Radiation Oncology/Liver/Treatment/Whole Liver RT

External Beam
Given the low whole-liver tolerance (~30 Gy), whole liver RT has been used historically (prior to development of conformal therapy) for palliation of painful primary and metastatic liver disease. Up to 90% of patients may report improvement in pain control. Overall survival is short (~6 months), and not improved with RT. Several RTOG attempts at improving whole-liver RT efficacy have not shown much benefit (hyperfractionation, misonidazole radiosensitization, radiolabelled antiferritin antibody).


 * Meta-RTOG PMID 9612600 -- Survival results among patients with alpha-fetoprotein-positive, unresectable hepatocellular carcinoma: analysis of three sequential treatments of the RTOG and Johns Hopkins Oncology Center. (1998 Abrams RA, Cancer J Sci Am. 1998 May-Jun;4(3):178-84.)
 * Meta-analysis of 1) RTOG 83-19, 2) Hopkins pilot study, 3) RTOG 88-23 during 1983-1991
 * Induction (EBRT 21.0 Gy at 3.0 Gy/fx) + radiosensitizing chemo, followed by 1) doxorubicin + 5-FU +/- 131-I-antiferritin, 2) intrahepatic artery cisplatin, or 3) intrahepatic artery cisplatin +/- 131-I-antiferritin, respectively.
 * 131-I-antiferritin: no improvement on survival, dramatic increase in hematologic toxicity
 * Intrahepatic artery cisplatin: significantly better than doxorubicin/5-FU
 * Conclusion : "Patients with unresectable alpha-fetoprotein-positive hepatocellular carcinoma experienced improved survival and decreased toxicity when managed with post-induction cycles of intra-arterial cisplatin as compared with intravenous doxorubicin and 5-FU. Intravenous 131I-polyclonal antiferritin did not improve survival when added to either post-induction regimen but dramatically increased hematologic toxicities."


 * RTOG 84-05 PMID 8365932 -- Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: results of the RTOG dose escalating protocol. (1993 Russell AH, Int J Radiat Oncol Biol Phys. 1993 Sep 1;27(1):117-23.)
 * Phase I/II. Dose escalation 27 -> 33 Gy in 1.5 Gy BID
 * No patients at 30 Gy showed RILD, 10% patients at 33 Gy showed RILD (study closed)
 * No impact on OS
 * Conclusion : "The study design could not credibly establish a safe dose for hepatic irradiation, however, it did succeed in determining that 33 Gy in fractions of 1.5 Gy is unsafe, carrying a substantial risk of delayed radiation injury. The absence of apparent late liver injury at the 27 Gy and 30 Gy dose levels suggests that a prior clinical trial of adjuvant hepatic irradiation in patients with resected colon cancer may have employed an insufficient radiation dose (21 Gy) to fully test the question."


 * RTOG PMID 2180867 -- Accelerated fractionation radiation therapy for liver metastases: selection of an optimal patient population for the evaluation of late hepatic injury in RTOG studies. (1990 Leibel SA, Int J Radiat Oncol Biol Phys. 1990 Mar;18(3):523-8.
 * Retrospective review of RTOG 76-05 and 80-03 (both liver mets studies). 190 patients selected
 * Favorable characteristics: KPS >=80, CRC primary, no extrahepatic mets


 * RTOG PMID 2557307 -- 194 hepatocellular cancers treated by radiation and chemotherapy combinations: toxicity and response: a Radiation Therapy Oncology Group Study. (1989 Stillwagon GB, Int J Radiat Oncol Biol Phys. 1989 Dec;17(6):1223-9.)
 * Prospective. HCC. Arms were 1) 135 patients (70% mets/recurrent) EBRT 21.0 Gy (3.0 Gy/fx) + low dose Adriamycin vs. 2) 59 patients (80% mets/recurrent) hyperfractionated EBRT 24.0 Gy (1.2 Gy/fx BID) + low dose Adriamycin
 * Response: single fraction 22% vs. BID fraction 18% (p=NS)
 * Toxicity: Esophagitis and thrombocytopenia significantly higher in BID arm
 * Conclusion : "Hyperfractionated radiation did not demonstrate a significant benefit over standard daily radiation, but acute toxicity appeared to be higher."


 * RTOG 8003 PMID 3597149 -- A comparison of misonidazole sensitized radiation therapy to radiation therapy alone for the palliation of hepatic metastases: results of a Radiation Therapy Oncology Group randomized prospective trial. (1987 Leibel SA, Int J Radiat Oncol Biol Phys. 1987 Jul;13(7):1057-64.)
 * Phase III. EBRT (whole liver to 21 Gy in 3 Gy/fx) +/- misonidazole. 187 patients
 * Conclusion : "The addition of misonidazole did not significantly improve the therapeutic response to radiation therapy in any of the parameters studied."


 * PMID 2950753 -- Treatment of liver metastases with a combination of chemotherapy and hyperfractionated external radiation therapy. (1987 Raju PI, Am J Clin Oncol. 1987 Feb;10(1):41-3.)
 * Prospective. 12 patients with CRC liver mets treated with intraarterial 5-FUdR + RT (21 Gy in 1.5 Gy/fx BID)
 * Conclusion : "Hyperfractionated external radiotherapy with concomitant 5-FUdR hepatic artery of 5-FU i.v. infusion therapy for liver metastases was well-tolerated, and both subjective and objective response and quality of survival were noted."


 * RTOG 76-05 PMID 6168623 -- The palliation of hepatic metastases: results of the Radiation Therapy Oncology Group pilot study. (1981 Borgelt BB, Int J Radiat Oncol Biol Phys. 1981 May;7(5):587-91.)
 * Prospective, non-randomized. 109 patients with liver mets.
 * RT: Single met: 30.4/19 +/- 20 Gy boost or 30/15 +/- 20 Gy boost; Multiple mets: 30/15 or 25.6/16 or 20/10 or 21/7
 * Toxicity: No RILD.
 * Conclusion: 21/7 best palliative regimen


 * PMID 77184 -- Palliation of hepatic metastasis. (1978 Sherman DM, Cancer. 1978 May;41(5):2013-7.)
 * Retrospective. 55 patients, 24 Gy in 3 Gy/fx; 31 patients concomitant chemotherapy
 * 90% had significant palliation of symptoms
 * Median survival 4.5 months; median survival 9 months of excellent responders (38%) comparable to arterial CT
 * Conclusion : "The median survival of patients having an excellent response to radiation is comparable to that of patients having regional arterial chemotherapy while incuring fewer complications."


 * PMID 66224 -- Irradiation of hepatic metastases. (1977 Prasad, Int J Radiat Oncol Biol Phys. 1977 Jan-Feb;2(1-2):129-32.)
 * No abstract.


 * PMID 47404 -- Palliative irradiation for liver metastases. (1975 Turek-Maischeider M, JAMA. 1975 May 12;232(6):625-8.)
 * Retrospective. 11 patients treated to 25 Gy at 1.5 Gy/fx
 * 8 good response, 2 moderate response, 1 failure
 * Conclusion : "The impression is that radiation therapy is valuable for the treatment of symptomatic liver metastases in the young patient who does not have a terminal condition."

Radiolabeled antibodies
The studies with 131-I Antiferritin and 131-I CEA were done in the 1980's in an effort to improve efficacy of whole liver RT.

131-I-Antiferritin
 * PMID 9612600 -- Survival results among patients with alpha-fetoprotein-positive, unresectable hepatocellular carcinoma: analysis of three sequential treatments of the RTOG and Johns Hopkins Oncology Center. (1998 Abrams RA, Cancer J Sci Am. 1998 May-Jun;4(3):178-84.)
 * Meta-analysis of 1) RTOG 83-19, 2) Hopkins pilot study, 3) RTOG 88-23 during 1983-1991
 * Induction (EBRT 21.0 Gy at 3.0 Gy/fx) + radiosensitizing chemo, followed by 1) doxorubicin + 5-FU +/- 131-I-antiferritin, 2) intrahepatic artery cisplatin, or 3) intrahepatic artery cisplatin +/- 131-I-antiferritin, respectively.
 * 131-I-antiferritin: no improvement on survival, dramatic increase in hematologic toxicity
 * Intrahepatic artery cisplatin: significantly better than doxorubicin/5-FU
 * Conclusion : "Patients with unresectable alpha-fetoprotein-positive hepatocellular carcinoma experienced improved survival and decreased toxicity when managed with post-induction cycles of intra-arterial cisplatin as compared with intravenous doxorubicin and 5-FU. Intravenous 131I-polyclonal antiferritin did not improve survival when added to either post-induction regimen but dramatically increased hematologic toxicities."


 * PMID 1850722 -- A randomized prospective trial comparing full dose chemotherapy to 131I antiferritin: an RTOG study. (1991 Order S, Int J Radiat Oncol Biol Phys. 1991 May;20(5):953-63.)
 * Phase I/II (83-01). Non-resectable HCC. EBRT + CRT induction followed by 131-I Antiferritin
 * Response: 48% CR/PR, AFP+ median survival 5 months, AFP- median survival 10.5 months
 * Phase III (83-19). Non-resectable HCC. EBRT + CRT induction followed by randomization to 131-I Antiferritin or doxorubicin/5-FU
 * Response: Comparable in 2 arms (20-30% response; 6 month survival)


 * PMID 1847127 -- Prognostic factors in unresectable hepatocellular cancer: Radiation Therapy Oncology Group Study 83-01. (1991 Stillwagon GB, Int J Radiat Oncol Biol Phys. 1991 Jan;20(1):65-71.)
 * Phase I/II. HCC. 198 patients (74% mets/recurrent). Induction (EBRT + low-dose 5-FU and doxorubicin), followed 1 month later by radiolabelled I-131 antiferritin
 * Median survival: 4.9 months (AFP- 8.5 months vs. AFP+ 4.6 months, p=0.006)
 * Multivariate predictors: KPS, ascites, bilirubin, SGOT, AlkPhos
 * Conclusion : "Our recommendations for structuring future prospective randomized trials are discussed and include stratification by AFP status."


 * PMID 2415692 -- Iodine 131 antiferritin, a new treatment modality in hepatoma: a Radiation Therapy Oncology Group study. (1985 Order SE, J Clin Oncol. 1985 Dec;3(12):1573-82.)
 * Phase I/II. 3 sequential protocols. 105 patients total. Induction EBRT + CT followed by 131-I-antiferritin.
 * Conclusion : "These studies have demonstrated the toxicity and therapeutic activity of 131I antiferritin and the emerging role of radiolabelled antibody in cancer therapy."


 * PMID 6085756 -- Comparative tumor dose from 131I-labeled polyclonal anti-ferritin, anti-AFP, and anti-CEA in primary liver cancers. (1984 Leichner PK, Cancer Drug Deliv. 1984 Fall;1(4):321-8.)
 * Dosimetric studies for 30 patients with HCC and 5 patients with hepatic CCA.
 * Hepatoma (30 mCi day 0, 20 mCi day 5): mean dose anti-ferritin 11 Gy, anti-AFP 3.5 Gy, combination anti-ferritin/anti-AFP 9.6 Gy
 * CCA (20 mCi day 0, 10 mCi day 5): mean dose 6.2 Gy
 * Total-body irradiation for these injection schedules ranged from 0.3 to 0.50 Gy


 * PMID 6307515 -- Dosimetry of 131I-labeled antiferritin in hepatoma: specific activities in the tumor and liver. (1983 Leichner PK, Cancer Treat Rep. 1983 Jul-Aug;67(7-8):647-58.)
 * Dosimetric studies for 22 patients with hepatoma
 * Conclusion : "These data, in conjunction with toxicity studies and tumor effective half-life measurements, led to the present treatment regimen of administering 30 mCi of polyclonal antiferritin IgG on Day 0 and 20 mCi on Day 5 following the first injection."


 * PMID 6275989 -- Phase I-II study of isotopic immunoglobulin therapy for primary liver cancer. (1982 Ettinger DS, Cancer Treat Rep. 1982 Feb;66(2):289-97.)
 * 14 patients evaluated for toxicity. Dose-limiting factor hematologic toxicity
 * Conclusion : "Present results suggest that further clinical studies with isotopic immunoglobulin are indicated."


 * PMID 6268576 -- Dosimetry of 131I-labeled anti-ferritin in hepatoma: a model for radioimmunoglobulin dosimetry. (1981 Leichner PK, Int J Radiat Oncol Biol Phys. 1981 Mar;7(3):323-33.)
 * No abstract

131-I-Anti-CEA
 * PMID 3032877 -- Multi-modality treatment of primary nonresectable intrahepatic cholangiocarcinoma with 131I anti-CEA--a Radiation Therapy Oncology Group Study. (1987 Stillwagon GB, Int J Radiat Oncol Biol Phys. 1987 May;13(5):687-95.)
 * Phase I/II. 37 patients. EBRT (21 Gy in 3.0 Gy/fx) + CT (Adriamycin + 5-FU) induction, followed 1 month later by CT (Adriamycin + 5-FU) + 131-I-anti-CEA
 * Toxicity: 3% Grade IV hematologic
 * Response: 27% PR; median survival 6.5 months


 * PMID 6085756 -- Comparative tumor dose from 131I-labeled polyclonal anti-ferritin, anti-AFP, and anti-CEA in primary liver cancers. (1984 Leichner PK, Cancer Drug Deliv. 1984 Fall;1(4):321-8.)
 * Dosimetric studies for 30 patients with HCC and 5 patients with hepatic CCA.
 * Hepatoma (30 mCi day 0, 20 mCi day 5): mean dose anti-ferritin 11 Gy, anti-AFP 3.5 Gy, combination anti-ferritin/anti-AFP 9.6 Gy
 * CCA (20 mCi day 0, 10 mCi day 5): mean dose 6.2 Gy
 * Total-body irradiation for these injection schedules ranged from 0.3 to 0.50 Gy