Yoshikazu Kagami

Phase I/II Study of Concurrent Chemoradiotherapy for Localized Nasal Natural Killer/T-Cell Lymphoma: Japan Clinical Oncology Group Study JCOG0211

PURPOSE To explore a more effective treatment for localized nasal natural killer (NK)/T-cell lymphoma, we conducted a phase I/II study of concurrent chemoradiotherapy. PATIENTS AND METHODS Treatments comprised concurrent radiotherapy (50 Gy) and 3 courses of dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC). Patients with a newly diagnosed stage IE or contiguous IIE disease with cervical node involvement and a performance status (PS) of 0 to 2 were eligible for enrollment. The primary end point of the phase II portion was a 2-year overall survival in patients treated with the recommended dose. RESULTS Of the 33 patients enrolled, 10 patients were enrolled in the phase I portion and a two thirds dose of DeVIC was established as the recommended dose. Twenty-seven patients (range, 21 to 68; median, 56 years) treated with the recommended dose showed the following clinical features: male:female, 17:10; stage IE, 18; stage IIE, 9; B symptoms present, 10; elevated serum lactate dehydrogenase, 5; and PS 2, 2. With a median follow-up of 32 months, the 2-year overall survival was 78% (95% CI, 57% to 89%). This compared favorably with the historical control of radiotherapy alone (45%). Of the 26 patients assessable for a response, 20 (77%) achieved a complete response, with one partial response. The overall response rate was 81%. The most common grade 3 nonhematologic toxicity was mucositis related to radiation (30%). No treatment-related deaths were observed. CONCLUSION Concurrent chemoradiotherapy using multidrug resistance-nonrelated agents and etoposide is a safe and effective treatment for localized nasal NK/T-cell lymphoma and warrants further investigation.

A Phase II Trial of Chemoradiotherapy for Stage I Esophageal Squamous Cell Carcinoma: Japan Clinical Oncology Group Study (JCOG9708)

OBJECTIVE The study objective was to evaluate the efficacy and toxicity of chemoradiotherapy with 5-fluorouracil (5-FU) plus cisplatin in patients with Stage I esophageal squamous cell carcinoma (ESCC). The primary endpoint was proportion of complete response (%CR). METHODS Patients with Stage I (T1N0M0) ESCC, aged 20-75 years, without indication of endoscopic mucosal resection were eligible. Treatment consisted of cisplatin 70 mg/m(2) (day 1) and 5-FU 700 mg/m(2)/day (days 1-4) combined with 30 Gy radiotherapy (2 Gy/day, 5 days/week, days 1-21). The cycle was repeated twice with 1-week split. Salvage surgery was recommended for residual tumor or local recurrence. RESULTS From December 1997 to June 2000, 72 patients were enrolled. No ineligible patient or major protocol violation was observed. There were 63 CRs for %CR of 87.5% [95% confidence interval (CI): 77.6-94.1]. Six patients with residual tumor successfully underwent esophagectomy. There was no Grade 4 toxicity. Four-year survival proportion was 80.5% (95% CI: 71.3-89.7), and 4-year major relapse-free survival proportion was 68% (95% CI: 57.3-78.8) (mucosal recurrence removed by endoscopy was not counted as an event). CONCLUSIONS High CR proportion and survival proportion with mild toxicity suggest that this regimen could be considered as a candidate of new standard treatment to be compared with surgery in patients with Stage I ESCC.

Fractionated stereotactic radiotherapy of brain metastases from renal cell carcinoma

PURPOSE To retrospectively evaluate the effectiveness of fractionated stereotactic radiotherapy (FSRT) for brain metastases from renal cell carcinoma (RCC). METHODS AND MATERIALS From May 1983 to September 1998, 35 patients with brain metastases from RCC underwent radiotherapy at the National Cancer Center Hospital, Tokyo; 10 patients treated initially with FSRT (FSRT group); 11 with surgery followed by conventional radiotherapy (S/CR group); and 14 with conventional radiotherapy (CR group). Survival and local control rates were determined for patients who had an ECOG performance status of 0-2. RESULTS Overall median survival rate was 18 months, and actuarial 1- and 2-year survival rates were 57.6% and 31.0%, respectively. Median survival rates were 25.6 months for the FSRT group, 18.7 months for the S/CR group, and 4.3 months for the CR group. Significant prognostic factors associated with survival were age less than 60 years and good performance status. In patients treated with FSRT, imaging studies revealed that 21 of 24 tumors (88%) were locally controlled during a median follow-up time of 5.2 months (range 0.5-68). Actuarial 1- and 2-year local control rates were 89.6% and 55.2%, respectively. No patient suffered from acute or late complications during and following FSRT. CONCLUSIONS FSRT offers better tumor control and prolonged survival over the S/CR or CR groups, and should be considered as primary treatment for brain metastases from RCC. Patients under 60-years-old and those with a good performance status at the beginning of radiotherapy had a better prognosis.

FRACTIONATED STEREOTACTIC RADIOTHERAPY FOR CHOROIDAL MELANOMA

Stereotactic radiotherapy used for the treatment of choroidal melanoma made use of a 6-MeV linac with built-in multileaf collimators and a simple plastic head mold. The latter provided excellent head and ocular immobilization. The system resulted in highly localized dose distributions with a maximum 2-mm targeting error during fractionated treatments. Based on these techniques, sixteen patients with choroidal melanoma have so far been treated. Majority of patients received a total dose of 48 Gy in 8 fractions. Fourteen patients who presented with small- to moderate-sized tumors have remained free of relapse or major complications during the follow-up period of 3-42 months. Two patients who presented with an extensive tumor eventually required enucleation after irradiation. Technical precision required for stereotactic radiotherapy and reproducibility for fractionation appear adequate. Encouraging preliminary results justify further studies to evaluate its efficacy as an alternative to other conventional therapeutic approaches.

Intracavitary brachytherapy combined with external-beam irradiation for squamous cell carcinoma of the thoracic esophagus

During the 15 year period from 1974 to 1988, 277 patients with previously untreated, histologically confirmed, squamous cell carcinoma of the thoracic esophagus were treated with the Time Dose and Fractionation (TDF) factor of more than 99. Of these, 161 patients were treated with external beam irradiation combined with intracavitary brachytherapy. Intracavitary brachytherapy was done for all patients for whom insertion of an outer applicator 1 cm in diameter was possible and for whom a relatively good performance status was seen at completion of external beam irradiation. Except for mild radiation-induced esophagitis, no acute radiation injuries were noted. The early clinical effect of radiation upon the esophageal lesion was determined by esophagography and esophagoscopy, approximately 1 month after the combined radiotherapy; a complete response was observed in 86 (53.4%) of the 161 patients. Furthermore, after a 5 year follow-up, local control of esophageal cancer was found to have been successful in 51 (31.7%) of the 161 patients. The highest rate of local control was associated with the following criteria: Stage I, T1, tumor length less than 5 cm, and superficial or tumorous type of tumor. The 5-year actuarial survival rates were 43.3% for Stage I, 21.1% for Stage II, and 0% for both Stages III and IV. Benign radiation-induced esophageal ulcerations or strictures did develop in five of the long-term survivors, suggesting that the dosage is close to the maximal tolerance of the esophagus. We recommend that 1500-2000 cGy in two or three fractions is the optimal dosage for intracavitary radiation of the esophageal mucosa after external irradiation of 5500 cGy in 22 fractions for 5.5 weeks or 6000 cGy in 30 fractions for 6 weeks. We believe that intracavitary treatment of esophageal carcinoma is a highly effective and a safe therapeutic modality, not only as a palliative therapy, but also as a radical treatment for patients in Stages I and II.

Multi-institutional Analysis of Solitary Extramedullary Plasmacytoma of the Head and Neck Treated with Curative Radiotherapy

PURPOSE The purpose of this study was to elucidate the efficacy and optimal method of radiotherapy in the management of solitary extramedullary plasmacytoma occurring in the head and neck regions (EMPHN). METHODS AND MATERIALS Sixty-seven patients (43 male and 24 female) diagnosed with EMPHN between 1983 and 2008 at 23 Japanese institutions were reviewed. The median patient age was 64 years (range, 12-83). The median dose administered was 50 Gy (range, 30-64 Gy). Survival data were calculated by the Kaplan-Meier method. RESULTS The median follow-up duration was 63 months. Major tumor sites were nasal or paranasal cavities in 36 (54%) patients, oropharynx or nasopharynx in 16 (23%) patients, orbita in 6 (9%) patients, and larynx in 3 (5%) patients. The 5- and 10-year local control rates were 95% and 87%, whereas the 5- and 10-year disease-free survival rates were 56% and 54%, respectively. There were 5 (7.5%), 12 (18%), and 8 (12%) patients who experienced local failure, distant metastasis, and progression to multiple myeloma, respectively. In total, 18 patients died, including 10 (15%) patients who died due to complications from EMPHN. The 5- and 10-year overall survival (OS) rates were 73% and 56%, respectively. Radiotherapy combined with surgery was identified as the lone significant prognostic factor for OS (p = 0.04), whereas age, gender, radiation dose, tumor size, and chemotherapy were not predictive. No patient experienced any severe acute morbidity. CONCLUSIONS Radiotherapy was quite effective and safe for patients with EMPHN. Radiotherapy combined with surgery produced a better outcome according to survival rates. These findings require confirmation by further studies with larger numbers of patients with EMPHN.

Results of cesium needle interstitial implantation for carcinoma of the oral tongue

One hundred thirty previously untreated patients with invasive squamous cell carcinoma of the oral tongue received interstitial radiotherapy with curative intent using cesium needles. Ninety-nine patients were treated with interstitial radiotherapy alone and 31 patients received interstitial radiotherapy combined with external beam irradiation. The recurrence-free rates in the primary lesions were 94.4% (17/18) in T1, 91.2% (52/57) in T2, and 70.9% (22/31) in T3 lesions. The local recurrence-free rates with single-plane and two-plane implantation were good: 89.7% (70/78) and 85.7% (12/14), respectively. The rate of 64.2% (9/14) for volume implantation was significantly poorer (p < 0.05). It is evident that tumor volume is an important factor in the control of cancer following interstitial therapy. The overall incidence of ulceration of the tongue and mandibular complication was 20% (26/130) and 13% (17/130), respectively. Using both interstitial and external radiotherapy, the incidence was 22.5%, compared with 10.1% using interstitial radiotherapy alone. The mandibular complication incidence of 8.9% with single-plane implants was much lower than 20.8% for two-plane and 23.5% for volume implants. Interstitial radiotherapy is most suitable in T1 and T2 cases in which single-plane implantation is possible; for these patients interstitial radiotherapy, which has the advantage of preserving the structure and function of the tongue, should continue to be used in the future in spite of the progress in reconstructive surgery.

Prospective multi-institutional study of definitive radiotherapy with high-dose-rate intracavitary brachytherapy in patients with nonbulky (<4-cm) stage i and II uterine cervical cancer (JAROG0401/JROSG04-2)

PURPOSE To determine the efficacy of a definitive radiotherapy protocol using high-dose-rate intracavitary brachytherapy (HDR-ICBT) with a low cumulative dose schedule in nonbulky early-stage cervical cancer patients, we conducted a prospective multi-institutional study. METHODS AND MATERIALS Eligible patients had squamous cell carcinoma of the intact uterine cervix, Federation of Gynecologic Oncology and Obstetrics (FIGO) stages Ib1, IIa, and IIb, tumor size <40 mm in diameter (assessed by T2-weighted magnetic resonance imaging), and no pelvic/para-aortic lymphadenopathy. The treatment protocol consisted of whole-pelvis external beam radiotherapy (EBRT) of 20 Gy/10 fractions, pelvic EBRT with midline block of 30 Gy/15 fractions, and HDR-ICBT of 24 Gy/4 fractions (at point A). The cumulative biologically effective dose (BED) was 62 Gy(10) (α/β = 10) at point A. The primary endpoint was the 2-year pelvic disease progression-free (PDPF) rate. All patients received a radiotherapy quality assurance review. RESULTS Between September 2004 and July 2007, 60 eligible patients were enrolled. Thirty-six patients were assessed with FIGO stage Ib1; 12 patients with stage IIa; and 12 patients with stage IIb. Median tumor diameter was 28 mm (range, 6-39 mm). Median overall treatment time was 43 days. Median follow-up was 49 months (range, 7-72 months). Seven patients developed recurrences: 3 patients had pelvic recurrences (2 central, 1 nodal), and 4 patients had distant metastases. The 2-year PDPF was 96% (95% confidence interval [CI], 92%-100%). The 2-year disease-free and overall survival rates were 90% (95% CI, 82%-98%) and 95% (95% CI, 89%-100%), respectively. The 2-year late complication rates (according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer of Grade ≥ 1) were 18% (95% CI, 8%-28%) for large intestine/rectum, 4% (95% CI, 0%-8%) for small intestine, and 0% for bladder. No Grade ≥ 3 cases were observed for genitourinary/gastrointestinal late complications. CONCLUSIONS These results suggest that definitive radiotherapy using HDR-ICBT with a low cumulative dose schedule (BED, 62 Gy(10) at point A) can provide excellent local control without severe toxicity in nonbulky (<4-cm) early-stage cervical cancer.

Radiotherapy for locoregional recurrent tumors after resection of non-small cell lung cancer

Thirty-two patients with locoregional recurrence without documented distant metastasis after resection of non-small cell lung cancer were treated with radiotherapy. There were 29 male patients and three female patients. The age range was 49-79 years (median 66 years). Twenty patients had squamous cell carcinoma, 11 patients adenocarcinoma and one patient large cell carcinoma. Ten patients had bronchial stump recurrence alone, 14 patients bronchial stump recurrence with mediastinal and/or supraclavicular fossa lymph nodes recurrence, and eight patients mediastinal and/or supraclavicular fossa lymph nodes recurrence without bronchial stump recurrence. The total dose delivered ranged from 47.5 to 65 Gy. We achieved good results on improving on subjective complaints. Eighty-nine percent (17/19) of patients indicated subjective improvement. Eight of 32 (25%) patients showed a complete response, and 13 of 32 (40.6%) patients showed a partial response. Only one of seven patients (14.3%) with less than 60 Gy showed a complete response, but seven of 25 patients (28%) with 60 Gy and more showed a complete response. The survival rate was 56.2% at 1 year and 12.5% at 5 years. Four patients have survived more than 5 years. The survival rate of the patients with complete response was 50% at 3 and 5 years, that of the patients with non-complete was 12.5% at 3 years and 0% at 5 years (Cox-Mantel test, P < 0.05). In conclusion, high-dose radiotherapy for locoregional recurrent tumors after resection was effective for palliation and improved survival.

FRACTIONATED STEREOTACTIC RADIOTHERAPY OF SMALL INTRACRANIAL MALIGNANCIES

PURPOSE To retrospectively evaluate the effectiveness of fractionated stereotactic radiotherapy (FSRT) in patients with small intracranial malignancies. METHODS AND MATERIALS From July 1991 to March 1997, 80 patients with a total of 121 brain or skull-base tumors were treated with FSRT alone, and were followed for periods ranging from 3 to 62 months (median 9.8). The majority of patients received 42 Gy in 7 fractions over 2.3 weeks, but in July 1993, protocols using smaller fraction doses were introduced for patients whose radiation-field diameters were larger than 3 cm or whose tumors were close to critical normal tissues. RESULTS For 64 patients with metastatic brain tumors the overall median survival was 8.3 months and 1-year actuarial survival rate was 33%. Significant prognostic factors were: the presence of extracranial tumors, pre-treatment performance status, and the lung as a primary site. Patients without extracranial tumors prior to FSRT had a median survival of 21.2 months. For seven patients with high-grade glioma, 1-year actuarial local control rate was 75%, with a median survival of 10.3 months. For patients with skull-base tumors the local control was achieved in 6 of 6 patients (100%), with a median survival of 30.7 months. No one suffered from acute complications, but three patients, two of whom had undergone FSRT as the third course of radiotherapy, developed late radiation injuries. CONCLUSION Overall high local control and low morbidity rates suggest that FSRT is an effective and safe modality, even for those with a history of prior irradiation. However, patients with risk factors should be treated with smaller fraction doses.