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Purpose: Proton beam therapy (PBT), compared with conventional radiotherapy, can deliver high-dose radiation to a tumor, while minimizing doses delivered to surrounding normal tissues. The better dose distribution of PBT may contribute to the improvement in local control rate and reduction in late adverse events. We evaluated therapeutic results and toxicities of PBT combined with selective intra-arterial infusion chemotherapy (PBT-IACT) in patients with stage III-IVB squamous cell carcinoma of the tongue., Materials and Methods: After 2 systemic chemotherapy courses and whole-neck irradiation (36 Gy in 20 fractions), we administered concurrent chemoradiotherapy comprising PBT for the primary tumor [28.6-33 Gy(RBE) in 13-15 fractions] and for the metastatic neck lymph node [33-39.6 Gy(RBE) in 15-18 fractions] with weekly retrograde intra-arterial chemotherapy by continuous infusion of cisplatin with sodium thiosulfate., Results: Between February 2009 and September 2012, 33 patients were enrolled. The median follow-up duration was 43 months. The 3-year overall survival, progression-free survival, local control rate, and regional control rate for the neck were 87.0, 74.1, 86.6, and 83.9 %, respectively. Major acute toxicities >grade 3 included mucositis in 26 cases (79 %), neutropenia in 17 cases (51 %), and dermatitis in 11 cases (33 %). Late grade 2 osteoradionecrosis was observed in 1 case (3 %)., Conclusions: PBT-IACT for stage III-IVB tongue cancer has an acceptable toxicity profile and showed good treatment results. This protocol should be considered as a treatment option for locally advanced tongue cancer.

Objective: This study aimed to evaluate the efficacy and toxicity of proton beam therapy combined with cisplatin intra-arterial infusion via a superficial temporal artery as treatment for maxillary sinus carcinoma., Methods: Twenty-six patients with confirmed maxillary sinus carcinoma were enrolled in this study from May 2009 to April 2011. Patients underwent proton beam therapy and intra-arterial infusion chemotherapy with cisplatin., Results: The median total dose was 70.4 GyE per 32 fractions, and the median dose of cisplatin was 300 mg/body for six cycles of intra-arterial infusion. The 3-year overall survival rate was 58% for all patients (n = 26), 58% for patients with stage T4 disease (n = 12), 57% for patients with

Purpose: To evaluate, in Japan Clinical Oncology Group study 0403, the safety and efficacy of stereotactic body radiation therapy (SBRT) in patients with T1N0M0 non-small cell lung cancer (NSCLC)., Methods and Materials: Eligibility criteria included histologically or cytologically proven NSCLC, clinical T1N0M0. Prescribed dose was 48 Gy at the isocenter in 4 fractions. The primary endpoint was the percent (%) 3-year overall survival. The threshold % 3-year survival to be rejected was set at 35% for inoperable patients, whereas the expected % 3-year survival was 80% for operable patients., Results: Between July 2004 and November 2008, 169 patients from 15 institutions were registered. One hundred inoperable and 64 operable patients (total 164) were eligible. Patients' characteristics were 122 male, 47 female; median age 78 years (range, 50-91 years); adenocarcinomas, 90; squamous cell carcinomas, 61; others, 18. Of the 100 inoperable patients, the % 3-year OS was 59.9% (95% confidence interval 49.6%-68.8%). Grade 3 and 4 toxicities were observed in 10 and 2 patients, respectively. No grade 5 toxicity was observed. Of the 64 operable patients, the % 3-year OS was 76.5% (95% confidence interval 64.0%-85.1%). Grade 3 toxicities were observed in 5 patients. No grade 4 and 5 toxicities were observed., Conclusions: Stereotactic body radiation therapy for stage I NSCLC is effective, with low incidences of severe toxicity. This treatment can be considered a standard treatment for inoperable stage I NSCLC. This treatment is promising as an alternative to surgery for operable stage I NSCLC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This study investigated the maximum tolerated dose (MTD) of S-1 with concurrent radiotherapy in patients with head and neck cancer, based on the frequency of dose-limiting toxicities (DLT). S-1 was administered orally at escalating doses from 40 mg/m(2) b.i.d. on the days of delivering radiotherapy, which was given at a total dose of 64-70 Gy in 32-35 fractions over 6-7 weeks. A total of 12 patients (3 patients at 40 mg/m(2), 6 patients at 60 mg/m(2), and 3 patients at 80 mg/m(2)) were enrolled in this trial. At the dose of 80 mg/m(2), two of the three patients developed DLT (Grade 3 anorexia and rhabdomyolysis) due to S-1, so the MTD was determined to be 80 mg/m(2). Among the 12 enrolled patients, 9 (75%) showed a complete response and 3 (25%) showed a partial response. The overall response rate was 100%. The recommended dose of S-1 with concurrent radiotherapy is 60 mg/m(2).

Background: Secondary cancers are severe complications in patients who have had allogeneic bone marrow transplantation for childhood leukemia. We describe here a case of squamous cell carcinoma (SCC) of the buccal mucosa in a young adult patient who had had allogeneic bone marrow transplantation for childhood acute leukemia., Methods and Results: The primary tumor was treated with interstitial brachytherapy, and lymph node metastasis was treated by supraomohyoid neck dissection. The patient had a history of acute lymphoblastic leukemia (ALL) at 11 years of age and had received an allogeneic bone marrow transplant from a female donor. Further investigation of the tissue specimens by fluorescent in situ hybridization (FISH) revealed that an XX chromosome pattern was dominant in the tumor region, and this suggested that donor-derived cells might affect carcinogenesis in the recipient., Conclusions: This case presents an incidence of secondary oral cancer associated with allogeneic bone marrow transplantation.

Background and Purpose: Hyperfractionated accelerated radiotherapy without a split (AF) has been performed to improve the local control probability of early glottic carcinomas since 1990 in the authors' institution. Here, they report their experience treating early glottic cancer patients with AF in a single institution who have a long follow-up period., Patients and Methods: 131 T1 N0 M0 glottic cancers and 65 T2 N0 M0 glottic cancers were treated with conventional fractionation (CF) from 1984 to 1989 and with AF since 1990. CF consisted of five daily fractions of 2 Gy per week, to a total dose of 64 Gy. AF consisted of 1.72 Gy per fraction, two fractions per day, 5 days a week, to a total dose of 55 or 58.5 Gy., Results: The 5-year local control probability for T1 tumors was 94% with 58.5 Gy and 87% with 55 Gy of AF, whereas it amounted to 80% with CF. For T2 tumors, it was 56% with 58.5 Gy and 68% with 55 Gy of AF, whereas it amounted to 64% with CF. The data of T2 should be evaluated with caution due to the small number of patients. Patients with AF had more severe mucosal reactions but no severe late reactions., Conclusion: AF significantly improved the local control rates for T1 glottic cancer.

Purpose: The goal of this study was to clarify the dynamics of oxygenation (partial pressure of oxygen, pO(2)) in SCC VII murine tumors in mice after X-ray irradiation., Materials and Methods: Changes in pO(2) in tumors were measured by 1.2-GHz electron paramagnetic resonance (EPR) spectroscopy after they were exposed to various doses of irradiation. The pO(2) in tumors was followed for up to six days after irradiation at doses of 0, 5, 10, 15, and 20 Gy. Paramagnetic crystals were used as an oximetry probe and implanted into normal or tumor tissues in mice for prolonged periods., Results: The pattern of tumor oxygen after a single dose of radiation with the 5-Gy dose was different from those with other doses (10, 15, and 20 Gy). After 5 Gy, pO(2) increased rapidly (P<0.01, Student's t test) and then returned to the level observed before irradiation by 12h (P<0.01). In contrast, after 10, 15, or 20 Gy, pO(2) increased rapidly by 6h after irradiation, continued to increase until at least 24h (P<0.01), and then gradually decreased., Conclusions: In tumors that received 5 Gy, post-irradiation increases in pO(2) at 4h after irradiation were detected by EPR oximetry (P<0.01) noninvasively.

Purpose: To analyze the outcomes of patients with early hypopharyngeal cancer treated with radical radiotherapy (RT)., Methods and Materials: Ten institutions combined the data from 115 patients with Stage I-II hypopharyngeal squamous cell carcinoma treated with definitive RT between 1990 and 2001. The median patient age was 67 years; 99 patients were men and 16 were women. Of the 115 patients, 39 had Stage I and 76 had Stage II disease. Conventional fractionation was used in 98 patients and twice-daily RT in 17 patients; chemotherapy was combined with RT in 57 patients. The median follow-up period was 47 months., Results: The overall and disease-specific 5-year survival rate for 95 patients without synchronous malignancies was 66.0% and 77.4%, respectively. The 5-year disease-specific survival rate by T stage was 95.8% for patients with T1 disease and 70.1% for patients with T2 disease (p=0.02). Of the 115 patients, local control with laryngeal voice preservation was achieved in 34 of 39 patients with T1 lesions, including 7 patients successfully salvaged, and in 56 of 76 patients with T2 lesions. Sixty-five patients (56.5%) had synchronous or metachronous cancers. Of the 115 patients, 19 died of hypopharyngeal cancer, 10 died of second primary cancers, and 14 died of other causes during the study and follow-up periods., Conclusions: Patients with early hypopharyngeal cancer tended to have a good prognosis after RT. However, second malignancies had an adverse effect on the overall outcomes of patients with early hypopharyngeal cancer.

Background: To investigate and analyze changes in irradiated salivary gland function of patients with head and neck tumors treated with radiotherapy., Methods: Thirty-seven patients with head and neck tumors, who received 40-70 Gy of irradiation to all major salivary glands, were analyzed. The weights of saliva secreted for 10 minutes at rest, and for 5 minutes with vitamin C stimulation, were measured. The salivary gland function was defined by the weight of saliva., Results: With vitamin C stimulation, the weight of saliva in patients whose doses were < or =50 Gy, was significantly higher than that of patients whose doses were > or = 58 Gy (2.48 +/- 0.33 g vs. 0.73 +/- 0.18 g, P = 0.0003). When doses administered to salivary glands were < or =50 Gy, the stimulated saliva secretion recovered over time, after irradiation. However, when the doses of irradiation were > or = 58 Gy, there was no recovery in saliva secretion even after a few years. Multiple regression analysis showed that age and chemotherapy may not affect salivary gland function even years after radiotherapy., Conclusion: When salivary glands were irradiated with doses < or =50 Gy, gradual recovery of salivary gland function was observed over time, whereas there was no significant recovery when the irradiation dose was >58 Gy.

The results of definitive radiotherapy to elucidate the optimal doses of external irradiation (ERT) and low-dose-rate intraluminal brachytherapy (ILBT) were analyzed. Between 1979 and 1998, 100 patients with esophageal cancer were treated with ERT and ILBT. ERT was given at a dose of 40-65 Gy/25-32 fractions and ILBT at 10-24.3 Gy/2-3 fractions. The 5-year actuarial survival rate for all cases was 13% and that for patients with tumors of 5 cm or less in length was 22.64%, while for patients with tumors longer than 5 cm the rate was 5% (p < 0.005). In patients with tumors of 5 cm or less in length, the local control rate of those whose ILBT dose was 20 Gy or more was 83%, and for those with an ILBT dose of less than 20 Gy the control rate was 26.5% (p = 0.014). In patients with tumors of 5 cm or less in length, the results of treatment with 60 Gy ERT and 20 Gy ILBT were promising and did not cause severe late complications.

Purpose: A comparison of treatment outcomes in response to various methods of radiotherapy for superficial esophageal cancer (SEC) was carried out for a large series of patients., Methods and Materials: During the period from March 1987 to November 1998, 147 patients with superficial esophageal cancer received definitive radiation therapy at nine radiotherapy institutions in Japan. Fifty-five patients were treated with external radiation therapy alone, 69 with high-dose-rate intracavitary radiation therapy with or without external radiation therapy, and 23 with low-dose-rate intracavitary radiation therapy and external radiation therapy., Results: The 5-year survival rates for mucosal and submucosal cancer patients were 62% and 42%, respectively. The 5-year cause-specific survival rates for mucosal and submucosal cancer patients were 81% and 64%, respectively (p = 0.013). There was no statistically significant difference in the survival rates for either mucosal or submucosal cancer patients between treatment groups. Metastasis was observed only in submucosal cancer patients. Esophageal ulcers developed only in patients who received intracavitary radiation therapy, and were especially common in patients treated with a fraction size of 5 Gy or more., Conclusions: The use of intracavitary radiation therapy does not influence the survival or local control rate of SEC. Optimal radiotherapy methods for SEC should be determined by a randomized clinical trial.

Purpose: DNA-dependent protein kinase (DNA-PK), a serine/threonine kinase composed of p470 catalytic subunit (DNA-PKcs) and p85/p70 heterodimer (Ku antigen), is considered a critical enzyme in the repair of the DNA double-strand breaks (DSB) that are the major lethal lesions induced by ionizing radiation. We investigated the expression of DNA-PK subunits in human tumors., Materials and Methods: We examined immunohistochemically the biopsy specimens of 44 patients with oropharyngeal carcinoma and 32 patients with hypopharyngeal carcinoma who had been treated with radiotherapy., Results: Immunopositivity to Ku85 and DNA-PKcs was found in all patients. The staining of Ku85 and DNA-PKcs was nuclear, with none of the normal epithelial cells or malignant cells exhibiting cytoplasmic or membrane immunoreactivity. Normal epithelial cells were all stained intensely. In tumors, intense nuclear staining of DNA-PKcs was seen in 75 of 76 tumors, while that of Ku85 was seen in all 76 patients. The radiation responses of a primary tumor that was stained weakly with DNA-PKcs were excellent., Conclusion: Our results suggest the possibility of predicting the intrinsic radiosensitivity of human tumors in clinics able to perform immunohistochemical analysis of DNA-PK.

Purpose: Hyperfractionated and accelerated radiotherapy without a split was performed to improve the local control probability of early glottic carcinomas. We analyzed the results of this regimen by using the Ki-67 index., Methods and Materials: Over a 12-year period, 85 T1N0M0 glottic cancers and 50 T2N0M0 glottic cancers were treated with conventional fractionation (CF) from 1984 to 1989 and with accelerated fractionation (AF) since 1990. The CF program consisted of five daily fractions of 2 Gy per week, for a total of 64 Gy. The AF program consisted of 1.72 Gy per fraction, two fractions per day, 5 days a week, for a total of 55 or 58 Gy. The specimens, taken before radiotherapy, were immunohistochemically stained with anti-Ki-67 antibody., Results: The 5-year local control probability for T1 tumors was 79.6 +/- 6.9% with CF treatment, whereas with AF it was 86.9 +/- 5.6%. For T2 tumors it was 62.7 +/- 12.2% with CF, whereas it was 74.7 +/- 7.8% with AF. The difference between CF and AF did not reach the point of statistical significance. However, when T1 tumors had a Ki-67 index lower than 50%, the local control rate achieved with AF was significantly better than that with CF (p = 0.018). When the tumors had a Ki-67 index that was 50% or more, there was no difference in the local control rate between CF and AF, whether they were T1 or T2. The peak mucosal reactions at the larynx and/or hypopharynx were much more severe and appeared at smaller doses and earlier in AF than in CF. The patients with AF showed no severe late complications., Conclusions: AF could not obtain statistically significant improvement in local control probability of T1 or T2 glottic carcinomas.

Sixty-three patients with squamous cell carcinoma of the hypopharynx were treated at the University of Tokyo between 1985 and 1993. Twelve patients were treated with surgery alone, 16 with preoperative irradiation, 26 with postoperative irradiation, and nine with irradiation alone. A tumor dose of 50 Gy (25 fractions/5 weeks) was used in postoperative irradiation, 40-60 Gy in preoperative irradiation, and 70 Gy in irradiation alone. When "number of indications," including, for example, partial pharyngectomy, positive or close (< or = 5 mm) margin, and extracapsular extension, was used for multivariate analysis in patients who underwent surgery, it proved to be the only significant prognostic factor for gross survival. Six of seven patients with a positive surgical margin or close margin who received postoperative irradiation had local recurrence. A tumor dose of 50 Gy (25 fractions/5 weeks) in postoperative irradiation is not enough. It is difficult to cure by irradiation metastases to the parapharyngeal lymph nodes large enough to be detected with CT. It is necessary to irradiate parapharyngeal lymph nodes prophylactically, but 50 Gy in postoperative irradiation may not be enough from our results. The same may be true for metastases to the paratracheal nodes, which lie close to the lower poles of the thyroid gland or within the superior mediastinum and are difficult to access through surgery. In the patients who were operated on, N stage and the number of lymph node metastases were significant for gross survival. When "number of indications" was used for analysis, "number of indications" proved to be the most significant prognostic factor for gross survival.

We report our experience with radiotherapy for three patients with cervical carcinoma in whom surgery had been downgraded to the performance of exploratory laparotomy only, because of extensive primary tumor or nodal invasion to the surrounding organs and vessels. Tumor invasion to the bladder, side wall invasion or unresectable nodal disease at the time of exploration prevented definitive surgery in our case series. After laparotomy, we carried out radiation therapy consisting of external irradiation to the pelvis and intracavitary irradiation with high dose rate 60Co or low dose rate 137Cs sources. Local and regional control was obtained in all three patients, and there was no locoregional recurrence during > 5 years of follow-up. One patient died of paraaortic lymph node metastases, but she had no pelvic recurrence. Several authors have reported an increased risk of small bowel obstruction in patients who undergo laparotomy before radiotherapy. None of our patients developed small bowel obstruction, although one had anal bleeding which was cured by conservative therapy. Radiotherapy was effective for locoregional control in all three patients with unresectable cervical carcinoma.

Between 1985 and 1990, 20 patients with stage 2 and 3 esophageal cancer without esophagopulmonary fistulas were treated with alternating radiotherapy and chemotherapy (cisplatin, methotrexate, and peplomycin). Patients given the combined therapy received courses of chemotherapy during weeks 1 and 6 and radiotherapy during weeks 2-5 and 7-9. Chemotherapy consisted of i.v. cisplatin (80 mg/ m2 of body surface area) on day 1, i.v. methotrexate (40 mg/ m2) on day 2, and s.c. peplomycin (10 mg/day) continuously from day 2 to day 5. Radiotherapy was external irradiation with or without intracavitary irradiation. In seven cases, external irradiation alone was administered at 65-70 Gy, and in 13 cases, external irradiation (50-55 Gy) was combined with intracavitary irradiation (14-20 Gy). At the end of treatment, the rate of complete response was 60% with an overall response rate of 95%. Five-year total survival was 25%; cause-specific survival was 36.8%. The most common acute toxicities were bone marrow suppression, hepatic and renal damage, pneumonitis, and esophagitis. There was no life-threatening toxicity.

Collagen disease are frequently associated with malignant tumors. Recently, radiotherapy combined with chemotherapy has been recommended for improving the efficacy of treatment for nasopharyngeal carcinoma. Two patients with nasopharyngeal carcinoma complicated by collagen diseases (dermatomyositis in one, and Sjögren's syndrome with mixed connective tissue disease in the other) were given radiotherapy combined with chemotherapy consisting of cis-platinum and 5-fluorouracil. Following this combination therapy, both patients developed retropharyngeal abscess and ulceration of the mucosal membrane on the posterior wall of the oropharynx; there was no tumor cell involvement. Because these injuries were more severe than would have been expected from radiotherapy alone, it is recommended that special attention be paid to combination therapy in patients with nasopharyngeal carcinoma complicated by collagen disease.

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.

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.

Between 1974 and 1980, 61 primary esophageal squamous cell carcinoma were treated by external irradiation combined with additional intracavitary radium therapy. The esophageal primary control rate was 36% (22/61) and the 5-year survival rate was 24.7%. We believe that external radiation therapy followed by additional intracavitary radium irradiation produces good results.

Carcinomas are known to develop after radiation therapy for benign or malignant lesions. However, the development of primary carcinoma of the rectum following radiotherapy is relatively rare. This paper presents a case of adenocarcinoma of the rectum in which the history strongly suggested a radiation-induced carcinoma 12 years after initial radiotherapy for carcinoma of the cervix. Furthermore, it was interesting that metastatic adenocarcinoma of the skin was localized only over the pelvic and perineal area that had mild brown pigmentation from the previous irradiation. The relation between the effect of irradiation and a second primary cancer in the irradiated skin is discussed.

There has been some controversy concerning dose-time correction in continuous irradiation at low dose rates. We present the results of carcinoma of the tongue in a patient complicated by chronic renal failure, for which he was undergoing hemodialysis three times a week. This patient was treated with a single implant but with a doubling of 137Cs needles for double strength. The actual dose was given in a shorter treatment time than recommended, with the dose-time adjustment following the Paterson-Parker system. The patient has been alive and well for eight years.

Between 1974 and 1982, 78 primary esophageal squamous cell carcinomas were treated by external irradiation combined with additional intracavitary radium therapy. 50 to 60 Gy were given by external irradiation, and 5 to 20 Gy were delivered on the surface of the esophageal mucosa. The combined dose ranged from TDF 110 to 140 on the esophageal mucosa and TDF 95 to 120 at a depth of 5 mm from the esophageal mucosa. The 5-year survival rate was 19.3% by this combined radiotherapy alone. We conclude that the optimal dose of the combined therapy for esophageal cancer ranges from TDF 95 to 120 at a depth of 5 mm from the esophageal mucosa.

Late local recurrence of cervical cancer more than 10 years after successful initial treatment is very rare. We now present 17 patients with late local recurrence. Only one patient had undergone primary surgery alone; the other 16 patients had received various types of radiotherapy. All 17 patients received radiotherapy as the second treatment. Local control was achieved in 9 patients, 4 of these survived for more than 5 years after the second treatment. Longterm follow-up for more than 10 years is important for the early detection of late local recurrence.