Transcript
This is our team for our liver transplant program and liver tumor treatment at New York Medical College. And my colleague, Dr. Facciuto, is in the audience. And we have radiation oncology team of Dr. Saleh, Dr. Cohen, and Lynn Shih, Ronald Rocchio, Alan Alfieri, radiation biologist.
What I would like to do is start with introduction to hepatocellular carcinomas, and then pre-transplant treatment modalities that are available currently, and what are the limitations? Conventional radiation methods and the risks, and then making a case for high-dose hypofractionation radiation, which is New York Medical College study, which I will go over the rationale, criteria of selection, techniques, preliminary results, and conclusions.
Pre-transplant adjuvant treatments. The limitations are liver resection, less than 5% meet the criteria, high recurrence rates. Trans-arterial chemoembolization is invasive. No effective chemotherapy agents are available. Percutaneous ethanol injection is usually not feasible if ascites, coagulopathies, or thrombocytopenia. And radiofrequency ablation is invasive. Response rates are 50% to 60%, but not sustained. And transplant waiting times are anywhere between 6 to 14 months, during which time progression and dropout rates can be quite high.
And the conventional radiation limitations are, there have been not many studies to see a radiation therapy toxicity in cirrhotic livers. And the radiation-induced liver disease with high doses, the definition being anicteric elevation of alkaline phosphatase levels, twofold. Elevated aminotransferases of at least fivefold upper limit of pre-treatment. And this RILD is not seen if less than 25% of the non-tumor liver is included. Five percent incidence of the liver injury, if 33% of liver is taken to 90 gray, 67% volume to 47. If the entire liver, 37 gray given conventional fractionations.
So, the purpose of our study, which we started in March of 2006, that's two years ago, objectives being to evaluate the toxicity of high-dose hypofractionated radiation delivered to limited volume of liver. To evaluate the effectiveness of HD...high-dose hypofractionated radiation in small hepatocellular carcinomas, which are candidates for transplant, prior to transplant.
Secondary goal being to evaluate in future if the dropout rates for transplants can be reduced by reducing the progression of the disease. That means there are certain criteria for transplant. And if there is significant delay of a transplant, the tumor's size increases, and then they go outside the range of transplant criteria.
So, the rationale of the study being high progression rates while waiting for transplant. Available pre-transplant adjuvant treatments are invasive, not effective or associated with complications. And hypofractionated-IMRT happens to be non-invasive compared to other pre-transplant therapies. And limited volume of radiation may have less toxicity and allow higher doses, and, hopefully, better controls. High dose delivered in short time allows convenience and comfort to the patient.
The criteria for our study are: more than 18 years of age with clinical or pathological diagnosis of cirrhosis, clinical-radiological diagnosis of HCC T1 and T2 lesions, which are listed as a candidate for transplant with WBC, or white count of 4,000, platelets of more than 50,000. All patients undergo CT of the chest and abdomen, and an MRI scan, Karnofsky performance of more than 70, with no prior treatment.
And this is a staging, T1 or T2. Most of our lesions are 3 centimeters or less. The treatment planning, I don't want to go too many details in here, because I would like to concentrate on some of the results. Triple-phase CT scan with MRI fusion. Target volumes are outlined GTV, CTV, and PTV. And, what we do is cephalocaudally, 1 centimeter, and laterally, we put 0.5 centimeter margin. This is to allow...because, in one of the studies by Dr. Harfat [SP], they thought that if they did not give adequate margin cephalocaudally, they might miss the tumor.
And normal tissues are outlined: liver, gall bladder...sorry for the spelling, colon, stomach, duodenum, kidneys, and spinal cord. Dose given is 2,800 centigray, 700 centigray per fraction (bid). And all the patients received the dose without any deviations. But 90% of the prescribed dose not to exceed 25% of the non-tumor volume. No more than 50% of the liver receives 50% of the prescribed dose of 350 centigray per fraction.
Study period, March 2006 to 2008. We had 19 patients, 15 to 4, male to female, 61 years of median age. Twelve lesions were single, seven multiple lesions. We accepted no more than three lesions [inaudible 00:06:15] and less than 3 centimeters. Size, less than 3 centimeters all. Seventeen with hep C cirrhosis, two alcohol-related. And out of that, 7 out of 19 were transplanted for until now. And IMRT-to-transplant period being 15 to 180 days, with a follow-up of 12 patients reaching the 3 months.
And we followed the criteria of MELD score. Majority of them, 90% of them had MELD score median of 12 or lower. And hematologic response. No significant change in the white count, hemoglobin, hematocrit, or platelets. And biochemical, this liver function test, AST, ALT, and T. bilirubin, total bilirubin. No significant increase in all of these values. In fact, some of the patients, there is decrease in bilirubin, AST, ALT in the same patients.
And radiological response, three month post-IMRT. We detected smaller size of the lesion in 7 out of 12 patients. And, in fact, one patient initially did not have any response at all at three months, but at five months, the patient had complete response. And histopathological response in explanted liver. Seven patients underwent transplant, and response rate of 71%. Two complete responses. This is less than CR, which includes partial response and stable disease, 43%. Progression, two out of seven.
And complications. Clinical, edematous or ascitic decompression, portal hypertension-related bleeding, radiation-induced gastritis, thrombocytopenia, leukopenia, or hemoglobin, hematocrit drop. Or biochemical, AST, ALT, or renal failure, we did not notice in any of the patients. Radiological, one patient, and necrosis outside the target volume. I'll explain to you why. Histopathological, necrosis outside the target volume, one.
And briefly, initially we were using the fiducial markers, and the target is outlined. This is single lesion. And then, also, when we do multiple lesions, what we tend to do is, in order to minimize the dose that overlaps, we also created an additional outline of the volume of liver, and called it "organ at risk," to see whether we can reduce the dose in between the lesions.
And this is the PTV, GTV, and liver, if you look at 50% of the liver, receiving less than 25% of the dose. And some of the radiological responses. This is the patient I was talking to you about. This patient had, at three months, still persistence of enhancement. And so our medical oncologist wanted to give chemoembolization, but somehow the patient did not receive the chemoembolization at five months when the scan was repeated.
CT scan showed a significant response with this contrast-enhanced ring, that can also...I'll show you the slide exactly how this looks like in this patient, what the central necrosis looks like, and what the contrast-enhanced area looks like. And some other histopathological responses. This is a patient who had biopsy-proven 3.2 cm lesion. And I do not have the histopathology slides for certain legal reasons. Fibrotic-hyalinized nodule where the tumor was with complete destruction of the tumor, and no disease histologically.
And this patient had persistent tumor here, but adjacent to that, there is this development of necrotic area, that, again, I'll discuss briefly. But most of these tumors in explanted livers has a significant demarcation of your 90% dose, or high-dose region, that is approximately corresponding to the PTV. And, again, histopathologically, when you look at it, there's a sharp demarcated area of necrosis, and the ring-enhanced area that is fibrotic area. So this is that patient with a significant, nearly 90% or higher necrosis, but with viable cells mixed with area of necrosis.
This is another patient with 95% necrotic lesion. As you can see, 95% necrosis, and cirrhotic liver. This patient, a complete response and no viable cells. And this is another patient with 2.5 centimeter lesion. And this patient had a partial response with mixed radiation-induced changes in the tumor, mixed with viable cells, and given time possibilities there that they might necrose.
In conclusion, high-dose hypofractionated IMRT given at 2,800 centigray, 700 centigray (bid) appears to be well-tolerated in the preliminary study. Our preliminary results in this small series show encouraging responses, radiologically and histopathologically. And, however, we don't know yet whether this dose is adequate or not for controls.
So this is a dose escalation study, and we are planning to give...the next study will be 1,200 (bid) instead of 700 (bid) for 2,400 centigray. CT scan at three months post-therapy to evaluate may not be the right tool, and we may have to wait until five to six months, or we have to look for alternative tools like MRI spectroscopy. Future, dose escalation and single dose. Thank you.
What I would like to do is start with introduction to hepatocellular carcinomas, and then pre-transplant treatment modalities that are available currently, and what are the limitations? Conventional radiation methods and the risks, and then making a case for high-dose hypofractionation radiation, which is New York Medical College study, which I will go over the rationale, criteria of selection, techniques, preliminary results, and conclusions.
Pre-transplant adjuvant treatments. The limitations are liver resection, less than 5% meet the criteria, high recurrence rates. Trans-arterial chemoembolization is invasive. No effective chemotherapy agents are available. Percutaneous ethanol injection is usually not feasible if ascites, coagulopathies, or thrombocytopenia. And radiofrequency ablation is invasive. Response rates are 50% to 60%, but not sustained. And transplant waiting times are anywhere between 6 to 14 months, during which time progression and dropout rates can be quite high.
And the conventional radiation limitations are, there have been not many studies to see a radiation therapy toxicity in cirrhotic livers. And the radiation-induced liver disease with high doses, the definition being anicteric elevation of alkaline phosphatase levels, twofold. Elevated aminotransferases of at least fivefold upper limit of pre-treatment. And this RILD is not seen if less than 25% of the non-tumor liver is included. Five percent incidence of the liver injury, if 33% of liver is taken to 90 gray, 67% volume to 47. If the entire liver, 37 gray given conventional fractionations.
So, the purpose of our study, which we started in March of 2006, that's two years ago, objectives being to evaluate the toxicity of high-dose hypofractionated radiation delivered to limited volume of liver. To evaluate the effectiveness of HD...high-dose hypofractionated radiation in small hepatocellular carcinomas, which are candidates for transplant, prior to transplant.
Secondary goal being to evaluate in future if the dropout rates for transplants can be reduced by reducing the progression of the disease. That means there are certain criteria for transplant. And if there is significant delay of a transplant, the tumor's size increases, and then they go outside the range of transplant criteria.
So, the rationale of the study being high progression rates while waiting for transplant. Available pre-transplant adjuvant treatments are invasive, not effective or associated with complications. And hypofractionated-IMRT happens to be non-invasive compared to other pre-transplant therapies. And limited volume of radiation may have less toxicity and allow higher doses, and, hopefully, better controls. High dose delivered in short time allows convenience and comfort to the patient.
The criteria for our study are: more than 18 years of age with clinical or pathological diagnosis of cirrhosis, clinical-radiological diagnosis of HCC T1 and T2 lesions, which are listed as a candidate for transplant with WBC, or white count of 4,000, platelets of more than 50,000. All patients undergo CT of the chest and abdomen, and an MRI scan, Karnofsky performance of more than 70, with no prior treatment.
And this is a staging, T1 or T2. Most of our lesions are 3 centimeters or less. The treatment planning, I don't want to go too many details in here, because I would like to concentrate on some of the results. Triple-phase CT scan with MRI fusion. Target volumes are outlined GTV, CTV, and PTV. And, what we do is cephalocaudally, 1 centimeter, and laterally, we put 0.5 centimeter margin. This is to allow...because, in one of the studies by Dr. Harfat [SP], they thought that if they did not give adequate margin cephalocaudally, they might miss the tumor.
And normal tissues are outlined: liver, gall bladder...sorry for the spelling, colon, stomach, duodenum, kidneys, and spinal cord. Dose given is 2,800 centigray, 700 centigray per fraction (bid). And all the patients received the dose without any deviations. But 90% of the prescribed dose not to exceed 25% of the non-tumor volume. No more than 50% of the liver receives 50% of the prescribed dose of 350 centigray per fraction.
Study period, March 2006 to 2008. We had 19 patients, 15 to 4, male to female, 61 years of median age. Twelve lesions were single, seven multiple lesions. We accepted no more than three lesions [inaudible 00:06:15] and less than 3 centimeters. Size, less than 3 centimeters all. Seventeen with hep C cirrhosis, two alcohol-related. And out of that, 7 out of 19 were transplanted for until now. And IMRT-to-transplant period being 15 to 180 days, with a follow-up of 12 patients reaching the 3 months.
And we followed the criteria of MELD score. Majority of them, 90% of them had MELD score median of 12 or lower. And hematologic response. No significant change in the white count, hemoglobin, hematocrit, or platelets. And biochemical, this liver function test, AST, ALT, and T. bilirubin, total bilirubin. No significant increase in all of these values. In fact, some of the patients, there is decrease in bilirubin, AST, ALT in the same patients.
And radiological response, three month post-IMRT. We detected smaller size of the lesion in 7 out of 12 patients. And, in fact, one patient initially did not have any response at all at three months, but at five months, the patient had complete response. And histopathological response in explanted liver. Seven patients underwent transplant, and response rate of 71%. Two complete responses. This is less than CR, which includes partial response and stable disease, 43%. Progression, two out of seven.
And complications. Clinical, edematous or ascitic decompression, portal hypertension-related bleeding, radiation-induced gastritis, thrombocytopenia, leukopenia, or hemoglobin, hematocrit drop. Or biochemical, AST, ALT, or renal failure, we did not notice in any of the patients. Radiological, one patient, and necrosis outside the target volume. I'll explain to you why. Histopathological, necrosis outside the target volume, one.
And briefly, initially we were using the fiducial markers, and the target is outlined. This is single lesion. And then, also, when we do multiple lesions, what we tend to do is, in order to minimize the dose that overlaps, we also created an additional outline of the volume of liver, and called it "organ at risk," to see whether we can reduce the dose in between the lesions.
And this is the PTV, GTV, and liver, if you look at 50% of the liver, receiving less than 25% of the dose. And some of the radiological responses. This is the patient I was talking to you about. This patient had, at three months, still persistence of enhancement. And so our medical oncologist wanted to give chemoembolization, but somehow the patient did not receive the chemoembolization at five months when the scan was repeated.
CT scan showed a significant response with this contrast-enhanced ring, that can also...I'll show you the slide exactly how this looks like in this patient, what the central necrosis looks like, and what the contrast-enhanced area looks like. And some other histopathological responses. This is a patient who had biopsy-proven 3.2 cm lesion. And I do not have the histopathology slides for certain legal reasons. Fibrotic-hyalinized nodule where the tumor was with complete destruction of the tumor, and no disease histologically.
And this patient had persistent tumor here, but adjacent to that, there is this development of necrotic area, that, again, I'll discuss briefly. But most of these tumors in explanted livers has a significant demarcation of your 90% dose, or high-dose region, that is approximately corresponding to the PTV. And, again, histopathologically, when you look at it, there's a sharp demarcated area of necrosis, and the ring-enhanced area that is fibrotic area. So this is that patient with a significant, nearly 90% or higher necrosis, but with viable cells mixed with area of necrosis.
This is another patient with 95% necrotic lesion. As you can see, 95% necrosis, and cirrhotic liver. This patient, a complete response and no viable cells. And this is another patient with 2.5 centimeter lesion. And this patient had a partial response with mixed radiation-induced changes in the tumor, mixed with viable cells, and given time possibilities there that they might necrose.
In conclusion, high-dose hypofractionated IMRT given at 2,800 centigray, 700 centigray (bid) appears to be well-tolerated in the preliminary study. Our preliminary results in this small series show encouraging responses, radiologically and histopathologically. And, however, we don't know yet whether this dose is adequate or not for controls.
So this is a dose escalation study, and we are planning to give...the next study will be 1,200 (bid) instead of 700 (bid) for 2,400 centigray. CT scan at three months post-therapy to evaluate may not be the right tool, and we may have to wait until five to six months, or we have to look for alternative tools like MRI spectroscopy. Future, dose escalation and single dose. Thank you.