Results of a multi-institutional, randomized, non-inferiority, phase III trial of accelerated fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer: Japan Clinical Oncology Group Study (JCOG0701).

Background: We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and methods: In this multi-institutional, randomized, phase III trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1-2N0M0, age 20-80, Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. Patients were randomly assigned to receive either SF of 66-70 Gy (33-35 fractions), or AF of 60-64.8 Gy (25-27 fractions). The primary end point was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results: Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4-85.4) for SF and 81.7% (95% CI 75.4-87.0) for AF (difference 1.8%, 91% CI-5.1% to 8.8%; one-sided P = 0.047 > 0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year overall survival (OS) between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1 (0.5%) in the SF/AF arms. Conclusion: Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared with SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC. Clinical trials registration: UMIN Clinical Trial Registry, number UMIN000000819.

Predictive factors for radiation pneumonitis in oesophageal cancer patients treated with chemoradiotherapy without prophylactic nodal irradiation.

OBJECTIVE: The objective of this study was to identify clinical and dosimetric factors for the development of radiation pneumonitis (RP) among patients with oesophageal cancer treated with three-dimensional radiotherapy without prophylactic nodal irradiation. METHODS: 125 patients with oesophageal cancer had undergone dose-volume histogram (DVH) metrics and received chemoradiotherapy (CRT). Several clinical and dosimetric factors with regard to the lung were evaluated as predictive factors for the development of symptomatic RP. RESULTS: 26 patients (20.8%) developed symptomatic RP classified as greater than or equal to Grade 2. By univariate analysis, body weight loss, tumour length, Stage IV, response to treatment and all DVH parameters proved to be significant factors for the development of RP (p < 0.05). By multivariate analysis, Stage IV and all dosimetric factors were independent predictive factors for the development of symptomatic RP (p < 0.05). Recursive partitioning analysis indicated that V10 values of 24.8% or more and Stage IV were associated with higher development of RP (odds ratio 6.53). CONCLUSIONS: Our study demonstrated that severe RP was also developed in patients treated with the minimal radiation field. Stage IV and the dosimetric factors were identified as independent predictive factors for symptomatic RP in oesophageal cancer patients treated with CRT without prophylactic nodal irradiation.

Factors associated with nodal metastasis in nasopharyngeal cancer: an approach to reduce the radiation field in selected patients.

OBJECTIVES: The purpose of this study was to investigate factors associated with lymph node (LN) metastasis to identify which nasopharyngeal cancer (NPC) patients can undergo a reduction in the prophylactic radiation field. MRI of biopsy-proven NPC patients was evaluated to determine primary tumour extension and the existence of LN metastasis. METHODS: Sex, age, pathological type, T stage, primary tumour size, existence beyond the midline of the nasopharynx at the primary site and parapharyngeal extension of the primary tumour were assessed regarding their impact on the laterality of LN metastasis using the χ(2) test. RESULTS: Of the 167 patients, 149 (89%) showed nodal involvement. The existence beyond the midline of the nasopharynx was significantly associated with the laterality of LN metastasis (p<0.0001). Most patients (82%) with primary tumour presence within the midline showed only ipsilateral LN metastasis or no LN metastasis. In addition, contralateral LN metastases were seen only at Level II and the retropharyngeal LN among most of other patients. CONCLUSION: These results suggest that LN areas other than Level II and the retropharyngeal LN on the contralateral side could be omitted in patients with primary tumour presence within the midline and without the contralateral Level II or the retropharyngeal LN. Whether disease control is compromised by reducing the radiation field for subclinical diseases is a problem that should be solved in the future by prospective study.

A comparison of radiation treatment plans using IMRT with helical tomotherapy and 3D conformal radiotherapy for nasal natural killer/T-cell lymphoma.

The purpose of this study was to compare radiation treatment plans (RTPs) that used intensity-modulated radiation therapy (IMRT) with helical tomotherapy (HT) or three-dimensional conformal radiation therapy (3D-CRT) for nasal natural killer/T-cell lymphoma (NNKTL). We created RTPs that used IMRT with HT or 3D-CRT for eight NNKTL patients previously treated at our institution and conducted a pilot comparison between the two modalities using the parameters of the target coverage and homogeneity for the planning target volume (PTV) and the maximum and mean doses for organs at risk (OARs). The clinical target volume (CTV) included the gross tumour volume with an additional margin of 1.5 cm and the nasopharynx, palates and nasal cavity; the PTV with the CTV plus a 2 mm margin received a total dose of 50 Gy. IMRT achieved significantly better PTV coverage, with more than 99% of the PTV receiving 90% and 95% of the prescribed dose, whereas 3D-CRT could not provide adequate coverage of the PTV, with 89.1+/-2.6% and 84.5+/-2.7% of the PTV receiving 90% and 95% of the prescribed dose, respectively (both p <0.0001). The homogeneity index was 0.29+/-0.06 for IMRT and 0.046+/-0.022 for 3D-CRT, which was statistically significant (p <0.0001). IMRT tended to provide equivalent or slightly better OAR avoidance than 3D-CRT. In conclusion, 3D-CRT could not provide adequate coverage of the PTV because the PTV was close to many OARs. IMRT should be used for NNKTL because a lack of optimal RTPs could cause local failure.

False-positive positron emission tomography appearance with 18F-fluorodeoxyglucose after definitive radiotherapy for cancer of the mobile tongue.

(18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) is an effective tool for evaluating the results of radiotherapy. However, some false-positive appearances caused by physiological or pathological accumulation are reported. We report on three patients who showed a high accumulation of FDG in the lingual muscles but had no recurrent tumour after definitive radiotherapy for the mobile tongue. All patients had squamous cell carcinoma of the tongue and received interstitial radiotherapy with small sources. High uptake was seen in the lingual muscles without recurrence or inflammation, based on physical and MR examinations. This false-positive appearance is thought to relate to ill-balanced high activity of the lingual muscles after definitive radiotherapy.

Helical tomotherapy for brain metastases: dosimetric evaluation of treatment plans and early clinical results.

The purpose of this study was to evaluate the feasibility and treatment plans of intensity-modulated radiation therapy using helical tomotherapy (HT) for brain metastases. Twenty-three patients with 1 to 4 brain metastases were treated with HT. In combination with whole-brain radiotherapy (simultaneous plans), metastatic lesions, and the whole brain were treated with 50 Gy and 30 Gy, respectively, in 10 fractions, with a simultaneous integrated boost technique. In patients treated for brain metastases alone (focal plans), metastatic lesions were treated with 35 or 37.5 Gy in 5 fractions. The treatment plans were compared regarding the conformation number (CN) and homogeneity index (HI), and differences in these indexes between simultaneous and focal plans were examined by Student's t-test. Seven and 16 patients were treated with simultaneous plans and focal plans, respectively. The mean +/- SD of CN and HI values were 0.75 +/- 0.13 and 0.063 +/- 0.042, respectively, for simultaneous plans, and 0.73 +/- 0.12 and 0.052 +/- 0.023, respectively, for focal plans. The CN and HI between the two plans were not significantly different. Response rates in 13 patients with follow-up imaging were approximately 90% for both plans and the local control rate at 1 year was 69%. One patient with a huge tumor (34.0 cc) and WHO performance status 3 treated with focal plans experienced severe headache, requiring prolongation of the treatment time, and died at 8 days after completion of treatment. The exact cause of deterioration was uncertain as no radiological investigation was performed in this patient. No late complications were observed during follow-up periods up to 20 months. HT is a viable non-invasive technique for treatment of brain metastases and achieves high accuracy in terms of dose conformity and homogeneity.

Identifying patients with peripheral-type early non-small cell lung cancer (T1N0M0) for whom irradiation of the primary focus alone could lead to successful treatment.

We investigated the indication of radiotherapy in operable patients with peripheral-type early non-small cell lung cancer (T1N0M0 (TNM staging in 1997)). The subjects comprised 396 patients with non-small cell lung cancer in whom the clinical stage was evaluated as IA. We examined age, gender, Brinkmann's index, histopathological type, the grade of histopathological differentiation, tumour diameter and the level of carcinoembryonic antigen as factors involved in lymph node metastasis. Lymph node metastasis was detected in 79 patients (20%). Factors such as the grade of histopathological differentiation and tumour diameter were involved in lymph node metastasis. In well-differentiated lesions, the probability of metastasis was <10% even when the tumour diameter exceeded 2 cm. However, the probability rapidly increased with tumour size in moderately and poorly differentiated lesions. Among the patients with peripheral-type early non-small cell lung cancer (T1N0M0), the risk of lymph node metastasis was low in those with well-differentiated carcinoma and those with moderately differentiated lesions measuring

Treatment results of boron neutron capture therapy using intra-arterial administration of boron compounds for recurrent head and neck cancer.

The effect of boron neutron capture therapy (BNCT) is correlated with the density of boron in the tumour. BNCT using intra-arterial administration of boron compounds was performed for recurrent head and neck cancer. Of the five patients treated, one achieved a complete response and four achieved a partial response. There was one case of transient headache but no severe adverse effects were observed. The advantages of using an intra-arterial administration route for BNCT, which causes the selective killing of tumour cells, might offer a new option in the treatment of recurrent head and neck malignancies. These promising results require further verification and optimization of the BNCT schedule; however, dose escalation would appear to be justified because the toxicity appears to be very low.

Intra-arterial chemoradiotherapy for locally advanced oral cavity cancer: analysis of therapeutic results in 134 cases.

The objective of this study was to investigate the therapeutic results of arterial injection therapy via the superficial temporal artery for 134 cases of stages III and IV (M0) oral cavity cancer retrospectively, and to clarify the prognostic factors. We administered intra-arterial chemoradiotherapy by continuous infusion of carboplatin in 65 cases from January 1993 to July 2002. Systemic chemotherapy was performed on 26 cases at the same time. We administered intra-arterial chemoradiotherapy by cisplatin with sodium thiosulphate in 69 cases from October 2002 to December 2006. Systemic chemotherapy was performed on 48 cases at the same time. The 3-year local control rate was 68.6% (T2-3: 77.9%; T4: 51.3%), and the 3-year survival rate was 53.9% (stage III: 62.9%; stage IV: 45.3%). Regarding the results of multivariate analysis of survival rates, age (<65), selective intra-arterial infusion, and the use of cisplatin as an agent for intra-arterial infusion were significant factors. The therapeutic results of intra-arterial chemoradiotherapy via the superficial temporal artery were not inferior to the results of surgery. In particular, the results of arterial injection therapy by cisplatin with sodium thiosulphate were excellent, so we believe that it will be a new therapy for advanced oral cavity cancer.

Relationship between the growth pattern of nasopharyngeal cancer and the cervical lymph nodes based on MRI findings: can the cervical radiation field be reduced in patients with nasopharyngeal cancer?

To identify patients with nasopharyngeal cancer in whom the cervical radiation field can be reduced, we classified the growth patterns of nasopharyngeal cancer based on MRI findings into 4 types and performed an evaluation. Based on MRI findings, we classified the growth patterns of primary cancer in 94 patients with nasopharyngeal cancer into Type 1 (superficial type), Type 2 (lateral invasive type), Type 3 (upward invasive type), and Type 4 (anterior extension type), and further classified Type 2, based upon nasopharyngoscopic findings, into Type 2a (unilateral invasive type) and Type 2b (bilateral invasive type). The cervical lymph node metastasis areas were evaluated according to these types. Type 2 showed a significantly higher incidence of cervical lymph node metastasis only on the ipsilateral side than the other types (p = 0.0024). In particular, all patients with Type 2a had cervical lymph node metastasis only on the ipsilateral side (p = 0.0212). This study suggests that the distribution of metastasised cervical lymph nodes depends on the pattern of tumour extent of the primary site.

Continuous selective intraarterial chemotherapy in combination with irradiation for locally advanced cancer of the tongue and tongue base.

We retrospectively evaluated the results of the concurrent combination therapy of selective continuous intraarterial chemotherapy and radiotherapy in 39 patients with locally advanced cancer of the tongue and tongue base between September 1992 and January 2000. Thirty patients were fresh cases (stage II, 10 patients; stage III, 15; stage IV, five) and nine were recurrent cases. The primary lesion was present in the mobile tongue in 33 patients and the tongue base in six. External irradiation (median dose, 48.6 Gy) was performed in all patients, and interstitial brachytherapy using an Au grain or Cs needle (median dose, 50 Gy) in 21. In intraarterial chemotherapy, a catheter was selectively inserted into the lingual artery via the superficial temporal artery, and carboplatin (CBDCA) was continuously infused (median dose, 460 mg/m(2)) concurrently with radiotherapy. In 13 patients with cervical lymph node metastasis, two courses of systemic chemotherapy with 5-FU (700 mg/m(2) x 5 days) and cisplatin (40-50 mg/m(2)x2 days) or its analog was also performed. In 37 (94.9%) of the 39 patients in whom this combination therapy was completed, the response rate was 94.6%. The 3-year local control rate, progression-free survival rate, and overall survival rate by Kaplan-Meier's method were 79.2, 53.2, and 58.9%, respectively. This combination therapy was effective for locally advanced cancer of the tongue and tongue base without causing severe adverse side effects, and a local control rate comparable to that by surgery can be expected.

Alternating chemoradiotherapy for nasopharyngeal cancer using cisplatin and 5-fluorouracil: a preliminary report of phase II study.

Alternating chemoradiotherapy was performed in 35 patients with locally advanced nasopharyngeal cancer. The median duration of follow-up was 20 months, and the 2-year progression free and overall survival rates were 83% (95% confidence interval: 66~101%) and 94% (95% CI: 84~105%), respectively. This method may be useful in treating nasopharyngeal cancer.

Therapeutic effects of simultaneous intraluminal irradiation and intraluminal hyperthermia on oesophageal carcinoma.

An applicator enabling simultaneous intraluminal radiotherapy and intraluminal hyperthermia delivery was developed to improve the treatment results for locally advanced oesophageal carcinoma. Eight inoperable cases were treated by this method. Six cases received 40 Gy external irradiation followed by simultaneous intraluminal hyperthermia and radiotherapy (3 Gy and 4 Gy in three cases each) once weekly for 3 weeks; the remaining two cases received 50 Gy external irradiation followed by simultaneous intraluminal hyperthermia and radiotherapy (4 Gy) once weekly for 2 weeks. Hyperthermia was delivered by a radiofrequency current thermotherapy instrument for 30 min at an output that raised the oesophageal mucosal surface temperature to 42-43 degrees C. Intraluminal radiotherapy was delivered with a microSelectron to a submucosal depth of 5 mm after the first 15 min of hyperthermia. Four cases achieved complete response, with all demonstrating local control. Partial response was obtained in four cases, and three of these patients died of local recurrence. There were no significant adverse side effects apart from fistula in one case. In conclusion, simultaneous intraluminal radiotherapy and hyperthermia may improve the current treatment results for locally advanced oesophageal carcinoma.

Aichi Cancer Center 10-year experience with conservative breast treatment of early breast cancer: retrospective analysis regarding failure patterns and factors influencing local control.

PURPOSE: We analyzed the clinical results of conservative breast therapy in our institute to determine the risk factors influencing local and distant disease recurrence. METHODS AND MATERIALS: From 1989 to 1997, 301 breasts of 295 women with early breast cancer were treated with conservative surgery and adjuvant radiotherapy. There were 212 incidences of Stage I breast cancer, and 89 of Stage II. Patients were routinely treated with local resection, axillar dissection, and 46--50 Gy irradiation given in 23--25 fractions. Some also received a radiation boost to the tumor bed. RESULTS: The 5-/8-year overall survival, disease-free survival, and local control rates were 93.2/91.5%, 86.0/80.6%, and 95.1/92.5%, respectively. Using both univariate and multivariate analyses, tumor volume, estrogen receptor status, and age < 40 years were significant prognostic factors for disease-free survival. Both age < 40 years and surgical method had a strong effect on local control by uni- and multivariate analysis. Surgical margin status was a significant prognostic factor for local control at the univariate level (p < 0.0001), though it had only borderline significance at the multivariate level (p = 0.08). No patient experienced severe morbidity due to radiotherapy. CONCLUSION: The results obtained are comparable to previously reported data. Although the follow-up period was too short to draw definite conclusions about long-term outcomes, the outcome from conservative breast treatment was acceptable.

External irradiation and intraluminal irradiation using middle-dose-rate iridium in patients with roentgenographically occult lung cancer.

PURPOSE: Therapeutic results were analyzed in 39 patients with roentgenographically occult lung cancer (ROLC), and the significance and optimal dose of this therapy were evaluated. METHODS AND MATERIALS: The subjects were 39 patients who underwent intraluminal irradiation between May 1987 and August 1999. Radiotherapy was performed by combining external irradiation with intraluminal irradiation using middle-dose-rate iridium (four 370-MBq wires) through a catheter with a spacer, which held the source in the center of the bronchus. The doses of radiation were 22-66 Gy (median value 45 Gy) by external irradiation and 10-46 Gy (median value 28 Gy) by intraluminal irradiation. RESULTS: The therapeutic effect was CR in 38 patients and PR in 1, and local recurrence was observed in a PR case and 3 of the 38 patients who showed CR. The 3-year and 5-year relapse-free survival rates were both 87%. No severe radiation injury was observed. CONCLUSIONS: Considering that ROLC often occurs as multiple cancers and that many patients with ROLC have reduced lung function, radiation therapy by a combination of intraluminal irradiation and external irradiation is expected to replace surgery as the first choice for the treatment of this disease in the twenty-first century.

[Two cases of squamous cell carcinoma of the anal canal treated with chemoradiotherapy].

We recently treated 2 patients with squamous cell carcinoma in the anal canal with bilateral inguinal nodal metastases using chemoradiotherapy. Chemotherapy (CT) consisted of 5-fluorouracil 700 mg/m2/day (continuous intravenously) on days 1-5 and cisplatin 50 mg/m2/day (continuous intravenously) on days 6-7. Chemotherapy was administered before the beginning of radiotherapy. In one patient, 2 cycles of CT were performed, and in the other patient 1 cycle only. The total radiation dose was 57.6 Gy to the primary lesion in each patient, and 53.6 Gy, 55.8 Gy to the nodal metastases, respectively. As a primary treatment response, CR was obtained in both patients. Acute grade 3-4 hematologic toxicities were observed in one patient. The patients have had 7 and 9 months survival without disease, and excellent function of the anal sphincter after treatment.

Therapeutic results of alternating chemoradiotherapy for nasopharyngeal cancer using cisplatin and 5-fluorouracil: its usefulness and controversial points.

BACKGROUND: The present study was conducted to evaluate the therapeutic results of alternating chemoradiotherapy for locally advanced nasopharyngeal cancer (NPC). METHODS: The subjects consisted of six patients with stage III nasopharyngeal cancer and 26 patients with stage IV nasopharyngeal cancer. Using 6 MV photons, radiotherapy was performed at an exposure of 1.8-2.0 Gy five times per week. That is, a total absorbed dose of 36-40 Gy was irradiated between the base of the skull and supraclavicular fossa. After decreasing the irradiation field, an absorbed dose of 26-30 Gy was additionally given thereafter. One course of chemotherapy consisted of the administration of 5-fluorouracil (5-FU) at a dose of 700 mg/m2/24 h for 5 days (days 1-5) and cisplatin (CDDP) at a dose of 50 mg/m2/24 h for 2 days (days 6-7) and a total of 2-3 courses of chemotherapy were performed. During the alternating chemoradiotherapy, chemotherapy was performed initially and 3-5 days after completing the chemotherapy, radiotherapy was performed for 3-4 weeks. Thereafter, chemotherapy and radiotherapy were performed alternately. RESULTS: The scheduled courses of alternating chemoradiotherapy were completed in 30 (94%) of 32 patients. Although one patient developed shock induced by metal allergy to CDDP, no severe adverse effects were noted in any other patients. In these 32 patients, the overall 5-year survival rate was 75% (95% confidence interval: 60-90%) and the progression-free survival rate was 63% (95% CI: 46-89%). CONCLUSIONS: This method of alternating chemoradiotherapy yielded higher or at least similar survival rates and lower toxicities than concurrent chemoradiotherapy and is worth trying in a multi-institutional study.

A combination therapy of continuous superselective intraarterial carboplatin infusion and radiation therapy for locally advanced head and neck carcinoma. Phase I study.

BACKGROUND: To improve the treatment result for locally advanced head and neck carcinoma, the authors used a combination of radiotherapy with superselective continuous intraarterial therapy using carboplatin. The dose limiting toxicity (DLT), maximum tolerated dose (MTD), and treatment effectiveness were tested in Phase I and II protocols. PATIENTS AND METHODS. Thirty-five patients were entered into the study from August 1992 to May 1997. The target arteries were the lingual artery in 18 cases, facial artery in 5 cases, maxillary artery in 11 cases, and external carotid artery initially changing to lingual artery in 1 case. Escalating daily carboplatin doses were tested, starting from 10 mg/m(2) (total dose, 360 or 400 mg/m(2)) to 15 mg/m(2) (total dose, 405 or 450 mg/m(2)) and then 20 mg/m(2) (total dose, 460 or 500 mg/m(2)). Radiotherapy was administered using a 6-megavolt linear accelerator to a total dose of 50-60 grays. Interstitial radiotherapy boost also was used for carcinoma of the tongue. RESULTS: Excluding 3 patients who discontinued treatment, the treatment results of 32 patients were complete response in 21 cases, partial response in 10 cases, and no change in 1 case. Neutropenia was the DLT, and the MTD was 500 mg/m(2). The local control rate was 64%. CONCLUSIONS: Superselective continuous intraarterial carboplatin and concurrent radiation therapy can be delivered safely with good efficacy for locally advanced carcinomas of the tongue and base of the tongue. Surgical treatment of these diseases usually incurs severe functional loss. This current approach may be a breakthrough in these cancers.