Chapter 13 Proton Therapy for Thoracoabdominal Tumors

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1 Chapter 13 Proton Therapy for Thoracoabdominal Tumors Hideyuki Sakurai, Toshiyuki Okumura, Shinji Sugahara, Hidetsugu Nakayama, and Koichi Tokuuye Abstract In advanced-stage disease of certain thoracoabdominal tumors, proton therapy (PT) with concurrent chemotherapy may be an option to reduce side effects. Several technological developments, including a respiratory gating system and implantation of fiducial markers for image guided radiation therapy (IGRT), are necessary for the treatment in thoracoabdominal tumors. In this chapter, the role of PT for tumors of the lung, the esophagus, and liver are discussed Introduction Thoracoabdominal tumors are common worldwide and mostly include cancers arising from respiratory and gastrointestinal organs such as lung, esophagus, and liver. In comparison with head and neck tumors or urological and gynecological malignancies, most thoracoabdominal tumors are considered to be treatment resistant; i.e., the outcome is insufficient even after several multimodal therapies. The reasons for the poor prognosis include a high rate of distant metastases and a high rate of local recurrences after local therapy, indicating that more intensive local treatment is required for tumors in this category. A new technique such as stereotactic body radiation therapy (SBRT) has improved local control in early-stage lung and liver cancer through intensive dose delivery. Proton therapy (PT) has a further advantage of excellent dose localization that gives a reduced treatment volume in normal tissues, and dose-escalation protocols with no increase in the dose to normal tissue have been conducted. However, thoracoabdominal tumors in a more advanced stage are more difficult to treat. Concurrent chemoradiotherapy as a multimodal approach is now the standard H. Sakurai ( ) Proton Medical Research Center, Department of Radiation Oncology, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki , Japan hsakurai@pmrc.tsukuba.ac.jp U. Linz (ed.), Ion Beam Therapy, Biological and Medical Physics, Biomedical Engineering, DOI / , Springer-Verlag Berlin Heidelberg

2 208 H. Sakurai et al. treatment for advanced lung and esophageal cancer. In chemoradiotherapy, the high rate of treatment-related morbidity of the lung, heart, and gastrointestinal tract is a concern, because radiosensitization occurs not only in tumor tissue but also in the irradiated normal tissue. PT with concurrent chemotherapy has not been studied widely, but may be a suitable combination because of the reduced volume of irradiated normal tissue. Thoracoabdominal tumors can also be characterized as tumors that move with respiration. Treatment of lung and liver tumors requires exact patient positioning and precise control of respiratory movement. Intensity-modulated radiation therapy (IMRT) is now used for head and neck and intrapelvic tumors, but because of the complexity of the beam arrangement and the long time required for beam delivery, IMRT is not practical for tumors that are subject to respiratory movement. Conversely, PT with its simple beam arrangement seems predestined for that kind of treatments. Several technological developments including a respiratory gating system and the implantation of fiducial markers for IGRT have enabled the Proton Medical Research Center (PMRC) at the University of Tsukuba to administer proton beams at high energy levels to deep-seated tumors of the lung, esophagus, and liver Lung Lung cancer is the leading cause of cancer death worldwide [1]. Surgery plays a major role as curative treatment for non-small cell lung cancer (NSCLC). Patients with inoperable or unresectable NSCLC treated with conventional radiation therapy (RT) show inferior outcomes in terms of local control and survival rates [2, 3]. However, more sophisticated treatment techniques, such as SBRT, have recently produced improvements in local control for early-stage lung cancer. Dosimetric analyses have suggested that PT can achieve a greater reduction of doses to normal tissue, including lung, spinal cord, heart, and esophagus, compared with the dose of 3D conformal RT (3D-CRT) for patients with NSCLC [4 6] Stage I NSCLC Five-year survival rates of surgical resection for stage I NSCLC have been reported as 60 70% [2,3]. For patients with inoperable cancer and those who refused surgery 5-year local control and survival rates of only 30 50% and 10 30%, respectively, have been found after conventional, fractionated RT [7, 8]. Since Blomgren et al. showed the potential efficacy of high-dose SBRT for NSCLC [9], high local control rates of stage I NSCLC have been reported in many countries [10 12]. In this context, Bush et al. first reported the results of a prospective study of PT for patients with NSCLC at Loma Linda University Medical Center (LLUMC) [13].

3 13 Proton Therapy for Thoracoabdominal Tumors 209 In that study, patients received X-rays of 45 Gy in 25 fractions for a gross tumor including the mediastinum with a concurrent proton boost to the gross tumor of an additional 28.8 GyE in 16 fractions. Thus, a total dose of 73.8 Gy in 41 fractions was given to the tumor. In patients with intercurrent diseases, 51 GyE in ten fractions was given to the tumor using PT alone. The 2-year disease-free and overall survival rates for 27 patients with stage I NSCLC were 87% and 39%, respectively. The majority of patients had poor pulmonary function (average forced expiratory volume in 1 second, FEV1: 1.1 l); none, however, developed clinical radiation pneumonitis. The conclusion from this study was that high-dose PT could be administered safely to patients with poor underlying pulmonary function. Five years after their first report, Bush et al. reported a second series of results for PT in 68 patients with stage I NSCLC, including 63 with inoperable cancer [14]. Twenty-two patients received 51 GyE in ten fractions and 46 patients received 60 GyE in ten fractions targeted to the primary site using PT alone. The 3-year local control rates in patients with stage IA and IB cancer were 87% and 49%, respectively, and the difference between these rates was significant. The 3-year local control and cause-specific survival rates were 74% and 72%, respectively, which are similar to those reported for surgical series. None of the patients suffered from radiation pneumonitis. Shioyama et al. reported retrospective results for 28 patients with stage I NSCLC at the University of Tsukuba [15]. Doses of GyE for stage IA and GyE for stage IB cases were targeted only to the primary tumor when this was located in a peripheral site or to the primary tumor and the ipsilateral hilum when the tumor was adjacent to the hilum. The 5-year local control and overall survival rates were 89% and 70% respectively, for stage IA cases, and 39% and 16%, respectively, for stage IB. The 5-year local control rate was significantly higher for stage IA cases and similar to the results of Bush et al. [14]. Only one patient suffered from grade 3 toxicity. Nihei et al. reported results for 37 patients who underwent PT of GyE targeted to the primary tumor at the National Cancer Center Hospital East (NCCHE) in Kashiwa, Japan [16].The2-yearlocal controland overallsurvivalrates were80% and 84%, respectively, and three patients experienced grade 3 pulmonary toxicity or greater. Based on this study, PT was concluded to be a promising treatment modality for stage I NSCLC. Nakayama et al. treated 58 tumors (T1: 30, T2: 28) in patients with stage I NSCLC, including 55 inoperable cases, with PT at the new facility of the University of Tsukuba [17]. A total dose of 66 GyE in ten fractions was given to peripherally located tumors, whereas 72.6 GyE in 22 fractions was given for centrally located tumors. The 2-year overall survival and local control rates were 97.8% and 97.0%, respectively, and the 2- and 3-year progression-free survival rates for all patients were 88.7% and 78.9%, respectively. The average FEV1 was limited to 1.1 l in this study; however, only two patients showed deterioration of pulmonary function. These encouraging results from three institutions indicate that PT may be favorable for treatment of inoperable stage I NSCLC. Representative images of the dose distribution are shown in Fig. 13.1a, and the reports of stage I NSCLC treatment are summarized in Table 13.1.

4 210 H. Sakurai et al. Fig (a) A case of proton therapy (PT) for a patient with stage I NSCLC and bronchial ectasia. (b) a case of PT for a patient with stage III NSCLC and atelectasis Table 13.1 PT for stage I NSCLC patients. Reports from the literature References Year Institution No. of Proton dose patients (GyE/#Fx) Bush et al. [13] Bush et al. [14] Shioyama et al. [15] Local control rate % (at n years) Overall survival %(atn years) 1999 LLUMC 27 51/10 87 a (2) 39 (2) 45/25 (Photon)C28.8/16 (Proton) 2004 LLUMC 68 51/10 74 (3) 44 (3) 60/10 IA: 87 IB: U Tsukuba ( ) IA: 89 (5) 23 b (5) IB: 39 Nihei 2006 NCCHE /10 80 (2) 84 (2) et al. [16] Hata et al U Tsukuba 21 55/10 95 (2) 74 (2) [18] 66/10 Nakayama 2010 U Tsukuba 55 66/10 97 (2) 97.8 (2) et al. [17] 72.6/22 a Includes eight stage III patients b Includes nine stage II patients #Fx number of fractions, LLUMC Loma Linda University Medical Center, NCCHE National Cancer Center Hospital East, Kashiwa

5 13 Proton Therapy for Thoracoabdominal Tumors Stage II III NSCLC Five-year survival rates after curative resection in stage II and stage IIIA NSCLC have been reported to be 30 40% and 15 30% [2, 3]. Radiotherapy is mainly performed for the more advanced stage of IIIB, but the outcomes are insufficient. In a study of PT in a small series, Bush et al. found 2-year local control and overall survival rates in eight patients with stage III NSCLC of 87% and 13%, respectively [13]. Shioyama et al. reported 2-year cause-specific and overall survival rates of 70% and 62%, respectively, in nine patients (eight with stage III and one with stage IV NSCLC) [15]. From November 2001 to July 2008, PT alone was performed at the new facility of the University of Tsukuba for 35 patients with stage II III NSCLC who refused standard therapy or were unsuitable for standard therapy because of intercurrent diseases. The patients included 5, 12, and 18 cases of stage II, IIIA, and IIIB NSCLC, respectively. The total doses were 77.0 GyE in 35 fractions in 13 patients, 83.6 GyE in 38 fractions in seven patients, 72.6 GyE in 22 fractions in six patients, 74.0 GyE in 37 fractions in three patients, and various dose fractionations in six patients. The 1- and 2-year local progression-free survival rates for stage II III patients were 93.3% and 65.9%, respectively, and the respective 1- and 2-year overall survival rates were 81.8% and 58.9%. No treatment-related toxicity of grade 3 or higher was observed. Radiation therapy using 3D planning with concurrent chemotherapy is currently increasing the survival rates for advanced-stage NSCLC [19, 20]. Additionally, several phase I/II trials with escalation of radiation doses up to 74 Gy in 37 fractions with combined chemotherapy have resulted in improved survival [21 23]. In principle, PT is advantageous since it allows an increased dose to the target and a decrease to the surrounding organ using Bragg peak properties (Fig. 13.1b). Therefore, further investigations of dose-escalation PT combined with chemotherapy for the treatment of advanced-stage NSCLC is recommended Esophagus Surgical resection is the current treatment of choice for esophageal carcinoma. Recently, chemoradiotherapy, and combined therapies such as chemoradiotherapy followed by surgery have been established for patients with advanced-stage esophageal cancer [24 26]. From 1983, the Tsukuba group has used PT to treat more than 100 patients with esophageal carcinoma [27 29]. Other than these studies, little information is available on results of PT for esophageal cancer. Therefore, in the following section we introduce our experience in comparison to X-ray treatment.

6 212 H. Sakurai et al Survival, Local Control, and Sequelae for Esophageal Cancer At the former PT facility at Tsukuba [27 29], 46 patients with esophageal cancer who had an intercurrent disease or refused surgery underwent PT or PT combined with X-ray therapy between 1985 and All patients had locoregionally confined disease and all but one had squamous cell carcinoma. Twenty-three patients had a T1 stage tumor and another 23 had T2, T3, or T4 tumors. Of the 46 cases, 22 were judged inoperable because of intercurrent disease, including cardiovascular (n D 6) and chronic pulmonary diseases (n D 6), liver cirrhosis (n D 4), renal failure (n D 2), rheumatoid arthritis (n D 1), Crohn s disease (n D 1), chronic pancreatitis (n D 1), and cerebral infarction (n D 1). Four patients had other malignancies: hypopharyngeal cancer (n D 2), gastric cancer (n D 1), and uterine cervical cancer (n D 1), all of which were under control when the esophageal cancer was treated. The characteristics of the 46 patients are shown in Table Forty patients received combined therapy of X-rays (median 48 Gy) and protons (median 34 GyE) as a boost. The median total dose of this therapy for the 40 patients was 78 GyE (range GyE). The other six patients received PT alone (median 86 GyE, range GyE). The 5-year actuarial survival rates for all the patients, for T1, and T2 4 were 34%, 55%, and 13%, respectively, and the respective 5-year disease-specific survival rates were 67%, 95%, and 33%. The 5-year local control rates for T1 and T2 4 lesions were 83% and 29%, respectively. The sites of the first relapse were locoregional for 16 patients and distant for two patients. Acute and late treatmentrelated toxicities of greater than grade 2 were observed in five patients, each. These data suggest that PT is useful for giving high doses to a limited volume of the esophagus with a low rate of toxicity Treatment Procedures for Esophageal Cancer Practiced at the PMRC Hyperfractionated regimens are currently being used for esophageal carcinoma [29]. To reduce the severe side effects of esophageal ulcer by decreasing the dose fraction, it has been tried to use a schedule of combined X-rays with protons to a total dose of 75 GyE in 44 fractions over approx. 7 weeks. During the first 5 weeks, a larger CTV encompassing the primary tumor and the regional lymph nodes were irradiated with X-rays to a dose of 45 Gy in 25 fractions at 1.8 Gy per day. During the same period, protons were used to deliver a concomitant boost to a smaller target volume encompassing the clinically evident tumor, with 12 GyE given in ten fractions over 5 weeks (twice a week). During weeks 6 and 7, a smaller target volume is irradiated encompassing the clinically evident tumor with protons alone, with 18 GyE in nine fractions over 1.8 weeks. Nineteen patients have been treated with this regimen as of September The tumors were locally controlled in 13 of 18 patients in whom

7 13 Proton Therapy for Thoracoabdominal Tumors 213 Table 13.2 Characteristics of 46 patients treated with PT for esophageal cancer at the PMRC Age Median 72 Range Gender [No. of patients and (%)] Male 40 (87) Female 6 (13) Histology [No. of patients and (%)] Squamous cell carcinoma 45 (98) Adenocarcinoma 1 (2) Primary length (cm) Median 4.0 Range Primary tumor site [No. of patients and (%)] Upper thoracic 4 (8.7) Middle thoracic 29 (63) Lower thoracic 12 (26.1) Abdominal 1 (2.2) TNM classification [No. of patients and (%)] T1 23 (50) T2 5 (11) T3 13 (28) T4 5 (11) N0 39 (85) N1 7 (15) sufficient follow-up data were available. The 5-year survival rate was 41%.Clinical images of a representative case are shown in Fig We cannot draw any conclusions from our results for PT in patients with esophageal cancer because of the limited number of patients. However, the results appear comparable to the best surgical [30, 31] and chemoradiotherapy [25] series. Definitive chemoradiotherapy followed by surgery has been established as an important therapy for advanced-stage esophageal cancer [24 26]. Data from the RTOG trial showed that a total dose of 64.8 Gy in 36 fractions did not improve survival in comparison to 50.4 Gy in 28 fractions in combination with cisplatin chemotherapy, due to increased treatment-related toxicity in the high-dose group [32]. PT has a better dose distribution than conventional RT [33], so simply switching from conventional RT to PT has the potential to reduce toxicity and improve outcomes. A phase II study is ongoing at Tsukuba to examine whether PT increases the local control rate with acceptable toxicity levels in combination with chemotherapy.

8 214 H. Sakurai et al. a before PT b after PT Fig Images of a 77-year-old man who developed esophageal carcinoma staged as ct3n1m0. (a) An esophagogram and endoscopic image before PT showed a primary tumor (indicated by the arrows). A total dose of 82 GyE was administered in 46 fractions using a concomitant boost regimen. (b) An esophagogram and endoscopic image taken 6 months after PT showed complete response of the primary tumor and persistence of a slight esophageal constriction. The white arrows indicate fiducial markers implanted at the cranial and caudal boundary of the primary tumor. Normal esophageal function was maintained 27 months after therapy 13.4 Liver Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide [34]. Most HCC cases occur in either sub-saharan Africa or in Eastern Asia [35]. The geographic variability in the incidence of primary liver cancer is largely explained by the distribution and natural history of the hepatitis B (HBV) and C (HCV) viruses. HBV is the most frequent underlying cause of HCC, whereas chronic HCV infection is a major risk factor in Spain and Japan [35]. The incidence of liver cancer is also increasing in several developed countries, including the United States, where proportional increases occurred in HCV-related HCC as compared to HBV-related HCC, which seems to be stable [35]. Overall age-adjusted incidences of HCC tripled between 1975 and 2005, rising from 1.6 to 4.9 per 100,000 persons [36]. In selected areas of some developing countries, the incidence of liver cancer

9 13 Proton Therapy for Thoracoabdominal Tumors 215 has decreased, possibly as a result of the introduction of HBV vaccine [37]. Risk factors for liver cancer other than hepatitis viruses include alcohol, tobacco, oral contraceptives, and aflatoxins [35]. HCC accounts for approx % of primary liver cancers [38]. Other histologies of primary liver cancer include intrahepatic cholangiocellular carcinoma (CCC), mixed HCC/CCC, and other rare neoplasms such as hepatoblastoma or sarcoma. In patients with chronic hepatitis or cirrhosis on the basis of HBV or HCV infection, a variety of hepatocellular lesions, such as dysplastic nodule (DN), adenomatous hyperplasia (AH) and, finally, HCC can be found [39] and a multistep hepatocarcinogenesis process from high-grade DN to HCC has been documented [40, 41] General Management of HCC Surgical resection is the mainstay of therapy for HCC, although the majority of patients are not eligible for surgery because of underlying liver cirrhosis or the extent of the tumor. Resection of the gross tumor with a margin of 1 2 cm of normal liver is aimed at. Liver transplantation is another surgical option for patients with a solitary tumor of 5 cm or up to three nodules with a tumor size <3 cm [42]. Radiofrequency ablation (RFA) [43] or percutaneous ethanol injection (PEI) [44] are alternatives for patients with early-stage HCC who are unsuitable for surgical treatment. Since HCC is a highly vascular tumor supplied mainly by the hepatic or adjoining arteries, treatment combining intraarterial embolization with iodized oil and chemotherapy (TACE: transarterial chemoembolization) is also an effective option for unresectable tumors [45]. Radiation therapy has played a limited role in the treatmentof hepaticmalignancies because of the low tolerance of the whole liver for ionizing radiation. There is a 5% risk for radiation-induced liver disease (RILD) if the whole liver is irradiated with Gy of photons in 2-Gy fractions [46, 47]. However, high-dose radiation can be delivered safely provided that a substantial portion of the normal liver is spared. In this context, HCC has recently been recognized as a radiosensitive tumor PT Procedure for HCC Liver tumors are among the most difficult tumors to treat with ion beam therapy because they are difficult to visualize and have a large internal target volume due to respiratory movement. For precise target localization on diagnostic images, in-situ fiducial marker placement or preceding transarterial embolization with iodized oil is recommended [48]. Surgical spacer placement can also be helpful if the tumor lies adjacent to the gastrointestinal tract and is included in a high-dose area [49].

10 216 H. Sakurai et al. Table 13.3 Clinical results of PT for HCC. Reports from the literature References Kawashima et al. [55] Bush et al. [56] Fukumitsu et al. [57] Mizumoto et al. [58] Nakayama et al. [54] Patient number Proton dose (GyE/#Fx) ED (Gy) Prior therapy % Local control %(atn years) Overall survival %(atn years) 30 76/ (2) 66 (2) 34 63/ (2) 55 (2) 51 66/ (3) 49.2 (3) / (3) 45.1 (3) / /22 Proton dose (GyE) was calculated with an RBE of 1.1 ED equivalent dose (Gy), #Fx number of fractions (3) 64.7 (3) Control of respiration-related tumor motion using respiratory gating [50], tumor tracking [51], or restoration of respiratory movement [52] is essential to reduce the internal target volume. IGRT can also help to minimize treatment volumes [53]. Treatment planning CT scans are obtained during the expiratory phase. The clinical target volume (CTV) encompasses the gross tumor volume (GTV) with a 5- to 10- mm margin. The planning target volume (PTV) is designed to cover the CTV with a 5- to 10-mm margin and an additional 5-mm margin in the caudal direction to account for respiratory target movement [54] Clinical Outcome of PT for HCC Several institutions have reported the feasibility and effectiveness of PT for HCC (Table 13.3). Clinically significant acute liver toxicity has not been observed during and immediately after focal proton treatment [55, 56, 59 62]. Late toxicity such as RILD, biliary tract stenosis, dermatitis, gastrointestinal bleeding, and rib fracture have been reported, although the incidences were low [54 56, 62]. Slow regression of tumor volumes associated with gradual atrophy of surrounding noncancerous liver tissue is generally observed [63, 64]. Clinical trials for HCC have been performed at the University of Tsukuba. The eligibility criteria for PT for HCC in recent years have included Child-Pugh classification A or B, 3 nodules or less, and tumor sizes up to 15 cm. Most of the cases were considered to be inappropriate for local tumor control using other treatment modalities. All tumors are irradiated using the respiratory gating method. The dose is determined according to the characteristics of the disease in individual patients, as follows:

11 13 Proton Therapy for Thoracoabdominal Tumors 217 Fig Single nodular type HCC with a maximum dimension of 7.5 cm. The tumor was markedly enhanced with intravenous contrast agent (a). Two portals were arranged to encompass the gross tumor volume with a PTV margin of 1 cm. A fiducial marker was implanted on the tumor boundary. The innermost red line represents the 95% dose, and the outermost blue line represents the 10% dose (b). Lesion shrank and contrast enhancement disappeared 7 months after PT: 66 GyE/ 10 fractions/15 days (c) Protocol I: 66 GyE/10 fractions for peripheral HCC. Protocol II: 72.6 GyE/22 fractions for a tumor close to the main portal vein. Protocol III: 74 GyE/37 fractions for a tumor very close to the stomach or intestine. The 5-year overall actuarial survival rate in 318 patients treated at PMRC was 44.6%. Child-Pugh liver function, T-stage, performance status, and planning target volume were significant factors affecting survival. The 5-year survival rates were 55.9% for patients with Child-Pugh A disease and 44.5% for those with Child-Pugh B disease [54] For peripheral tumors, a dose of 66 GyE in ten fractions (2 weeks) was applied to the tumor (Fig. 13.3). This protocol yielded local control rates of 94.5% after 3 and 87.8% after 5 years [57]. Only a minor acute reaction was seen, and 5.9% of the patients developed rib fracture as a chronic complication, which was successfully treated with conservative treatment. Tumors located within 2 cm of the main portal vein were treated with 72.6 GyE in 22 fractions [58]. Sugahara et al. reported clinical results for tumors larger than 10 cm that were treated using the same dose fractionation. Approximately, half of the patients developed portal vein tumor thrombosis of several grades. The tumor control rate at 2 years was 87% and the overall survival at 2 years was 36% [65]. The predominant tumor progression pattern was new hepatic tumor development outside the irradiated field. These results demonstrate that a large tumor volume can be treated using a high dose without significantly increasing the dose exposure of the functional liver. Development of a portal vein tumor thrombus (PVTT) is a serious problem in many clinical courses of HCC. RFA and TACE are not effective in such cases and only a few cases can be treated by curative surgery. In a series of 35 cases with tumor thrombi in the main trunk or major branches of the portal vein, PT at a

12 218 H. Sakurai et al. a b c d Fig Massive-type HCC with tumor thrombus invading the main portal trunk. The tumor was present in the anterior segment of the right liver (a) and a tumor thrombus (white arrow) was observed in the main trunk of the portal vein (b). Three months after PT (72.6 GyE/22 fractions/37 days), the main tumor showed apparent shrinkage (c) and the tumor thrombus had disappeared from the main portal trunk (d) median total dose of 72.6 GyE in 22 fractions was delivered to the PVTT including the primary lesion. The median survival time was 22 months. Local control was achieved in 91% of the patients and about half showed recanalization of the portal vein (Fig. 13.4). These results indicate that PT can improve local control and prolong survival significantly in patients with PVTT [66]. In conclusion, PT gives excellent local control for patients with relatively large and inoperable HCC because a high dose can be delivered to the tumor along with a lower dose to normal liver tissue. The overall local control rate is about 90% and approx. 50% of the patients survive for at least 5 years even if they have a worse condition than those treated with surgery. Especially elderly HCC patients, patients with insufficient liver function, and patients with PVTT seem to profit from PT.

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