# Radiation Oncology/Liver/Treatment

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials

## EBRT Whole Liver

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 and CEA antibodies).
Please see the Whole Liver RT section for literature review.

## EBRT Conformal

* Guangxi China 1999-03 PMID 15812834 -- Hypofractionated three-dimensional conformal radiation therapy for primary liver carcinoma. (2005 Liang SX, Cancer. 2005 May 15;103(10):2181-8.)
** Retrospective. 128 patients with inoperable primary liver CA; mean GTV 459 cm3, mean dose 53.6 Gy at average 4.9 Gy/fx
** Response: 55%, median survival 20 months
** Toxicity: RILD 15%, GI 8/125 patients
** Conclusion: "Hypofractionated 3DCRT is effective in carefully selected patients with PLC. Gastrointestinal complications and RILD were the most distinct complications."
* Changhua Taiwan 1999-03 PMID 15466827 -- Three-dimensional conformal radiation therapy for unresectable hepatocellular carcinoma patients who had failed with or were unsuited for transcatheter arterial chemoembolization. (2004 Liu MT, Jpn J Clin Oncol. 2004 Sep;34(9):532-9.)
** Retrospective. 44 patients treated with 3D-CRT after failed/unsuitable for TACE
** Response: 61%, median survival 15.2 months
** Conclusion: "Although we do not know whether there is a survival benefit through the use of this treatment, 3DCRT seems to be a practical method of salvage for this subset of patients."
* Yonsei Korea
** 1994-00 PMID 12957204 -- Clinical results of 3-dimensional conformal radiotherapy combined with transarterial chemoembolization for hepatocellular carcinoma in the cirrhotic patients. (2003 Seong J, Hepatol Res. 2003 Sep;27(1):30-35.
*** Retrospective. 50 HCC with liver cirrhosis (38 Child A, 12 Child B). Mean tumor size 8.3cm. Treated with TACE + 3D-CRT (mean 50.1 Gy) determined by fraction liver getting 50% dose
*** Toxicity: 26% LFTs (no Grade 4), 12% RILD, 14% GI toxicity
*** Partial response 66%; 3-year survival 43%
*** Conclusion: "Radiotherapy using 3-DCRT combined with TACE can achieve a substantial tumor response and survival rate for HCC in the cirrhotic patients.
** 1992-00 PMID 12527045 -- Clinical results and prognostic factors in radiotherapy for unresectable hepatocellular carcinoma: a retrospective study of 158 patients. (2003 Seong J, Int J Radiat Oncol Biol Phys. 2003 Feb 1;55(2):329-36.)
*** Retrospective. 158 unresectable HCC treated with RT (67 Stage III, 91 Stage IVA). Mean tumor 9.0cm, liver cirrhosis in 142. RT + transarterial chemo (107 patients) or salvage (51 patients). Mean RT dose 48.2 Gy
*** 2-year (5-year) OS: 30% (9%). Response rate 67%. RT dose only predictor of survival
*** Conclusion: "Local RT achieved substantial tumor regression and survival. The radiation dose was found to be a significant prognostic factor in the RT of hepatocellular carcinoma."
** 1992-00 PMID 12182985 -- Dose-response relationship in local radiotherapy for hepatocellular carcinoma. (2002 Park HC, Int J Radiat Oncol Biol Phys. 2002 Sep 1;54(1):150-5.)
*** Retrospective. 158 patients, no mets, no cirrhosis Class C, or tumor >2/3 volume
*** 2-year survival (response): 20% (67%)
*** Dose-response: <40 Gy 29%, 40-50 Gy 69%, >50 Gy 77%
*** Toxicity: liver <40 Gy 4.2%, 40-50 Gy 5.9%, >50 Gy 8.4%; GI 4.2%, 9.9%, 13.2%
*** Conclusion: "The present study showed the existence of a dose-response relationship in local radiotherapy for primary HCC. Only the radiation dose was a significant factor for predicting an objective response."
* Taipei Taiwan Paper link -- Hyperfractionated Three-dimensional Conformal Radiotherapy for Small Hepatocellular Carcinoma: A Pilot Study (2002 Wang PM, Chin J Radiol 2002; 27: 281-287)
** Retrospective. 39 patients with HCC (<5 cm) treated with 3D-CRT (45-75 Gy at 1.5 Gy/fx BID)
** Median survival: 16.5 months
** Toxicity: acute leukopenia 26%, LFTs 23%, GI toxicity 33%
** Conclusion: "hyperfractionated 3-D conformal RT may be a safe, effective treatment modality in small HCC patients with preserved liver function even if they have already been treated with other therapies."
* Tsuchiura Japan PMID 11422619 -- Radiation therapy in combination with transcatheter arterial chemoembolization for hepatocellular carcinoma with extensive portal vein involvement. (2001 Tazawa J, J Gastroenterol Hepatol. 2001 Jun;16(6):660-5.)
** Prospective. 24 patients with HCC and extensive portal vein thrombosis treated with RT + TACE
** PVTT response: 50% CR/PR; Child's class only factor associated with local response
** Conclusion: "The combined therapy is feasible and may be useful to reverse PVTT in patients with good hepatic function reserve."
* Michigan
** 2000 PMID 10829040 -- Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. (Dawson LA, J Clin Oncol. 2000 Jun;18(11):2210-8.)
*** Prospective, phase I. 43 patients with unresectable intrahepatic hepatobiliary cancer (27 patients) and colorectal liver mets (16 patients). Large tumors (10x10x8). Median dose 58.5 Gy (1.5 BID) with concurrent FUdR.
*** Escalated RT dose associated with improved OS and PFS.
*** Conclusion: "The excellent response rate, prolonged intrahepatic control, and improved survival in patients treated with RT doses of 70 Gy or more motivate continuation of dose-escalation studies for patients with intrahepatic malignancies."
** 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, RT dose escalation + IAH FdUrd. RT given as 1.5-1.65 Gy/fx BID split-course to 48-72.6 Gy, depending on liver volume treated
*** Response: 50% CR/PR; median survival 20 months. PR - 2 in-field failures, SD/PD - 5 in-field failures
*** Toxicity: no clinical RILS
*** Conclusion: "Combined conformal radiation therapy and IAH FdUrd can produce an objective response in 50% of patients with hepatic metastases from colorectal cancer. However, response was not durable, and hepatic progression was frequent. Improvements in hepatic tumor control for patients with metastatic colorectal cancer may require higher doses of conformal radiation and/or improved radiosensitization. In an effort to increase radiosensitization, we have recently initiated a clinical trial combining IAH bromode-oxyuridine, a thymidine analog radiosensitizer, with conformal high dose radiation therapy."
** 1993 PMID 8391066 -- Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy. (Robertson JM, J Clin Oncol. 1993 Jul;11(7):1286-93.)
*** 26 patients with non-met primary HB cancer (6 diffuse HCC, 11 localized HCC, 9 CCA) treated with conformal RT (48-72.6 Gy @ 1.5/1.65 Gy/fx BID) + intraarterial FdUrd (see 1991 Lawrence below)
*** Toxicity: 2 patient radiation hepatitis, 7 patients >= Grade III toxicity (5/7 whole liver RT)
*** Conclusion: "These findings suggest that three-dimensional planned focal liver radiation and IAH FdUrd can produce a high, durable response rate and an encouraging median survival duration in patients with nondiffuse, unresectable primary hepatobiliary cancer."
** 1991 PMID 1847363 -- Treatment of cancers involving the liver and porta hepatis with external beam irradiation and intraarterial hepatic fluorodeoxyuridine. (Lawrence TS, Int J Radiat Oncol Biol Phys. 1991 Mar;20(3):555-61.)
*** Phase I/II trial of RT (30 Gy total liver @ 1.5 Gy/fx BID + 15/30 Gy boost depending on DVH) + intraarterial FdUrd as radiosensitizer; 33 patients reported
*** 20 patients whole liver only, 6 patients 15 Gy boost, 7 patients 30 Gy boost
*** Toxicity: GI but <=Grade 2, 2 radiation hepatitis
*** Response: 48% (14/29) had objective CT-scan response
*** Conclusion: "These data suggest that the treatment of intrahepatic malignancies can be guided by the concept of DVH analysis of the normal liver to allow the safe administration of doses of radiation that are potentially tumoricidal and are well above those that would be predicted to be tolerable for the whole liver."
* Yonsei Korea 1993-97 PMID 10889387 -- Local radiotherapy for unresectable hepatocellular carcinoma patients who failed with transcatheter arterial chemoembolization. (2000 Seong J, Int J Radiat Oncol Biol Phys. 2000 Jul 15;47(5):1331-5.)
** Prospective. 27 patients with unresectable HCC who failed TACE; mean tumor 7.2 cm, treated with conformal RT mean 51.8 Gy in 1.8 Gy/fx
** Response: 67% PR/CR, median survival 14 months from RT
** Toxicity: acute LFTs, thrombocytopenia, gastroduodenal ulcer/duodenitis
** Conclusion: "In unresectable HCC patients who failed with TACE, local RT induced a substantial tumor response of 66.7%, with a 3-year survival rate of 21.4% and a median survival time of 14 months. Toxicity was significant but manageable. Although we do not know if there is survival benefit through this treatment, local RT in these patients seems to be valuable as a salvage for TACE-failed HCC."
* Taiwan 1993-96 PMID 10530500 -- A pilot study of three-dimensional conformal radiotherapy in unresectable hepatocellular carcinoma. (1999 Cheng SH, J Gastroenterol Hepatol. 1999 Oct;14(10):1025-33.)
** Prospective. 13 patients (9 3D-CRT alone, 4 3D-CRT + TACE)
** Tumor median 15 cm (6-25cm); dose 40-60 Gy; PR 58%
** Conclusion: "Our experience indicates that HCC is more radiosensitive than it was traditionally expected. Three-dimensional reconstruction of tumour and surrounding organs helps to avoid excessive exposure of the liver and adjacent organs to RT and makes it a safer treatment modality for unresectable HCC."
* Yonsei Korea 1992-94 PMID 10030267 -- Combined transcatheter arterial chemoembolization and local radiotherapy of unresectable hepatocellular carcinoma. (1999 Seong J, Int J Radiat Oncol Biol Phys. 1999 Jan 15;43(2):393-7.)
** Prospective. 30 patients with unresectable HCC. TACE + RT (mean 44 Gy)
** 2-year survival (response): 33% (63%)
** Toxicity: transient LFTs, fever 67%, thrombocytopenia 13%
** Conclusion: "Combined TACE and local RT is feasible and tolerable. It gives a 63.3% response rate with median survival of 17 months. We feel that this regimen would be a new promising modality in unresectable HCC."
* Yonsei Korea
** 1988-91 PMID 7975734 -- Combined treatment of radiotherapy and hyperthermia for unresectable hepatocellular carcinoma. (1994 Seong J, Yonsei Med J. 1994 Sep;35(3):252-9.)
*** Prospective. 84 patients treated with hyperthermia ~40C + EBRT 30.6 Gy
*** Response: 40% regression >50% tumor volume; symptomatic improvement in 79%
*** Median survival (2-year OS): 6 months (20%)
*** Conclusion: "In view of acceptable toxicities and the current rate of survival, further evaluation of combined treatment of radiotherapy and hyperthermia for unresectable hepatocellular carcinoma is warranted."
** 1988 PMID 1281042 -- Phase II trial for combined external radiotherapy and hyperthermia for unresectable hepatoma. (1992 Kim BS, Cancer Chemother Pharmacol. 1992;31 Suppl:S119-27.)
*** Phase II. Hyperthermia + EBRT 30.6 Gy
*** Median survival: 34% (50% for partial response). Partial response 40%, relief in abdominal pain 79%.
*** Conclusion: "although this study is being continued, the results obtained thus for indicate that combined radiotherapy and hyperthermia seem to be effective in providing local tumor control and pain palliation in unresectable hepatocellular carcinoma while producing an acceptable level of toxicity."
* Michigan PMID 2211241 -- An application of dose volume histograms to the treatment of intrahepatic malignancies with radiation therapy. (1990 Lawrence TS, Int J Radiat Oncol Biol Phys. 1990 Oct;19(4):1041-7.)
** Protocol using DVH to determine dose to be delivered (45 Gy if >50% liver could be excluded, 60 Gy if >75% liver could be excluded)
** Conclusion: "These results show that intrahepatic tumors can be safely treated with high doses of radiation when dose prescription is guided by the dose volume histogram of the normal liver."

### EBRT Treatment Planning

* Michigan PMID 16095848 -- Evaluating the influence of setup uncertainties on treatment planning for focal liver tumors. (2005 Balter JM, Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(2):610-4.)
** 8 patients on protocol with online setup measurement/adjustment. Ventilatory immobilization.
** L-R variation: individual 2.5-5.7 mm, group 4.2 mm
** A-P variation: individual 2.1-8.3 mm, group 4.1 mm
** C-C variation: individual 4.1-10.8 mm, group 7.0 mm
** Initial static plan overestimated volume of liver treated to high dose, shifting some areas to lower doses due to setup uncertainties
* Duke PMID 16317267 -- Retrospective clinicopathologic correlation of gross tumor size of hepatocellular carcinoma: implications for stereotactic body radiotherapy. (2005 Kelsey CR, Am J Clin Oncol. 2005 Dec;28(6):576-80.)
** Retrospective. 18 patients with 27 tumors. Pre-op CT or MRI imaging compared to gross path
** Median radiographic size 2.9cm, median pathologic size 2.5cm. Radiographic size greater in 81% tumors
** Conclusion: "Our study shows that in most instances (81%), imaging by CT or MRI overestimates true gross pathologic size of HCC. Nineteen percent of tumors appeared smaller on preoperative imaging than on the final pathologic specimen. Radiation therapy utilizing a 0.5 or 1.0 cm margin around the radiographic tumor would have encompassed the gross pathologic tumor in 93% and 100% of cases, respectively."
* Michigan PMID 15890602 -- Benefit of using biologic parameters (EUD and NTCP) in IMRT optimization for treatment of intrahepatic tumors. (2005 Thomas E, Int J Radiat Oncol Biol Phys. 2005 Jun 1;62(2):571-8.)
** 15 patients initially planned with 3D-CRT, replanned with IMRT to maximize generalized equivalent uniform dose (gEUD) and NTCP
** IMRT significantly increased max gEUD by 11 Gy (high grade), 18 Gy (low grade), and 10 Gy (nonoverlap)
** Conclusion: "We have successfully used mathematical/biologic models directly as cost functions within the optimizing process to produce IMRT plans that maximize the gEUD while maintaining compliance with a well-defined protocol for the treatment of intrahepatic cancer. For both PTV-organ-at-risk overlap and nonoverlap situations, IMRT has the capacity to improve the maximal dose achievable across the PTV, expressed in terms of the gEUD. The use of multiple noncoplanar beams appears to confer an advantage over fewer beams in cases with PTV-organ-at-risk overlap. When liver toxicity is the dose-limiting factor, high gEUD values are obtained most frequently when the field arrangement is chosen to provide the shortest possible transhepatic path length."
* Princess Margaret ASTRO Abstract A Prospective Comparison Study of Liver Tumour Target Definition Based on Triphasic CT and Gadolinium MR (2005 Voroney JJ, ASTRO 2005 #2088)
** 23 patients (CCA 4, HCC 10, liver mets 9) on protocol; liver immobilized using ABC/voluntary breath hold. Best CT (arterial phase for HCA, venous phase for CCA and mets), best MRI T1 gado
** Average GTV difference 11cc (1-263); CT GTV larger in 3/7 mets, 4/4 CCA, 6/11 HCA
** Conclusion: "MR defined GTVs can be significantly different than CT defined GTVs and this should be considered for high precision liver cancer radiotherapy."
* Princess Margaret PMID 14752735 -- Interventions to reduce organ motion effects in radiation delivery. (2004 Dawson LA, Semin Radiat Oncol. 2004 Jan;14(1):76-80.)
** Review of 1) altering breathing patterns and 2) breath holding techniques
* Michigan PMID 14630287 -- Alterations in normal liver doses due to organ motion. (2003 Rosu M, Int J Radiat Oncol Biol Phys. 2003 Dec 1;57(5):1472-9.)
** Recalculation of 40 patients to include effect of setup undertainties and liver motion due to patient breathing
** Actual minimum CTV dose met or exceeded PTV dose from static plan in 39/40 cases (=>adquate PTV)
** However, clinically and statistically significan change in NTCP for tumors at top and bottom of liver (range from +12% to -12%); corresponding to dose adjustment -4 Gy to +8 Gy for original NTCP
** Conclusion: "Although the PTV concept can ensure adequate CTV coverage, the doses to normal liver are incorrectly modeled without including patient-related geometric uncertainties."
* Memorial PMID 12573753 -- Respiratory gating for liver tumors: use in dose escalation. (2003 Wagman R, Int J Radiat Oncol Biol Phys. 2003 Mar 1;55(3):659-68.)
** Prospective. 10 patients, 177 treatments. Evaluation of Varian Real-Time Positioning Monitor
** Reproducible decrease in organ motion with gating enabled reduction in GTV-to-PTV margin from 2 to 1 cm. Calculated dose increased 7%-27% (median 21%)
** Conclusion: "Gating of radiotherapy for liver tumors enables safe margin reduction on tumor volume, which, in turn, may allow for dose escalation."
* Taiwan PMID 12694843 -- Dosimetric analysis and comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy for patients with hepatocellular carcinoma and radiation-induced liver disease. (2003 Cheng JC, Int J Radiat Oncol Biol Phys. 2003 May 1;56(1):229-34.)
** Retrospective. 12/68 HCC patients developed RILD, and replanned with IMRT 5F step-shoot
** Comparable target coverage, IMRT better with SC, similar kidney, stomach. IMRT significant reduction in NTCP (24% vs. 37%, p=0.009) but significant increase in mean dose (29.2 vs. 25.0 Gy, p=0.009)
** Conclusion: "IMRT is capable of preserving acceptable target coverage and improving or at least maintaining the nonhepatic organ sparing for patients with HCC and previously diagnosed RILD after 3D-CRT. The true impact of this technique on the liver remains unsettled and may depend on the exact volume effect of this organ."
* Michigan PMID 11728702 -- The reproducibility of organ position using active breathing control (ABC) during liver radiotherapy. (2001 Dawson LA, Int J Radiat Oncol Biol Phys. 2001 Dec 1;51(5):1410-21.)
** Conclusion: "Radiotherapy using ABC for patients with intrahepatic cancer is feasible, with good intrafraction reproducibility of liver position using ABC. However, the interfraction reproducibility of organ position with ABC suggests the need for daily on-line imaging and repositioning if treatment margins smaller than those required for free breathing are a goal."
* PMID 2998178 -- Computed tomography assisted volumetric analysis of primary liver tumor as a measure of response to therapy. (1985 Ettinger DS, Am J Clin Oncol. 1985 Oct;8(5):413-8.)
** Volumetric CT analysis in 33 patients.
** Conclusion: "In spite of small changes in total liver volume, there may be concomitantly substantial changes in tumor volume.

## Stereotactic Radiotherapy

* Ongoing: RTOG 04-38 (2005-ongoing)
** Dose escalation. 35 Gy to 50 Gy in 10 fractions.
* Colorado; 2009 PMID 19255321 -- "Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases." (Rusthoven KR; J Clin Oncol 2009 April 1; 27(10):1572-1578)
** Prospective phase I/II trial of 47 patients with 63 liver metastases.
** Required to (1) have 3 or fewer lesions and (2) largest lesion be <6cm in greatest dimension.
** Dose escalated from 36Gy/3fx to 60Gy/3fx in phase I w/o DLT
** Phase II dose 60Gy/3fx
** Local control at 1yr and 2yr was 95% and 92%, respectively
** Local control for lesions <3cm was 100%
** Median survival 20.5mo
** Conclusion: SBRT results in excellent LC for liver metastases. May be able to acheive long term DFS in well selected patients with favorable histology
* Rotterdam (The Netherlands)
** 2006 PMID 16982547 -- "Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii study." (Mendez Romero A, Acta Oncol. 2006;45(7):831-7.)
*** Phase I/II. 25 patients with 45 liver tumors (34 mets, 11 HCC). Median F/U 13 months. RT 25/5 or 30/3 or 37.5/3. Median lesion 3.2cm (0.5-7.2)
*** Outcome: 2-year local control: 82%
*** Toxicity: 3 mets patients Grade 3, 1 HCC patient Grade 5 (liver failure), 1 late toxicity (portal HTN)
** 2007 PMID 17996394 -- "Quality of Life After Stereotactic Body Radiation Therapy for Primary and Metastatic Liver Tumors." (Romero AM, Int J Radiat Oncol Biol Phys. 2007 Nov 7 [Epub ahead of print])
*** QoL secondary end point. 28 patients. Evaluated with EQ-5D, EQ-5D VAS, and QLQ C-30 quality of life instruments
*** Outcome: No change after SBRT, tendency toward improvement
*** Conclusion: SBRT high local control with no significant change in quality of life
* Rochester, 2006 PMID 17197128 -- "Hypofractionated stereotactic body radiation therapy (SBRT) for limited hepatic metastases." (Katz AW, Int J Radiat Oncol Biol Phys. 2006 Dec 28)
** Prospective. 69 patients, 174 liver mets from colon (20), breast (16), pancreas (9), lung (5). Median F/U 14 months
** Median lesion 2.7 cm (0.6-12.2). SRT median dose 48 Gy in 2-6 Gy/fx.
** 20-month LC: 57% tumor-based. Median OS 14 months
** Toxicity: no Grade 3+
* Multi-institutional US
** 2006 PMID 16982549 -- "Interim analysis of a prospective phase I/II trial of SBRT for liver metastases." (Kavanagh BD, Acta Oncol. 2006;45(7):848-55.)
*** Phase I/II. 7 institutions. 36 patients, mets from lung (10), CRC (9), breast (4), other (13)
*** Criteria: diameter <6 cm, <=3 lesions, 700 cm3 liver <=15 Gy. PTV = GTV + 5-10 mm. RT 20Gy x3
*** Toxicity: No Grade 4, 1 Grade 3
*** 18-month local control: 93%
** 2005 PMID 16029795 -- "A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases." (Schefter TE, Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1371-8.)
*** Phase I. RT 12Gy x3 escalation to 20Gy x3. Criteria as above.
*** No dose-limiting toxicity. Basis for Phase II of 20Gy x3
* Princess Margaret, 2006 PMID 16982550 -- "Individualized image guided iso-NTCP based liver cancer SBRT." (Dawson LA, Acta Oncol. 2006;45(7):856-64.)
** Phase I/II. 79 patients with HCC (33), IHC (12) or liver mets (34).
** RT: prescription based on NTCP to maintain given risk of RILD to max 60/6 (median dose 36.6/6)
* Wuerzburg (Germany)
** 2006 PMID 16982548 -- "Stereotactic radiotherapy of primary liver cancer and hepatic metastases." (Wulf J, Acta Oncol. 2006;45(7):838-47.)
*** Prospective. 39 patients with 51 liver mets and 5 patients with HCC. RT "low dose" (30/3, 28/4) or "high dose" (36/3, 37.5/3, 26/1). Median F/U 15 months
*** Local control: 1-year 92% (low dose 86% vs. high dose 100%), 2-year 66% (low dose 58% vs. high dose 82%)
*** OS: 1-year 72%, 2-year 32%
*** Toxicity: None severe
** 2001 PMID 11789403 -- "Stereotactic radiotherapy of targets in the lung and liver" (Wulf J, Strahlenther Onkol. 2001 Dec;177(12):645-55.)
*** Phase I. 51 patients (27 lung, 24 liver). Median F/U 9 months
*** Crude local control: 85% pulmonary and 83% hepatic targets
*** 1-year OS: 48%
*** Toxicity: no acute Grade 3-5; 2 late toxicities (Grade 3 esophageal ulceration, Grade 5 pulmonary artery bleeding)
* Aarhus, 2006 (Denmark) PMID 16982546 -- "Phase II study on stereotactic body radiotherapy of colorectal metastases." (Hoyer M, Acta Oncol. 2006;45(7):823-30.)
** Phase II. 64 patients with 141 CRC mets in liver (44), lung (12), LNs (3) or other (5). RT: 15 Gy x3. Median F/U 4.3 years
** 2-year LC: 86% tumor-based, 63% patient-based. 19/64 patients without progression
** OS: 2-year 38%; 5-year 13%
** Side effects: 1 death from hepatic failure, 1 colonic perforation, 2 duodenal ulcerations
* Stanford, 2005 ASTRO Abstract "Phase I Dose Escalation Study of CyberKnife Stereotactic Radiosurgery for Liver Malignancies" (Lieskovsky YC, ASTRO 2005 #2089)
** Phase I. 6 patients/7 tumors (1 IH-CCA, 7 mets). Tumors <5cm. Treatment delivered with motion tracking of implanted fiducials
** Dose escalation: 3 tumors with 18 Gy, 4 tumors with 22 Gy. MTD not reached. Toxicity: 1 GI Grade 1
** Response: 4 PR
** Conclusion: "Results thus far indicate that single fractions of 18 and 22 Gy are safe to administer to liver tumors with the CyberKnife. We have not yet reached the MTD at 22 Gy. We plan to dose-escalate to 30 Gy."
* Heidelberg (Germany)
** 2004 PMID 15458194 -- "Stereotactic radiation therapy of liver metastases: update of the initial phase-I/II trial." (Herfarth KK, Front Radiat Ther Oncol. 2004;38:100-5.)
*** No abstract
** 2003 PMID 12957256 -- "Assessment of focal liver reaction by multiphasic CT after stereotactic single-dose radiotherapy of liver tumors." (Herfarth KK, Int J Radiat Oncol Biol Phys. 2003 Oct 1;57(2):444-51.)
*** 131 CT scans in 36 patients
*** Response: 74% of posttherapeutic scans showed sharply demarcated hypodense area surrounding treated tumor, at median 1.8 months. Reaction volume decreased with longer follow-up
*** Conclusion: "A focal radiation reaction occurs after stereotactic single-dose therapy in the liver. The volume of the reaction decreases and changes its radiologic appearance during follow-up. This reaction has to be differentiated from recurrent tumor."
** 2001 PMID 11134209 -- "Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial." (Herfarth KK, J Clin Oncol. 2001 Jan 1;19(1):164-70.)
*** Phase I/II. 37 patients, 60 tumors (4 primary, 56 mets). Dose escalation 14 to 26 Gy.
*** Toxicity: no major side effects
*** Tumor control: 81% at 18 months (max 16 months); 4 CR, 28 PR, 22 SD at 6 weeks
*** Conclusion: "Stereotactic single-dose radiation therapy is a feasible method for the treatment of singular inoperable liver metastases with the potential of a high local tumor control rate and low morbidity."
** 2000 PMID 10661339 -- "Extracranial stereotactic radiation therapy: set-up accuracy of patients treated for liver metastases." (Herfarth KK, Int J Radiat Oncol Biol Phys. 2000 Jan 15;46(2):329-35.)
*** Phase I/II. 24 patients with liver mets. Liver movement reduced by abdominal pressure
*** Movement: diaphragm 7 mm (3-13), lateral 1.8 mm (0.3-5.0), AP 2.0 mm (0.8-3.8), CC <5mm. Repositioning necessary in 16/26 occasions
*** Conclusion: "In patients with liver metastases, a high set-up accuracy of the body and the target can be achieved. This allows a high-dose focal radiotherapy of these lesions. However, a control CT scan should be performed directly before therapy to confirm set-up accuracy and possibly prompt necessary corrections.
* Karolinska (Sweden)
** 2003 PMID 14571698 -- "Radiosurgery for recurring liver metastases after hepatectomy." (Gunven P, Hepatogastroenterology. 2003 Sep-Oct;50(53):1201-4.)
*** Retrospective. 14/18 liver recurrences after resection suitable for RS (20 Gy x2 or 15 Gy x3)
*** 100% local control, 2 CR. Only 1 recurrence in liver.
*** Conclusion: "Radiosurgery of liver tumors merits further study, and may offer a less demanding alternative to resection for selected liver tumors with the prospect of long-term survival."
** 1995 PMID 7576756 -- "Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients." (Blomgren H, Acta Oncol. 1995;34(6):861-70.)
*** Initial report. 42 tumors in 31 patients (liver, lung, retroperitoneal)
*** CTV mean 78 cm3 (2-622), PTV dose mean 41 Gy (6-66)
*** No progression in 80% during follow-up (1.5-38)

### SBRT Treatment Planning

* Michigan; 2008 PMID 17855011 -- "Liver function after irradiation based on computed tomographic portal vein perfusion imaging." (Cao Y, Int J Radiat Oncol Biol Phys. 2008 Jan 1;70(1):154-60. Epub 2007 Sep 12.)
** Dynamic CT-based portal vein flow evaluation, after RT. Dose 45-84 Gy
** Outcome: Volume of liver with no flow ranged 0-39% at 1 month; significant correlation with indocyanine green clearance
** Conclusion: Substantial individual variability in liver sensitivity to radiation. Hepatic perfusion imaging may be a marker useful for individualizing therapy
* Charite, 2006 (Germany) PMID 16982554 -- "Image guided respiratory gated hypofractionated Stereotactic Body Radiation Therapy (H-SBRT) for liver and lung tumors: Initial experience." (Wurm RE, Acta Oncol. 2006;45(7):881-9.)
** Novalis. Patients with liver and lung.
** RT 8-11 fractions, dose 74.8-79.2 Gy. Average daily marker deviation 4mm from plan.
** Conclusion: Novalis is accurate and feasible for real-time respiratory gating
* Virginia
** 2006 PMID 16904845 -- "Dose as a function of liver volume and planning target volume in helical tomotherapy, intensity-modulated radiation therapy-based stereotactic body radiation therapy for hepatic metastasis." (Baisden JM, Int J Radiat Oncol Biol Phys. 2006 Oct 1;66(2):620-5.)
*** Dosimetry analysis for HiArt TomoTherapy up to 20 Gy x3.
*** Development of predictive equation for maximum tolerated dose
** 2005 ASTRO Abstract Helical Tomotherapy SBRT for Liver Metastases: Recommendations for Potential Candidates Based on Tumor Size and Location. (Baisden JM, ASTRO 2005, Abstract 2095)
*** Inverse treatment stimulation in several liver locations to determine size and location treatable. Liver divided into L lobe, RU lobe, RL lobe; 5mm radial expansion of GTV to create PTV. Minimum dose 60 Gy in 3fxs.
*** Conclusion: "The HiArt Helical Tomotherapy system is capable of performing high dose liver SBRT that meets the specified target and normal organ constraints. This study provides broad initial screening eligibility criteria for patients with hepatic metastases who may be suitable for TomoTherapy-based liver SBRT. These guidelines are: for left lobe tumors; a GTV of 3 cm in diameter and a GTV that is at least 13 mm from the heart and 8 mm from the stomach; for right upper lobe tumors; a GTV of 5 cm in diameter that is at least 13 mm from the heart; for right lower lobe tumors; a GTV of 5 cm in diameter that is at least 8 mm from small bowel."
* Aarhus, 2005 PMID 16246744 -- Comparison of two dose calculation methods applied to extracranial stereotactic radiotherapy treatment planning. (Traberg Hansen A, Radiother Oncol. 2005 Oct;77(1):96-8.)
** Retrospective. 18 patients with single lung tumor, 8 patients with single liver tumor
** Comparison of pencil beam convolution vs. collapsed cone convolution
** Liver: CTV dose almost identical
** Lung: Mean CTV dose different by up to 20%

## Interstitial brachytherapy

* Ohio State 1989-02 ASTRO Abstract Long Term Follow-Up of Patients of Intrahepatic Malignancies Treated with Iodine-125 Brachytherapy (2005 Nag S, ASTRO 2005 #2086)
** Retrospective. 64 patients (54 mets CRC, 2 mets non-CRC, 4 CCA) treated with permanent BT 160 Gy; R1 59%, R2 41%; median follow-up 13.2 years
** Median survival (5-year OS): 20 months (5%). Higher for small implants and without prior resection
** Local control (5-year): median 9 months (22%)
** Conclusion: "Permanent I-125 brachytherapy is a safe and effective adjuvant treatment for unresectable intrahepatic malignancies. It is a simple technique with morbidity and mortality rates comparable to liver resection alone. Patients considered good candidates for I-125 brachytherapy include those with small volume implants, those without prior liver resection, and those with solitary liver metastases.
* Berlin Germany
** PMID 15050329 -- CT-guided interstitial brachytherapy of liver malignancies alone or in combination with thermal ablation: phase I-II results of a novel technique. (2004 Ricke J, Int J Radiat Oncol Biol Phys. 2004 Apr 1;58(5):1496-505.)
*** Phase II. 37 patients. 21 patients treated with CT-guided HDR alone, 16 patients BT after MRI-guided LITT (laser-induced thermotherapy). BT alone if tumor >5cm, adjacent to CBD or adjacent to major vessels, technical failure of LITT.
*** Mean tumor size 4.6cm (2.5-11cm); severe complications in 2 patients (liver failure, obstructive jaundice)
*** Local control: 73% LITT+BT, 87% BT alone
*** Conclusion: "CT-guided brachytherapy using three-dimensional CT data for dosimetry is safe and effective alone or in combination with LITT. Brachytherapy as a stand-alone treatment displayed genuine advantages over thermal tumor ablation."
** PMID 15525748 -- Liver malignancies: CT-guided interstitial brachytherapy in patients with unfavorable lesions for thermal ablation. (2004 Ricke J, J Vasc Interv Radiol. 2004 Nov;15(11):1279-86.)
*** Phase II. 20 patients (19 liver mets, 1 cholangiocarcinoma) treated with CT-guided HDR. Group A (n=11, liver tumors >5cm), Group B (n=9, liver tumors <5cm adjacent to hilum). Average dose 17 Gy (12-25 Gy). Median follow-up 13 months
*** Severe side effects 2 patients (10%): obstructive jaundice from tumor edema, intra-abdominal hemorrhage. Frequent LFT elevation without clinical symptoms
*** 1-year local tumor control: Group A 40%, Group B 71%. After CT-guided HDR retreatment 93% overall control
*** Conclusion: "CT-guided brachytherapy based on individual dose plans and 3D CT data sets generated encouraging results in large liver malignancies as well as in tumors located adjacent to the liver hilum."

## Microsphere therapy

Two products utilizing $^{90}$yttrium microspheres:
* TheraSpheres (Wikipedia entry; MDS Nordion) - glass beads bound with Y-90
* SIR-Spheres (Sirtex) - resin with Y-90 in matrix
Y-90 characteristics: pure beta emitter, average energy 0.94 MeV, tissue penetration 2.5 mm, maximum range 1.1 cm. Half life 64.2 hrs.
* REBOC Recommendations (Radioembolization Brachytherapy Oncology Consortium)
** 2007 - PMID 17448867 — Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. (Kennedy A, Int J Radiat Oncol Biol Phys. 2007 May 1;68(1):13-23.)
* SIRFLOX Trial (2006-2013) -- mFOLFOX6 vs mFOLFOX6 + SIRT
** Randomized. 530 patients. Chemotherapy naïve metastatic colorectal cancer, with liver mets plus/minus limited extrahepatic mets.
** PMID 26903575 -- "SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer." (van Hazel GA, J Clin Oncol. 2016 Feb 22. pii: JCO661181. [Epub ahead of print])
*** Outcome: Median PFS at any site control 10.2 vs SIRT 10.7 (NS). Median PFS in liver 12.6 vs 20.5 months (SS)
*** Toxicity: Grade 3+ in 73% vs 85%
*** Conclusion: Addition of SIRT to FOLFOX did not improve PFS at any site, but significantly delayed disease progression in the liver