A prospective nonrandomized phase I/II study of carbon ion radiotherapy in a favorable subset of locally advanced non-small cell lung cancer (NSCLC).

BACKGROUND: Although concurrent chemoradiotherapy (CCRT) has become the standard approach for unresectable locally advanced non-small cell lung cancer (LA-NSCLC), most patients are not candidates for this treatment because of comorbidities. We evaluated the safety and efficacy of carbon ion radiotherapy (CIRT) in LA-NSCLC patients. METHODS: Patients with stage IIA to IIIA (UICC 7th edition) LA-NSCLC were enrolled in a sequential phase I/II trial. For a phase I dose escalation study, the total prescribed dose was increased by 4 Gray equivalents (GyE) in 2 steps, from 68 to 72 GyE and then to 76 GyE, using 16 fractions over 4 weeks. After determining the recommended dose, the phase II trial was started in an expanded cohort. RESULTS: Of the 36 patients treated in phase I, 2 grade 3 adverse events (radiation pneumonitis and tracheoesophageal fistula) were observed in the 76 GyE group. Accordingly, for phase II, the next consecutive 26 patients were treated with 72 GyE, with no grade 3 to 5 toxicities resulting. A total of 62 eligible patients were recruited. The majority of patients (49 of 62) were N0 or N1 patients, and the rest (13 of 62) were single-station N2 patients. The median follow-up period was 25.2 months. The 2-year local control rate (LCR) and overall survival (OS) for the entire cohort were 93.1% and 51.9%, respectively. In particular, patients with cT3-4N0 had an excellent prognosis; the 2-year OS and LCR were 69.3% and 100%, respectively. CONCLUSIONS: Short-course CIRT monotherapy shows promise as an effective nonsurgical treatment for inoperable LA-NSCLC.

Anatomical attention can help to segment the dilated pancreatic duct in abdominal CT.

PURPOSE: Pancreatic duct dilation is associated with an increased risk of pancreatic cancer, the most lethal malignancy with the lowest 5-year relative survival rate. Automatic segmentation of the dilated pancreatic duct from contrast-enhanced CT scans would facilitate early diagnosis. However, pancreatic duct segmentation poses challenges due to its small anatomical structure and poor contrast in abdominal CT. In this work, we investigate an anatomical attention strategy to address this issue. METHODS: Our proposed anatomical attention strategy consists of two steps: pancreas localization and pancreatic duct segmentation. The coarse pancreatic mask segmentation is used to guide the fully convolutional networks (FCNs) to concentrate on the pancreas' anatomy and disregard unnecessary features. We further apply a multi-scale aggregation scheme to leverage the information from different scales. Moreover, we integrate the tubular structure enhancement as an additional input channel of FCN. RESULTS: We performed extensive experiments on 30 cases of contrast-enhanced abdominal CT volumes. To evaluate the pancreatic duct segmentation performance, we employed four measurements, including the Dice similarity coefficient (DSC), sensitivity, normalized surface distance, and 95 percentile Hausdorff distance. The average DSC achieves 55.7%, surpassing other pancreatic duct segmentation methods on single-phase CT scans only. CONCLUSIONS: We proposed an anatomical attention-based strategy for the dilated pancreatic duct segmentation. Our proposed strategy significantly outperforms earlier approaches. The attention mechanism helps to focus on the pancreas region, while the enhancement of the tubular structure enables FCNs to capture the vessel-like structure. The proposed technique might be applied to other tube-like structure segmentation tasks within targeted anatomies.

A cascaded fully convolutional network framework for dilated pancreatic duct segmentation.

PURPOSE: Pancreatic duct dilation can be considered an early sign of pancreatic ductal adenocarcinoma (PDAC). However, there is little existing research focused on dilated pancreatic duct segmentation as a potential screening tool for people without PDAC. Dilated pancreatic duct segmentation is difficult due to the lack of readily available labeled data and strong voxel imbalance between the pancreatic duct region and other regions. To overcome these challenges, we propose a two-step approach for dilated pancreatic duct segmentation from abdominal computed tomography (CT) volumes using fully convolutional networks (FCNs). METHODS: Our framework segments the pancreatic duct in a cascaded manner. The pancreatic duct occupies a tiny portion of abdominal CT volumes. Therefore, to concentrate on the pancreas regions, we use a public pancreas dataset to train an FCN to generate an ROI covering the pancreas and use a 3D U-Net-like FCN for coarse pancreas segmentation. To further improve the dilated pancreatic duct segmentation, we deploy a skip connection on each corresponding resolution level and an attention mechanism in the bottleneck layer. Moreover, we introduce a combined loss function based on Dice loss and Focal loss. Random data augmentation is adopted throughout the experiments to improve the generalizability of the model. RESULTS: We manually created a dilated pancreatic duct dataset with semi-automated annotation tools. Experimental results showed that our proposed framework is practical for dilated pancreatic duct segmentation. The average Dice score and sensitivity were 49.9% and 51.9%, respectively. These results show the potential of our approach as a clinical screening tool. CONCLUSIONS: We investigate an automated framework for dilated pancreatic duct segmentation. The cascade strategy effectively improved the segmentation performance of the pancreatic duct. Our modifications to the FCNs together with random data augmentation and the proposed combined loss function facilitate automated segmentation.

Carbon ion radiotherapy for elderly patients 80 years and older with stage I non-small cell lung cancer.

Surgical resection is the standard treatment for stage I non-small cell lung cancer (NSCLC). However, elderly patients with NSCLC often suffer from other conditions, such as chronic obstructive pulmonary disease (COPD) or cardiovascular disease, and are not suitable candidates for surgery. Different modalities to treat stage I NSCLC have been developed, such as stereotactic radiotherapy (SRT), proton beam radiotherapy and carbon ion radiotherapy (CIRT). Between April 1999 and November 2003, we treated 129 patients with stage I NSCLC using CIRT. In this study, we focused on 28 patients aged 80 years and older who underwent CIRT, and analyzed the effectiveness of CIRT in treating their lung cancer and the impact on their activity of daily life (ADL). The 5-year local control rate for these patients was 95.8%, and the 5-year overall survival rate was 30.7%, but there were no patients who started home oxygen therapy or had decreased ADL. Our data demonstrate that CIRT was effective in treating elderly patients with stage I NSCLC.

Effects of carbon ion beam alone or in combination with cisplatin on malignant mesothelioma cells in vitro.

Malignant mesothelioma (MM) is extremely aggressive and a typical refractory cancer. In this study we investigated how effective on killing MM cells by carbon ion beam alone or in combination with cisplatin (CDDP) in vitro. Carbon ion beam (at the center of SOBP with 50 keV/µm of average LET) dose-independently suppressed MM cells MESO-1 and H226 cell viability and in combination with CDDP (25 µM) significantly enhanced its action. Relative biological effectiveness (RBE) values at 73 keV/µm and 13 keV/µm portion of carbon ion beam was estimated as 2.82-2.93 and 1.19-1.22 at D10 level relative to X-ray, respectively by using colony formation assay. Quantitative real time PCR analysis showed that expression of apoptosis-related BAX and autophagy-related Beclin1 and ATG7 was significantly enhanced by carbon ion beam alone or in combination with CDDP. Apoptosis analysis showed that caspase 3/7 activity and the percentage of apoptotic cells was dose-dependently increased after carbon ion beam and it was further increased when combined with CDDP. Spheroid formation ability of cancer stem like CD44+/CD26+ cells was significantly inhibited by carbon ion beam combined with CDDP. Besides, carbon ion beam combined with cisplatin significantly inhibited cell cycle progression (sub-G1 arrest) and induced more large number of γH2AX foci. In conclusion, carbon ion beam combined with CDDP has superior potential to kill MM cells including CSCs with enhanced apoptosis.

Curative treatment of Stage I non-small-cell lung cancer with carbon ion beams using a hypofractionated regimen.

PURPOSE: A phase I/II study on carbon ion radiotherapy for Stage I non-small-cell lung cancer (NSCLC) was first conducted between 1994 and 1999 and determined the optimal dose. Second, a Phase II study using the optimal dose was performed. The purpose of the present study was to clarify the local control and 5-year survival rates. METHODS AND MATERIALS: Between April 1999 and December 2000, 50 patients with 51 primary lesions were treated. Using a fixed dose of 72 GyE in nine fractions over 3 weeks, the primary tumors were irradiated with carbon ion beams alone. The average age of the patients was 74.5 years. Thirty-three (66%) of these were medically inoperable. Local control and survival were determined by using the Kaplan-Meier method and the data were statistically processed by using the log-rank test. RESULTS: All patients were observed for a minimum of 5 years or until death with a median follow-up time of 59.2 months (range, 6.0-83.0 months). The local control rate for all patients was 94.7%. The patients' 5-year cause-specific survival rate was 75.7% (IA: 89.4; IB: 55.1), and overall survival 50.0% (IA: 55.2; IB: 42.9). No toxic reactions in the lung greater than Grade 3 were detected. CONCLUSIONS: Carbon ion radiotherapy, a new treatment modality with superior benefits in terms of quality of life and activity of daily living, has been proven as a valid alternative to surgery for Stage I NSCLC and to offer particular benefits, especially for elderly and inoperable patients.

Inhibition of potential lethal damage repair and related gene expression after carbon-ion beam irradiation to human lung cancer grown in nude mice.

Using cultured and nude mouse tumor cells (IA) derived from a human lung cancer, we previously demonstrated their radiosensitivity by focusing attention on the dynamics of tumor clonogens and the early and rapid survival recovery (potential lethal damage repair: PLD repair) occurring after X-ray irradiation. To the authors' knowledge, this is the first study demonstrating gene expression in association with PLD repair after carbon-ion beam or X-ray irradiation to cancer cells. In this study we tried to detect the mechanism of DNA damage and repair of the clonogens after X-ray or carbon-ion beam irradiation. At first, colony assay method was performed after irradiation of 12 Gy of X-ray or 5 Gy of carbon-ion beam to compare the time dependent cell survival of the IA cells after each irradiation pass. Second, to search the genes causing PLD repair after irradiation of X-ray or carbon-ion beam, we evaluated gene expressions by using semi-quantitative RT-PCR with the selected 34 genes reportedly related to DNA repair. The intervals from the irradiation were 0, 6, 12 and 24 hr for colony assay method, and 0, 3, 18 hr for RT-PCR method. From the result of survival assays, significant PLD repair was not observed in carbon-ion beam as compared to X-ray irradiation. The results of RT-PCR were as follows. The gene showing significantly higher expressions after X-ray irradiation than after carbon-ion beam irradiation was PCNA. The genes showing significantly lower expressions after X-ray irradiation rather than after carbon-ion beam irradiation were RAD50, BRCA1, MRE11A, XRCC3, CHEK1, MLH1, CCNB1, CCNB2 and LIG4. We conclude that PCNA could be a likely candidate gene for PLD repair.

Assessment of the homogeneous efficacy of carbon ions in the spread-out Bragg peak for human lung cancer cell lines.

PURPOSE: The aim of this study was to assess the radiosensitivities and homogeneous efficacy in the spread-out Bragg peak (SOBP) for lung cancer cell lines exposed to carbon ions. MATERIALS AND METHODS: The dose-dependent survival rates of seven cell lines exposed to carbon ions, fast neutrons, and photons were obtained using colony-forming assays in vitro. The relative biological effectiveness (RBE) of carbon ions and fast neutrons to photons was determined by comparing the doses at the 10% and 1% survival levels. RESULTS: The RBEs at 13, 40, 50, and 80 keV/microm were 1.20-1.29, 1.55-1.80, 1.57-2.00, and 1.69-2.58, respectively, at the 10% survival level. The RBE of 290 MeV carbon ions increased with increasing linear energy transfer. The biological dose (relative physical dose x RBE) distributions in the SOBP did not statistically differ at the proximal, mid, or distal points at the 10% (p = 0.945) and 1% (p = 0.211) survival levels, respectively; however, deviation of the biological dose at 10% and 1% survival were 3%-16% and 6%-24%, respectively. Furthermore, 290 MeV carbon ions at 80 keV/microm in the SOBP were nearly equivalent to 30 MeV fast neutrons. CONCLUSION: Our results demonstrate nearly homogeneous effectiveness in the SOBP, although we are aware of the deviation in some cell lines.

A Dose Escalation Clinical Trial of Single-Fraction Carbon Ion Radiotherapy for Peripheral Stage I Non-Small Cell Lung Cancer.

OBJECTIVES: Our objective was to report initial results of a dose escalation trial of single-fraction carbon ion radiotherapy for peripheral stage I NSCLC. METHODS: Between April 2003 and February 2012, a total of 218 patients were treated. The total dose was raised from 28 to 50 Gy (relative biological effectiveness [RBE]). There were 157 male and 61 female patients, with a median age of 75 years. Of the tumors, 123 were stage T1 and 95 were stage T2. A total of 134 patients (61.5%) were medically inoperable. By histological type, there were 146 adenocarcinomas, 68 squamous cell carcinomas, three large cell carcinomas, and one mucoepidermoid carcinoma. RESULTS: The median follow-up was 57.8 months (range 1.6-160.7). The overall survival rate at 5 years was 49.4%. The local control (LC) rate was 72.7%. A statistically significant difference in LC rate (p = 0.0001, log-rank test) was seen between patients receiving 36 Gy (RBE) or more and those receiving less than 36 Gy (RBE). In 20 patients irradiated with 48 to 50 Gy (RBE), the LC rate at 5 years was 95.0%, the overall survival rate was 69.2%, and the progression-free survival rate was 60.0% (median follow-up was 58.6 months). With dose escalation, LC tended to improve. As for adverse lung and skin reactions, there were no patients with grade 3 or higher reactions, and less than 2% had a grade 2 reaction. Regarding chest wall pain, only one patient had grade 3 late toxicity. CONCLUSIONS: We have reported the outcome of a dose escalation study of single-fraction carbon ion radiotherapy for stage I NSCLC, showing the feasibility of obtaining excellent results comparable to those with previous fractionated regimens.

Examination of GyE system for HIMAC carbon therapy.

PURPOSE: A retrospective analysis was made to examine appropriateness in the estimation of the biologic effectiveness of carbon-ion radiotherapy using resultant data from clinical trials at the heavy-ion medical accelerator complex (HIMAC) at the National Institute of Radiological Sciences in Chiba, Japan. METHODS AND MATERIALS: At HIMAC, relative biologic effectiveness (RBE) values of therapeutic carbon beams were determined based on experimental results of cell responses, on values expected with the linear-quadratic model, and based on experiences with neutron therapy. We use fixed RBE values independent of dose levels, although this apparently contradicts radiobiologic observations. Our RBE system depends only on LET of the heavy-ion radiation fields. With this RBE system, over 2,000 patients have been treated by carbon beams. With data from these patients, the local control rate of non-small-cell lung cancer was analyzed to verify the clinical RBE of the carbon beam. The local control rate was compared with rates published by groups from Gunma University and Massachusetts General Hospital. Using a simplified tumor control probability (TCP) model, clinical RBE values were obtained for different levels of TCP. RESULTS: For the 50% level of the clinical TCP, the RBE values nearly coincide with those for in vitro human salivary gland cell survival at 10%. For the higher levels of clinical TCP, the RBE values approach closer to those adapted in clinical trials at HIMAC.

Dose escalation study of carbon ion radiotherapy for locally advanced carcinoma of the uterine cervix.

PURPOSE: To evaluate the toxicity and efficacy of carbon ion radiotherapy (CIRT) for locally advanced cervical cancer by two phase I/II clinical trials. METHODS AND MATERIALS: Between June 1995 and January 2000, 44 patients were treated with CIRT. Thirty patients had Stage IIIB disease, and 14 patients had Stage IVA disease. Median tumor size was 6.5 cm (range, 4.2-11.0 cm). The treatment consisted of 16 fractions of whole pelvic irradiation and 8 fractions of local boost. In the first study, the total dose ranged from 52.8 to 72.0 gray equivalents (GyE) (2.2-3.0 GyE per fraction). In the second study, the whole pelvic dose was fixed at 44.8 GyE, and an additional 24.0 or 28.0 GyE was given to the cervical tumor (total dose, 68.8 or 72.8 GyE). RESULTS: No patient developed severe acute toxicity. In contrast, 8 patients developed major late gastrointestinal complications. The doses resulting in major complications were > or =60 GyE. All patients with major complications were surgically salvaged. The 5-year local control rate for patients in the first and second studies was 45% and 79%, respectively. When treated with > or =62.4 GyE, the local control was favorable even for the patients with stage IVA disease (69%) or for those with tumors > or =6.0 cm (64%). CONCLUSIONS: In CIRT for advanced cervical cancer, the dose to the intestines should be limited to <60 GyE to avoid major complications. Although the number of patients in this study was small, the results support continued investigation to confirm therapeutic efficacy.

Single-Fraction Carbon-Ion Radiation Therapy for Patients 80 Years of Age and Older With Stage I Non-Small Cell Lung Cancer.

PURPOSE: In an aging society, many senior citizens want less invasive treatment because of potential medical complications. The National Institute of Radiological Sciences has started to treat stage I lung cancer with single-fraction carbon-ion radiation therapy (CIRT) as a dose escalation prospective phase 1/2 trial. We evaluated the efficacy and safety of CIRT for patients 80 years of age and older, undergoing single-fraction CIRT. METHODS AND MATERIALS: Peripheral non-small cell lung cancer patients who were treated with single-fraction CIRT were prospectively followed. We analyzed the data from among these patients 80 years of age and older. RESULTS: There were 70 patients. Median age was 83 years (range: 80-89) and median follow-up period was 42.7 months (range: 12-128 months). Three-year local control, cause-specific survival, and overall survival rates were 88.0%, 81.6%, and 72.4%, respectively. Five-year local control, cause-specific survival, and overall survival rates were 85.8%, 64.9%, and 39.7%, respectively. There were no adverse effects higher than grade 2 either in the acute or late phase in terms of skin and lung. Analgesic agents were necessary for only 5 patients (7.1%), to relieve muscular or rib fracture pain caused by irradiation. CONCLUSIONS: Single-fraction CIRT was low-risk and effective, even for the elderly.

Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas.

PURPOSE: To evaluate the tolerance for and effectiveness of carbon ion radiotherapy in patients with unresectable bone and soft tissue sarcomas. PATIENTS AND METHODS: We conducted a phase I/II dose escalation study of carbon ion radiotherapy. Fifty-seven patients with 64 sites of bone and soft tissue sarcomas not suited for resection received carbon ion radiotherapy. Tumors involved the spine or paraspinous soft tissues in 19 patients, pelvis in 32 patients, and extremities in six patients. The total dose ranged from 52.8 to 73.6 gray equivalent (GyE) and was administered in 16 fixed fractions over 4 weeks (3.3 to 4.6 GyE/fraction). The median tumor size was 559 cm(3) (range, 20 to 2,290 cm(3)). The minimum follow-up was 18 months. RESULTS: Seven of 17 patients treated with the highest total dose of 73.6 GyE experienced Radiation Therapy Oncology Group grade 3 acute skin reactions. Dose escalation was then halted at this level. No other severe acute reactions (grade > 3) were observed in this series. The overall local control rates were 88% and 73% at 1 year and 3 years of follow-up, respectively. The median survival time was 31 months (range, 2 to 60 months), and the 1- and 3-year overall survival rates were 82% and 46%, respectively. CONCLUSION: Carbon ion radiotherapy seems to be a safe and effective modality in the management of bone and soft tissue sarcomas not eligible for surgical resection, providing good local control and offering a survival advantage without unacceptable morbidity.

Radiosensitivity of hypoxic and proliferating clonogen in a human lung cancer grown in nude mice.

Using cultured and nude mouse tumor cells (IA) derived from a human lung cancer, we studied their radiosensitivity by focusing attention on the dynamics of tumor clonogens. The movement of clonogens in the regrowing IA tumor after irradiation can be divided into three phases: first, the early and rapid survival recovery (PLD repair) phase; second, the delay phase involving a certain lag in survival change; and third, the repopulation phase consisting of two stages: the anoxic repopulation before angiogenesis and the hypoxic repopulation in the presence of a poorly developed vascular network. Clonogens in a regrowing tumor after irradiation were found to actively proliferate even in an anoxic environment before angiogenesis and under the hypoxic conditions prevailing after the formation of a tumor with a poorly developed vascular system. This re-grown tumor was found to be more radioresistant than a sham-treated control tumor. It is believed that these clonogens are genetically selected under hypoxic conditions throughout the process of tumor growth and regrowth, and may be primarily involved in tumor recurrence or accelerated repopulation in fractionated irradiation.

Growth factor-mediated interaction between tumor cells and stromal fibroblasts in an experimental model of human small-cell lung cancer.

Malignant tumors induce development of their own stromal tissues during the processes of growth, progression and metastasis. Since the vascular architecture among the various stromal elements is well known to facilitate tumor growth and has been a target of therapy, the importance of stromal fibroblasts has recently been established. To elucidate the interaction between the tumor and its stromal fibroblasts, the present study took advantage of a unique experimental model consisting of a human small-cell lung cancer cell line, WA-ht, and its mouse stromal fibroblast cell line, WA-mFib, both originally derived from a xenograft tumor in a mouse subcutis. Co-culture with the WA-mFib cells significantly augmented the plating efficiency of WA-hT cells in vitro, and their co-inoculation in nude mice shortened latency and tumor doubling time. Histochemical detection of beta-gal, transfected into WA-mFib cells, demonstrated their contribution to the nude mouse xenograft tumor formation as its tumor stroma. Elevated hepatocyte growth factor (HGF) from fibroblasts followed by elevated production of vascular endothelial growth factor (VEGF) from both tumor cells and fibroblasts were demonstrated by ELISA in supernatants of their co-culture, accompanied by enhanced colonogenicity of the tumor cells; these enhanced features were not observed in their respective monocultures. Antisense oligonucleotides to HGF cancelled these augmentation effects with co-culture. The findings highlight the substantial roles of tumor stromal fibroblasts, interacting with soluble growth factors, in promoting the malignant propensity of the tumor.

Carbon ion radiotherapy for unresectable sacral chordomas.

PURPOSE: The purpose is to evaluate the efficacy and toxicity of carbon ion radiotherapy for unresectable sacral chordomas. EXPERIMENTAL DESIGN: We performed a retrospective analysis of 30 patients with unresectable sacral chordomas treated with carbon ion radiotherapy at the Heavy Ion Medical Accelerator in Chiba, Japan. Twenty-three patients presented with no prior treatment, and the remaining 7 patients had locally recurrent disease following previous surgical resection. The median clinical target volume was 546 cm(3). The applied carbon ion dose ranged from 52.8 to 73.6 GyE (gray equivalent, median 70.4) in 16 fixed fractions over 4 weeks. RESULTS: At median follow-up of 30 months (range, 9 to 87 months), 26 patients were still alive and 24 patients remained continuously disease-free. Overall and cause-specific survival rates at 5 years were 52 and 94%, respectively. The overall local control rate at 5 years was 96%. Two patients experienced severe skin/soft tissue complications requiring skin grafts. No other treatment-related surgical interventions, including colostomy or urinary diversion, were carried out. All patients have remained ambulatory and able to stay at home after carbon ion radiotherapy. CONCLUSIONS: Carbon ion radiotherapy is effective and safe in the management of patients with unresectable sacral chordomas and offers a promising alternative to surgery.

Radiographic pulmonary and pleural changes after carbon ion irradiation.

PURPOSE: For the treatment of Stage I non-small-cell lung cancers, a Phase I/II study of carbon ion irradiation was undertaken. In the present study, we focus on posttreatment radiographic lung damage: specifically, its timing, features, and relation to dose-volume factors. MATERIALS AND METHODS: Forty-three patients with 44 Stage I non-small-cell lung cancers were treated with carbon ion irradiation ranging from 59.4 to 95.4 photon Gy equivalent dose (GyE) in 18 fractions over 6 weeks, according to our dose escalation protocols. Primary lesions were irradiated by 2-4 portals. Follow-up evaluation with computed tomography (CT) was sequentially performed to assess changes in the lung. CT findings were classified into two categories: pulmonary reaction and pleural reaction. A dose-volume histogram for each patient was calculated, using a three-dimensional CT planning system. Statistical analysis was conducted using Spearman's rank test. RESULTS: The median appearance period of pulmonary reactions was 3 months after the start of carbon ion irradiation, whereas the maximum period was 6 months. The severity of pulmonary reactions statistically correlated with lung volumes irradiated no less than 20 GyE (vol. 20) and 40 GyE (vol. 40) (p = 0.017 and p = 0.0089). Geometrically unique findings in the irradiated fields were observed in 7 patients (16%). The median appearance period of pleural reactions was 4 months after the start of carbon ion irradiation. The occurrence of pleural reactions significantly correlated with planning target volume (p = 0.000098), vol. 20 (p = 0.00011), and vol. 40 (p = 0.00097). CONCLUSIONS: Lung damage after carbon ion irradiation was observed in the parenchyma and in the pleura. The severity of pulmonary reactions was correlated with dose-volume factors. These findings might provide useful information in the planning and management of carbon ion irradiation.

Results of the first prospective study of carbon ion radiotherapy for hepatocellular carcinoma with liver cirrhosis.

PURPOSE: To evaluate the toxicity and antitumor effect of carbon ion radiotherapy for hepatocellular carcinoma within a Phase I-II trial. METHODS AND MATERIALS: Between June 1995 and February 1997, 24 patients with histopathologically proven hepatocellular carcinoma were treated to 15 fractions within 5 weeks in a step-wise dose-escalation study. The disease stage was Stage II in 10, IIIA in 6, and IVA in 8 patients. The Common Toxicity Criteria, Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer criteria, and Child-Pugh score were used to evaluate toxicity. The antitumor effect was evaluated by the tumor response, cumulative local control, and survival rates. RESULTS: During a median follow-up of 71 months (range, 63-83 months), no severe adverse effects and no treatment-related deaths occurred. The Child-Pugh score did not increase by >2 points after the start of therapy. In 78% and 75% of all patients, the score did not increase by >1 point in the early and late phase, respectively. The overall tumor response rate was 71%. The local control and overall survival rate was 92% and 92%, 81% and 50%, and 81% and 25% at 1, 3, and 5 years, respectively. CONCLUSION: Carbon ion radiotherapy appears safe and effective for patients with hepatocellular carcinoma. Additional clinical studies using a larger subject group are required to confirm the therapeutic efficacy.

Local control and recurrence of stage I non-small cell lung cancer after carbon ion radiotherapy.

BACKGROUND AND PURPOSE: For a proper evaluation of the relationship between carbon ion beam dose escalation and local control in the 81 patients with 82 lesions of stage I non-small cell lung cancer, we have identified the incidence of in-field recurrence by collating the dose distribution with the CT images. PATIENTS AND METHODS: Eighteen fractions over 6 weeks for 47 patients (48 lesions) and nine fractions over 3 weeks for 34 patients were applied in the carbon dose escalation method from 59.4 to 95.4 gray equivalents (GyE) by a 10% increment and from 68.4 to 79.2GyE by a 5% increment, respectively. The radiation target consisted of primary tumor. Image analysis of the patients with local recurrence was systematically performed after the treatment by focusing attention on the enhanced thin slice CT images of the primary lesion. By superimposing the dose distribution on the planning CT image and marking the anatomically identified loci of recurrence, it was possible to establish the relationship between the dose distribution and the incipient loci of recurrence and to classify the recurrence patterns from the differences in the recurrence loci. RESULTS: Local recurrence was found in 19 (23.2%) out of a total of 82 lesions. It is possible to distinguish between three recurrence patterns: Pattern 1 representing marginal recurrence and patterns 2a and 2b, which are both instances of in-field recurrence. In pattern 1, four recurrences take place from a region on the upper tumor margin. In pattern 2a, 13 recurrences take place from the center of the tumor. In pattern 2b, two recurrences take place from the near-center of the tumor. CONCLUSIONS: For the 15 in-field recurrence lesions (patterns 2a and 2b) after excluding the four marginal recurrence lesions (patterns 1), we have established that the local control shows dose-dependence. Based on this, we have determined the optimal therapeutic dose.

Carbon ion radiotherapy for stage I non-small cell lung cancer.

BACKGROUND AND PURPOSE: Heavy ion radiotherapy is a promising modality because of its excellent dose localization and high biological effect on tumors. Using carbon beams, a dose escalation study was conducted for the treatment of stage I non-small cell lung cancer (NSCLC) to determine the optimal dose. MATERIALS AND METHODS: The first stage phase I/II trial using 18 fractions over 6 weeks for 47 patients and the second one using nine fractions over 3 weeks for 34 patients were conducted by the dose escalation method from 59.4 to 95.4 Gray equivalents (GyE) in incremental steps of 10% and from 68.4 to 79.2 GyE in 5% increments, respectively. The local control and survival rates were obtained using the Kaplan-Meier method. RESULTS: Radiation pneumonitis at grade III occurred in three of 81 patients, but they fully recovered. This was not a dose-limiting factor. The local control rates in the first and second trials were 64% and 84%, respectively. The total recurrence rate in both trials was 23.2%. The infield local recurrence in the first trial was significantly dependent on carbon dose. The doses greater than 86.4 GyE at 18 fractions and 72 GyE at nine fractions achieved a local control of 90% and 95%, respectively. The 5 year overall and cause-specific survivals in 81 patients were 42% and 60%, respectively. CONCLUSIONS: With our dose escalation study, the optimum safety and efficacy dose of carbon beams was determined. Carbon beam therapy attained almost the same results as surgery for stage I NSCLC although this was a I/II study.