11.1 Introduction
Locally ablative therapy is an interesting option for patients with irresectable metastatic disease or primary hepatic malignomas confined to the liver. The aim is the complete ablation of all he-patic lesions or at least the achievement of a lo¬cal tumor control. Specifically, radio-frequency ablation (RFA) has captured increasing interest, since it is easy to use even as an outpatient pro-cedure in selected patients (Meyers et al. 2003). Laser-induced thermotherapy (LITT) offers the opportunity of real-time therapy monitoring by magnetic-resonance thermometry, which is thought to be advantageous to other locally ab-lative procedures (e.g., RFA) (Nolsoe et al. 1993; Vogl et al. 1995). However, these procedures have limitations concerning number and localization, as well as size and shape, of tumor lesions.
More recently, there is growing interest in applying radiotherapy to hepatic malignancies. Compared to local thermoablative procedures, radiation efficacy is not affected by cooling ef-fects of neighboring vessels or bile ducts, which are known to be a potential source of local tumor progression after RFA or LITT. Adjacent organs such as the colon or the hilar bile ducts play a minor role for possible complications. The size and shape of the radiation target volume is not restricted to less than 5 cm in diameter and spheroid lesions. However, as the tolerance dose of liver parenchyma is lower than that of most tumor tissues, the therapeutic efficacy of percu-taneous irradiation interferes with the manda¬tory maintenance of a sufficient liver function. The main problems are the breathing excursion of the liver and the flat dose shoulder surround¬ing the target volume, resulting in a relatively high radiation exposure of the normal hepatic parenchyma. Even though there do exist in-novations such as respiratory gated irradiation, stereotactic irradiation, or tomotherapy devices, these problems have not generally been solved to date (Herfarth et al. 2004; Wurm et al. 2006).
The drawbacks of external beam radiotherapy can be overcome when irradiation is brought next to or into the tumor, offering a steep dose decrease to the periphery around the irradiated focus and independency from breathing motion. This approach is referred to as brachytherapy. As a high dose rate, hypofractionated radiation therapy, this technique is used, e.g., for endo-bronchial or endovaginal irradiation of lung and cervical cancer, or interstitial irradiation of superficial tumors (e.g., breast cancer, head and neck cancer). It is usually realized in an af-terloading technique, where a radiation source, e.g., iridium-192, is inserted into prepositioned catheters, a technique that offers the opportunity of high dose rate irradiation (HDR, >12 Gy/h) with minimal exposure of neighboring tissues. The sites accessible for traditional noninvasive brachytherapy are limited, as body cavities such as the trachea or the vagina are needed to insert the afterloading catheter, or invasive implanta¬tion of catheters is required.
Concerning brachytherapy of hepatic ma-lignomas, intraoperative radiation therapy has been successfully used in the past. However, as most of the indications are palliative approaches, minimally invasive procedures with a low risk of morbidity and mortality are warranted. This can be achieved by employing radiological interven-tional procedures, which are mainly based on im¬age guidance. To treat hepatic malignancies, the afterloading technique is combined with the pro¬cedure of image-guided interventional, locally ablative treatment. Inserting a radiation source into the tumor in an afterloading technique via transhepatic catheters implanted percutaneously under computed tomography (CT) guidance is largely independent of breathing motion and of¬fers a steep dose reduction toward the periphery around the target volume for optimally focused dosing of the tumor. This technique is invasive and thus requires a short radiation time and is therefore applied as a single session HDR brachy-therapy (Ricke et al. 2004a).
In the following sections, aspects of interstitial brachytherapy with CT-guided afterloading will be discussed including patient selection, treat-ment planning, procedures, technical consider-ations, adverse effects, and clinical outcome.
11.2 CT-Guided
High Dose Rate Brachytherapy via Interstitial Afterloading
11.2.1 Background
High dose rate brachytherapy for the treatment of unresectable liver metastases has been used previously in an intraoperative setting. Efficacy and safety have been proved in several studies. In these trials the minimal target doses covering the entire tumor ranged between 15 and 30 Gy; internal dose inhomogeneities inside the target volume, depending on the radiation technique, were tolerated (Nauta et al. 1987; Dritschilo et al. 1988; Thomas et al. 1993). In a study with 22 pa-tients suffering from irresectable liver metastases, irradiation was realized with laparotomy and in-terstitial HDR brachytherapy using iridium-192 with doses in the tumor periphery ranging from 20 to 30 Gy (Thomas et al. 1993). There was no acute or chronic radiation toxicity observed at a median follow-up of 11 months. Median actuar-ial local control at irradiated sites was 8 months, with 26% actuarial local control at 26 months by CT or magnetic resonance imaging (MRI). This phase I/II trial demonstrates the feasibility of single fraction HDR brachytherapy in the treat-ment of liver metastases.
However, as most of these procedures are palliative, a minimally invasive approach with¬out the risk of laparotomy is favorable. This may be achieved by image-guided procedures, e.g., CT-guided percutaneous puncture of the hepatic tumor and catheter placement for subsequent af-terloading as described by Ricke et al. (2004a). This interventional radiological approach has been successfully employed for treatment of sev-eral secondary and primary hepatic malignomas, and also in malignomas of the lung and other sites (Ricke et al. 2004a, 2005a).
11.2.2 Patient Selection
In general, locally ablative treatment should be preserved for patients with a limited number of tumor deposits, regionally confined disease, or symptomatic lesions. Local overtreatment as an unnecessary risk should be avoided. Whether a patient might profit from locally ablative treat-ment depends on the tumor entity, tumor spread, and the overall clinical condition. Fluorodeoxy-glucose-positron emission tomography (FDG-PET) has proved to be a valuable adjunctive to the conventional staging modalities in the evalu¬ation of patients prior to locally ablative treat¬ment (Amthauer et al. 2006). The indication has to be made individually after thorough ex¬amination and careful assessment of alternative treatment options. Clinical and paraclinical par¬ameters such as comorbidity, liver function, and blood coagulation have to be taken into consid¬eration, as well as the patient's wishes.
Theoretically, minimally invasive interstitial afterloading is applicable to many potential tumor localizations. It has already been success-fully applied for treatment of pulmonary and he-patic malignomas, but also in the mediastinum, in the retroperitoneum, and bone. The main limitation is of course the technical feasibility of catheter placement, as a minimal risk of the pro-cedure has to be ensured. Additional limitations are surrounding tissues at risk for adverse effects of irradiation, such as bowel, stomach, spinal ca-nal, skin, neuronal tissue, etc. The number and size of the lesions to treat is also an issue. How-ever, the procedure can be adapted to achieve a sufficient dose coverage in target volumes that are much larger than those suitable for thermal ablation techniques (Ricke et al. 2004b). In large tumor volumes or numerous target lesions, the procedure can be completed with several step-by-step sessions. Additionally, it has been shown that CT-guided interstitial brachytherapy is in¬dependent from the cooling effects of large ves¬sels or bile ducts in the ablation zone, which have been identified as potential causes of inadequate heating and local recurrent tumor growth in thermal ablation techniques (Ricke et al. 2004b). Furthermore, as one of the major advantages compared to thermal ablation techniques, the shape of the ablation zone can be adapted to the irregular geometries of target lesions after the catheter implantation by modulating the dwell locations and dwell times of the radiation source inside the afterloading sheaths. Thus, the achiev¬able ablation volume is not only defined by the CT-guided puncture, but also by the planning af¬ter a contrast-enhanced CT scan is obtained with optimal demarcation of the tumor lesions and the implanted catheters.
The widest experience has been with hepatic malignomas and the following will mainly focus on interstitial HDR brachytherapy of liver me-tastases via percutaneous transhepatic afterload-ing. However, these technical aspects of locally ablative treatment apply not only for hepatic malignomas but also for other organs invaded by tumors, such as the lung, where patients may benefit from interstitial therapy, predominantly in a palliative scenario (Ricke et al. 2005a).
11.2.3 Therapy Procedure
The application of CT-guided interstitial brachy-therapy consists of five steps. After appropriate patient selection with staging and assessment of the feasibility based on local findings, the steps are (1) planning the access, (2) CT-guided cath-eter implantation, (3) radiation planning, (4) ac-tual irradiation via afterloading, and (5) removal of applicators.
For access planning, cross sectional imag¬ing (whether CT or MRI) is needed (Fig. 11.1a). The chosen imaging modality must be capable of outlining the tumor precisely against the sur-rounding tissue, vessels, and central bile ducts. A gross planning of catheter positions is done us¬ing the axial slices, as this is the orientation of the fluoroscopic CT monitoring of the intervention. Besides the puncture direction, dose coverage of the clinical target volume and sparing of sur-rounding tissues at risk has to be respected dur-ing catheter placement. It is recommendable to place the needle that way, that a bridge of liver parenchyma lies between the liver capsule and the tumor border. This buffer provides a hold for the catheter and prevents bleeding of commonly hypervascularized tumors and the potential spill-ing of tumor cells into the abdominal cavity.
The patient is positioned supine in the CT scanner and monitored for blood oxygenation and heart frequency. The intervention is per¬formed under aseptic conditions and CT guid¬ance after intravenous analgosedation as well as local anesthesia at the cutaneous puncture site. The puncture is monitored by CT fluoroscopy. A guide wire is inserted through the needle, and then a flexible catheter sheath replaces the needle (opaque on X-ray). After removal of the guide wire, an afterloading catheter is placed into the catheter sheath. The system is stitched to the skin for fixation. If more than one afterloading cath-eter is needed, the procedure is repeated.
Upon completion of catheter placement, a contrast-enhanced scan of the liver is acquired
for documentation of the exact catheter location in relation to the tumor (Fig. 11.1d). These data are the basis for 3D reconstructions and radiation therapy planning on a dedicated workstation by outlining the gross tumor volume, the catheters, and the surrounding risk tissues (e.g., bowel, stomach wall, gall bladder, kidney, spinal canal, skin) (Fig. 11.1b, e). This technique with retro-spective registration of the catheter positions is highly accurate and less complex as compared to prospectively arranged catheter positions with templates or intraoperative raster placement (To-nus et al. 2001; Kolotas et al. 2003). With a se¬lected minimal target dose, usually 15-25 Gy, an afterloading plan is generated giving dwell loca¬tions and dwell times for the iridium-192 source [half-life, 78.8 days; decay, beta (672 keV) and gamma (<469 keV)] inside the afterloading cath¬eters. This plan needs control and can be adjusted manually if necessary. The goal is to modulate a planned target volume covering the entire gross tumor volume and a safety margin while spar¬ing healthy surrounding tissue, especially risk organs, as much as possible. An optimization of target volume definition and consecutively the dose coverage of the tumor can be achieved by registration of the previously acquired FDG-PET images with the CT data (Denecke et al. 2006). Although the number of catheters is theoretically unlimited, it is recommendable not to exceed 6-8 catheters, depending on the tumor size and shape. Because of the stress situation, the radia¬tion time should be limited to a maximum of 1 h, depending on the patient's condition.
Using this plan, the afterloading procedure is performed and subsequently the catheters are slowly removed, sealing the puncture channels with tissue glue or other thrombogenic material to prevent bleeding.
11.2.3 Undesired Side Effects
Complications can be subdivided into acute complications, occurring during or immedi¬ately after treatment, and late complications. The inadvertent acute events are mainly due to mechanical alterations caused by the puncture and catheter placement (e.g., bleeding, perfora-tion of bowel, stomach, or gall bladder). These inadvertent events, however, occur very rarely, as CT-guided puncture of the liver is a safe way to avoid severe injuries of nontarget tissues. Major bleeding from the liver is an extremely rare com-plication and can be prevented by sufficient seal-ing of the puncture channel during retraction of the catheter sheaths. Other acute side effects are emesis, pain, and shivers, which are to be treated medically.
Delayed side effects besides infectious com-plications are mainly related to radiation expo-sure of nontarget tissues. Treating hepatic ma-lignomas, exposure of surrounding healthy liver tissue to a relevant radiation doses is desired as a safety margin. However, a sufficient hepatic re¬serve has to be ensured before treating hepatic malignomas, particularly in patients with large and/or multiple lesions, preexisting liver disease (e.g., hepatocellular carcinoma in cirrhosis, por¬tal vein thrombosis), previously irradiated liver
(dose accumulation), or otherwise impaired liver function reserve due to prior chemotherapy. The tolerance dose of a healthy liver is approximately 30 Gy to the whole organ or 50 Gy to one-third of the liver volume. For external radiotherapy, the clinical endpoints are liver failure and severe hepatitis. If the irradiated volume of normal liver tissue is reduced to approximately 100 ml or less, the tolerated doses are much higher—in prin¬ciple, without any upper limit with respect to the clinical endpoints mentioned. Additionally, the different radiobiological effects of a single high dose fraction to the tissue compared to fraction¬ated strategies has to be considered. It is well known that healthy tissue tolerates larger doses applied in multiple fractions. The options for the irradiated liver tissue are either destruction or recovery to normal liver function. Additionally, compensative mechanisms of the remaining non-irradiated liver parenchyma has to be taken into account. A recent study showed that for intersti¬tial brachytherapy in an afterloading technique with an iridium-192 source, the tolerance dose causing an early function loss of hepatocytes as determined in MRI with hepatocyte specific con¬trast material 6 week after irradiation was 9.9 Gy (±2.3 standard deviation) (Ricke et al. 2004b). This and the careful assessment of the hepatic re¬serve have to be taken into consideration when planning the treatment to avoid posttherapeutic hepatic failure.
Other tissues at risk are, e.g., bile ducts, gall bladder, gastrointestinal tract, skin, kidney, and spinal cord. Previously described complications have included rare events such as strictures of the common bile duct or gastric ulcers (Ricke
et al. 2004a; Streitparth et al. 2006). Concern¬ing gastric complications, a threshold dose of 15.5 Gy/ml tissue for the clinical endpoint ul-ceration of gastric mucosa has been estimated (Streitparth et al. 2006). This in vivo assessment is in accordance with tolerance data by Emami et al. (1991). Regarding the small and large bowel, dose thresholds have not been estimated yet, but it has been hypothesized that they are similar to those described for the gastric wall; overall, however, these complications and late ef¬fects are rare, to which patients with repeated ir¬radiation close to the risk tissues are more prone (Ricke et al. 2004a, 2005b). Concerning gastric exposure, a proton pump inhibitor therapy is be¬ing recommended as ulcer prophylaxis. Potential risk and benefit have to be thoroughly evaluated before treatment initiation and during radiation planning.
11.2.4 Efficacy
Local tumor ablation has become a valuable tool in oncological treatment concepts. The majority of locally ablative procedures are performed by applying thermal ablation, such as RFA or LITT. However, with respect to the limitations of ther-mal ablation modalities (i.e., tumor size, tumor shape, tumor location, adjacent risk structures), novel techniques combining brachytherapy with interventional techniques have demonstrated favorable outcomes. In contrast to thermal abla-tion, CT-guided brachytherapy is independent of complex geometric configurations of the lesions, as dwell times and dwell locations of the source within the applicators can be adjusted to fit the outlines of the tumor (Ruhl and Ricke 2006). Fur-thermore, adjacent ducts and vessels do not in-fluence the ablation zone as brachytherapy is not prone to disturbing cooling effects. In contrast to external beam radiation, breathing motions are not an issue, because the afterloading catheters move with the tumor (Ricke et al. 2004b).
Early studies on CT-guided brachytherapy showed local tumor control rates of 87% after 6 months at minimal dose levels of 12-20 Gy (Ricke et al. 2004a). An analysis of the treatment of 200 colorectal liver metastases between 1 and 11 cm (median 4 cm) recruited for a phase III study revealed a local tumor control rate of 96% after 12 months when applying 25 Gy, and 67% when applying 20 Gy as the minimal tumor dose. Major adverse events were hemorrhage in 3 pa-tients (2%), which ceased after blood transfusion
(Ricke et al. 2005c).
The use of interstitial brachytherapy is not limited to its application inside the liver, as treatment of lung malignancies has also dem-onstrated promising results with respect to local tumor control and side effects. In a phase I trial, 15 patients with 28 lung metastases and nons-mall cell lung cancer in 2 cases were treated with a single fraction of at least 20 Gy inside the entire clinical target volume. No major adverse events were reported. Minor events included radio-graphically visible local hemorrhage in 2 patients (Ricke et al. 2005a). In contrast to thermal abla¬tion techniques, air cavities in the lung were not seen. Radiobiologically, the cytotoxic effect after single-fraction, high-dose rate irradiation shows within weeks to months, with only moderate acute injury (Manning et al. 2001).
11.3 The Role of CT-Guided Interstitial
Brachytherapy in Pancreatic Cancer
The widest experience with CT-guided brachy-therapy has been with colorectal cancer, breast cancer, and hepatocellular carcinoma. In con¬trast, pancreatic neoplasias are less favorable for locally ablative treatment, depending on the his-tological subtype.
Regarding liver metastases from neuroen-docrine gastroenteropancreatic tumors, locally ablative treatment has been used successfully for cell reduction, tumor eradication, and symptom relief in functionally active tumors (Elvin et al. 2005; O'Toole and Ruszniewski 2005). In this context, a special focus of CT-guided brachy-therapy is the treatment of lesions unfavorable for LITT or RFA because of size, shape, and lo¬cation. Even though some of these tumors are known to be less sensitive to radiation therapy, it has to be emphasized that in the setting of single session HDR brachytherapy with doses above 20 Gy and core doses above 50-100 Gy, the cri¬terion radiosensitivity of tumor tissues plays a minor role. Therefore, CT-guided brachytherapy for locally ablative treatment of liver metastases appears to be a promising tool in this subset of pancreatic neoplasias.
Concerning the treatment of pancreatic duc-tal adenocarcinoma, there are no data available yet assessing the use of this novel technique. Ductal adenocarcinoma represents the majority (90%-95%) of pancreatic malignancies and is known to have a poor prognosis (5-year overall survival, 1%-2%) (Wagner et al. 1999; Tsiotos et al. 1999; Brand and Tempero 1998; Rosewicz and Wiedenmann 1997). The resection of the primary tumor currently being the only poten¬tially curative treatment (5-year overall survival after R0 resection, approximately 20%), most of the affected patients (approximately 80%) are ir-resectable at the time of first diagnosis, owing to distant metastases or local tumor extent (Lopez-Hanninen et al. 2002; Wagner et al. 1999; Tsiotos et al. 1999; Brand and Tempero 1998; Rosewicz and Wiedenmann 1997). Even though there are promising developments in both surgical tech¬nique and chemotherapeutic agents, the outcome remains rather poor. This emphasizes the need for innovative treatment strategies as adjuncts to the traditional therapeutic approach.
The efforts being made toward treating the primary pancreatic ductal adenocarcinoma by lo-cally ablative procedures such as RFA and LITT, as well as external beam irradiation for neoadju-vant or palliative therapy, have met with varying success (Stroszczynski et al. 2001; Varshney et al. 2006). As most adenocarcinomas are located in the pancreatic head (approximately 75%) the le¬sions are difficult to reach by CT-guided local ab¬lation. Surrounding vessels and risk structures, such as the bile ducts, the duodenum, and the stomach, as well as the pancreatic parenchyma itself, limit the ablation volume for either modal¬ity. Even in intraoperative RFA of pancreatic ma¬lignancies, there have been severe complications observed, such as necrotizing pancreatitis (Elias et al. 2004). The primary tumor, especially when judged as irresectable, is a diffuse mass with an irregular growth pattern. Therefore, the inclu¬sion of the entire tumor is often impossible and it can be questioned whether local tumor destruc¬tion exposes the patient unnecessarily to risks that outweigh the potential benefit. Even though CT-guided brachytherapy is more flexible re-garding the configuration of the target volume, these limitations apply here as well. On the other hand, retarding the local tumor progression only by a few months has to be considered a success, as alternative treatment options are rare and of¬fer only moderate response rates and rather poor outcomes.
Referring to hematogenous distant metas-tases, these are most commonly located in the liver. Even though the progression of the disease is rapid and, in most cases of metachronous liver metastases, further micrometastases are present that are invisible to diagnostic imaging, hepatic metastases in theory can be considered as a lim¬ited disease. Thus, it can be considered whether a patient might profit from removal of the me-tastases if the primary tumor has been resected. There are currently no data showing an advan¬tage of hepatic surgery in such a scenario, and any unnecessary risk has to be kept as low as pos¬sible in the palliative setting. Therefore, the use of minimally invasive ablation of liver metastases is a promising alternative to surgery, not only in irresectable patients. Treating hepatic metastases by thermal ablation in pancreatic cancer patients implies an additional issue. As most adenocar-cinomas are seated in the pancreatic head, the resection includes a biliodigestive anastomosis. This condition allows ascending bacterial colo¬nization of the biliary tree, which supports the development of abscesses in the necrotic ablation zones after thermal tumor coagulation (Thomas et al. 2004). A similar condition is present in palliative treatment of irresectable patients with stents in the common bile duct. In contrast to thermal ablation, brachytherapy induces a pro-longed tumor inactivation along with ongoing organization of the developing necrosis, which is accessible to the immune system, and therefore the rate of abscesses is extremely low compared to thermal tumor destruction. Infection of the ablation zone therefore appears to be a minor problem for interstitial afterloading in this spe-cific patient group.
To create reasonable indications for the use of locally ablative treatment in pancreatic cancer patients, it has to be implemented into a mul-tidisciplinary approach including surgery and chemotherapy in an individualized therapeutic strategy. A possible indication for locally abla¬tive treatment would be the eradication of liver metastases to facilitate resection of the primary tumor. For illustration of this multidisciplinary individualized approach, we present a case with an undifferentiated osteoclastic-type giant cell tumor of the pancreatic corpus (Fig. 11.1).
The patient presented with two liver metasta-ses in the right lobe and a portal vein thrombosis of the left branch at initial diagnosis. Chemo¬therapy maintained stable disease, but caused in¬tolerable sensory irritation in the hands and the feet. The patient was referred to our department for CT-guided interstitial HDR brachytherapy of the liver metastases in order to retard local tumor progression. Because of inaccessibility and the previously mentioned risks of locally ablative therapy inside the pancreas, the primary tumor was not treated. After ensuring a good local control of the liver metastases by MRI 3 months after brachytherapy of the two liver lesions and exclusion of new intra- and extrahepatic metas-tases by CT, a R0 resection of the pancreatic tail and corpus with the primary was performed. Eighteen months after brachytherapy the patient is still free of tumor with a good quality of life.
To summarize, CT-guided brachytherapy of liver metastases may be reasonable in patients with local resectability and a limited number of liver metastases, when stable disease is ensured by a sufficient surveillance interval. Here and in previously resected patients with metachronous liver metastases, the palliative use of CT-guided brachytherapy might prove beneficial in the fu-ture and appears to be advantageous compared to thermal ablation because of the reduced rate of abscesses in the ablation zone.
11.5 Conclusion
Combining the features of substantially different therapies, such as the safety of CT-guided or¬gan puncture, efficacy of brachytherapy, and the principles of the afterloading technique, a novel therapeutic approach in radiation oncology has been developed. Percutaneous afterloading of hepatic malignomas enables effective treatment, even in those patients who are not suitable to undergo surgical or thermal ablations because of tumor size or location. There are promising data for the treatment of hepatocellular carcinoma and colorectal liver metastases, and further stud¬ies are pending. For pancreatic cancer, the poten¬tial indications for CT-guided brachytherapy are currently limited to the treatment of liver metas-tases. Despite the lack of controlled trials, there is probably a role for this therapeutic approach in an individualized multidisciplinary therapeutic approach in a carefully selected patient group.
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