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Radiation therapy's role in the management of liver metastases
Inf. 1. Radiation
Oncology
Bid.
Phys..
RADIATION
1976, Vol.
1, pp. 977-979.
Pcrgamon
Pres%
Print4
in the U.S.A.
THERAPY’S ROLE IN THE MANAGEMENT OF LIVER METASTASES JOSEPH W.
KRAUT, M.D.
Department of Radiation Therapy, O’Connor Hospita1 and Santa Clara Valley Medical Center, San Jose, CA 94128, U.S.A. and Department of Radiation Therapy, Stanford University, Stanford, CA 94305, U.S.A.
and JOHN D. EARLE, M.D. Department Radiation
of Radiation Therapy, Stanford University,
therapy,
Liver metastases,
Stanford, CA 94305, U.S.A.
Complications.
clinically associated syndrome of potentially fata1 radiation hepatitis was described,’ consisting of hepatomegaly, ascites, and hepatic failure. With this description came the clear dose-related evidente that the normal tissue tolerante of the adult liver when irradiated in its entirety, was in the range of 2500-3000 rad, far short of the tumoricidal dose for most malignancies. For pediatrie patients, lower doses of 1200-1500rad may be the tolerante level.‘. Although adequate data are not yet available, the disturbing suggestion from the delayed fractionation in some of those patients in whom the syndrome developed is that prolonged fractionation may not be a protective factor. Finally, particularly in patients receiving the relatively higher doses of whole liver irradiation, the interval from the conclusion of such therapy to the development of the syndrome has been noted to be brief, as little as 2-4 weeks.‘.” Therefore, the normal tissue tolerante of the liver, marking it as a relatively radiosensitive organ, remains a challenge to the application of extemal radiation to the liver. Innovative efforts have attempted to circumvent this barrier in specialized circumstances of relatiiely radiosensitive malignant disease, such as the lymphomas,” and especially Hodgkin’s disease.6.’ In an effort to
One of the first clinical reports of a series of patients who underwent irradiation of the entire liver for metastatic carcinoma” indicated that there were no adverse hepatic effects of that radiation and inferred the relative radioresistence of that organ, in spite of earlier suggestions to the contrary.’ Coincident in time with this attitude was the medical application of megavoltage radiation equipment’ which provided the capability of delivering larger and more homogenous doses of radiation at a depth within patients. It was hoped, therefore, that tumor control in the face of metastatic liver disease might be possible by utilizing whole liver irradiation. Likewise, it was considered feasible to apply prophylactic whole abdominal irradiation, inclusive of the entire liver, either by the technique of multiple wide portals of irradiation or that of the moving-strip, to other patients who were at risk for the development of diffuse intra-abdominal carcinoma or lymphoma.’ As patient data began to be analyzed, however, it became apparent that complications ensued when the entire liver was irradiated to high doses. First, there was the identification of damage to the centra1 vein region of the hepatic lobule as the pathologie lesion induced by the radiation.‘0*‘2 Next, the 977
978
Radiation Oncology ??Biology 0 Physics
September-October
avoid the centra1 vein injury, combination external and isotopie irradiation was carried out to the entire liver in the former and to the “localized” lymphoma-prone portal triads by the latter, utilizing intravenously injected radioactive colloidal gold (‘%Au). Despite the avoidance of any reported cases of radiation hepatitis and some interesting and gratifying results in tumor control within the liver, this approach remains of limited applicability. This is primarily because although liver involvement may be controlled, disease extension may occur in other sites that are not affected by this combined radiation approach. The development of systemic multiple drug regimens’ capable of controlling these other sites, with or without adjuvant nodal irradiation, has supplanted the combined external and isotopie liver radiation approach even for the lymphomas; possible exceptions exist in patients in whom al1 other measures have failed to control symptom-producing hepatic lymphoma. Furthermore, external irradiation alone to tolerante dose levels may be al1 that can be carried out if total nodal irradiation and chemotherapy are to be utilized also; one of the major problems associated with the use of the radioactive agent may be bone marrow suppression prohibitive to, or compromising of, such combined therapy. Despite this background to the current status of irradiation of the liver, nevertheless there remains a role for radiation therapy in the management of hepatic metastases. Some tumors are relatively radiosensitive, in that relatively low-dose irradiation alone may provide a palliative effect. This may be seen in some of the lymphomas, seminomas, and even in some of the rapidly-dividing carcinomas. Likewise, some gratifying results have occurred in the adjuvant use of radiation and chemotherapeutic agents in both the lymphomas and carcinomas such as oat cel1 carcinoma of lung, various ovarian histologies and gastrointestinal malignancies.3.8 Therefore, in certain cases of liver metastases, it is reasonable to consider combination treatment of the whole liver to radiation dose levels of around 2500 rad in the adult, with an appropriate chemotherapeutic regimen, in an attempt to provide relief of distressing symptomatol-
1976, Vol. I, Number 9 and Number 10
ogy. As mentioned, lower radiation doses are indicated in pediatrie patients. Even in the more radioresistant tumors, patients are encountered in whom bulky symptom-producing hepatic malignancy may be confined to a portion of the liver. In this situation, there have been palliative successes in irradiating that portion of the liver to high doses of radiation in the order of 4000 rad or more. So long as a reasonable portion of the liver is not irradiated to levels beyond the tolerante dose for the whole organ, radiation hepatitis can be avoided. Concomitant and/or subsequent maintenance chemotherapy appropriate for the tumor type may also be considered. On occasion, those patients who have symptomatic malignancy involving organs adjacent to the liver (such as unresected gastrointestinal or renal maiignancies, or nodal metastases in the para-aortic, celiac or porta hepatis regions), may benefit from high dose radiation therapy alone or in combination with chemotherapeutic agents. Hepatic complications can be avoided in these situations, by being certain that the entire liver does not lie within such fields of high-dose irradiation. Should liver irradiation be carried out even with the dose-volume admonitions mentioned, the patient must be observed carefully for any signs of hepatic failure that may result from a radiation effect, for in fact, the liver in these patients may already be compromised by the metastatic disease being treated. Consideration also must be given to the timing and use of adjuvant chemotherapeutic agents requiring detoxification by the liver.14 If it is documented that radiation is the etiology for aberrant liver function, treatment similar to that for other causes of liver failure may need to be carried out, i.e. rest, appropriate diet, salt restriction and diuretic management. The major implication of this review of radiation therapy of the liver is that of close liaison in the decision-making processs on behalf of the patient with liver metastases between the generalist, surgeon, pathologist, medical oncologist, and the radiation therapist. What must be borne in mind by this team are the salient factors of the volume-dose relationships involved in the radiation of the
Radiation therapy’s role in the management of liver metastases 0 J. W.
liver, the type and volume of tumor to be treated, the availability and biologie charac-
KRAUT
and J.
D. EARLE
979
teristics of adjuvant agents, and the goals of therapy. which in the main are palliative.
REFERENCES J.T., Warthin, A.S.: The occurrence of hepatic lesions in patients treated by intensive deep roentgen irradiation. Am. J. Roentgenol. 12: 27-46, July 1924. Delclos, L., Braun, D.J., Herrara, J.R., Sampiere, V.A.. Van Roosenbeck, E.: Whole abdominal irradiation of 6oCo moving strip technique. Radiology 81: 632-641, 1963. Eagan, R.T., Maurer, L.H., Forcier, R.J., Tulloh, M.: Smal1 cel1 carcinoma of the lung: staging. paraneoplastic syndromes, treatment, and survival. Cancer 33: 527-532, Feb. 1974. Ingold, J.A., Reed, G.B., Kaplan, H.S., Bagshaw, M.A.: Radiation hepatitis. Am. .l. Roentgenol. 93: 200-208, Jan. 1965. Kaplan, H.S., Bagshawt M.A.: Stanford Medical Linear Accelerator 111. Application of clinical problems of radiation therapy. Stanford M. Bulk 15: 141-151. 1957. Kaplan, H.S., Bagshaw, M.A.: Radiation hepatitis: possible prevention by combined isotopie and external radiation therapy. Radio1 ogv 91: 1214-1220, Dec. 1%8. Kraut, J.W., Kaplan, H.S., Bagshaw, M.A.: Combined fractionated isotopie and extemal irradiation of the liver in Hoclgkin’s diseasea study of 21 patients. Cancer 30: 39-46, July 1972. Moertel, C.G., Childs, Jr., D.S., Reitemeier, R.J., Colby, Jr., M.Y., Holbrook, M.A.: Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal
1. Case,
2.
3.
4.
5.
6.
cancer. Lancet 2: 865-867, Oct. 1969. 9. Moore, M.R., Jones, S.E., Bull, J.M., William, L.A., Rosenberg, S.A.: MOPP chemotherapy for advanced Hodgkin’s disease. Prognostic factors in 81 patients. Cancer 32: 52-60, July 1973. 10. Ogata, K., Hizawa. K., Yoshida, M., Kitamuro, T., Agaki, G., Kagawa, K., Fukada, F.: Hepatic injury following irradiation-a morphologic study. Tokushima J. Exper. Med. 9: 240-251, Feb. 1963. ll. Phillips, R., Karnofsky, D.A., Hamilton, L.D., Nickson, J.J.: Roentgen therapy of hepatic metastases. Am. J. Roentgenol. 71: 826-834, May 1954. 12. Reed, Jr., G.B., Cox, Jr., A.J.: The human liver after radiation injury: a form of veno-occlusive disease. Am. J. Path. 48: 597-611, Apr. 1966. of 13. Rubin, P., Levitt, S.N.: The response disseminated recticulum cel1 sarcoma to intravenous injection of colloidal radioactive gold. J. Nucl. Med. 5: 581-594, Aug. 1964. 14. Tefft, M., Mitus, A., Das, L., Vawter, G.F.. Filler, R.M.: Irradiation of the liver in children: review of experience in the acute and chronic phases, and in the intact normal and partially resected. Am. J. Roentgenol. 10% 365-385, Feb. 1970). 15. Wharton, J.T., Delclos, L., Gallager, S., Smith. J.P.: Radiation hepatitis induced by abdominal irradiation with the 6oC moving strip technique Am. J. Roentgenol 117: 73-80, 1973.
Oncology
Bid.
Phys..
RADIATION
1976, Vol.
1, pp. 977-979.
Pcrgamon
Pres%
Print4
in the U.S.A.
THERAPY’S ROLE IN THE MANAGEMENT OF LIVER METASTASES JOSEPH W.
KRAUT, M.D.
Department of Radiation Therapy, O’Connor Hospita1 and Santa Clara Valley Medical Center, San Jose, CA 94128, U.S.A. and Department of Radiation Therapy, Stanford University, Stanford, CA 94305, U.S.A.
and JOHN D. EARLE, M.D. Department Radiation
of Radiation Therapy, Stanford University,
therapy,
Liver metastases,
Stanford, CA 94305, U.S.A.
Complications.
clinically associated syndrome of potentially fata1 radiation hepatitis was described,’ consisting of hepatomegaly, ascites, and hepatic failure. With this description came the clear dose-related evidente that the normal tissue tolerante of the adult liver when irradiated in its entirety, was in the range of 2500-3000 rad, far short of the tumoricidal dose for most malignancies. For pediatrie patients, lower doses of 1200-1500rad may be the tolerante level.‘. Although adequate data are not yet available, the disturbing suggestion from the delayed fractionation in some of those patients in whom the syndrome developed is that prolonged fractionation may not be a protective factor. Finally, particularly in patients receiving the relatively higher doses of whole liver irradiation, the interval from the conclusion of such therapy to the development of the syndrome has been noted to be brief, as little as 2-4 weeks.‘.” Therefore, the normal tissue tolerante of the liver, marking it as a relatively radiosensitive organ, remains a challenge to the application of extemal radiation to the liver. Innovative efforts have attempted to circumvent this barrier in specialized circumstances of relatiiely radiosensitive malignant disease, such as the lymphomas,” and especially Hodgkin’s disease.6.’ In an effort to
One of the first clinical reports of a series of patients who underwent irradiation of the entire liver for metastatic carcinoma” indicated that there were no adverse hepatic effects of that radiation and inferred the relative radioresistence of that organ, in spite of earlier suggestions to the contrary.’ Coincident in time with this attitude was the medical application of megavoltage radiation equipment’ which provided the capability of delivering larger and more homogenous doses of radiation at a depth within patients. It was hoped, therefore, that tumor control in the face of metastatic liver disease might be possible by utilizing whole liver irradiation. Likewise, it was considered feasible to apply prophylactic whole abdominal irradiation, inclusive of the entire liver, either by the technique of multiple wide portals of irradiation or that of the moving-strip, to other patients who were at risk for the development of diffuse intra-abdominal carcinoma or lymphoma.’ As patient data began to be analyzed, however, it became apparent that complications ensued when the entire liver was irradiated to high doses. First, there was the identification of damage to the centra1 vein region of the hepatic lobule as the pathologie lesion induced by the radiation.‘0*‘2 Next, the 977
978
Radiation Oncology ??Biology 0 Physics
September-October
avoid the centra1 vein injury, combination external and isotopie irradiation was carried out to the entire liver in the former and to the “localized” lymphoma-prone portal triads by the latter, utilizing intravenously injected radioactive colloidal gold (‘%Au). Despite the avoidance of any reported cases of radiation hepatitis and some interesting and gratifying results in tumor control within the liver, this approach remains of limited applicability. This is primarily because although liver involvement may be controlled, disease extension may occur in other sites that are not affected by this combined radiation approach. The development of systemic multiple drug regimens’ capable of controlling these other sites, with or without adjuvant nodal irradiation, has supplanted the combined external and isotopie liver radiation approach even for the lymphomas; possible exceptions exist in patients in whom al1 other measures have failed to control symptom-producing hepatic lymphoma. Furthermore, external irradiation alone to tolerante dose levels may be al1 that can be carried out if total nodal irradiation and chemotherapy are to be utilized also; one of the major problems associated with the use of the radioactive agent may be bone marrow suppression prohibitive to, or compromising of, such combined therapy. Despite this background to the current status of irradiation of the liver, nevertheless there remains a role for radiation therapy in the management of hepatic metastases. Some tumors are relatively radiosensitive, in that relatively low-dose irradiation alone may provide a palliative effect. This may be seen in some of the lymphomas, seminomas, and even in some of the rapidly-dividing carcinomas. Likewise, some gratifying results have occurred in the adjuvant use of radiation and chemotherapeutic agents in both the lymphomas and carcinomas such as oat cel1 carcinoma of lung, various ovarian histologies and gastrointestinal malignancies.3.8 Therefore, in certain cases of liver metastases, it is reasonable to consider combination treatment of the whole liver to radiation dose levels of around 2500 rad in the adult, with an appropriate chemotherapeutic regimen, in an attempt to provide relief of distressing symptomatol-
1976, Vol. I, Number 9 and Number 10
ogy. As mentioned, lower radiation doses are indicated in pediatrie patients. Even in the more radioresistant tumors, patients are encountered in whom bulky symptom-producing hepatic malignancy may be confined to a portion of the liver. In this situation, there have been palliative successes in irradiating that portion of the liver to high doses of radiation in the order of 4000 rad or more. So long as a reasonable portion of the liver is not irradiated to levels beyond the tolerante dose for the whole organ, radiation hepatitis can be avoided. Concomitant and/or subsequent maintenance chemotherapy appropriate for the tumor type may also be considered. On occasion, those patients who have symptomatic malignancy involving organs adjacent to the liver (such as unresected gastrointestinal or renal maiignancies, or nodal metastases in the para-aortic, celiac or porta hepatis regions), may benefit from high dose radiation therapy alone or in combination with chemotherapeutic agents. Hepatic complications can be avoided in these situations, by being certain that the entire liver does not lie within such fields of high-dose irradiation. Should liver irradiation be carried out even with the dose-volume admonitions mentioned, the patient must be observed carefully for any signs of hepatic failure that may result from a radiation effect, for in fact, the liver in these patients may already be compromised by the metastatic disease being treated. Consideration also must be given to the timing and use of adjuvant chemotherapeutic agents requiring detoxification by the liver.14 If it is documented that radiation is the etiology for aberrant liver function, treatment similar to that for other causes of liver failure may need to be carried out, i.e. rest, appropriate diet, salt restriction and diuretic management. The major implication of this review of radiation therapy of the liver is that of close liaison in the decision-making processs on behalf of the patient with liver metastases between the generalist, surgeon, pathologist, medical oncologist, and the radiation therapist. What must be borne in mind by this team are the salient factors of the volume-dose relationships involved in the radiation of the
Radiation therapy’s role in the management of liver metastases 0 J. W.
liver, the type and volume of tumor to be treated, the availability and biologie charac-
KRAUT
and J.
D. EARLE
979
teristics of adjuvant agents, and the goals of therapy. which in the main are palliative.
REFERENCES J.T., Warthin, A.S.: The occurrence of hepatic lesions in patients treated by intensive deep roentgen irradiation. Am. J. Roentgenol. 12: 27-46, July 1924. Delclos, L., Braun, D.J., Herrara, J.R., Sampiere, V.A.. Van Roosenbeck, E.: Whole abdominal irradiation of 6oCo moving strip technique. Radiology 81: 632-641, 1963. Eagan, R.T., Maurer, L.H., Forcier, R.J., Tulloh, M.: Smal1 cel1 carcinoma of the lung: staging. paraneoplastic syndromes, treatment, and survival. Cancer 33: 527-532, Feb. 1974. Ingold, J.A., Reed, G.B., Kaplan, H.S., Bagshaw, M.A.: Radiation hepatitis. Am. .l. Roentgenol. 93: 200-208, Jan. 1965. Kaplan, H.S., Bagshawt M.A.: Stanford Medical Linear Accelerator 111. Application of clinical problems of radiation therapy. Stanford M. Bulk 15: 141-151. 1957. Kaplan, H.S., Bagshaw, M.A.: Radiation hepatitis: possible prevention by combined isotopie and external radiation therapy. Radio1 ogv 91: 1214-1220, Dec. 1%8. Kraut, J.W., Kaplan, H.S., Bagshaw, M.A.: Combined fractionated isotopie and extemal irradiation of the liver in Hoclgkin’s diseasea study of 21 patients. Cancer 30: 39-46, July 1972. Moertel, C.G., Childs, Jr., D.S., Reitemeier, R.J., Colby, Jr., M.Y., Holbrook, M.A.: Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal
1. Case,
2.
3.
4.
5.
6.
cancer. Lancet 2: 865-867, Oct. 1969. 9. Moore, M.R., Jones, S.E., Bull, J.M., William, L.A., Rosenberg, S.A.: MOPP chemotherapy for advanced Hodgkin’s disease. Prognostic factors in 81 patients. Cancer 32: 52-60, July 1973. 10. Ogata, K., Hizawa. K., Yoshida, M., Kitamuro, T., Agaki, G., Kagawa, K., Fukada, F.: Hepatic injury following irradiation-a morphologic study. Tokushima J. Exper. Med. 9: 240-251, Feb. 1963. ll. Phillips, R., Karnofsky, D.A., Hamilton, L.D., Nickson, J.J.: Roentgen therapy of hepatic metastases. Am. J. Roentgenol. 71: 826-834, May 1954. 12. Reed, Jr., G.B., Cox, Jr., A.J.: The human liver after radiation injury: a form of veno-occlusive disease. Am. J. Path. 48: 597-611, Apr. 1966. of 13. Rubin, P., Levitt, S.N.: The response disseminated recticulum cel1 sarcoma to intravenous injection of colloidal radioactive gold. J. Nucl. Med. 5: 581-594, Aug. 1964. 14. Tefft, M., Mitus, A., Das, L., Vawter, G.F.. Filler, R.M.: Irradiation of the liver in children: review of experience in the acute and chronic phases, and in the intact normal and partially resected. Am. J. Roentgenol. 10% 365-385, Feb. 1970). 15. Wharton, J.T., Delclos, L., Gallager, S., Smith. J.P.: Radiation hepatitis induced by abdominal irradiation with the 6oC moving strip technique Am. J. Roentgenol 117: 73-80, 1973.