Fig. 18.1
Patient with oligometastatic pancreatic cancer with an enlarging right hepatic lobe segment 6 lesion measuring 1.8 cm, treated with stereotactic body radiation, 54 Gy in three fractions. Axial (a) and coronal (b) computerized tomography imaging illustrating the final treatment plan
18.7.2 Dose Constraints for SBRT Liver Metastases
Surgical series have demonstrated as much as 80 % of normal liver can be resected without causing liver failure [18, 19].
Prior to SBRT, radiation had a limited role in ablative treatment of liver metastases due to low whole-liver tolerance with a 5 % risk of radiation-induced liver disease (RILD) with whole-liver doses of 30–35 Gy in 2 Gy per fraction [20, 21].
RILD syndrome is characterized by anicteric ascites with elevated alkaline phosphatase and liver transaminases, which typically occurs several weeks to months after radiation therapy.
RILD can lead to liver failure and death.
18.8 Potential Toxicities from Treatment
18.8.1 Hepatotoxicity
Most commonly utilized dose-tolerance model used in SBRT for normal parenchyma is that at least 700 mL of normal liver receive <15 Gy of total dose.
Model was first introduced by Schefter and colleagues [15] in a phase I dose-escalation trial for hepatic metastases.
In this study, dose was escalated from 36 Gy to 60 Gy in three fractions, and a “critical volume” model requiring at least 700 ml of normal receive <15 Gy of total dose was implemented.
There was no grade 3 or higher hepatotoxicity reported.
Currently, there are no reported prospective dose-escalation trials that have reached a maximum-tolerated dose (MTD) for hepatotoxicity [14–17, 22, 23].
The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) therefore suggest ≥700 mL of normal liver receives ≤15 Gy in three to five fractions [24].
Additional QUANTEC recommendations of mean normal liver dose for SBRT liver metastases include <15 Gy for liver metastases, in three fractions, and <20 Gy for liver metastases, in six fractions.
Other available liver constraints include limiting the V15 and V21 to 50 % and 30 %, respectively, for three fractions [25].
A number of models estimating volume dependence of normal tissue toxicity in liver have been used.
The Lyman model was one of the first which assumes a sigmoid relationship between a dose of uniform radiation given to a volume on an organ and the chance of a complication occurring.
However, as dose distributions are not uniform, additional calculations needed to be made.
Effective liver volume (Veff) irradiated is defined as the normal liver volume minus all GTVs, which if irradiated uniformly to the treatment dose would be associated with the same risk of toxicity or normal tissue complication probability (NTCP) as the nonuniform dose distribution [26].
Dawson and colleagues [27] analyzed the risk of RILD in 203 patients followed prospectively after being treated with conformal liver RT, using the Lyman-Kutcher-Burman (LKB) NTCP model.
Mean liver dose was 32 Gy, and the majority was treated with partial liver radiation.
The lower Veff correlated with significantly lower risks of RILD, demonstrating that in the setting of dose escalation, high doses can be delivered as long as the mean dose to the liver is taken into account.
In their analysis, a threshold volume effect was demonstrated with nearly zero incidence of RILD at an effective liver volume of less than one-third.
Cirrhotic livers are known to have lower tolerances to SBRT [24, 28], and therefore most prospective trials excluded patients with Child-Pugh B classification or higher [15–17, 22].
Overall, RILD occurs in less than 5 % of all reported SBRT cases.
In the phase II SBRT liver metastases study conducted by Méndez-Romero and colleagues [28], there were two cases of RILD, one classic and one nonclassic; an additional patient with hepatocellular carcinoma and baseline Child-Pugh B experienced portal hypertension and nonhepatic infection and died within 2 weeks of treatment.
Hoyer and colleagues [29] prospectively evaluated 61 patients treated with SBRT for colorectal metastases to 45 Gy in three fractions and observed severe liver toxicity in one patient who died of hepatic failure 7 weeks after completing radiation; 60 % of the liver received ≥10 Gy.
Princess Margaret Hospital performed two phase I trials of SBRT for primary liver tumors [30] and liver metastases [31] deriving total SBRT dose from a normal tissue complication probability (NTCP) modeling.
The study included patients with primary hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and hepatic metastases.
Approximately 17 % of patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma were found to progress from Child-Pugh A to B within 3 months after radiation.
In contrast, there were only two grade 3 liver enzyme changes in the liver metastases cohort, likely demonstrating that those with liver metastases present with healthier baseline liver parenchyma.
To minimize the risk of RILD, the current QUANTEC recommendations suggest that mean normal liver dose should be less than 6 Gy for primary liver cancer and Child-Pugh B undergoing 3–6 Gy per fraction [24].
However, in contrast to patients presenting with hepatocellular carcinoma, the majority of patients with hepatic metastases do not present with underlying cirrhosis and are therefore less susceptible to RILD.
18.8.2 Chest Wall Toxicity
Chest wall pain and rib fracture, while rare, can be very painful. The most commonly used metric is the volume of chest wall receiving ≥30 Gy (V30) [32–34].
Dunlap and colleagues [34] combined SBRT data in lung cancer from multiple institutions, including 60 patients treated with three to five fractions of SBRT to peripheral lung lesions.
Reported no incidences of pain or fracture when the V30 was maintained below 30 cc, whereas 30 % of patients experienced chest wall toxicity when the V30 exceeded 35 cc.
Cleveland Clinic group validated the findings of V30 and went further by developing a modified equivalent uniform dose (mEUD) model, accounting for variability in dose-fraction regimens and inhomogeneity [35].
Memorial Sloan-Kettering Cancer Center prospectively followed 126 patients treated with SBRT with doses ranging between 40 and 60 Gy in 3–5 fractions for non-small cell lung cancer and found chest wall V30 ≥70 cc significantly correlated with grade 2 or higher chest wall pain [36].
18.8.3 Gastrointestinal Toxicity
Peripheral and hilar liver lesions may place patients at risk for gastrointestinal toxicities including ulcerations and perforations.
Blomgren and colleagues [7]: one patient experienced hemorrhagic gastritis when less than one-third of the stomach received more than 7 Gy, another patient had a duodenal ulcer after the distal stomach, and proximal duodenum received 5 Gy in four treatments.
Hoyer and colleagues [29]: one patient experienced a colonic perforation, which required surgical intervention, and two additional patients had duodenal ulcers, which were treated conservatively.
Additional SBRT studies suggest that the point dose to the duodenum should not exceed 10 Gy per fraction for three fraction regimens [15]. In all three settings, intestinal doses exceeded 30 Gy [15, 37].
More recent trials using conservative dose constraints have reported minimal gastrointestinal toxicity, and normal tissue tolerance estimates for single and multiple fraction SBRT have been published [38].
Organ at risk | Dose constraints (QUANTEC) | Dose constraints RTOG 0438 (hypofractionation) |
|---|---|---|
Liver | ≥700 cc of normal liver receives ≤15 Gy in 3–5 fractions Mean normal liver dose: <15 Gy in 3 fractions or <20 Gy in 6 fractions | V27 less than or equal to 30 % V24 less than or equal to 50 % |
Spinal cord | Max dose <50 Gy (0.2 % risk myelopathy) | Max dose ≤ 34 |
Stomach | D100 <45 Gy (<7 % risk ulceration) | Max dose 37 Gy to 1 cc |
Small bowel | V45 <195 cc (<10 % risk grade 3 + toxicity) (peritoneal cavity) | Max dose 37 Gy to 1 cc |
Bilateral kidneys | Mean <15–18 Gy (<5 % risk clinical dysfunction) | No more than 33 % of combined volume ≥18 Gy |
18.9 Future Directions
Delivering SBRT to large tumors (>7 cm) continues to be a challenge and in general was an exclusion criteria in the currently published prospective studies discussed.
Novel planning and delivery techniques are necessary to approach these larger tumors with similar ablative doses, while minimizing toxicity.
Further, tumors adjacent to critical structures including bowel also pose a challenge.
A recent strategy to treat these larger tumors discussed by Crane and Koay [39] is called simultaneous integrated boost (SIB) with simultaneous integrated protection (SIP).
The technique involves hypofractionation to achieve a biologically equivalent dose (BED) of 100 Gy in 15–25 fractions, followed by decreasing the CTV and PTV margins within normal liver tolerance, creating margins around organs at risk (OARs), and then treating the hypoxic center of the tumor to a BED >140 Gy if possible.
Improvements in imaging to delineate normal liver parenchyma will also be important, and there are currently several imaging modalities being investigated [39].
Indocyanine green (ICG) is a water-soluble compound that binds to albumin and is selectively taken up by hepatocytes.
Its uptake correlates with hepatic function and can be used during planning to attempt sparing of normal liver tissue.Related posts:
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