# Radiation Oncology/Toxicity/Liver

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## Radiation-Induced Liver Disease (RILD)

* Normal tissue complication probability (NTCP) endpoint which limits dose delivered
* Historically called "radiation hepatitis"
* Clinical syndrome: fatigue, RUQ pain, ascites, anicteric hepatomegaly, elevated LFTs (esp. alkaline phosphatase)
* Pathologic changes: veno-occlusive disease, marked central venous congestion, sparing of large veins, entrapment of erythrocytes, atrophy of adjactent hepatocytes
** Clinically similar to TBI or high-dose chemotherapy
* Pathophysiology: deposition of fibrin in central veins, injury to endothelial cells rather than hepatocytes, TGF-beta and TNF-alpha activation
* Develops usually 1–2 months after RT (range 2 weeks - 8 months)
* Treatment: supportive; most patients recover, but can lead to liver failure and death
* Stanford, 1966 PMID 5327788 -- "The human liver after radiation injury. A form of veno-occlusive disease." (Reed GB Jr, Am J Pathol. 1966 Apr;48(4):597-611.)
** Seminal paper on RILD. 12 patients with total liver irradiation for metastatic disease. RT: 30 – 59 Gy over 6 weeks. 5 patients received chemotherapy
** Pathology: Acutely: pronounced hyperemia; Chronic: veno-occlusive disease with marked hepatocyte atrophy
** Re-establishment of effective circulation and normalization of hepatic structure after 4 months

## Normal Liver Tolerance

* First reported liver radiation was in 1924. Liver cells were felt to be resistant to radiation
* Several RTOG studies in the 1970s and 1980s determined whole liver tolerance to be 30-35 Gy. This allowed reasonable but short palliation, and no possibility of cure
* First rigorous (based on CT) partial liver tolerance analysis came from Lawrence Berkeley Lab in 1985, using heavy ions.
** If whole liver dose was 18 Gy, then doses >30-35 Gy should be confined to <30% of liver
* Emami report in 1991 established baseline partial liver tolerances. These were mostly speculative
** TD5/5: 1/3 = 50 Gy, 2/3 = 35 Gy, 3/3 = 30 Gy
** TD50/5: 1/3 = 55 Gy, 2/3 = 45 Gy, 3/3 = 40 Gy
* Burman report in 1991 fitted these values into the Lyman model, with the following parameters:
** n = 0.32, m = 0.15
* Lawrence report in 1992 (University of Michigan data), adjusted the Lyman model parameters:
** n = 0.69
* Jackson report in 1995, University of Michigan data), modeled liver as a parallel organ:
** TD50 = 41.6 Gy (in 1.5 Gy BID), V50 (mean functional reserve) = 49.7%
* Dawson report in 2002 (University of Michigan data), further adjusted the Lyman model parameters:
** n = 1.1, m = 0.18
** TD5/5 (in 1.5 Gy BID): 1/3 = 107 Gy (~94 Gy in 2Gy/fx), 2/3 = 54 Gy (~48 Gy in 2Gy/fx), 3/3 = 37 Gy (~32 in 2Gy/fx)
** Due to parallel nature, mean liver dose is directly proportional to risk of RILD. Thus, 5% risk of RILD for whole liver RT is at 32 Gy
** Small liver volumes (<25%) can tolerate doses >100 Gy
** There is a difference between normal liver tolerance (with liver mets) and HCC liver tolerance (which is quite a bit lower)
Partial Liver Tolerance
* University of Michigan data
** 2002 PMID 12095546 -- "Analysis of radiation-induced liver disease using the Lyman NTCP model." (Dawson LA, Int J Radiat Oncol Biol Phys. 2002 Jul 15;53(4):810-21.)
*** 203 patients treated with conformal liver RT and CT prospectively followed; 19 developed RILD
*** No cases developed for mean liver dose <31 Gy
*** Conclusion: "These data demonstrate that the liver exhibits a large volume effect for RILD, suggesting that the mean liver dose may be useful in ranking radiation plans. The inclusion of clinical factors, especially the diagnosis of primary hepatobiliary cancer vs. liver metastases, improves the estimation of NTCP over that obtained solely by the use of dose-volume data."
*** Comment: PMID 15001282 -- "Analysis of radiation-induced liver disease using the Lyman NTCP model: in regard to Dawson et al. IJROBP 2002;53:810-821." (Tome WA, Int J Radiat Oncol Biol Phys. 2004 Mar 15;58(4):1318-9; author reply 1319–20.)
**** Discussion of fraction size and mean liver dose calculation
** 1998 PMID 9626227 -- "Treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model." (McGinn CJ, J Clin Oncol 1998; 16:2246-52.)
*** Dose-escalation protocol based on <10% probability of developing RILD estimated by NTCP modeling
*** 21 patients with primary hepatobiliary or liver mets treated with RT + hepatic artery FUdR
*** Protocol allows delivery of significantly higher dose (56.6 Gy vs. 46 Gy)
*** Complication rate of 4.8% well within predicted 8.8% (goal to keep <10%)
*** Conclusion: "Our results suggest that an NTCP model can be used prospectively to safely deliver far greater doses of radiation for patients with intrahepatic cancer than with previous approaches."
** 1995 PMID 7751185—The treatment of colorectal liver metastases with conformal radiation therapy and regional chemotherapy. (Robertson JM, Int J Radiat Oncol Biol Phys. 1995 May 15;32(2):445-50.)
*** Phase I/II. 22 patients with CRC mets, DVH-based RT dose escalation + IAH FdUrd. RT given as 1.5-1.65 Gy/fx BID to 48–72.6 Gy, depending on liver volume treated
*** RT protocol: if liver fraction treated to 50% isodose was >66%, dose 33 Gy; if fraction 33-66%, dose escalation 48–52.8 Gy; if fraction <33%, dose 66–72.6 Gy
*** Toxicity: no clinical RILD
** 1992 PMID 1618671 -- "The use of 3-D dose volume analysis to predict radiation hepatitis." (Lawrence TS, Int J Radiat Oncol Biol Phys. 1992;23(4):781-8.)
*** 9 of 79 patients developed clinical radiation hepatitis
*** All had mean liver dose >37 Gy
* Wisconsin, 1994 PMID 7511326 -- "Radiation tolerance of the transplanted liver. A histopathologic study in three cases." (Janjan NA, Am J Clin Oncol. 1994 Apr;17(2):129-33.)
** Retrospective. 3 patients s/p liver transplant treated with 30 Gy at 1.5 Gy/fx BID (2 patients) or 45 Gy to hilus + 5-FU infusion.
** Conclusion: "Transplanted livers exhibit responses to radiation similar to those normally observed."
* Lawrence Berkeley, 1986 PMID 3080390 -- "Dose volume histogram analysis of liver radiation tolerance." (Austin-Seymour MM, Int J Radiat Oncol Biol Phys. 1986 Jan;12(1):31-5.)
** 11 patients treated with heavy charged particles, whole liver 10-24 GyE, tumor 53.5-70 GyE
** 1 radiation hepatitis
** Conclusion: "Liver doses in excess of 30 to 35 GyE should be limited to 30% of the liver or less when 18 GyE of whole liver radiation is delivered at 2 GyE per fraction"
Whole Liver Tolerance
* 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
** Outcome: No patients at 30 Gy showed RILD, 10% patients at 33 Gy showed RILD (study closed)
** Conclusion: 33 Gy in 1.5 Gy BID is unsafe
* RTOG 76-09 PMID 6168623 -- "The palliation of hepatic metastases: results of the Radiation Therapy Oncology Group pilot study." (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
* Stanford, 1965 PMID 14243011 -- "Radiation Hepatitis." (Ingold JA, Am J Roentgenol Radium Ther Nucl Med. 1965 Jan;93:200-8.)
** Retrospective. 40 patients with total liver irradiation for metastatic disease. RT using 5.3 MeV and 6 MeV beams
** Development of radiation hepatitis:
*** None <30 Gy
*** 1/8 patients at 30 – 35 Gy
*** 5/9 patients at 35 – 40 Gy
*** 7/18 patients at >40 Gy
** Conclusion: The liver is not a radioresistant structure when irradiated in its entirety. Doses <35 Gy not as likely to result in radiation hepatitis
* MSKCC, 1954 PMID 13148429 -- "Roentgen therapy of hepatic metastases." (Phillips R, Am J Roentgenol Radium Ther Nucl Med. 1954 May;71(5):826-34.)
** Hepatic mets from breast, lung, and GI. Treated with 1 MeV beam, SSD 70–100 cm
** Good palliation
** No radiation damage from 20 – 37.5 Gy
* Michigan, 1924 -- "The occurence of hepatic lesions in patients treated by intensive deep roentgen irradiation" (Case JT, Am J Roentgenol Radium Ther Nucl Med 12:27, 1924)
** First English report of RT use in humans. RT 200 kVp, SSD 50 cm, 200 milli-ampere minutes.
** Autopsy: Atypical lymphoid tissue with areas of necrosis. Marked changes in epithelium of intrahepatic biles ducts, including necrosis and syncytial giant cell formation. Comparatively mild changes in hepatocytes
** Conclusion: Liver cells are resistant to irradiation
Review Articles
* Michigan
** 2005 PMID 16183482 -- "Partial volume tolerance of the liver to radiation." (Dawson LA, Semin Radiat Oncol. 2005 Oct;15(4):279-83.)
*** If the effective liver volume irradiated is <25%, can give dose >100 Gy with little risk of RILD
*** Mean liver doses associated with a 5% risk of classic RILD for HCC is 28 Gy in 2 Gy/fx, for liver mets is 32 in 2 Gy/fx
** 2001 PMID 11447581 -- "Partial irradiation of the liver." (Dawson LA, Semin Radiat Oncol. 2001 Jul;11(3):240-6.)
*** 5% risk of RILD: 1/3 90 Gy, 2/3 47 Gy, 3/3 31 Gy
*** If <25% liver treated, there may be no upper limit on dose
*** No RILD reported with mean liver dose <31 Gy
** 1995 PMID 7713785 -- "Hepatic toxicity resulting from cancer treatment." (Lawrence TS, Int J Radiat Oncol Biol Phys. 1995 Mar 30;31(5):1237-48.)

## Hepatocellular Carcinoma Tolerance

* Seoul, 2006 (Korea) PMID 16328032 -- "Temporal cDNA microarray analysis of gene expression in human hepatocellular carcinoma upon radiation exposure." (Jeong J, Oncol Rep. 2006 Jan;15(1):33-48.)
** Conclusion: "DNA repair-promoting genes were up-regulated in radio-resistant cells and down-regulated or unchanged in radiation-sensitive cells. The present findings indicate that different subsets of genes are sequentially working and DNA repair capacity may control the radiation sensitivity of human hepatocellular carcinoma cells more than any other physiological factor."
* Taiwan
** 2005 PMID 15990021 -- "Inclusion of biological factors in parallel-architecture normal-tissue complication probability model for radiation-induced liver disease." (Cheng JC, Int J Radiat Oncol Biol Phys. 2005 Jul 15;62(4):1150-6.)
*** HBV carrier status significant independent predictor for RILD
*** Conclusion: "RILD is described with a parallel-architecture NTCP model for HBV carriers and noncarriers with a threshold effect greater than 0.4. The main difference is in slope parameter for subunit dose-response."
** 2002 PMID 12182986 -- "Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma: dosimetric analysis and implication." (Cheng JC, Int J Radiat Oncol Biol Phys. 2002 Sep 1;54(1):156-62.)
*** Retrospective. 93 patients treated, 68 HCC and complete 3D data evaluated. 50 had chronic viral hepatitis (B or C). Median dose 50.2 Gy in 1.8/2 Gy/fx, no whole liver RT.
*** 18% developed RILD. No difference in patient characteristics, mean hepatic dose higher (25.0 vs. 19.7 Gy). Lyman NTCP volume effect 0.40, curve steepness 0.26, TD(50) 43 Gy. NTCP higher (26% vs. 16%, p=0.006)
*** Conclusion: "Dose-volume histogram analysis can be effectively used to quantify the tolerance of the liver to RT. Patients with RILD had received a significantly higher mean dose to the liver and a significantly higher NTCP. The fitted volume effect parameter of the Lyman NTCP model was close to that from the literature, but much lower in our patients with HCC and prevalent chronic viral hepatitis than that reported in other series with patients with normal liver function. Additional efforts should be made to test other models to describe the radiation tolerance of the liver for Asian patients with HCC and preexisting compromised hepatic reserve."
* University of Michigan, 2005 PMID 16183482 -- "Partial volume tolerance of the liver to radiation." (Dawson LA, Semin Radiat Oncol. 2005 Oct;15(4):279-83.)
** Review article
** "The mean liver doses associated with a 5% risk of classic RILD for primary and metastatic liver cancer are 28 Gy and 32 Gy, respectively, in 2 Gy per fraction."

### Radiation + Chemotherapy

* Yonsei, 2003 (Korea) PMID 12909244 -- "Lethal hepatic injury by combined treatment of radiation plus chemotherapy in rats with thioacetamide-induced liver cirrhosis." (Seong J, Int J Radiat Oncol Biol Phys. 2003 Sep 1;57(1):282-8.)
** Rat model of cirrhosis. Treated with partial RT, 5-FU, or partial RT + 5-FU
** Conclusion: "In a rat cirrhosis model with mildly impaired liver function, combined treatment of partial RT plus 5-FU resulted in significantly high incidence of lethal liver injury. The results in this study show that a combined treatment of RT plus chemotherapy in cirrhotic patients should be applied with extreme caution."

## Other

* China (Shanghai), 2006 - PMID 16690430 — Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: The risk factors and hepatic radiation tolerance. (Liang SX, Int J Radiat Oncol Biol Phys. 2006 Jun 1;65(2):426-34.)
* Mean dose to normal liver (MDTNL) of 23 Gy was tolerable.
* Tolerable MDTNL could be estimated by MDTNL (Gy) = -1.686 + 0.023 * normal liver volume (cm3).
* For cumulative dose–volume histogram (DVH), the tolerable volume percentages would be less than:
| Radiation Dose (Gy) | Percentage of Whole Liver |
| V5 | 86% |
| V10 | 68% |
| V15 | 59% |
| V20 | 49% |
| V25 | 35% |
| V30 | 28% |
| V35 | 25% |
| V40 | 20% |
Another 2002 article suggested that when the effective liver volume is 1.0 (i.e., whole liver irradiation), the dose with 5% RILD incidence is 24Gy, and dose with 50% RILD incidence is 43Gy. However, if the effective liver volume irradiated is 0.5 (i.e., half the liver), the 5% RILD incidence occurs at 32Gy. Liang