**4.2. Chemotherapy**

TARE is usually not indicated in elderly patients, who often have a compromised liver function, and therefore, risks of liver failure and death are high. TARE can be performed in elderly with good performance status and liver functionality as a second-line treatment in patients

TARE has not been shown superior to sorafenib in treating advanced HCC; therefore, sorafenib could be a safer treatment in elderly patients who can tolerate chemotherapy [53].

PEI induces cell necrosis through dehydration, protein denaturation, and small vessel disruption. It is not often used since it can only be performed in lesions <2 cm and it has a higher recurrence ratio than percutaneous ablation. It has indication only in lesions that are not con-

Compared to PEI, RF has shown better outcomes in terms of overall survival, survival at 1, 2, and 3 years, and cancer-free survival at 1, 2, and 3 years. This is probably due to the better performance of RF in terms of complete necrosis of the lesion and the low percentage of local

RF requires fewer treatment sessions and shorter hospitalization than ethanol injection: although the quality of life of these patients was not evaluated, there was a decrease in hos-

Cell death with cryoablation is different than that with thermal ablation. The freezing process results in both intracellular and extracellular ice formation, both of which can result in cellular death, but by different mechanisms. Since the ablation zone is reperfused after the ice ball melts, the result is a rapid release of cellular debris into the systemic circulation. This probably explains the systemic complications of cryoablation (i.e., cryoshock) that are rare with heat-based ablation. Thermoablation is the preferred ablation method for treating HCC in patients with cirrhosis because of the increased risk of bleeding and of disseminated intravascular coagulation-like reaction (called cryoshock) associated with cryoablation [55, 56]. Therefore, although many studies have shown that small-volume cryoablation is feasible in patients with cirrhosis and HCC, it is difficult to justify the additional risk of cryoablation in

The term laser ablation refers to the thermal tissue destruction by conversion of absorbed light (usually infrared) into heat. Infrared energy penetrates tissue for 12–15 mm in depth; heat is conducted beyond this range thereby creating a larger ablation area. Optical penetration has been shown to be increased in malignant tissue compared to normal parenchyma [57].

these patients when viable heat-based alternatives are available [55].

with treatment failure following TACE.

*4.1.4.1. Percutaneous ethanol injection (PEI)*

sidered safe for ablation due to their localization [54].

*4.1.4. Other*

44 Liver Cancer

recurrence [54].

pitalization rates [54].

*4.1.4.2. Cryoablation*

*4.1.4.3. Laser ablation (LA)*

Systemic therapy is recommended for HCC patients in stage BCLC-C with conserved liver functionality (Child-Pugh A), good performance status, advanced disease, and/or extrahepatic diffusion. Systemic therapy is also recommended for patients with progressive HCC after locoregional treatments or HCC with vascular invasion not enrollable for other local treatments [17].

Target therapy with sorafenib proved to give survival benefits versus either placebo or cytotoxic and hormonal therapy [61].

Observational studies suggest that sorafenib administration in Child-Pugh B patients is as safe as administration in class A patients [62].

Recently, RESORCE trial showed survival benefit in regorafenib administration vs. placebo for HCC patients that went to tumor progression after sorafenib administration; all patients had tyrosine kinases-associated adverse effects [63].

**4.3. Best supportive care**

lopathy. Abdominal pain and asthenia are common.

tion risk, and resistant ascites development.

50% of patients and partial in 80–90% [66].

ments available against HCC.

adverse effects.

fractions [12, 71].

Palliative treatments and supportive care aim at ameliorating patients QoL and at giving relief by symptoms. Terminal-stage HCC may have several symptoms associated with liver dysfunction due to cirrhosis, such as ascites, esophageal hemorrhage, and hepatic encepha-

HCC in Elderly Patients. Curative Intraoperative Strategies and Management in Recurrences

http://dx.doi.org/10.5772/intechopen.79748

47

Paracetamol and opioids are the safest drugs for pain control in hepatopathics; Non Steroideal Antinflammatory Drugs (NSAIDs) shall be avoided due to hemorrhage risk, kidney dysfunc-

Radiotherapy is effective in pain control due to bone metastases; control results complete in

Percutaneous cementoplasty is effective in controlling HCC vertebral metastases' pain [67]. Brain metastases are rare and selected cases can be treated with stereotaxic radiotherapy [68]. Malnutrition and cachectic-state is common in end-stage oncological patients, in particular if affected by noncontrolled cirrhosis which enhances weight loss and muscular tissue loss.

Nutritional state assessment is important in HCC patients and was observed that prognostic

Hadrontherapy or heavy charged particle therapy (CPT) is one of the newest palliative treat-

Hadrontherapy technology is based on charged particles (carbon ions), which accelerated by cyclotrons or synchrotrons are conveyed into a beam to irradiate the tumor. Different from X-rays, charged particles have a sharp Bragg's peak which is even sharper than the one of protons; therefore, they release a great part of their energy at a specific level of tissue penetra-

This technology allows to concentrate cellular damage into a very small area; therefore, CPT has higher tumor control probability (TCP) and relative biological effectiveness (RBE) than other radiotherapy techniques, it can also reduce organs at risk (OAR) and nonmalignant

Due to the physical properties of charged particles and, in particular, the possibility to generate a heavy concentrated damage, hypofractioning is possible with good results in terms of

Clinical trials on CPT are still running; first data are hopeful; in a Japanese study that used CPT in nontreatable HCC, a 5-year local control rate was 81% and survival was 33%; results are similar to those for proton therapy with 20 fractions, but by using a total of 4 fractions in 2 days [71]. Good results are also obtained with difficult to treat porta-hepatis HCC [69]. As for HCC metastases, they can be treated with a 50.4 Gy irradiation in 12

nutritional index can predict survival expectancy in HCC patients [69].

**4.4. Frontiers in palliative treatment of HCC: hadrontherapy**

tion which is proportional to their kinetic energy.

tissue complications probability (NTCP) [70].

Cytotoxic chemotherapy, such as doxorubicin or FOLFOX4 scheme, can be considered in patients with conserved liver functionality and after that sorafenib therapy has suspended for adverse effects [17] (**Table 5**).

Adverse effects of sorafenib especially dermatological, hypertension, or diarrhea in the first month of treatment are a frequent cause of treatment failure; it was proved that half-dose administration after adverse effects is associated with survival benefits [64].

In some cases, for fit and super-selected patients, intolerant to sorafenib, in case of oligometastatic disease, a different disease management can be done. Mini-invasive surgical therapy along with intervention radiology may be able to remove several metastases and treat them as they show; once the primitive tumor is surgically resected, a chronic metastatic disease can be surgically controlled with survival benefits [12]. Only case reports on this field have been published, but these authors believe that more research shall be done with multicentric clinical trials to prove what has been shown only in case reports.

Elderly can hardly ever be treated with surgical therapy due to their frailty and low PS even if in many cases, biological age does not correspond to chronological age. Sorafenib showed similar results in terms of safety and effectiveness in elderly and younger HCC populations. When administering systemic therapy, careful baseline evaluation is needed for patient's selection in elderly population, including discussion about antiplatelet therapy discontinuation, and caution in PS ≥ 1 patients, as well as active management of toxicity.

Asthenia and bleeding are more frequent in the elderly. The higher frequency of bleeding is explained by concomitant antiplatelet treatments, and major asthenia is frequent in PS ≥ 1 elderly patients [65].

A multidimensional evaluation is crucial for elderly patients and also in advanced HCC, and decision to start systemic therapy shall be made by experienced and dedicated units.


**Table 5.** Most common adverse effects of Sorafenib.

#### **4.3. Best supportive care**

Recently, RESORCE trial showed survival benefit in regorafenib administration vs. placebo for HCC patients that went to tumor progression after sorafenib administration; all patients

Cytotoxic chemotherapy, such as doxorubicin or FOLFOX4 scheme, can be considered in patients with conserved liver functionality and after that sorafenib therapy has suspended for

Adverse effects of sorafenib especially dermatological, hypertension, or diarrhea in the first month of treatment are a frequent cause of treatment failure; it was proved that half-dose

In some cases, for fit and super-selected patients, intolerant to sorafenib, in case of oligometastatic disease, a different disease management can be done. Mini-invasive surgical therapy along with intervention radiology may be able to remove several metastases and treat them as they show; once the primitive tumor is surgically resected, a chronic metastatic disease can be surgically controlled with survival benefits [12]. Only case reports on this field have been published, but these authors believe that more research shall be done with multicentric

Elderly can hardly ever be treated with surgical therapy due to their frailty and low PS even if in many cases, biological age does not correspond to chronological age. Sorafenib showed similar results in terms of safety and effectiveness in elderly and younger HCC populations. When administering systemic therapy, careful baseline evaluation is needed for patient's selection in elderly population, including discussion about antiplatelet therapy discontinuation, and caution in PS ≥ 1 patients, as well as active management of

Asthenia and bleeding are more frequent in the elderly. The higher frequency of bleeding is explained by concomitant antiplatelet treatments, and major asthenia is frequent in PS ≥ 1

A multidimensional evaluation is crucial for elderly patients and also in advanced HCC, and

decision to start systemic therapy shall be made by experienced and dedicated units.

administration after adverse effects is associated with survival benefits [64].

clinical trials to prove what has been shown only in case reports.

had tyrosine kinases-associated adverse effects [63].

adverse effects [17] (**Table 5**).

46 Liver Cancer

toxicity.

elderly patients [65].

**Table 5.** Most common adverse effects of Sorafenib.

Palliative treatments and supportive care aim at ameliorating patients QoL and at giving relief by symptoms. Terminal-stage HCC may have several symptoms associated with liver dysfunction due to cirrhosis, such as ascites, esophageal hemorrhage, and hepatic encephalopathy. Abdominal pain and asthenia are common.

Paracetamol and opioids are the safest drugs for pain control in hepatopathics; Non Steroideal Antinflammatory Drugs (NSAIDs) shall be avoided due to hemorrhage risk, kidney dysfunction risk, and resistant ascites development.

Radiotherapy is effective in pain control due to bone metastases; control results complete in 50% of patients and partial in 80–90% [66].

Percutaneous cementoplasty is effective in controlling HCC vertebral metastases' pain [67]. Brain metastases are rare and selected cases can be treated with stereotaxic radiotherapy [68].

Malnutrition and cachectic-state is common in end-stage oncological patients, in particular if affected by noncontrolled cirrhosis which enhances weight loss and muscular tissue loss.

Nutritional state assessment is important in HCC patients and was observed that prognostic nutritional index can predict survival expectancy in HCC patients [69].

#### **4.4. Frontiers in palliative treatment of HCC: hadrontherapy**

Hadrontherapy or heavy charged particle therapy (CPT) is one of the newest palliative treatments available against HCC.

Hadrontherapy technology is based on charged particles (carbon ions), which accelerated by cyclotrons or synchrotrons are conveyed into a beam to irradiate the tumor. Different from X-rays, charged particles have a sharp Bragg's peak which is even sharper than the one of protons; therefore, they release a great part of their energy at a specific level of tissue penetration which is proportional to their kinetic energy.

This technology allows to concentrate cellular damage into a very small area; therefore, CPT has higher tumor control probability (TCP) and relative biological effectiveness (RBE) than other radiotherapy techniques, it can also reduce organs at risk (OAR) and nonmalignant tissue complications probability (NTCP) [70].

Due to the physical properties of charged particles and, in particular, the possibility to generate a heavy concentrated damage, hypofractioning is possible with good results in terms of adverse effects.

Clinical trials on CPT are still running; first data are hopeful; in a Japanese study that used CPT in nontreatable HCC, a 5-year local control rate was 81% and survival was 33%; results are similar to those for proton therapy with 20 fractions, but by using a total of 4 fractions in 2 days [71]. Good results are also obtained with difficult to treat porta-hepatis HCC [69]. As for HCC metastases, they can be treated with a 50.4 Gy irradiation in 12 fractions [12, 71].

It is strongly believed, by this multidisciplinary team, that early diagnosis is the key for HCC eradication in general population and in particular in elderly: dealing with a lowerstaged cancer allows to use both less invasive and more radical treatments. Patients would then suffer less hospitalization time; would have faster recovery and lower infection risk [4]. Hospitalization time and subsequent infections are the most common cause of death for hospitalized elderly patients. Early-HCCs grow slowly when they develop in elderlies and when removed surgically or with interventional radiology mean (RFTA or MWA) recurrences appear after a sufficient time latency thus to make it possible to chronicize the disease and

HCC in Elderly Patients. Curative Intraoperative Strategies and Management in Recurrences

The elderlies are a very heterogenic population; therefore, this kind of patients cannot be treated with a standardized protocol, but a tailored approach is needed. Each patient has its own comorbidities that must be taken into account; moreover, aging itself is an extremely individual process and different patients may have wide differences in performance status and therefore different treatment indications. Life expectancy, comorbidities, liver functionality, cancer progression, patient's therapy compliance, psychological status, and performance status shall be all taken into account when cases are discussed into multidisciplinary teams in

, Leonardo Luca Chiarella1

2 Department of Radiological Sciences, University of Rome La Sapienza, Policlinico Umberto I,

[1] Cabibbo G, Enea M, Attanasio M, Bruix J, Craxí A, Camm̀a, C. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carci-

[2] El-Serag HB, Rudolph KL. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology. 2007;**132**(7):2557-2576. DOI: 10.1053/j.gastro.2007.04.061 [3] Basso U, Monfardini S. Multidimensional geriatric evaluation in elderly cancer patients: A practical approach. European Journal of Cancer Care. 2004;**13**(5):424-433. DOI:

, Katia Fazzi1

,

http://dx.doi.org/10.5772/intechopen.79748

49

allow to reach survival rates not different from general population [4].

order to assure the best treatment, and therefore, the best OS and QoL.

\*, Simone Bini1

and Mario Bezzi2

\*Address all correspondence to: stefania.brozzetti@uniroma1.it

1 Department of Surgery "Pietro Valdoni", University of Rome La Sapienza,

noma. Hepatology. 2010;**51**(4):1274-1283. DOI: 10.1002/hep.23485

**Author details**

Stefania Brozzetti<sup>1</sup>

Rome, Italy

**References**

Michele Di Martino2

Policlinico Umberto I, Rome, Italy

10.1111/j.1365-2354.2004.00551

**Figure 1.** Summary—HCC treatment decision chart in elderly recipients.

These treatments are still experimental but results of trials until now are encouraging, in the next future hadrontherapy may be one of the pillaRs of advance HCC treatment.

Hadrontherapy may be extremely interesting as a treatment also for elderlies, since it has little adverse effect and thanks to hypofractioning and noninvasivity; in the future, it may become a treatment of choice for difficult-to-treat HCC in elderly and for metastatic disease. It may ensure long-time tumor control and good QoL even in people advanced in age; the only issue of this treatment is its high cost-effectiveness ratio, even though cost-effectiveness trials for CPT are not still published a CPT apparatus costs around US\$ 200 million; only three carbon ion centers are available in Western Europe, seven in Asia (Japan and China), and none in US [65] (**Figure 1**).

#### **5. Conclusion**

The aim of this chapter is to give information and indications about the most recent operative and nonoperative existing techniques to treat HCC. Focus on older adults' case evaluation is of extreme importance; because lifespan enlargement will produce, in next decades, a sharp rise in HCC incidence among elderlies [2].

It is strongly believed, by this multidisciplinary team, that early diagnosis is the key for HCC eradication in general population and in particular in elderly: dealing with a lowerstaged cancer allows to use both less invasive and more radical treatments. Patients would then suffer less hospitalization time; would have faster recovery and lower infection risk [4]. Hospitalization time and subsequent infections are the most common cause of death for hospitalized elderly patients. Early-HCCs grow slowly when they develop in elderlies and when removed surgically or with interventional radiology mean (RFTA or MWA) recurrences appear after a sufficient time latency thus to make it possible to chronicize the disease and allow to reach survival rates not different from general population [4].

The elderlies are a very heterogenic population; therefore, this kind of patients cannot be treated with a standardized protocol, but a tailored approach is needed. Each patient has its own comorbidities that must be taken into account; moreover, aging itself is an extremely individual process and different patients may have wide differences in performance status and therefore different treatment indications. Life expectancy, comorbidities, liver functionality, cancer progression, patient's therapy compliance, psychological status, and performance status shall be all taken into account when cases are discussed into multidisciplinary teams in order to assure the best treatment, and therefore, the best OS and QoL.
