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.

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.

Urinary human growth hormone measurement using a highly sensitive sandwich enzyme immunoassay: diagnostic and therapeutic uses in patients with growth hormone deficiency.

Several reports indicate that urinary hGH excretion is significantly lower in patients with either partial (PGHD) or complete GH deficiency (CGHD) than in normal but short children (NSC) or normal children (NC). However, there is an overlap between the NSC and NC groups and the PGHD group. Using a highly sensitive sandwich enzyme immunoassay, we investigated whether the measurement of urinary hGH can clearly separate the PGHD and CGHD groups from the NSC and NC groups. In addition, we measured the urinary excretion of synthetic methionyl-hGH (met-hGH) in PGHD and CGHD after sc injections of 2 and 4 IU and im injections of 4 IU in an attempt to determine the optimal replacement dose. Total 24-h urinary hGH excretion in each patient examined for 2 consecutive days varied from 1 day to the next. There were no differences in urinary hGH excretions between the NSC group and the NC group. The lower values for daily urinary hGH excretion in the NSC group overlapped some of the higher values in the PGHD group. However, when the mean urinary hGH level of both days was used, the 24-h urinary hGH excretion clearly separated the PGHD (5.5 +/- 2.3 ng/day; range, 1.3-9.2; n = 21) and CGHD (1.9 +/- 0.9 ng/day; range, 0.6-3.6; n = 14) groups from the NSC (12.8 +/- 3.1 ng/day; range, 9.3-17.5; n = 10) and NC (14.6 +/- 3.1 ng/day; range, 10.6-19.0; n = 6) groups without any overlap. A mean urinary hGH value less than 9.0 ng/day during a 2-day collection strongly suggested GH deficiency. Ten of 16 patients with PGHD and CGHD who received 2 IU met-hGH, sc, had urinary hGH levels within the range of the mean +/- SD in NSC. These patients received daily sc 0.097 +/- 0.024 IU/kg hGH injections. These results suggest that the measurement of 24-h urinary hGH excretion is noninvasive, accurate, and useful for the screening of GH deficiency. The mean value on 2 days of 24-h urinary hGH excretion for the screening of GH deficiency is estimated to be less than 9.0 ng/day. The optimal dose of GH as therapy for GH deficiency is demonstrated as daily sc injection of 0.1 IU/kg hGH, 0.7 IU/kg/week. To convert international units of met-hGH to milligrams, divide by 2.4.

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.

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.

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.

Radioimmunoreactive plasma bradykinin levels and histological changes during the course of cerulein-induced pancreatitis in rats.

The plasma bradykinin (BK) and serum amylase levels and histological changes in rats during the course of acute pancreatitis induced by a large dose of cerulein were examined. Animals were given four intraperitoneal injections of 20 micrograms/kg body wt of cerulein at hourly intervals. The plasma concentration of BK-like immunoreactivity (BK-LI), measured by a highly sensitive and specific radioimmunoassay established in this study, was found to reach a peak 6 h after the first injection of cerulein and then to remain elevated. On the other hand, the serum amylase and the histological alterations (i.e., interstitial edema, vacuolization, and inflammatory infiltration) were maximal 9 h after the first injection and returned to nearly normal after 24 h. These observations suggest that the BK generation is indicative of the participation of the kallikrein-kinin system in the pathophysiological change and that the plasma BK-LI level is a good marker of cellular damage and inflammation within the pancreas during the course of acute pancreatitis.

The normal range of the plasma immunoreactive glucagon level during a 75 g oral glucose tolerance test.

In order to establish a normal value of plasma glucagon immunoreactivity (GI) and glucagon-like immunoreactivity (GLI) during a newly adopted 75 g OGTT, 50 normals (N), 102 individuals with IGT and 20 diabetics (D) were subjected to the OGTT, and their plasma GI and GLI levels were determined at various intervals by radioimmunoassay using 2 kinds of the C-terminal region specific antibody, OAL123 and 30K, and of the antibody specific for the N-terminal and/or central region of glucagon, OAL196, respectively. The basal levels of OAL123-GI and 30K-GI and OAL196-GLI in the 3 groups were as follows; N, 114.3, 80.8, and 335.5; IGT, 107.6, 76.1, and 338.5; and D, 135.7, 76.9, and 342.2 pg/ml. After glucose administration, a significant decrease in plasma GI and increase in plasma GLI were observed in the 3 groups, although their changes from the basal levels were variable. The plasma samples of inexplicably high GI concentration were chromatographed to clarify the nature of the hyperglucagonemia. The apparent GI was mostly eluted in the Vo component, but negligibly at the 3500 mol.wt. glucagon fraction. There was a marked difference in the Vo peak depending upon the antiserum used. These facts suggest that plasma GI values are dependent on the amount of BPG present in particular samples, and the antibody used.

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.

Effect of diltiazem on silent ischemic episodes, plasma bradykinin and prostaglandin metabolism.

Plasma bradykinin and prostaglandin metabolism are related to the anginal pain modulating system in patients with ischemic heart disease. We carried out a placebo controlled single blind test of diltiazem (30 mg three times a day) in 15 patients with chronic stable angina. The effect of diltiazem was evaluated by exercise treadmill testing and 48-h ambulatory electrocardiographic monitoring. Plasma bradykinin, thromboxane B2, and 6-keto-prostaglandin F1 alpha levels were determined by radioimmunoassay prior to and during diltiazem therapy. Diltiazem significantly increased the exercise time and reduced episodes of angina. Diltiazem, however, did not appreciably improve either the frequency of silent myocardial ischemic episodes or the total duration of the silent myocardial ischemic episodes. Diltiazem also tended to decrease plasma bradykinin, thromboxane B2, and 6-keto-prostaglandin F1 alpha levels. When ischemic episodes on ambulatory electrocardiographic monitoring are categorized according to heart rate change at the onset of episode (type A, preceded by heart rate increase > or = 5 beats/min; type B, no preceding heart rate increase), diltiazem was only effective on type A ischemic episodes as well as on symptomatic ischemia. Further, bradykinin was significantly decreased by diltiazem only in patients with exercise-induced silent ischemia or no exercise-induced ischemia, while the thromboxane B2/6-keto-prostaglandin F1 alpha ratio was unaffected by the administration of diltiazem. Thus, silent and symptomatic ischemia may be associated with different bradykinin and prostaglandin responses.

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.

18 years of conformation radiotherapy at Nagoya University Hospital.

Conformation radiotherapy is one of the best techniques for minimizing the radiation dose absorbed by the surrounding normal tissue while delivering a high dose to a cancerous target area. The cases of all patients who underwent external irradiation at Nagoya University Hospital from 1975 to 1992 were reviewed. A total of 5740 patients with 6179 lesions were irradiated during this time, and 3795 treatment plans involved radical intended irradiation. Of the 5740 patients, 1017 had head and neck cancer, 982 had cervical cancer, 506 had lung cancer, 439 had primary brain tumors, 308 had esophageal cancer, 1213 had metastatic tumors, and 1275 had other types of tumors. The total number of treatment plans per year decreased from 442 in 1975 to 292 in 1992. Likewise, the percentage of conformation radiotherapy performed in all patients decreased from 29.4% (130/442) in 1975 to 8.6% (25/292) in 1992. It occupied 14.5% (982/6179) of all intended plans, and 20% (775/3795) of radical treatment plans. The conformation technique was used in cases of cervical cancer (72%), esophageal cancer (65%) and primary brain tumors (25%). Boost Conformation radiotherapy represented 2% of all treatment planning and 29% of the conformation radiotherapy. Boost Conformation radiotherapy has recently become more popular and now represents more than 50% of conformation radiotherapy. With respect to cases of cervical cancer, the rates of local recurrence and late complications in cases treated by conformation radiotherapy were lower than in cases treated by two parallel opposed radiotherapy.

Effect of 24R,25-dihydroxyvitamin D3 in experimental renal insufficiency.

This placebo-controlled study in JCL-Wistar rats showed that 100 micrograms/kg 24R,25-dihydroxyvitamin D3, when given for 12 days consecutively, restored immune function which had deteriorated following aminonucleoside-induced nephrosis. Urinary creatinine excretion in five-sixths nephrectomized rats was also shown to be increased by 10 micrograms/kg 24R,25-dihydroxyvitamin D3. Hypophosphataemic effects in both these cases of experimentally-induced renal insufficiency was also shown following administration of 24R,25-dihydroxyvitamin D3.

Effect of 24R,25-dihydroxyvitamin D3 in experimental diabetic rats.

The results are presented of a controlled study in male Wistar rats into the effects of 24R,25-dihydroxyvitamin D3 on blood glucose levels, bone calcium content and ADP-induced platelet aggregation in streptozocin-induced diabetes mellitus. Blood glucose levels were shown to be decreased by 10 micrograms/kg 24R,25-dihydroxyvitamin D3. The reduced bone calcium content associated with diabetes mellitus was returned to normal levels with both 1 and 10 micrograms/kg 24R,25-dihydroxyvitamin D3. It was also shown to exhibit dose-dependent anti-platelet activity. The data suggest that 24R,25-dihydroxyvitamin D3 might have potential as a mild therapeutic agent in the treatment of osteoporosis and platelet hyperactivity associated with diabetes mellitus.

[The changes of serum gamma-Sm level in acute prostatitis].

gamma-Sm, the specific antigen of the prostate, is useful for the diagnosis and following-up of prostatic cancer. It is recognized as the tumor marker. The serum gamma-Sm is increased in some cases of acute prostatitis. We evaluated the serum gamma-Sm in patients with acute prostatitis. Serum gamma-Sm, PAP, CRP and WBC count were measured before treatment with antibiotics and 3 to 5 days and 1 week thereafter. In the acute phase of inflammation (before treatment) serum gamma-Sm increased in 62.5% of the cases. Then it decreased quickly and was within the normal range 3 to 5 days later. This change of serum gamma-Sm is similar to that of WBC count, fever and urinalysis. But the decrease of serum gamma-Sm is earlier than that of CRP. PAP does not increase in any phase of inflammation. It suggests that the serum gamma-Sm reflects cell damages of the prostatic gland or increased permeability due to prostatitis.

[Alternating chemoradiotherapy for oropharyngeal cancer].

To evaluate the usefulness of chemoradiotherapy for oropharyngeal cancer, we retrospectively analyzed disease-free survival (DFS) and acute toxicities of the patients treated with this therapy. Between 1990 and 1998, 15 patients were treated with alternating chemoradiotherapy (CRT). Chemotherapy (CT) mainly consisted of 5-fluorouracil 700 mg/m2 (i.v.) on days 1-5 and nedaplatin 100-140 mg/m2 (i.v.) on day 6. Chemotherapy was administered before the beginning of radiotherapy. One cycle of this treatment consisted of CT and a subsequent 27 to 36 Gy of radiotherapy, as a general rule, two cycles were performed. Radiotherapy was delivered in single daily fractions of 1.8 to 2 Gy, to a total dose of 54 to 75 Gy for local lesions and 45 to 86.3 Gy for nodal metastases in the neck. As a historical control, 52 patients treated with curative radiotherapy between 1971 and 1990 were analyzed and compared with the CRT group in terms of DFS. The complete response rate with CRT was 100%. The three-year DFS were 87% and 38% with CRT and RT, respectively. There was a significant difference between the two groups (p = 0.0081). The most frequent and severe acute toxicity was mucositis, with grade 3-4 occurring in 47%. Acute hematologic toxicities were mild. Therefore, this CRT is considered to be an effective and tolerable treatment, and is expected to improve survival for oropharyngeal cancer patients.

[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.

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.