81%, suggesting that there's another 20% fall off in terms of survival, and most of that is neuroblastoma associated. Most of those are neuroblastoma associated deaths in those patients who survived 5 years. So this is years after the post 5 year post diagnosis time point. But there does appear to be a leveling off that, you know, the events happen. The deaths occur and then there's a leveling off of that survival. What if you never relapsed? So, if you never relapsed in that 1st 5 years, the likelihood of surviving 10 years is a little bit higher. So there's about, I can tell a parent that we're getting close to cure, I think. Um, so what did these patients die of? The major cause of death, as I said, was recurrence. Uh, there was one death from GVH, presumably a patient who underwent an allogeneic bone marrow transplant, not a recommended therapy for neuroblastoma at this point. One died of second cancer. It's an early time point for second cancer. Pulmonary infection, one unknown. The cumulative incidence of second cancer at 10 years was 3%. Again, seeing this emergence of sarcoma and then a variety of other second cancers. What about new therapies for high-risk neuroblastoma? What will the late effects be? We're using, um, uh, liquid radiation or targeted radiotherapy, um, uh, using, uh, MIBG which you probably know as a diagnostic, as a therapeutic, more and more. It targets, uh, metastatic sites for neuroblastoma. We're using it in our patients who have a poor response to upfront therapy, isotretinoin, which is also known as retinoic acid, immunotherapy, and ALK inhibitors. MIBG light effects, we really don't know a whole lot. There's a wide range of incidents of hypothyroidism, anywhere from 7% to 85%. This is because of uh unblocked uptake of the I-131 to the thyroid. Um, we try to block that with potassium iodide, but it's not always successful. Uh, one series showed 25% incidence of thyroid nodules. Second cancers have been observed, obviously, as you give radiation. Either way you get it, it's associated with the second cancer. We had a long-term survivor here, um, developed a mesothelioma, for example. Hypogonadism is an interesting um uh potential late effect that's been um described. Of course, there's a caveat with all of this is that almost all patients treated with, with I-131 MIBG have received multiple other exposures. So pinning an exposure or pinning an outcome on this particular exposure is a little bit difficult. However, in um, Holland in the Netherlands, they use um MIBG upfront uh for localized tumors as a way of getting shrinkage preoperatively. Um And so this is a report where they actually gave MIBG therapy to patients with localized tumors before they gave them anything else, and they saw primary ovarian insufficiency in these two cases. So it is of concern. You can see the sort of MIBG uptake in a pelvic tumor and can imagine what the dose of radiation to the ovaries was in that particular case. How about isotretinoin? We don't have a lot of information and again, it's hard to tease apart, but about the use of retinoids in neuroblastoma patients. These are very, very young patients compared to the other uses, um, which are in older children and older children and adults, including for acne, rosacea, and other dermatologic disorders. The observed light effects include mostly bone and um ligamental abnormalities that you can see here, um, including premature epiphyseal closure which has also been observed in neuroblastoma patients. Um, there's been a report of advanced bone age after exposure to retinoids for neuroblastoma associated with premature physeal closure and angular deformity required, requiring surgery. So this is something we'll have to keep an eye on as more patients survive. Immunotherapy. We have an approved drug called nituximab. It's given um after completion of all other therapy for neuroblastoma. It's given with cytokines. It's FDA approved, the first FDA approved drug for a pediatric cancer indication in years. Um, it appears to increase long-term survival quite significantly. However, we have no data on the long-term outcomes of exposure. It's, uh, associated with very, um, significant acute toxicities, but, uh, those appear to resolve after the drug is withdrawn, so we'll keep an eye on that. We have no data on, uh, cellular immunotherapy or, uh, checkpoint inhibition therapy. They haven't been used in neuroblastoma patients yet, although I'm sure they will be. And how about ALK inhibition? About 10 to 15% of patients who have neuroblastoma have an ALK mutation in their tumor, and we will be using ALK inhibitors as are used in adult cancer trials now or adult standards of care in ALK mutant tumors. Um, this is a, a, uh, tyrosine kinase inhibitor. We have a little bit of data on prolonged tyrosine kinase inhibition in children who are receiving. Um, drug for, um, other indications, uh, and we know that it impacts upon growth and possibly organ function including cardiac, um, function or the risk of congestive heart failure. So we'll be watching that one as well, but we have no information on that yet. And then, um, we do have an open study called the Late Effects after high-risk neuroblastoma or the LEARN study. Um, this is a cross-sectional non-therapeutic study, um, which we hope to enroll 367 high-risk neuroblastoma patients over the next 3 to 5 years. We opened about 10 months ago. We have 65 patients enrolled already. This is a national study sponsored by Saint Baldrick's and the Children's Oncology Group. Patients come into the COAG Institution where they're being followed and they have a full-day clinical evaluation. Their charts are abstracted to look at their primary therapy, their relapse therapy, any treatments for second cancers. We're looking at their MIBG scans as well as MIBG therapy. We're measuring outcomes both as recorded by their healthcare provider, laboratory studies, radiographic studies, and the parents will be filling out or the young adults will be filling out health-related quality of life forms through standardized questionnaires. We're collecting DNA and plasma specimens so we can go back and analyze the outcomes and compare, uh, and, um, align them with, um, uh, genetic and other uh biologic markers as they emerge. And this is, as I said, funded by Saint Baldrick's Consortium Award, um, Dr. Tara Henderson at the University of Chicago who trained here and myself are the, uh, national, uh, principal investigators. So I hope to come back in 5 years and tell you more about that. Maybe I'll have some of the answers. Um, and then what are the genetic risks for late effects? We don't really have enough samples that are well annotated for late effect, um, associate for doing late effect associations. We hope this study that I described will give us some insight into that. Second cancer risk is, um, there are other populations, not just neuroblastoma populations, where we're seeing, um, polymorphisms in DNA repair genes that might be associated with risk. We have whole exome sequencing going on in the childhood cancer survivor study. And as I said, there's an emerging awareness of risk of cancer predisposition syndrome in neuroblastoma survivors as more patients survive. Platinum-related hearing loss is another one where we keep looking for a genetic variant that can tell us which patients are at risk and which ones are relatively protected. The data are all over the place. Every time a candidate gene is identified, a validation study doesn't, it fails to validate that gene. So I think this will just take more patients and larger cohorts. So, in summary, the good news is that high-risk neuroblastoma can be cured, but this creates new concerns in patient care and opportunities for research. Um, as we expect more and more patients to be cured, we have to be aware of this and have more interventions during and before therapy. We'll be doing more and more fertility preservation including ovarian tissue harvest in these very young children, very young girls who, who are about to undergo neuroblastoma therapy. I think we'll be using more and more targeted radiotherapy. We refer our patients for proton beam therapy to Mass General right now. Hopefully, we'll have a proton beam machine ourselves someday in the future. And then, um, odorrotection trials, we do have some odoprotective agents that can be given with cisplatin and there's more and more data to help us figure out how not to protect the tumor as we protect uh hearing. Cancer screening after therapy main um is an important intervention um that we need to be rigorous about. Reproductive interventions after therapy, again, preserving, um, ovarian tissue if possible, referring patients to assisted reproductive, um, interventions, um, early on, and then making sure we transition our patients to appropriate adult health care where the, um, adult provider is aware of the, uh, late effects that the patient Um, may be, uh, subject to. I'll close with one more case. This is a patient of mine. I bet you can picture out, picture, you can pick out who is the patient. These 4 young women are 18 years old. They graduated from Brookline High School and went to London for their, um, uh, post-high school pre-college trip. Uh, my patient is a long-term survivor of high-risk neuroblastoma, having participated in one of our early double transplant trials. Um, you can imagine in terms of, uh, my delight that, and her parents' delight that she's a long-term survivor. You can also imagine, um, her self-awareness of her differences and, um, our obligation to, um, find better therapies so that, uh, she, that the future generations of children who have high-risk neuroblastoma. Um, don't have what I expect or, or what I know from this patient are significant challenges based upon the late effects that she's, um, that she has suffered. And with that, I'll end and thank you. Particularly, I want to thank Doctor Shamberger for inviting me. Um, it's been, um, one of the real pleasures of my career to work with Doctor Shamberger over all these years, uh, to learn from him, to have his mentorship and support, um, as I have, uh, developed our survivorship program and our neuroblastoma program. So thank you. And thanks to all my colleagues here and, um, elsewhere who have, uh, contributed to this work. And thank you for your attention. So much, that's a wonderful. Summary of where we are and and what we know today. I often confess that when I was a younger surgeon, I figured when I operated on the patient with Wilm's tumor and took out the tumor and the kids would get some chemotherapy afterwards, and then they were gonna be good for the rest of their life, so to speak. Um, the data subsequently has shown that nothing is. More wrong than that, that assumption. It's, it's interesting that in, in neuroblastoma, we've actually been pretty good about dialing back the therapy as we've identified which patients don't need as intensive therapy as we were giving in, in Wilm's tumor, we haven't done that yet with the molecular markers, we've identified patient cohorts that we think need more intensive therapy. But then we haven't dialed back the treatment that the patients that are left behind that would now be in a seemingly more favorable group and may not need quite such intensive therapy. We haven't been able to dial that back yet and it's, it's like we encountered with the um. The neuroblastoma study, the NCI does not like decreasing therapies on patients if they know they're doing well, and the number of increased scans and everything that they mandated that we did with that group sort of showed their reluctance to try to address the overall morbidity and mortality. So it's sort of ironic, and I'm sure they're going to. Those things are gonna be those issues are gonna be faced when we try to dial back the therapy when you take out, as I say, the, the higher risk cohorts. I'd be interested in your thoughts on how we can best do that. And also the other group that you didn't talk about is what um sort of scanning or uh studies we should do on patients that are at risk for thyroid disease. Um, so, uh, in terms of the first question, um, you know, as you know, we did a decision, um, model about, uh, dialing back therapy for, uh, Wilms tumor. Uh, you know, as many of you are aware, there are, uh, patients with, and as I mentioned, there are patients with, uh, very small Wilms tumors that are treated with surgery only and no adjuvant chemotherapy. And it, you know, you can sort of model if you allow a little bit extra relapse there, you actually bring in a whole um uh uh set of toxic therapies that for the overall group as a whole, you sort of are. Avoiding treating a small, a large number of patients with relatively non-toxic therapy to avoid having to treat a very small number of patients with very toxic therapy. So it's, it's sort of like a trade-off. And so in answer to your question, sometimes I think that this is really a patient or parent decision, um, uh, study that, uh, that people should in some ways just be able to decide their own risk aversion. Certainly in medical oncology. Because they have the numbers to give people, they can give people choices of you can have this or you can have this, and depending upon how risk aversive you are, you can decide whether you want adjuvant therapy, you can decide whether you want a resection or observation for a variety of adult onset tumors. In pediatrics, we haven't really done that to parents. I think it's a, a hard set of decisions for parents to make, but we may be heading in that direction where some of these reduction of therapy decisions are, I mean sort of done that with observation for the neuroblastoma cause there are some parents who just say, no, thank you, just take it out. Um, the study itself was really to um To follow those who didn't have it out, but in fact, there are some parents who sort of make that choice of just take the tumor out. So, I don't, I don't know the answer. I mean, the other thing that I would back at you is around partial nephrectomy. Are we ever going to get there with, um, with Wilms tumor patients? Anyway, and then the thyroid thing, you know, the data for thyroid screening is pretty poor. I mean, it, it, you know, thyroid, first of all, uh, examination is terrible. We pick up on nothing. Um, so, you know, we say examine the thyroid for our survivors. Um, but thyroid ultrasound is probably oversensitive. You pick up too many nodules and do too many biopsies. And so, in general, the recommendations of the, um, childhood cancer of the Children's oncology group survivorship guidelines do not indicate patients getting thyroid ultrasounds as part of their uh survivorship care even in the setting of having had neck radiation. Um, mostly because of the false positive rates that we see of, of nodules that are not, uh, clinical significance. Other questions? Additional questions for Dr. Diller. Doctor Fauza. Excellent review. Thank you. Uh, among the girls that survive either tumor and the, the ones that do manage to become pregnant, is there any data on the pregnancy complications, particularly placental insufficiency and IUGR? Yes, um, so we don't have a lot of pregnancy data on the high-risk neuroblastoma patients because they're not old enough yet. In the Wilms tumor survivors, yes, in fact, there are small for gestational age, um. And uh IUGR has been observed in Wilms tumor survivors. It's been associated with the radiation itself. There's been um studies of uterine blood flow um using Imaging, I think it was ultrasound, showing that the uterine blood flow in the setting of early pregnancy is reduced in patients who've had uterine. Uh, or have had radiation. Um, and then there have been um early labor as well has been observed in premature labor and um premature birth has been observed. I think that was in the National Wilms Tumor Study Group. Um, so yes, yes, there have been. The birth weight distribution is a little bit shifted low but not terribly. So um. The median birth weights are a little bit low, but not in a range that would be of concern. Um, The TBI treated patients, um, in general can't get pregnant and the high, um, the high-dose alkalating agent patients usually go through premature menopause. So the concern there is as we preserve ovarian tissue, um, or eggs or embryos, are we, um, really thinking that those will go back into the treated uterus or will those be needed to be carried by surrogate and if we're doing that, is that the right thing to do because that's a sort of a lot of steps ahead. But Additional questions for Doctor Diller. Doctor Diller, uh, congratulations on such a huge body of impressive work and your success and really over the years improving the outcomes in these patients with Wilm's tumor and neuroblastoma, and I imagine as you've walked us through the cumulative incidents and causespecific mortality. And all the risk factors and stratifying the patients, that that was sort of where the success really happened, right? You had to identify patients at high risk and then how to manage them better. So then in moving forward with the advances in care and therapy, How do you really separate? The patients who are at high risk in terms of their actual cause-specific mortality from what you call competing risk for other kinds of episodes and other comorbidities, intestinal obstruction, CHF, etc. How do you actually figure that all out? Cause it's pretty amazing. Well, I think a lot of kudos go to the uh forethought of my colleagues, uh Dan Green, um in the National Wilms Tumor Study, uh Les Robison in the Childhood cancer survivor Study, Mike Hawkins in the British uh Survive cohort study and all of them recognized as oncologists and epidemiologists, the importance of large numbers cause each of these late effects are, you know, are relatively rare. I mean, childhood cancer is rare, um, and so the careful, uh, chart abstraction, understanding how patients were treated. And then following them forward is a, is really uh an important feat and a difficult feat. There are different strategies that have been used, so, you know, national or national registry data, like the National Health Registry data in Britain versus self-report data in the United States in the childhood cancer survivor study versus uh clinical trials data in the National Wilms Tumor Study. Those are all different strategies and I think it's encouraging they all come to somewhat of the same place. I sort of shifted back and forth almost intentionally between the different studies to show you that we're not finding different things. You know, there was some concern originally about doing patient self-report. Um, which is the childhood cancer survivor study, but actually, it aligns quite nicely with the other methodologies. I think the key issue is what um Doctor Shamberger focused on is, you know, how do you tell a parent that we have a curative therapy. But we think that we could use less and still have a curative therapy, but we don't really know. Um, that's a hard calculus, a hard conversation with a family to say we want to do less. We don't think we're going to compromise cure, but our value around specific late effects is such that we don't want to risk that in a child. Radiation is the biggest one. Trying to avoid radiation when we know it's an important component of cure, yet we know that the risk of developing, you know, if you radiate a girl's chest, the risk of developing breast cancer. Approaches that of a BRCA1 or BRCA2 carrier by age 50. You know, we know that from our Hodgkin's patients. So, is that the right thing to do or can we get rid of that? And that's really the challenge of the past 1020 years in Hodgkin's disease therapy and will be the challenge in high-risk neuroblastoma therapy as we go forward is which of these things do we not need? If we're gonna have survivors, we better have them be healthier than what we expect we're gonna see with this therapy. And then there's always those challenges between survival versus quality of life. That's right. The decisions become, you know, quite complicated. That's right. Well, thank you very much, Lisa. Thank you. OK.
Click "Show Transcript" to view the full transcription (59146 characters)
Comments