Concurrent chemoradiotherapy using proton beams can reduce cardiopulmonary morbidity in esophageal cancer patients: a systematic review.

This systematic review was performed to investigate the superiority of proton beam therapy (PBT) to photon-based radiotherapy (RT) in treating esophageal cancer patients, especially those with poor cardiopulmonary function. The MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases were searched from January 2000 to August 2020 for studies evaluating one end point at least as follows; overall survival, progression-free survival, grade ≥ 3 cardiopulmonary toxicities, dose-volume histograms, or lymphopenia or absolute lymphocyte counts (ALCs) in esophageal cancer patients treated with PBT or photon-based RT. Of 286 selected studies, 23 including 1 randomized control study, 2 propensity matched analyses, and 20 cohort studies were eligible for qualitative review. Overall survival and progression-free survival were better after PBT than after photon-based RT, but the difference was significant in only one of seven studies. The rate of grade 3 cardiopulmonary toxicities was lower after PBT (0-13%) than after photon-based RT (7.1-30.3%). Dose-volume histograms revealed better results for PBT than photon-based RT. Three of four reports evaluating the ALC demonstrated a significantly higher ALC after PBT than after photon-based RT. Our review found that PBT resulted in a favorable trend in the survival rate and had an excellent dose distribution, contributing to reduced cardiopulmonary toxicities and a maintained number of lymphocytes. These results warrant novel prospective trials to validate the clinical evidence.

[Particle Therapy in Cancer Treatment-Current and Future Perspective].

Although local tumor controls in various cancers by radiation therapy(RT)are dose dependent, dose-volume effects on late toxicities of surrounding normal tissues have been also observed. Particle beam therapy(PBT)using protons and carbonions have physical advantages in RT for the treatment of various cancers because they can create a desirable dose distribution to the target volume using fewer portals compared with photon-based RT. Thus, dose-escalation using charged particles is a reasonable approach in RT, theoretically. Based on accumulation of the evidences that PBT shows the efficacy in treatment for several cancers, the number of particle therapy facilities have been rapidly increasing worldwide. The Japanese Society for Radiation Oncology organized a joint effort among research groups to establish standardized treatment policies of particle therapy according to disease through systematic reviews. Furthermore, multicenter prospective studies have been conducted for hepatocellular carcinoma and prostate cancer. At the present, PBT for pediatric tumors, prostate cancer, unresectable bone and soft tissue sarcomas, head and neck non-squamous cell carcinomas is covered by the Japanese national health insurance system. Boron neutron capture therapy(BNCT)is also a promising modality as biochemically targeted RT, but it has been performed in only limited facilities. Recent advances in technology, accelerator-based neutron sources will increase in BNCT facilities and lead to wider application of BNCT for various cancers.

Primary definitive radiotherapy with or without chemotherapy for squamous cell carcinoma of the temporal bone.

We aimed to evaluate the impact of concurrent chemoradiotherapy (CCRT) on the survival of patients with squamous cell carcinoma of the temporal bone. We retrospectively analyzed the data of 13 consecutive patients who were treated by definitive radiation therapy (RT) or CCRT as the initial treatment between 1999 and 2012. There were 5 patients with stage II disease, 5 with stage III, and 3 with stage IV, as classified according to the University of Pittsburgh system. Among these, 2, 4, and 3 patients, respectively, were treated by CCRT; whereas the remaining (3 patients with stage II and 1 with stage III) were treated by RT alone. Median follow-up duration was 39 months (12-106 months) in all cases, and 61.5 months (17-70 months) in censored cases. The 5-year overall survival (OS) rates were 51 % in all patients, and 40, 100, and 0 % in patients with stage II, stage III, and stage IV disease, respectively. In patients with stage II and III disease, the 5-year OS rates were 80 % in the CCRT group and 50 % in the RT-alone group. We found better prognosis in patients with stage II and III disease who were treated by CCRT. Only 2 patients treated by CCRT experienced adverse events more than grade 3, which were neutropenia and dermatitis. There was no late adverse event of bony necrosis. Our study results indicate that CCRT is safe and very effective as a first-line treatment for stage II and III squamous cell carcinoma of the temporal bone.

[Radical Chemoradiotherapy for Recurrent Esophageal Cancer after Curative Esophagectomy].

Recurrent esophageal cancer has a poor prognosis.However, we sometimes encounter cases with long-term survival after radical treatment for recurrent esophageal cancer.We perform radical chemoradiotherapy aggressively when recurrent esophageal cancer is present in a limited area and is sufficiently localized to be treated by radiation therapy.From June 2010 to December 2014, 150 patients underwent curative esophagectomy for esophageal cancer.Forty -one cases relapsed and we treated 13 of them with radical chemoradiotherapy.Complete response(CR), non-CR/non-PD, and progressive disease(PD) were observed in 5, 6, and 2 cases, respectively.The CR rate was 38.4%.The median survival time from recurrence was 500± 39.7 days, and the 1-year and 3-year survival rates were 84.6% and 28.7%, respectively. Four out of 5 CR cases were single site recurrences.The other case was multiple and regrowth of the cancer was identified 253 days after the CR.These results suggest that radical chemoradiotherapy for recurrent esophageal cancer after curative esophagectomy can achieve long time survival, especially in cases with single site lymph node recurrence.

Definitive radiotherapy for early-stage hypopharyngeal squamous cell carcinoma.

The present study analyzed the outcomes of patients with early-stage hypopharyngeal squamous cell carcinoma (HPSCC) treated with radical radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). We retrospectively reviewed the clinical records of 33 patients with early-stage HPSCC who underwent RT or CCRT between January 1999 and December 2011. Of the 33 patients who were treated, 12 had Stage I and 21 had Stage II disease. Patients with Stage I were typically treated with RT, while patients with Stage II were treated with CCRT (concurrent chemotherapy: 5FU, cisplatin or TS-1). The median follow-up period was 81 months, ranging from 15 to 155 months. The 5-year overall survival rates, cause specific survival rates, locoregional control rates, and progression-free survival rates were 58, 75, 56, and 49 %, respectively. Of the 33 patients, 51 % experienced second primary malignancies. Esophageal carcinoma occurred in several cases, and was diagnosed either during screening after treatment for the second primary malignancy or simultaneously with the second primary malignancy. Advanced-stage second malignancies significantly influenced the survival of the patients and the control rate for HPSCC. Treatment emphasizing the quality of life after treatment is needed, if a poor prognosis is expected because of advanced-stage second primary malignancy.

Definitive radiation therapy for invasive carcinoma of the vagina: impact of high-dose rate intracavitary brachytherapy.

BACKGROUND: This study was designed to evaluate the efficacy of definitive radiation therapy (RT) for invasive carcinoma of the vagina. METHODS: Twenty-six patients with invasive carcinoma of the vagina who received RT were studied retrospectively. The median age was 68 years. The pathologic subtype of vaginal carcinoma was squamous cell carcinoma in 24 patients, adenosquamous cell carcinoma in one patient, and adenocarcinoma in one patient. The distribution of clinical stage according to the International Federation of Gynecology and Obstetrics staging system was as follows: stage I, seven patients; stage II, 10 patients, stage III, seven patients; and stage IVA, two patients. Twenty patients received external beam radiation therapy (EBRT) combined with high-dose rate intracavitary brachytherapy (HDR-ICBT), and three received EBRT alone. The remaining three patients with stage I disease were given HDR-ICBT alone. The median dose was 50 Gy for EBRT, and 23 Gy for HDR-ICBT. Systemic chemotherapy was administered concurrently with RT to three patients. RESULTS: The median follow-up was 90 months. The initial rate of response to RT was 100%, and complete remission was attained in 21 patients (81%). The 5-year overall survival rate (OS) and the median survival time of the 26 patients were 57% and 97 months, respectively. The 5-year OS for the three patients who received HDR-ICBT alone was 100%. Severe toxicity occurred in three patients-grade 3 rectal hemorrhage in one, grade 3 cystitis in one, and grade 4 cystitis in one. CONCLUSIONS: Our results demonstrated that definitive RT with HDR-ICBT is effective for invasive carcinoma of the vagina, with acceptable toxicity.

[Three cases of radiotherapy combined with S-1 and mitomycin C for anal canal squamous cell carcinomas].

We report three cases of anal canal squamous cell carcinoma treated with radiotherapy combined with S-1 and mitomycin C(MMC). During radiotherapy, MMC was administered as intravenous bolus injection at a dose of 10mg/m2 on day 1 and 29. S-1 was administered orally at a dose of 80mg/m2 on days 1-14 and 29-43. Total radiation doses ranged 55. 8-60 Gy to pelvic lesions. The rates of grade 3 toxicity were: neutropenia, 100%; leucopenia, 100%; anemia, 33. 3%; anorexia, 66. 7%. These adverse events were tolerated. All of the three cases showed complete response without recurrences. These results suggested that this treatment schedule was safe and effective for anal canal carcinomas.

Proton beam therapy for hepatocellular carcinoma associated with inferior vena cava tumor thrombus.

PURPOSE: Hepatocellular carcinoma (HCC) with inferior vena cava tumor thrombus (IVCTT) is rare and regarded as an advanced disease stage with poor prognosis. Treatment effect data regarding HCC with IVCTT is scarce and clear evidence has not been established. This study, therefore, aims to examine the safety and effectiveness of proton beam therapy (PBT) for HCC patients with IVCTT. METHODS: From January 2005 to December 2014, a total of 21 HCC patients with IVCTT were analyzed. The total irradiation doses ranged from 50 to 74 (median 72.6) gray relative biological effectiveness. RESULTS: The follow-up period was 4-120 (median 21) months. Regarding acute toxicities, dermatitis of grade 1-2 was observed in all patients, while no grade 3 or higher late toxicity events were encountered. The overall survival (OS) rates for all patients were 62%, 33%, and 19% at 1, 2, and 3 years, respectively. No local recurrences for the treated lesions, including IVCTT, were observed. According to univariate analysis, IVCTT extension type was not associated with prognosis, but only tumor number significantly affected the OS rate (p = 0.003). For 10 single lesion patients, the longest survival time was 120 months with OS rates of 82%, 64%, and 36% at 1, 2, and 3 years, respectively. CONCLUSION: PBT is safe and effective for HCC patients with IVCTT, especially those with single lesion status. PBT is an important treatment option for HCC patients with IVCTT.

Heavy-ion-induced bystander killing of human lung cancer cells: role of gap junctional intercellular communication.

The aim of the present study was to clarify the mechanisms of cell death induced by heavy-ion irradiation focusing on the bystander effect in human lung cancer A549 cells. In microbeam irradiation, each of 1, 5, and 25 cells under confluent cell conditions was irradiated with 1, 5, or 10 particles of carbon ions (220 MeV), and then the surviving fraction of the population was measured by a clonogenic assay in order to investigate the bystander effect of heavy-ions. In this experiment, the limited number of cells (0.0001-0.002%, 5-25 cells) under confluent cell conditions irradiated with 5 or 10 carbon ions resulted in an exaggerated 8-14% increase in cell death by clonogenic assay. However, these overshooting responses were not observed under exponentially growing cell conditions. Furthermore, these responses were inhibited in cells treated with an inhibitor of gap junctional intercellular communication (GJIC), whereas they were markedly enhanced by the addition of a stimulator of GJIC. The present results suggest that bystander cell killing by heavy-ions was induced mainly by direct cell-to-cell communication, such as GJIC, which might play important roles in bystander responses.

Ceramide induces myogenic differentiation and apoptosis in Drosophila Schneider cells.

Cells exposed to genotoxic stress, such as ionizing radiation and DNA damaging reagents, either arrest the cell cycle to repair the genome, or undergo apoptosis, depending on the extent of the DNA damage. DNA damage also has been implicated in various differentiation processes. It has been reported that gamma-ray exposure or treatment with DNA-damaging agents could induce myogenic differentiation in Drosophila Schneider cells. However, the mechanism underlying this process has been poorly understood. In this study, exposure of Schneider cells to X-rays or energetic carbon ion beams caused increase of TUNEL-positive cells and conversion of round-shaped cells to elongated cells. Both upregulation of genes related to myogenesis and increase of myosin indicate that the radiation-induced morphological changes of Schneider cells were accompanied with myogenic differentiation. Because the intracellular ceramide was increased in Schneider cells after exposure to X-ray, we examined whether exogenous ceramide could mimic radiation-induced myogenic differentiation. Addition of membrane-permeable C(2)-ceramide to Schneider cells increased apoptosis and expression of myogenic genes. These results suggest that ceramide plays important roles in both apoptosis and the radiation-induced myogenic differentiation process.

Proton beam therapy for renal pelvis and ureter cancer: A report of 5 cases and a literature review.

Standard treatment for localized renal pelvis and ureter cancer is surgery. Previously, the primary role of radiation therapy (RT) in cancer treatment was to control pain and hemostasis as palliative or as adjuvant therapy following surgery. In this report, we describe 5 patients with the disease treated with proton beam therapy (PBT) as curative treatment. Between September 2009 and July 2013, 5 males with renal pelvis (n=3) or ureter (n=2) cancer were treated by PBT with hypofractionated [72.6 Gy relative biological effectiveness (RBE)/22 fractions] or conventional [64-66 Gy (RBE)/32-33 fractions] fractionation. The median patient age was 72 years (range, 59-85 years). Three patients were deemed unfit for surgery. Local hypofractionated PBT was performed in 2 patients with T1-2N0M0 diseases, while prophylactic lymph node irradiation using a patch irradiation technique was performed for the remaining 3 patients, who had T3-4 disease. Two patients with T3-4 disease received chemotherapy prior to definitive PBT. No serious acute or late toxicities were observed in any patient. Local tumor control was achieved in 3 patients (60%); however, distant metastases were observed in 2 patients. Four of the five patients (80%) evaluated in the present study survived for >3 years. The data is limited; however, PBT appears to be a potential option for patients with renal pelvis or ureter cancer, especially for those who are unsuitable for radical surgery.

Clinical outcomes of previously untreated patients with unresectable intrahepatic cholangiocarcinoma following proton beam therapy.

BACKGROUND: The effectiveness of proton beam therapy (PBT) as initial treatment for patients with unresectable intrahepatic cholangiocarcinoma (ICC) is unclear, particularly as related to ICC histological subtypes. We performed this study to address this gap in knowledge. METHODS: Thirty-seven patients with unresectable ICC who underwent PBT as their initial treatment were evaluated. Twenty-seven patients had Child-Pugh class A liver function, 11 exhibited jaundice, and 10 had multiple tumors. Nineteen, 7, and 11 tumors were classified as mass forming (MF), periductal infiltrating (PI), and intraductal growth (IG) types, respectively, based on gross appearance in imaging studies. Patients were classified into the curative group (n = 25) and palliative group (n = 12) depending on whether the planning target volume covered all the macroscopic tumors. RESULTS: The 1- and 2-year overall survival rates were 60.3, and 41.4%, respectively; the median survival time (MST) was 15 months for all patients. The MSTs for curative and palliative groups were 25 and 7 months, respectively. Curative treatment and adjuvant chemotherapy significantly improved overall survival, while the presence of periductal infiltrating type tumors was a negative prognostic factor. In the curative group, the 1- and 2-year local control rates were 100 and 71.5%, respectively, while the 1-, and 2-year progression-free survival rates were 58.5, and 37.6%, respectively. No severe acute toxicities were observed. Three patients experienced grade 3 biliary tract infection, although it was unclear whether this was radiotherapy-related. CONCLUSION: PBT may yield to improve survival and local tumor control among patients with unresectable ICC.

Concurrent chemoradiotherapy using proton beams for unresectable locally advanced pancreatic cancer.

BACKGROUND AND PURPOSE: We investigated clinical outcomes of proton beam concurrent chemoradiotherapy (CCRT) for unresectable, locally advanced pancreatic cancer (LAPC) patients. MATERIALS AND METHODS: Records from 42 unresectable LAPC patients (21 male and 21 female, 39-83 years old) with IIB/III clinical staging of 1/41 treated by proton beam CCRT were retrospectively reviewed. Twelve patients received a conventional 50 Gray equivalents (GyE) in 25 fractions protocol and 30 others received a higher dose protocol of 54.0-67.5 GyE in 25-33 fractions. Gemcitabine or S-1 (Tegafur, Gimeracil and Oteracil) was used concurrently. Toxicity, overall survival (OS) and local control (LC) were examined. RESULTS: Acute adverse events of grades 1, 2, 3 and 4 were found in 4, 15, 17 and 2 patients, respectively. All grade 3 and 4 events were hematologic. Late adverse events of grades 1 and 2 were found in 3 and 2 patients, respectively. No late adverse effects of grade 3 or higher were observed. The 1-year/2-year OS rates from the start of CCRT were 77.8/50.8% with median survival time (MST) of 25.6 months. The 1-year/2-year LC rate from CCRT start was 83.3/78.9% with a median time to local recurrence of more than 36 months. Total irradiation dose was the only significant factor in univariate analyses of OS and LC (p = 0.015 and 0.023, respectively). CONCLUSION: Proton beam CCRT lengthened survival periods compared to previous photon CCRT data and higher dose irradiation prolonged LC and OS for unresectable LAPC patients. Proton beam therapy is therefore safe and effective in these cases.

Prediction of response to definitive chemoradiotherapy in esophageal cancer using positron emission tomography.

BACKGROUND: Positron emission tomography (PET) with 18-F-fluorodeoxyglucose (FDG) has already proven useful in assessing the extension of esophageal carcinomas, detecting tumor recurrence and monitoring responses to therapy. The current study aims to assess the potential role of FDG-PET in predicting the response of esophageal squamous cell carcinoma (SCC) to definitive chemoradiotherapy (CRT). PATIENTS AND METHODS: Twenty-seven patients with thoracic esophageal SCC who received definitive CRT between January 2001 and December 2005 underwent PET before and after CRT. The clinical evaluation of the primary tumor response to treatment was classified as either complete response (CR) or non-CR. RESULTS: All patients had intensive FDG uptake in the primary tumor prior to CRT. The standardized uptake value (SUV) averaged 8.2+/-4.7 before CRT and decreased significantly to 2.8+/-1.8 after CRT (p<0.0001). The SUV before CRT averaged 10.2 in the non-CR group (n=17) and 4.9 in the CR group (n= 10). The SUV after CRT averaged 3.7 in the non-CR group and 1.4 in the CR group. The change in SUV for the CR group was higher than that in the non-CR group (p<0.05). The relationship between clinical features and clinical CR was analyzed using logistic regression analysis which revealed significant correlations between clinical CR and the longitudinal dimension of the tumor (p <0.05), SUV before CRT (p<0.05), SUV after CRT (p<0.01) and tumor classification (p <0.05). If the clinical features before CRT were limited, multivariate analysis revealed that the SUV before CRT was an independent predictor for clinical CR (p<0.05). CONCLUSION: In predicting clinical evaluation of therapy prior to CRT, we suggest that SUV prior to definitive CRT is one of the most reliable predictors of response, along with tumor dimensions and classification.

Radiotherapy for mucosa-associated lymphoid tissue (MALT) lymphoma of the rectum: a case report.

Extra-nodal mucosa-associated lymphoid tissue (MALT) lymphoma is frequently involved with the upper gastrointestinal tract, but rarely involved with the rectum. We report a case of rectal MALT lymphoma treated by radiotherapy (RT) alone. A 74-year-old woman with lower abdominal pain was diagnosed with MALT lymphoma by endoscopic mucosal resection (EMR). She was diagnosed as stage IE (Ann Arbor) MALT lymphoma by diagnostic work-up and review of EMR specimens. Definitive RT was performed with curative intent, totaling 30 Gy in 15 fractions. Complete response was confirmed by colonoscopy after RT with no progression observed at 5 years. Definitive RT is effective for rectal MALT lymphoma.

Prognostic value of volumetric FDG PET/CT parameters in patients with oral tongue squamous cell carcinoma who were treated by superselective intra-arterial chemoradiotherapy.

PURPOSE: This study aimed to evaluate the predictive and prognostic value of FDG PET/CT-based volumetric parameters in patients with oral tongue squamous cell carcinoma (OTSCC) treated by superselective intra-arterial chemoradiotherapy (IA-CRT). METHODS: We conducted a retrospective study including 33 patients with biopsy-proven OTSCC between May 2007 and February 2016. All of the patients were treated by IA-CRT. Pretreatment SUVmax and metabolic tumor volume (MTV) of the primary tumor were measured. The SUV thresholds of 2.5 and 5.0 were used. Progression-free survival (PFS) and overall survival (OS) were chosen as endpoints to evaluate prognosis. Univariate and multivariate analyses were performed to assess the potential independent effect of FDG PET/CT parameters. RESULTS: The median follow-up for surviving patients was 40.7 months (range 6.0-107.5 months). In univariate and multivariate analyses, SUVmax and MTV (5.0) were independent prognostic factors for PFS. In univariate analysis, SUVmax failed to predict OS. MTV (5.0) was a significant prognostic factor for OS, but multivariate analysis failed to show statistical independence because it could not exclude the possibility of an artifact due to N stage. CONCLUSIONS: FDG PET/CT-based volumetric parameters may be significant prognostic markers for survival of patients with OTSCC who are treated by IA-CRT.

Impact of combined modality treatment with radiotherapy and S-1 on T2N0 laryngeal cancer: Possible improvement in survival through the prevention of second primary cancer and distant metastasis.

BACKGROUND: In patients with head and neck cancer, the management of second primary cancer (SPC) is particularly important for improving survival because of its high incidence and associated mortality. We evaluated the impact of combination chemotherapy on survival and SPC. METHOD: We retrospectively analyzed data from 49 patients treated with definitive radiation therapy (RT) for T2N0M0 laryngeal squamous cell carcinoma between 2003 and 2011. Among them, 22 patients received combined modality treatment with radiotherapy and S-1 (RT+CT group). RESULTS: The median follow-up period was 71months (32-111months). A significant difference in overall survival (OS, P<0.01) was observed between the RT+CT group (n=22) and the RT alone group (n=27) though no significant differences were observed in local control and disease specific survival. Univariate analyses showed that an older age (P<0.05) and a higher grade (P<0.05) were associated with OS. Multivariate analysis identified chemotherapy as the most significant predictor of survival (OR, 0.056; 95% CI, 0.008-0.353, P<0.01). A significantly lower incidence of distant metastasis (DM)+SPC (5-year incidence: 5% vs. 19%, P<0.05) and fewer deaths from these causes (1 vs. 8: P<0.05) were observed in the RT+CT group. Multivariate analysis showed that chemotherapy was the most significant factor for the incidence of DM+SPC (OR, 0.074; 95% CI, 0.0065-0.84; P<0.05). CONCLUSION: The findings of this study suggest the possibility that combined modality treatment with radiotherapy and S-1 improve survival by preventing distant metastasis and second primary cancer.

Predictive Significance of Tumor Depth and Budding for Late Lymph Node Metastases in Patients with Clinical N0 Early Oral Tongue Carcinoma.

In clinical N0 early oral tongue carcinoma, treatment of occult lymph node metastasis is controversial. The purpose of this study was to assess the histopathological risk factors for predicting late lymph node metastasis in early oral tongue carcinoma. We retrospectively reviewed 48 patients with early oral tongue squamous cell carcinoma. Associations between the histopathological factors (depth of tumor, differentiation, blood vessel invasion, lymphatic invasion, and tumor budding) and late lymph metastasis were analyzed. Although the univariate analysis identified blood vessel invasion, lymphatic invasion, and high-grade tumor budding as predictive factors for neck recurrence (p < 0.001), the Cox proportional hazards model identified high-grade tumor budding as an independent predictive factor (p < 0.01). The combination of a tumor depth ≥ 3 mm and high-grade tumor budding yielded high diagnostic accuracy. Tumor depth and budding grade were identified as histopathological risk factors for late neck recurrence in clinical N0 early oral tongue carcinoma.

Radiation therapy for T2N0 laryngeal cancer: A retrospective analysis for the impact of concurrent chemotherapy on local control.

PURPOSE: The impact of concurrent chemotherapy on the local control in patients with T2N0 laryngeal cancer who receive radiation therapy (RT) was evaluated. METHODS AND MATERIALS: Sixty-three patients with T2N0 laryngeal cancer who were treated by definitive RT were analyzed. The primary site of the cancer was the glottis in 50 patients, the supraglottis in 9 patients, and the subglottis in 4 patients. Thirty-six patients were treated by RT alone and the remaining 27 patients received concurrent chemoradiotherapy (CRT). RESULTS: Complete response (CR) was obtained in 92% of the patients who received RT alone and 100% of the patients who received CRT. Voice preservation in the group who received CRT (89%) was significantly higher than that in the group treated by RT alone (61%). The 5-year disease-free survival rates in those who received concurrent CRT was significantly superior to that in the patients who received RT alone, although no significant difference was seen in the cause-specific survival rate between the 2 groups. The multivariate analysis revealed that the treatment method (RT alone vs. CRT) was the most significant risk factor that predicted recurrence after RT. CONCLUSION: Concurrent CRT had a positive impact on the local control of T2N0 laryngeal cancer.

Attenuation of chronic thermotolerance by KNK437, a benzylidene lactam compound, enhances thermal radiosensitization in mild temperature hyperthermia combined with low dose-rate irradiation.

PURPOSE: We investigated whether the attenuation of chronic thermotolerance by KNK437, a heat shock protein inhibitor, can modify the effect of thermal radiosensitization in mild temperature hyperthermia (MTH) combined with low dose-rate irradiation (LDRI). MATERIALS AND METHODS: The human lung adenocarcinoma cell line A549 was simultaneously exposed to LDRI with MTH at 41 degrees C and KNK437 at a dose of 100 microM. Cell survival was estimated by a clonogenic assay. Cell cycle change during treatment was analyzed by flow cytometry. Expression levels of the heat shock proteins hsp72, hsp27 and heat shock factor 1 (HSF-1) were measured by Western blotting. RESULTS: KNK437 inhibited the expression of inducible hsp72 and hsp27, but produced no change in the mobility shift of HSF-1. The cytotoxicity of LDRI was enhanced by MTH. The survival curve for LDRI + MTH revealed no development of chronic thermotolerance up to 48 h. Simultaneous LDRI and KNK437 treatment also resulted in enhanced cell killing. The radiosensitizing effect of KNK437 was enhanced by simultaneous exposure of the cells to MTH. Flow cytometry analysis of cell cycle progression demonstrated marked G2 arrest and mild G1 arrest with LDRI alone, but mild G1 arrest with MTH alone, and mild G2-M, S-phase accumulation with KNK437 alone. The marked G2 arrest caused by LDRI was partially suppressed by the addition of MTH, and was also suppressed by KNK437 treatment. CONCLUSIONS: Exposure of A549 cells to KNK437 caused inhibition of hsp72 and hsp27 expression. The addition of KNK437 increased not only thermosensitivity to MTH, but also radiosensitivity to LDRI. KNK437 also enhanced the MTH-induced radiosensitization under these experimental conditions.