Managements of recurrent hepatocellular carcinoma after liver transplantation: A systematic review

Table 1 Mean survival time after specific treatment modalities for local and systemic hepatocellular carcinoma recurrence in liver transplantation patients

Type of treatment for HCC recurrence in LT patients	No. of patients	Median survival1 (mo) (weighted mean ± SD)	Ref.
Loco-regional treatments for resectable local recurrence of HCC
Surgery	27	42 ± 24.45	Bates et al[38]
			Kornberg et al[50]
			Pfiffer et al[54]
			Kim et al[47]
			Chen et al[77]
			Sommacale et al[74]
TACE	40	11.2 ± 8.81	Tan et al[80]
			Kim et al[47]
			Pfiffer et al[54]
			Carr[39]
			Chen et al[77]
			Yamagami et al[64]
Systemic treatments for unresectable, advanced, multifocal recurrence of HCC
Sorafenib	76	12.1 ± 9.95	Tan et al[80]
			Yoon et al[65]
			Pfiffer et al[54]
			Staufer et al[76]
			Sposito et al[79]
			Pfeiffenberger et al[78]
			Alsina et al[73]
Sorafenib + mTOR	68	18.2 ± 6.53	Waidmann et al[34]
			Gomez-Martin et al[45]
			Weimann et al[63]
			Staufer et al[76]
			Sotiropoulos et al[58]
Systemic chemotherapy	35	5.79 ± 2.7	Lee et al[84]
			Kim et al[47]
Best supportive care	54	3.3 ± 2.12	Kim et al[47]
			Pfiffer et al[54]
			Yoon et al[82]
			Sposito et al[79]

¹Weighted mean survival (standard deviation) is calculated from the studies that reported the median survival in months from HCC recurrence diagnosis. TACE: Transarterial chemoembolization; HCC: Hepatocellular carcinoma; LT: Liver transplantation; mTOR: Mammalian target of rapamycin.

Table 2 Morbidity and mortality from surgical treatments for recurrent hepatocellular carcinoma in liver transplantation patients

Ref.	No. of patients	Surgical treatments	Post-operative morbidity	Post-operative mortality
		(No. of patients)
Regalia et al[75]	7	Liver resection (2), pulmonary lobectomy (2), omentectomy (1), bone resection (1), skin resection (1)	Uneventful	0
Castroagudìn et al[24]	1	Bilateral adrenalectomies in a successive manner	Uneventful	0
Catalano et al[40]	2	Liver resection (2)	Uneventful	0
Roayaie et al[55]	15	Liver resection (5), pulmonary resection (7), adrenalectomy (2), chest wall resection (1)	NR	0
Bates et al[38]	5	Pulmonary lobectomy (4), pulmonary lobectomy + rib resection after pre-transplant tumor biopsy (1)	NR	0
Kwon et al[71]	7	Pulmonary resection (7)	Uneventful	0
Marangoni et al[52]	4	Liver resection (4)	NS	0
Han et al[69]	12	Pulmonary resection (12)	NS	0
Kornberg et al[50]	7	Liver resection (2), pulmonary resection (2), cerebral tumor extirpation (1), adrenalectomy (1), chest wall resection after pre-transplant tumor biopsy (1)	NR	0
Valdivieso et al[61]	8	Liver resection (2), adrenalectomy (2), abdominal lymph node resection (2), pulmonary resection (2)	NR	0
Kitano et al[70]	3	Pulmonary resection (3)		0
Pfiffer et al[54]	7	Liver resection (1), extra-hepatic resection (6)	NR	NR
Kim et al[47]	3	Left adrenalectomy (1), splenectomy (1), lymph node resection	NR	0
Chen et al[77]	2	Pulmonary resection (1), adrenalectomy (1)	NR	0
Hwang et al[83]	23	Pulmonary resection (23)	Uneventful	0
Sommacale et al[74]	3	Liver resection (3)	100% (renal failure, respiratory sepsis, sub phrenic abscess)	0

NR: Not reported; HCC: Hepatocellular carcinoma; LT: Liver transplantation.

Table 3 Efficacy, safety and tolerability of loco-regional treatments for recurrent hepatocellular

Ref.	No. of patients	Treatment	No. of treatments per patient	Efficacy	Side effects	Tolerability	Safety
				(No.of patients)	(No. of patients)
Rivera et al[31]	1	SIRT (Y-90)	1	Efficacy demonstrated by tumor necrosis on imaging and decreased AFP level	Intermittent nausea Mild right upper quadrant abdominal pain	Well tolerated	No adverse consequence
Ho et al[27]	1	RFA	1	No evidence of local progression and normalization of AFP levels	None	Well tolerated	No adverse consequence
Ko et al[49]	28	TACE	2.5	Complete response (3), partial response (11), minimal response (5), stable disease (3), progressive disease (6)	In 17.9% of patients: Nausea, vomiting, diarrhea Hypertension, tachycardia Mild right upper quadrant abdominal pain	Well tolerated	No adverse consequence
Tan et al[80]	10	TACE	NR	According to RECIST criteria, partial response (1), stable disease (3), and progressive disease (6)	NR	Well tolerated	No adverse consequence
Carr[39]	6	TACE	8.2	Complete response (1), partial response (2), stable disease (1), progression (2)	Bilirubin toxicity (Grade 2) (1) Granulocyte toxicity (Grade 3) (3)	Well tolerated	No adverse consequence
Chen et al[77]	4	TACE	2.8	According to mRECIST criteria, complete or partial response in all patients	None	Well tolerated	No adverse consequence
Cheng et al[41]	11	TACE	NR	NR	NR	Well tolerated	No adverse consequence
Zhang et al[67]	10	CT 125I guided brachytherapy	3.9	Complete local control of HCC recurrence 72% of patients at 2 yr	Minor displacement of radioactive seeds (2)	Well tolerated	Hemothorax (1)
					Mild increase of white blood cell counts (3)		Hemosputum (3)
					Fever (4)

CT: Computed tomography; TACE: Transarterial chemoembolization; RFA: Radiofrequency ablation; SIRT: Selective internal radiotherapy treatment; HCC: Hepatocellular carcinoma; LT: Liver transplantation.

Table 4 Efficacy, safety and tolerability of Sorafenib for recurrent hepatocellular carcinoma in liver transplantation patients

Ref.	n	Treatments	Type of immunosuppression	Efficacy(No. of patients)	Most frequent side effects1	Tolerability	Safety(No. of patients)
Yeganeh et al[35]	1	Sorafenib (400 m bid)	Tacrolimus + mycophenolate mofetil	Complete resolution of his lung lesion	Diarrhea Hand-foot skin reactions	Dose reduction needed (200 mg bid)	No major adverse consequence
Bhoori et al[23]	1	Sorafenib (400 mg bid)	Everolimus	50% response according to RECIST criteria modifications after introduction of Everolimus	Hand-foot skin reactions (Grade 1)	Well tolerated	No major adverse consequence
Herden et al[26]	1	Sorafenib (200 mg bid)	Cyclosporine A	NR	Nausea Fever up to 39 °C Jaundice	Discontinuation after 5 d of treatment	Centrolobular hepatocellular necrosis and lymphoplasmacellular and granulocytic infiltration of portal tracts with significant eosinophilia (hyper allergic drug reaction)
Kim et al[48]	9	Sorafenib (200 to 400 mg bid)	Tacrolimus ± Sirolimus	Complete radiographic response (1), stable disease (4), progression (3)	Hand-foot skin reactions Fatigue and anorexia Diarrhea Mucositis	Discontinuation in 5 patients	No major adverse consequence nor deterioration of liver graft function
Tan et al[80]	10	Sorafenib (400 mg bid)	Tacrolimus	Stable disease (7), progressive disease (3)	Rash Hypertension Agrypnia Hand-foot skin reaction Diarrhea	Discontinuation in 1 patient	No major adverse consequence
Valdivieso et al[61]	5	Sorafenib (400 mg bid)	Everolimus	NR	NR	NR	NR
Wang et al[37]	1	Sorafenib (400 mg bid)	Tacrolimus/Sirolimus	Partial response (after introduction of Sirolimus)	Hand-foot skin reactions	Dose reduction needed (200 mg bid)	No major adverse consequence
Yoon et al[65]	13	Sorafenib (400 mg bid)	Calcineurin inhibitors ± mycophenolate mofetil	Stable disease (6)	Chest wall pain Hand-foot skin reactions Neutropenia, thrombocytopenia, anemia Rash Diarrhea	Dose reduction (200 mg bid) in 4 patients	No major adverse consequence
Kim et al[28]	1	Sorafenib (200 to 400 mg bid)	Sirolimus	Complete radiologic response	Hand-foot skin reactions Fatigue Mucositis	Dose reduction needed (200 mg bid)	No major adverse consequence
Takahara et al[33]	2	Sorafenib (200 to 400 mg bid)	Cyclosporine/Tacrolimus	Complete response (1)	Hypertension Diarrhea, anorexia	Dose reduction (200 mg bid) for 1 patient	No major adverse consequence
Waidmann et al[34]	3	Sorafenib (400 mg bid)	Everolimus/Sirolimus	Partial response after introduction of mTOR (1), progression (1)	Hand-foot skin reactions (Grade 3) Fatigue (Grade 3)	Discontinuation for 1 patient, dose reduction (200 mg bid) for 1 patient	Death for sepsis and multi-organ failure (1) after 3 wk of Sorafenib treatment
Gomez-Martin et al[45]	31	Sorafenib (400 mg bid)	Everolimus	Complete response (1), partial response (1), and stable disease (13)	Mild graft dysfunction Hand-foot skin reactions Asthenia Hypertension Diarrhea Thrombocytopenia	Dose reduction (200-300 mg bid) in 8 patients	Central nervous system hemorrhaging (1), severe biventricular heart failure (1), and upper digestive hemorrhaging (2) leading to death (1)
Sotiropoulos et al[58]	14	Sorafenib (400 mg bid)	mTOR	Progression (4)	NR	Discontinuation for 4 patients, dose reduction (100 to 200 mg bid) for 2 patients	NR
Staufer et al[76]	13	Sorafenib (400 mg bid)	mTOR/Cyclosporine A	Partial response (1), stable disease (4), progression (7)	Anemia, leukopenia Hand-foot skin reactions Increase of liver function tests Fatigue	Poor tolerability. Dose reduction (200 mg bid) in 10 patients	Centrolobular hepatocellular necrosis and lymphoplasmacellular infiltration of portal tracts (2) with eosinophilia (2)
Vitale et al[62]	10	Sorafenib (400 mg bid)	mTOR/Tacrolimus	According to mRECIST criteria, partial response (2), stable disease (6), progression (2)	Diarrhea Diarrhea Hand-foot skin reactions Fatigue	Dose reduction in 7 patients	No major adverse consequence
Weinmann et al[63]	11	Sorafenib (400 mg bid)	Sirolimus	Stable disease (4), progression (7)	Diarrhea Fatigue Nausea Hand-foot skin reactions Hair loss Weight loss	Discontinuation and dose reduction (200 mg bid) for 7 patients	No major adverse consequence
Pfeiffenberger et al[78]	8	Sorafenib (400 mg bid)	Tacrolimus/Tacrolimus + mycophenolate mofetil/Cyclosporin A	Progression (1)	Hand-foot skin reaction Diarrhea	Dose reduction for 6 patients	No major adverse consequence
Sposito et al[79]	15	Sorafenib (400 mg bid)	mTOR/Cyclosporine A/Tacrolimus	According to RECIST, stable disease (11), partial response (4)	Hand-foot skin reactions Diarrhea Fatigue	Dose reduction (200 mg bid) for 8 patients	No major adverse consequence
Waghray et al[81]	17	Sorafenib (400 mg bid)	Sirolimus	Complete response (2), partial response (1), stable disease (2), progression (5)	Diarrhea, nausea Fatigue Increase of liver function tests Hand-foot skin reactions	Dose reduction (100 to 200 mg bid) for 14 patients	No major adverse consequence
Zavaglia et al[66]	11	Sorafenib (400 mg bid)	Everolimus/Cyclosporine A	Partial response (2), stable disease (1), progression (6)	Fatigue, anorexia Hypophosphatemia Diarrhea, nausea, vomiting Hand-foot skin reactions	Discontinuation in 4 patients, dose reduction (200 mg bid) for 7 patients	Massive gastrointestinal bleeding leading to death after 4 mo of Sorafenib + mTOR
Alsina et al[73]	9	Sorafenib (400 mg bid)	Tacrolimus/Cyclosporine A ± mycophenolate mofetil	NR	Hand-foot skin reaction Rash Seizure Skin flushing	Dose reduction for 2 patients	No major adverse consequence
De Simone et al[43]	7	Sorafenib (400 mg bid)	Everolimus	According to mRECIST, progression (5)	Hand-foot skin reactions Hypertension Diarrhea Anorexia, asthenia Hoarseness Alopecia	Dose reduction for 3 patients, temporary discontinuation for 2 patients	No major adverse consequence
Perricone et al[53]	4	Sorafenib (200 mg bid)	Everolimus	Stable disease (1), progression (3)	Diarrhea (Grade 3)	Discontinuation for 1 patient	Severe diarrhea with progressive worsening of clinical condition, leading to coma then death (1) 4 mo after Sorafenib + mTOR

¹When available, Sorafenib-related adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (Grade I to V). RECIST: Response Evaluation Criteria in Solid Tumors; mTOR: Mammalian target of rapamycin; HCC: Hepatocellular carcinoma; LT: Liver transplantation.