Kiyoshi Nakamatsu

Prospective trial of concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil and cisplatin for T4 esophageal cancer with or without fistula.

PURPOSE A prospective trial of concurrent chemoradiotherapy (CT-RT) with a protracted infusion of 5-fluorouracil and cisplatin was performed to evaluate the safety and efficacy of this protocol for T4 esophageal cancer (UICC 1997). METHODS AND MATERIALS Between 1998 and 2000, 28 patients with T4 esophageal squamous cell carcinomas were treated with concurrent CT-RT. Of the 28 patients, 15 had Stage III, 5 Stage IVA, and 8 Stage IV disease. Five of the T4 tumors had evidence of fistula before treatment. Patients received a protracted infusion of 5-fluorouracil 300 mg/m(2)/24 h on Days 1-14, a 1-h infusion of cisplatin 10 mg/body on Days 1-5 and 8-12, and concurrent radiation at a dose of 30 Gy in 15 fractions during 3 weeks. This schedule was repeated twice, with a 1-week split, for a total RT dose of 60 Gy during 7 weeks for 25 patients. For the remaining 3 patients, 30 Gy of preoperative CT-RT was administered. RESULTS Of the 25 patients who were treated with the full dose of CT-RT, 14 (56%) completed the two courses of the CT-RT protocol, and 8 patients (32%) received the full dose of RT but a reduced dose of chemotherapy. Eight (32%) of the 25 tumors showed complete regression. Although Grade 3 hematologic toxicities were frequently noted, Grade 4 or more hematologic toxicities were few. Of the 5 T4 fistulous tumors, 2 demonstrated the disappearance of the fistula after CT-RT. However, the worsening or development of an esophageal fistula was noted in 5 patients. The 2-year survival rate for patients with Stage III was 27%, and the median survival time for those with Stage III and Stage IVA+IV was 12 and 5 months, respectively. CONCLUSION Despite its significant toxicity for esophageal fistula, this concurrent CT-RT protocol of protracted 5-fluorouracil infusion and cisplatin appears feasible and effective for T4 esophageal cancer with or without fistulas.

Single-agent gefitinib with concurrent radiotherapy for locally advanced non-small cell lung cancer harboring mutations of the epidermal growth factor receptor

INTRODUCTION A feasibility study was performed to examine the safety and toxicity profile of daily gefitinib (250 mg) administration with concurrent definitive thoracic radiation therapy (TRT) in patients with unresectable non-small cell lung cancer (NSCLC) of stage III. METHODS Patients received a 14-day induction therapy with gefitinib at 250 mg daily. TRT was initiated on day 15 in 2-Gy fractions administered five times weekly to a total dose of 60 Gy. The primary end point of the study was the rate of treatment completion. Mutation status of the epidermal growth factor receptor gene (EGFR) was evaluated for patients with available tumor specimens. RESULTS Nine eligible patients enrolled in the study received induction gefitinib monotherapy. Two patients were unable to begin TRT because of the development of progressive disease during the first 2 weeks of the protocol. Three of the remaining seven patients treated with gefitinib and concurrent TRT were unable to complete the planned treatment (two because of pulmonary toxicity and one because of progressive disease), and the study was therefore closed according to the protocol definition. Tumor samples were available for eight patients. EGFR mutations (deletion in exon 19) were detected in two patients, both of whom achieved a partial response and exhibited an overall survival of >5 years. CONCLUSIONS Our results do not support further trials of gefitinib and TRT for unselected NSCLC patients. This therapeutic strategy may hold promise, however, for locally advanced NSCLC in patients with sensitizing EGFR mutations.

A prospective clinical trial of tumor hypoxia imaging with 18F-fluoromisonidazole positron emission tomography and computed tomography (F-MISO PET/CT) before and during radiation therapy

To visualize intratumoral hypoxic areas and their reoxygenation before and during fractionated radiation therapy (RT), 18F-fluoromisonidazole positron emission tomography and computed tomography (F-MISO PET/CT) were performed. A total of 10 patients, consisting of four with head and neck cancers, four with gastrointestinal cancers, one with lung cancer, and one with uterine cancer, were included. F-MISO PET/CT was performed twice, before RT and during fractionated RT of approximately 20 Gy/10 fractions, for eight of the 10 patients. F-MISO maximum standardized uptake values (SUVmax) of normal muscles and tumors were measured. The tumor-to-muscle (T/M) ratios of F-MISO SUVmax were also calculated. Mean SUVmax ± standard deviation (SD) of normal muscles was 1.25 ± 0.17, and SUVmax above the mean + 2 SD (≥1.60 SUV) was regarded as a hypoxic area. Nine of the 10 tumors had an F-MISO SUVmax of ≥1.60. All eight tumors examined twice showed a decrease in the SUVmax, T/M ratio, or percentage of hypoxic volume (F-MISO ≥1.60) at approximately 20 Gy, indicating reoxygenation. In conclusion, accumulation of F-MISO of ≥1.60 SUV was regarded as an intratumoral hypoxic area in our F-MISO PET/CT system. Most human tumors (90%) in this small series had hypoxic areas before RT, although hypoxic volume was minimal (0.0–0.3%) for four of the 10 tumors. In addition, reoxygenation was observed in most tumors at two weeks of fractionated RT.

Long-term results of fractionated strontium-90 radiation therapy for pterygia

PURPOSE The long-term safety and effectiveness of fractionated strontium-90 radiation therapy (RT) for pterygium were reviewed retrospectively. METHODS AND MATERIALS Between 1984 and 1996, 399 patients with 490 pterygia were treated with a strontium-90 eye applicator following surgical removal of the pterygium. The median follow-up period was 61 months (range 2-178). Of the 490 pterygia, 452 were fresh, 17 were recurrences after surgical removal alone, and 21 were recurrences after surgical removal plus postoperative RT. Fractionated RT of 31-42 Gy/4-5 fractions/22-29 days was given for 95.1% of the pterygia. RESULTS In total, 58 (11.8%) local recurrences of pterygia were noted. The median time of local recurrences was 10 months, ranging from 2 to 93 months, and 16 recurrences (28%) were noted later than 24 months after treatment. The interval between surgery and the start of RT (1-3 days vs. >3 days) and recurrent pterygia were significant variables for local control in the multivariate analysis, while total RT dose (7-29 Gy vs. 31-50 Gy) was a marginally significant variable. Late toxicities that may be associated with strontium-90 RT were scleromalacia (scleral thinning) in 4 eyes, adhesion of eyelids in 3 eyes, and scleral ulcer in 2 eyes. CONCLUSION Fractionated strontium-90 RT of approximately 40 Gy/4-5 fractions was safe and effective for preventing recurrence of pterygia, when RT was started within 3 days of surgery.

Static and moving phantom studies for radiation treatment planning in a positron emission tomography and computed tomography (PET/CT) system

ObjectiveTo determine an appropriate threshold value for delineation of the target in positron emission tomography (PET) and to investigate whether PET can delineate an internal target volume (ITV), a series of phantom studies were performed.MethodsAn ellipse phantom (background) was filled with 1028 Bq/ml of [18F] fluoro-2-deoxyglucose (18FDG), and six spheres of 10 mm, 13 mm, 17 mm, 22 mm, 28 mm, and 37 mm in diameter inside it were filled with 18FDG activity to achieve source-to-background (S/B) ratios of 10, 15, and 20. In static phantom experiments, an appropriate threshold value was determined so that the size of PET delineation fits to an actual sphere. In moving phantom experiments with total translations of 10 mm, 20 mm, and 30 mm and a period of oscillation of 4 s, the maximum size of PET delineation with the appropriate threshold value was measured in both the axial and sagittal planes.ResultsIn the static phantom experiments, the measured maximum 18FDG activities of spheres of less than 22 mm were lower than 80% of the injected 18FDG activity, and those for the larger spheres ranged from 90% to 110%. Appropriate threshold values determined for the spheres of 22 mm or more ranged from 30% to 40% of the maximum 18FDG activity, independent of the S/B ratio. Therefore, we adopted an appropriate threshold value as 35% of the measured maximum 18FDG activity. In moving phantom experiments, the maximum 18FDG activity of spheres decreased significantly, dependent on the movement distance. Although the sizes of PET delineation with 35% threshold value tended to be slightly smaller (<3 mm) than the actual spheres in the axial plane, the longest sizes in the sagittal plane were larger than the actual spheres.ConclusionsWhen a threshold value of 35% of the measured maximum 18FDG activity was adopted, the sizes of PET delineation were almost the same for static and moving phantom spheres of 22 mm or more in the axial plane. In addition, PET images have the potential to provide an individualized ITV.

A randomized phase II study of cisplatin/5-FU concurrent chemoradiotherapy for esophageal cancer: Short-term infusion versus protracted infusion chemotherapy (KROSG0101/JROSG021)

PURPOSE A randomized phase II study was conducted to compare the toxicity and efficacy of combining short-term chemotherapy (CT) or protracted CT with radiotherapy (RT) for esophageal cancer. MATERIALS AND METHODS Eligible patients were <75 years and with performance status (PS) of 0-2, and had stages II-IVA esophageal cancer. Two cycles of cisplatin 70 mg/m(2) for 1 day and 5FU 700 mg/m(2) for 5 days (arm A) or cisplatin 7 mg/m(2) for 10 days and 5FU 250 mg/m(2) for 14 days (arm B) were given with RT of 60Gy/30 fractions/7 weeks (1-week split). RESULTS Of 91 patients enrolled, 46 were randomized to arm A and 45 to arm B. Two cycles of CT were given concurrently with RT for 89% in arm A and for 71% in arm B with significant difference (P=.031). The 2- and 5-year overall survival rates for arm A were 46% and 35%, while those for arm B were 44% and 24%, respectively, without significant difference. The 2- and 5-year progression-free survival rates for arm A were 30% and 30%, while those for arm B were 29% and 12%, respectively. CONCLUSIONS Protracted infusion CT with RT provides no advantage over standard short-term infusion CT with RT for esophageal cancer.

Erythropoietin/Erythropoietin-receptor system as an angiogenic factor in chemically induced murine hepatic tumors

BackgroundTo clarify the role of erythropoietin (Epo) in hepatic tumor angiogenesis, expression of Epo and its receptor (Epo-R) and content of Epo were investigated in murine chemically induced hepatic tumors.MethodsTo induce hepatic tumors and cirrhosis, diaminobenzidine was administered to Wistar rats for 5 months. In total, 30 hepatic tumors of greater than 3 mm in diameter were induced in 12 rats. The 30 hepatic tumors were resected with the surrounding hepatic tissues. The Epo content was measured by a radioimmunoassay (RIA) method. The number of tumor vessels in a definite area was counted in 100 areas of each tumor. To demonstrate the expression of Epo-R in tumors or surrounding liver tissues, immunohistochemial staining for Epo-R was performed.ResultsThe Epo content of tumors ranged from 6.1 to 97.8 mU/ml, with a median of 21.8 mU/ml, which was significantly higher than that of the cirrhotic tissues adjacent to the tumors. Epo was not detectable in the normal or cirrhotic liver tissues without tumors. A significant correlation between Epo content and vascular density was noted in the 30 hepatic tumors (correlation coefficient, 0.480; P = 0.01). Immunoreactive Epo-R was detectable in the endothelium of intervening vessels of all hepatic tumors examined.ConclusionThe Epo/Epo-R system is related to the angiogenesis of murine hepatic tumors.

Radiation Treatment Planning Using Positron Emission and Computed Tomography for Lung and Pharyngeal Cancers: A Multiple-Threshold Method for [18F]Fluoro-2-Deoxyglucose Activity

PURPOSE Clinical applicability of a multiple-threshold method for [(18)F]fluoro-2-deoxyglucose (FDG) activity in radiation treatment planning was evaluated. METHODS AND MATERIALS A total of 32 patients who underwent positron emission and computed tomography (PET/CT) simulation were included; 18 patients had lung cancer, and 14 patients had pharyngeal cancer. For tumors of <or=2 cm, 2 to 5 cm, and >5 cm, thresholds were defined as 2.5 standardized uptake value (SUV), 35%, and 20% of the maximum FDG activity, respectively. The cervical and mediastinal lymph nodes with the shortest axial diameter of >or=10 mm were considered to be metastatic on CT (LNCT). The retropharyngeal lymph nodes with the shortest axial diameter of >or=5 mm on CT and MRI were also defined as metastatic. Lymph nodes showing maximum FDG activity greater than the adopted thresholds for radiation therapy planning were designated LNPET-RTP, and lymph nodes with a maximum FDG activity of >or=2.5 SUV were regarded as malignant and were designated LNPET-2.5 SUV. RESULTS The sizes of gross tumor volumes on PET (GTVPET) with the adopted thresholds in the axial plane were visually well fitted to those of GTV on CT (GTVCT). However, the volumes of GTVPET were larger than those of GTVCT, with significant differences (p < 0.0001) for lung cancer, due to respiratory motion. For lung cancer, the numbers of LNCT, LNPET-RTP, and LNPET-2.5 SUV were 29, 28, and 34, respectively. For pharyngeal cancer, the numbers of LNCT, LNPET-RTP, and LNPET-2.5 SUV were 14, 9, and 15, respectively. CONCLUSIONS Our multiple thresholds were applicable for delineating the primary target on PET/CT simulation. However, these thresholds were inaccurate for depicting malignant lymph nodes.

Long-term follow-up of a randomized phase II study of Cisplatin/5-FU concurrent chemoradiotherapy for esophageal cancer (KROSG0101/JROSG021)

OBJECTIVE Long-term survival and late toxicities of a randomized Phase II study of chemoradiotherapy for esophageal cancer were analyzed. METHODS Eligible patients were <75 years old and performance status 0-2, and had Stages II-IVA esophageal cancer. For arm A (short-term infusion), cisplatin 70 mg/m(2) Days 1 and 29 and 5-fluorouracil 700 mg/m(2) Days 1-5 and 29-33 were given concurrently with radiotherapy of 60 Gy/30 fr/7 weeks (1 week split). For arm B (protracted infusion), cisplatin 7 mg/m(2) Days 1-5, 8-12, 29-33 and 36-40, and 5-fluorouracil 250 mg/m(2) Days 1-14 and 29-42 were given with the same radiotherapy. Two cycles of consolidation cisplatin/5-fluorouracil chemotherapy were given to both arms. RESULTS Between 2001 and 2006, 91 patients were enrolled; 46 were randomized to arm A, and 45 to arm B. The 2- and 5-year overall survival rates for arm A were 46 and 35% (95% confidence interval: 22-48%), while those for arm B were 44 and 22% (11-35%), respectively. Excluding four patients with early death, seven (17%) patients in arm A and eight (18%) in arm B showed late toxicities of Grade 3 or more. Most of the toxicities were cardiac or pleural toxicities. Patients with severe late toxicities often had coexistent hypothyroidism. There were three patients with a secondary malignancy possibly related to treatment. CONCLUSIONS Low-dose protracted infusion chemotherapy with radiotherapy is not superior to full-dose short-term infusion chemotherapy with radiotherapy for esophageal cancer. Late toxicities, including cardiac and pleural toxicities, hypothyroidism and secondary malignancy, should be carefully monitored.

Treatment outcomes and dose-volume histogram analysis of simultaneous integrated boost method for malignant gliomas using intensity-modulated radiotherapy

BackgroundThe aim of this article is to report the treatment outcomes, toxicities, and dosimetric feasibility of our simultaneous-boost intensity-modulated radiotherapy (SIB-IMRT) protocol.MethodsThirteen patients with malignant gliomas treated between December 2000 and September 2004 were enrolled in this study. Two planning target volumes (PTVs) were defined in the present study. Our IMRT regimen delivered 70 Gy/28 fractions (fr)/daily; 2.5 Gy to the gross tumor volume (GTV) with a 0.5-cm margin, defined as the PTV-G, and 56 Gy/28 fr/daily, with 2.0 Gy to the surrounding edema, defined as the planning target volume annulus (PTV-a). Eleven of the 13 patients received one or two courses of nimustine hydrochloride (ACNU) (100 mg/m2) and vincristine (1.2 mg/body) and interferon-β (3 × 106 units) three times weekly during the period of radiotherapy. Adjuvant chemotherapy, ACNU (100 mg/m2) and vincristine (1.2 mg/body), was repeated every 6 weeks and interferon-β was repeated every 2 weeks. The treatment outcomes, toxicity, and dosimetric feasibility were assessed.ResultsAll the patients experienced tumor recurrence. The median progression-free survival times for patients with grade III tumors and glioblastome were 7.5 and 8.0 months, respectively. The 1-year and 2-year overall survival rates for all the patients were 77% and 31%, respectively. Four patients experienced acute grade 1/2 toxicities during the treatment. No late toxicity related to radiotherapy has been seen. Analyses with dose-volume histograms confirmed excellent conformity of dose distributions in the two target volumes, PTV-G and PTV-a, with the sparing of organs at risk.ConclusionOur IMRT regimen did not prevent tumor progression. However, the ability of IMRT to deliver highly conformative doses to two contiguous targets, GTV and the surrounding edema, justifies its application to malignant gliomas.