Patterns of failure after postoperative intensity-modulated radiotherapy for locally advanced and recurrent head and neck cancer.

OBJECTIVE: To evaluate the feasibility of postoperative intensity-modulated radiotherapy for head and neck cancer by investigating the patterns of failure after this therapy. METHODS: A retrospective chart review was performed. RESULTS: Between March 2006 and December 2013, 122 consecutive patients with head and neck squamous cell carcinoma were treated by surgery followed by postoperative intensity-modulated radiotherapy. In regard to the site of the primary tumor, 59 (48%) patients had cancer of the oral cavity, 31 (26%) patients had cancer of the hypopharynx, 14 (11%) patients had cancer of the oropharynx, 10 (8%) patients had cancer of the larynx and 8 (7%) patients had cancer of unknown primary. The median follow-up period of the surviving patients was 54 months (range, 25-115). Concurrent chemotherapy was administered in 76 patients (62%). The median prescribed radiation dose was 66 Gy. The 3-year overall survival, progression-free survival, distant metastasis free survival and loco-regional control rates were 59%, 48%, 52.4% and 71%, respectively. Of the 122 patients, 32 developed loco-regional recurrence as the initial recurrence, including in-field recurrence in 26 patients, marginal recurrence in five patients and out-field recurrence in seven patients. Of the five patients with marginal recurrence, four have had two or more surgeries before the intensity-modulated radiotherapy and three had oral cavity cancer. Severe adverse events were not frequent, occurring at a frequency of <5%, except for mucositis. No severe toxicities associated with the flap reconstruction were observed either. CONCLUSION: Postoperative intensity-modulated radiotherapy appears to be effective and feasible for patients with head and neck squamous cell carcinoma.

Late toxicity of proton beam therapy for patients with the nasal cavity, para-nasal sinuses, or involving the skull base malignancy: importance of long-term follow-up.

BACKGROUND: Although several reports have shown that proton beam therapy (PBT) offers promise for patients with skull base cancer, little is known about the frequency of late toxicity in clinical practice when PBT is used for these patients. Here, we conducted a retrospective analysis to clarify the late toxicity profile of PBT in patients with malignancies of the nasal cavity, para-nasal sinuses, or involving the skull base. METHODS: Entry to this retrospective study was restricted to patients with (1) malignant tumors of the nasal cavity, para-nasal sinuses, or involving the skull base; (2) definitive or postoperative PBT (>50 GyE) from January 1999 through December 2008; and (3) more than 1 year of follow-up. Late toxicities were graded according to the common terminology criteria for adverse events v4.0 (CTCAE v4.0). RESULTS: From January 1999 through December 2008, 90 patients satisfied all criteria. Median observation period was 57.5 months (range, 12.4-162.7 months), median time to onset of grade 2 or greater late toxicity except cataract was 39.2 months (range, 2.7-99.8 months), and 3 patients had toxicities that occurred more than 5 years after PBT. Grade 3 late toxicities occurred in 17 patients (19%), with 19 events, and grade 4 late toxicities in 6 patients (7%), with 6 events (encephalomyelitis infection 2, optic nerve disorder 4). CONCLUSIONS: In conclusion, the late toxicity profile of PBT in patients with malignancy involving the nasal cavity, para-nasal sinuses, or skull base malignancy was partly clarified. Because late toxicity can still occur at 5 years after treatment, long-term follow-up is necessary.

Strontium-89 (Sr-89) chloride in the treatment of various cancer patients with multiple bone metastases.

BACKGROUND: Although the use of Sr-89 chloride in the treatment of patients with prostate and breast cancer has been widely reported, little information is available about its use for other malignancies. Here, we retrospectively analyzed the clinical profile of Sr-89 chloride in various patients with painful bone metastases. METHODS: Entry criteria were a pathologically proven malignancy, clinically diagnosed multiple bone metastases, and adequate organ function. Sr-89 chloride (Metastron) was given by single intravenous infusion at 2 MBq/kg over 2 min. Self-reported outcome measures were used as a response index, including pain diary data on a 0-10 numeric rating scale (NRS). RESULTS: Fifty-four consecutive patients with painful bone metastases were treated with Sr-89 chloride at the National Cancer Center Hospital East between March 2009 and July 2011, consisting of 26 with breast/prostate cancer and 28 with other malignancies (lung 8, head and neck 6, colorectal 6, others 8). Thirteen (24 %) patients experienced a transient increase in pain, which was categorized as a flare-up response. Grade 3-4 anemia was observed in 6 patients, 3 of whom required blood transfusion. Regarding efficacy, response rates and complete response rates were 71.2 % and 34.6 %, respectively, and time to response from the initiation of treatment was 36 days (range, 13-217). No significant difference in response rates was seen between patients with breast/prostate cancer and other cancers (breast/prostate 69.2 %, other 73.1 %; p = 0.76). CONCLUSIONS: As in patients with breast and prostate cancer, Sr-89 chloride is a promising agent for the treatment of painful bone metastases in patients with various other malignancies.

Locoregional control after intensity-modulated radiotherapy for nasopharyngeal carcinoma with an anatomy-based target definition.

OBJECTIVE: The objective of the study was to evaluate locoregional control after intensity-modulated radiotherapy for nasopharyngeal cancer using a target definition along with anatomical boundaries. METHODS: Forty patients with biopsy-proven squamous cell or non-keratinizing carcinoma of the nasopharynx who underwent intensity-modulated radiotherapy between April 2006 and November 2009 were reviewed. There were 10 females and 30 males with a median age of 48 years (range, 17-74 years). More than half of the patients had T3/4 (n = 21) and/or N2/3 (n = 24) disease. Intensity-modulated radiotherapy was administered as 70 Gy/33 fractions with or without concomitant chemotherapy. The clinical target volume was contoured along with muscular fascia or periosteum, and the prescribed radiotherapy dose was determined for each anatomical compartment and lymph node level in the head and neck. RESULTS: One local recurrence was observed at Meckel's cave on the periphery of the high-risk clinical target volume receiving a total dose of <63 Gy. Otherwise, six locoregional failures were observed within irradiated volume receiving 70 Gy. Local and nodal control rates at 3 years were 91 and 89%, respectively. Adverse events were acceptable, and 25 (81%) of 31 patients who were alive without recurrence at 2 years had xerostomia of ≤Grade 1. The overall survival rate at 3 years was 87%. CONCLUSIONS: Target definition along with anatomically defined boundaries was feasible without compromise of the therapeutic ratio. It is worth testing this method further to minimize the unnecessary irradiated volume and to standardize the target definition in intensity-modulated radiotherapy for nasopharyngeal cancer.

A Dermatitis Control Program (DeCoP) for head and neck cancer patients receiving radiotherapy: a prospective phase II study.

PURPOSE: We speculated that a systematic program to manage radiation dermatitis might decrease the incidence of severe or fatal cases in head and neck cancer patients receiving radiotherapy. Here, we conducted a prospective phase II study to clarify the clinical benefit of a Dermatitis Control Program (DeCoP) that did not use corticosteroids. PATIENTS AND METHODS: Head and neck cancer patients scheduled to receive definitive or postoperative radiotherapy were enrolled. Radiation dermatitis was managed with a DeCoP consisting of a three-step ladder: Step 1, gentle washing; Step 2, gentle washing and moistening of the wound-healing environment; Step 3, prevention against infection, gentle washing and moistening of the wound-healing environment. The primary endpoint was the incidence of grade 4 dermatitis. RESULTS: A total of 113 patients were registered between January 2009 and February 2010. Eighty patients received radiotherapy as an initial approach, while the remaining 33 received radiotherapy postoperatively. Grade 3 and 4 dermatitis events occurred in 11 (9.7%) and 0 (0%, 95% confidence interval 0-3.2%) patients, respectively. Median radiation dose at the onset of grade 2 dermatitis was 61.5 Gy (range 36-70 Gy) and median period between onset and recovery was 14 days (range 1-46 days). CONCLUSION: The Dermatitis Control Program has promising clinical potential. Radiation dermatitis might be manageable if gentle washing and moistening of the wound-healing environment is done.

Induction chemotherapy with docetaxel, cisplatin and S-1 followed by proton beam therapy concurrent with cisplatin in patients with T4b nasal and sinonasal malignancies.

OBJECTIVE: For the treatment of patients with T4b nasal and sinonasal malignancies, definitive chemoradiotherapy was contraindicated due to the risk of brain damage and blindness. However, combination chemotherapy with docetaxel, cisplatin and S-1 is well tolerated and effective. We conducted a retrospective analysis to evaluate the efficacy and feasibility of induction chemotherapy using docetaxel, cisplatin and S-1 followed by proton beam therapy concurrent with cisplatin. METHODS: Thirteen patients treated with docetaxel, cisplatin and S-1 were analyzed. Docetaxel, cisplatin and S-1 consisted of 60-70 mg/m(2)/day docetaxel on day 1, 70 mg/m(2)/day cisplatin on day 1 and 60-80 mg/m(2)/day S-1 on days 1-14. Treatment was repeated every 3-4 weeks with a maximum number of three treatment cycles. According to the response to docetaxel, cisplatin and S-1, patients received either proton beam therapy concurrent with 20 mg/m(2)/day cisplatin on days 1-4 every 3 weeks or proton beam therapy alone. RESULTS: Neutropenia represented the most common Grade 3/4 hematological toxicity (76.9%), while the most frequently observed non-hematological toxicity was nausea (23.0%). After the completion of docetaxel, cisplatin and S-1, the overall response rate was 38.4% (5 of 13), with 1 patient achieving complete response and 4 patients achieving partial response. Subsequently, 10 patients received proton beam therapy concurrent with cisplatin, 2 received proton beam therapy alone and 1 received palliative radiation. No severe toxicity was observed during proton beam therapy. After the completion of proton beam therapy, 11 patients (84.6%) achieved complete response and no brain damage or blindness occurred. CONCLUSIONS: Induction chemotherapy with docetaxel, cisplatin and S-1 followed by proton beam therapy concurrent with cisplatin is well tolerated and displays promising antitumor activity that warrants further investigation.

Phase II feasibility trial of adjuvant chemoradiotherapy with 3-weekly cisplatin for Japanese patients with post-operative high-risk squamous cell carcinoma of the head and neck.

OBJECTIVE: The current standard of care for post-operative high-risk squamous cell carcinoma of the head and neck is concurrent chemoradiotherapy with a 3-weekly cycle of cisplatin (3W-CDDP/RT). In previous pivotal trials, the complete delivery rate of three cycles of cisplatin and radiation therapy was only ~60%. Here, we evaluated the feasibility and safety of 3W-CDDP/RT in a Japanese population. METHODS: The study enrolled post-operative high-risk squamous cell carcinoma of the head and neck patients. High-risk factors were a microscopically incomplete resection, extracapsular extension and two or more lymph node metastases. Subjects received three cycles of cisplatin at a dose of 100 mg/m(2) concomitant with radiation therapy (66 Gy/33 Fr). RESULTS: From August 2006 to May 2009, 25 eligible subjects were accrued, including 13 males, with a median age of 59 years, Eastern Cooperative Oncology Group performance status 0/1 (18/7), Stage III/IVA/IVB/recurrent (1/18/1/5) and oral cavity/oropharynx/hypopharynx/larynx (17/4/3/1). Protocol completion rate was 80%. The lower limit of the one-sided 90% confidence interval was 66%, which met the predefined statistical criteria. Grade 3/4 acute and late toxicities were almost identical to those in previous pivotal trials. No treatment-related deaths were observed. With a median follow-up of 39 months, 14 have had progression and 10 have died. Estimated 3-year locoregional control rate, relapse-free survival and overall survival were 74, 43 and 60%, respectively. On univariate analysis, oral cavity cancer and a cumulative cisplatin dose below 240 mg/m(2) appeared to be poor prognostic factors. CONCLUSIONS: This is the first Phase II feasibility trial of adjuvant chemoradiotherapy with 3-weekly cisplatin for post-operative high-risk squamous cell carcinoma of the head and neck in a Japanese population. This treatment was feasible and the safety profile was identical to those in pivotal Phase III trials.

In vivo proton dosimetry using a MOSFET detector in an anthropomorphic phantom with tissue inhomogeneity.

When in vivo proton dosimetry is performed with a metal-oxide semiconductor field-effect transistor (MOSFET) detector, the response of the detector depends strongly on the linear energy transfer. The present study reports a practical method to correct the MOSFET response for linear energy transfer dependence by using a simplified Monte Carlo dose calculation method (SMC). A depth-output curve for a mono-energetic proton beam in polyethylene was measured with the MOSFET detector. This curve was used to calculate MOSFET output distributions with the SMC (SMC(MOSFET)). The SMC(MOSFET) output value at an arbitrary point was compared with the value obtained by the conventional SMC(PPIC), which calculates proton dose distributions by using the depth-dose curve determined by a parallel-plate ionization chamber (PPIC). The ratio of the two values was used to calculate the correction factor of the MOSFET response at an arbitrary point. The dose obtained by the MOSFET detector was determined from the product of the correction factor and the MOSFET raw dose. When in vivo proton dosimetry was performed with the MOSFET detector in an anthropomorphic phantom, the corrected MOSFET doses agreed with the SMC(PPIC) results within the measurement error. To our knowledge, this is the first report of successful in vivo proton dosimetry with a MOSFET detector.

Phase I trial of chemoradiotherapy with the combination of S-1 plus cisplatin for patients with unresectable locally advanced squamous cell carcinoma of the head and neck.

The aim of the present study was to determine the maximum tolerated dose (MTD) of S-1 in combination with chemoradiotherapy (CRT) in patients with unresectable locally advanced squamous cell carcinoma of the head and neck, and evaluate the difference in pharmacokinetics of S-1 when administered as a suspension via a feeding tube or orally as a capsule. Chemotherapy consisted of administration of S-1 twice daily on days 1-14 at escalating doses of 40, 60 and 80 mg/m(2) per day, and cisplatin at 20 mg/m(2) per day on days 8-11, repeated twice at a 5-week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently starting on day 1. Two additional cycles of chemotherapy were planned after the completion of CRT. Before starting CRT, each patient received S-1 via two different administration methods. Twenty-two patients were enrolled. The MTD was reached with S-1 at 80 mg/m(2) per day, with two of six patients experiencing febrile neutropenia lasting more than 4 days. All four patients whose creatinine clearance was decreased to <60 mL/min after the first cycle of chemotherapy developed febrile neutropenia lasting more than 4 days. Pharmacokinetic analysis revealed that the 5-fluorouracil area under the curve did not significantly differ by the administration route. S-1 at 60 mg/m(2) per day for 14 days was well tolerated with concurrent CRT. Administration of S-1 as a suspension or by whole capsule can be considered therapeutically interchangeable. Although these data are preliminary, activity was highly promising, and this approach warrants further investigation.

A pilot study of post-operative radiotherapy with concurrent chemotherapy for high-risk squamous cell carcinoma of the cervical esophagus.

OBJECTIVE: After complete resection of carcinomas of the head and neck, including carcinoma of the cervical esophagus, the pattern of first failure is more often locoregional than distant metastasis. We retrospectively evaluated the safety and efficacy of the combination of post-operative radiation and concurrent chemotherapy with low-dose cisplatin for high-risk squamous cell carcinoma of the cervical esophagus. METHODS: From 2005 through 2008, 34 patients with previously untreated squamous cell carcinoma of the cervical esophagus underwent cervical esophagectomy with or without laryngectomy. Of these 34 patients, 11 with disease-positive lymph nodes in the upper mediastinum (M1 lymph/Stage IV) confirmed by pathologic examination were enrolled. Patients received radiotherapy (66 Gy in 33 fractions) and concurrent low-dose cisplatin. RESULTS: Nine patients completed the planned radiotherapy and two or more courses of chemotherapy. Grade 3 toxicities during chemoradiotherapy were leukopenia (36% of patients), neutropenia (18%) and mucositis (9%). At a median follow-up time of 39.5 months, the overall 1- and 3-year survival rates were 91 and 71%, respectively. CONCLUSIONS: The combination of post-operative radiation and concurrent chemotherapy with low-dose cisplatin is well tolerated and has the potential to improve the rates of locoregional control and overall survival in patients with high-risk advanced squamous cell carcinoma of the esophagus.

Proton dose distribution measurements using a MOSFET detector with a simple dose-weighted correction method for LET effects.

We experimentally evaluated the proton beam dose reproducibility, sensitivity, angular dependence and depth-dose relationships for a new Metal Oxide Semiconductor Field Effect Transistor (MOSFET) detector. The detector was fabricated with a thinner oxide layer and was operated at high-bias voltages. In order to accurately measure dose distributions, we developed a practical method for correcting the MOSFET response to proton beams. The detector was tested by examining lateral dose profiles formed by protons passing through an L-shaped bolus. The dose reproducibility, angular dependence and depth-dose response were evaluated using a 190 MeV proton beam. Depth-output curves produced using the MOSFET detectors were compared with results obtained using an ionization chamber (IC). Since accurate measurements of proton dose distribution require correction for LET effects, we developed a simple dose-weighted correction method. The correction factors were determined as a function of proton penetration depth, or residual range. The residual proton range at each measurement point was calculated using the pencil beam algorithm. Lateral measurements in a phantom were obtained for pristine and SOBP beams. The reproducibility of the MOSFET detector was within 2%, and the angular dependence was less than 9%. The detector exhibited a good response at the Bragg peak (0.74 relative to the IC detector). For dose distributions resulting from protons passing through an L-shaped bolus, the corrected MOSFET dose agreed well with the IC results. Absolute proton dosimetry can be performed using MOSFET detectors to a precision of about 3% (1 sigma). A thinner oxide layer thickness improved the LET in proton dosimetry. By employing correction methods for LET dependence, it is possible to measure absolute proton dose using MOSFET detectors.

Apparent absence of a proton beam dose rate effect and possible differences in RBE between Bragg peak and plateau.

PURPOSE: Respiration-gated irradiation for a moving target requires a longer time to deliver single fraction in proton radiotherapy (PRT). Ultrahigh dose rate (UDR) proton beam, which is 10-100 times higher than that is used in current clinical practice, has been investigated to deliver daily dose in single breath hold duration. The purpose of this study is to investigate the survival curve and relative biological effectiveness (RBE) of such an ultrahigh dose rate proton beam and their linear energy transfer (LET) dependence. METHODS: HSG cells were irradiated by a spatially and temporally uniform proton beam at two different dose rates: 8 Gy/min (CDR, clinical dose rate) and 325 Gy/min (UDR, ultrahigh dose rate) at the Bragg peak and 1.75 (CDR) and 114 Gy/min (UDR) at the plateau. To study LET dependence, the cells were positioned at the Bragg peak, where the absorbed dose-averaged LET was 3.19 keV/microm, and at the plateau, where it was 0.56 keV/microm. After the cell exposure and colony assay, the measured data were fitted by the linear quadratic (LQ) model and the survival curves and RBE at 10% survival were compared. RESULTS: No significant difference was observed in the survival curves between the two proton dose rates. The ratio of the RBE for CDR/UDR was 0.98 +/- 0.04 at the Bragg peak and 0.96 +/- 0.06 at the plateau. On the other hand, Bragg peak/plateau RBE ratio was 1.15 +/- 0.05 for UDR and 1.18 +/- 0.07 for CDR. CONCLUSIONS: Present RBE can be consistently used in treatment planning of PRT using ultrahigh dose rate radiation. Because a significant increase in RBE toward the Bragg peak was observed for both UDR and CDR, further evaluation of RBE enhancement toward the Bragg peak and beyond is required.

[Use experience and problems in the optimization of intensity modulated radiation therapy (IMRT)--Focus on head & neck].

We present the main points of the optimization in IMRT. The skin surface of the planned target volume was reduced by a few millimeters, in view of the limitations of a calculation grid in accurately estimating the influence of build-up or contamination of electrons. Air cavities such as nasal or oral cavities were, in general, filled with water equivalent density in the dose calculation. Planned target volume was contracted by 5 mm when PTV of a higher prescribed dose was delineated adjacent to it. The 5 mm width of ring-shaped ROI was set at 5 mm outside of the entire PTV to eliminate hot spots. Physical quality assurance is extremely important to eradicate unexpected dose inhomogeneity, and meticulous efforts are required.

Proton-beam therapy for olfactory neuroblastoma.

PURPOSE: To analyze the feasibility and efficacy of proton-beam therapy (PBT) for olfactory neuroblastoma (ONB) as a definitive treatment, by reviewing our preliminary experience. Olfactory neuroblastoma is a rare disease, and a standard treatment strategy has not been established. Radiation therapy for ONB is challenging because of the proximity of ONBs to critical organs. Proton-beam therapy can provide better dose distribution compared with X-ray irradiation because of its physical characteristics, and is deemed to be a feasible treatment modality. METHODS AND MATERIALS: A retrospective review was performed on 14 patients who underwent PBT for ONB as definitive treatment at the National Cancer Center Hospital East (Kashiwa, Chiba, Japan) from November 1999 to February 2005. A total dose of PBT was 65 cobalt Gray equivalents (Gy(E)), with 2.5-Gy(E) once-daily fractionations. RESULTS: The median follow-up period for surviving patients was 40 months. One patient died from disseminated disease. There were two persistent diseases, one of which was successfully salvaged with surgery. The 5-year overall survival rate was 93%, the 5-year local progression-free survival rate was 84%, and the 5-year relapse-free survival rate was 71%. Liquorrhea was observed in one patient with Kadish's stage C disease (widely destroying the skull base). Most patients experienced Grade 1 to 2 dermatitis in the acute phase. No other adverse events of Grade 3 or greater were observed according to the RTOG/EORTC acute and late morbidity scoring system. CONCLUSIONS: Our preliminary results of PBT for ONB achieved excellent local control and survival outcomes without serious adverse effects. Proton-beam therapy is considered a safe and effective modality that warrants further study.

Influence of delayed tumor clearance on reliability of complete response rate in chemoradiotherapy for head and neck cancer.

OBJECTIVE: The relationship was studied between the timing of assessment of complete response and ultimate cure rate in the chemoradiotherapy of advanced head and neck cancer. METHODS: A retrospective review was conducted regarding tumor responses at 4 weeks, 3 months, and 6 months after concomitant chemoradiotherapy using cisplatin and 5-FU for 70 patients with stage III/IV squamous cell carcinoma of the oropharynx, hypopharynx and supraglottic larynx. Predictive values of tumor responses at these three time points for survival and tumor control at 2 years were tested using the chi-square test. RESULTS: Twelve (17%) patients achieved complete response (CR) at 4 weeks. Because of late regression or early recurrence, the CR rate changed to 18/70 (26%) and 24/70 (34%) at 3 and 6 months, respectively. CR or not at 6 months was significantly correlated with all survival endpoints (P < 0.001), but not those at 4 weeks and 3 months (P > 0.100). Kaplan-Meier estimate of overall survival at 5 years was 63% (95% CI 43-84%) for 24 CR patients at 6 months. CONCLUSION: CR rate at 6 months was a better surrogate endpoint than that at 4 weeks or 3 months in this series of patients.

Accelerated radiotherapy and larynx preservation in favorable-risk patients with T2 or worse hypopharyngeal cancer.

OBJECTIVE: To evaluate the advantage of accelerated fractionation radiotherapy for patients with hypopharyngeal cancer requiring total laryngectomy. METHODS: Seventy patients with previously untreated, technically resectable hypopharyngeal cancer who received larynx-preserving treatment with radiotherapy between April 1992 and June 2004 were analyzed. No patients had previous history of other malignancy or poor performance status that would possibly affect the outcomes. A total RT dose of > or = 60 Gy/6 weeks was determined depending on the tumor clearance during treatment before December 1998, and fixed to 70 Gy in all patients thereafter. Accelerated fractionation (70 Gy/<49 days) was completed in 35 patients during the latter period. Concomitant platinum-based chemotherapy was used in 41 patients after May 1998. RESULTS: Local control rates at 2 years were 72 and 68% for patients with T2 and T3/T4 disease, respectively. Patients who had received 70 Gy/<49 days achieved a better local control rate than those who had received other, more conservative total dose/overall treatment time with statistical significance (91% versus 50% at 2 years, P < 0.001). Multivariate analysis involving 70 Gy/<49 days of radiotherapy, T-classification (T2 versus T3/4), and use of chemotherapy revealed that administering 70 Gy/<7 weeks was the only independent prognostic factor (P = 0.007) for better local control. CONCLUSIONS: Our experience in radiotherapy for hypopharyngeal cancer mirrored the results of previously conducted large randomized trials for various head and neck cancers. Encouraging local control in this study warrants prospective study to test the long-term oncological and functional outcome of larynx-preserving treatment in patients with advanced but resectable volume of this disease.

Feasibility study of single agent Cisplatin and concurrent radiotherapy in Japanese patients with squamous cell carcinoma of the head and neck: preliminary results.

BACKGROUND: Concurrent chemoradiotherapy with the single agent cisplatin (CDDP + RT) has been recognized worldwide as the standard treatment for unresectable locally advanced SCCHN. The objective of this study was to clarify the feasibility of CDDP + RT in Japanese patients. Patients and methods Patients with unresectable squamous cell carcinoma of the head and neck were given single daily fractionated radiation (70 Gy at 2 Gy/day) and chemotherapy consisting of a 2 h infusion of CDDP 100 mg/m(2) on days 1, 22 and 43. The primary endpoint was the rate of completion of CDDP + RT. RESULTS: Between November 2005 and January 2007, 20 patients were enrolled, 19 males and one female with a median age of 61.5 years (range 50-74). One patient had recurrent unresectable disease after surgery and the remaining 19 had stage IV disease. No grade 4 hematologic toxicities were observed. The incidence of grade 3 mucositis was 55% and no treatment-related death occurred. Full-dose irradiation was performed in all patients, with a median duration of radiotherapy of 50 days (range 48-54). Although all patients received the first two administrations of CDDP, the third dose was administed in 17 patients (85%). The rate of completion of CDDP + RT was 85% and the dose intensity of CDDP was 28.9 mg/m(2)/week (relative dose intensity 89%). Overall complete response rate was 50% and the rate of primary complete response was 90%. CONCLUSION: Concurrent chemoradiation therapy with the standard dose of CDDP is feasible in Japanese patients. Treatment modification based on racial differences is not necessary.

A phase I study of hypofractionated radiotherapy followed by systemic chemotherapy with full-dose gemcitabine in patients with unresectable locally advanced pancreatic cancer.

BACKGROUND/AIMS: Hypofractionated radiotherapy can shorten the irradiation period and allow systemic chemotherapy with full-dose gemcitabine to be started earlier. The purpose of this study was to determine the feasible dose of hypofractionated radiotherapy that could be followed by full-dose gemcitabine in patients with locally advanced pancreatic cancer. METHODOLOGY: Nine patients with unresectable locally advanced pancreatic cancer were enrolled in this study. Three patients received radiotherapy at 45Gy in 15 fractions (level 1) and six at 40 Gy in 8 fractions (level 2). Systemic chemotherapy with gemcitabine was started 3 months after the start of irradiation and was administered as a 30-minute intravenous infusion of a dose of 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. RESULTS: No patients experienced dose-limiting toxicity at either level of radiotherapy. Gemcitabine was started in two of the three patients treated at the level 1 on schedule. At level 2, grade 3 nausea, vomiting and anorexia was observed in all 6 patients, and gemcitabine could not be started on schedule in 4 of the 6 patients. Two (22%) of the 9 patients achieved a partial response. The median time to progression was 5.8 months and the median overall survival time was 9.5 months. CONCLUSIONS: Hypofractionated radiotherapy with 40 Gy in 8 fractions was not feasible in patients with locally advanced pancreatic cancer.

Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma.

PURPOSE: To evaluate the safety and efficacy of proton beam radiotherapy (PRT) for hepatocellular carcinoma. PATIENTS AND METHODS: Eligibility criteria for this study were: solitary hepatocellular carcinoma (HCC); no indication for surgery or local ablation therapy; no ascites; age >/= 20 years; Zubrod performance status of 0 to 2; no serious comorbidities other than liver cirrhosis; written informed consent. PRT was administered in doses of 76 cobalt gray equivalent in 20 fractions for 5 weeks. No patients received transarterial chemoembolization or local ablation in combination with PRT. RESULTS: Thirty patients were enrolled between May 1999 and February 2003. There were 20 male and 10 female patients, with a median age of 70 years. Maximum tumor diameter ranged from 25 to 82 mm (median, 45 mm). All patients had liver cirrhosis, the degree of which was Child-Pugh class A in 20, and class B in 10 patients. Acute reactions of PRT were well tolerated, and PRT was completed as planned in all patients. Four patients died of hepatic insufficiency without tumor recurrence at 6 to 9 months. Three of these four patients had pretreatment indocyanine green retention rate at 15 minutes of more than 50%. After a median follow-up period of 31 months (16 to 54 months), only one patient experienced recurrence of the primary tumor, and 2-year actuarial local progression-free rate was 96% (95% CI, 88% to 100%). Actuarial overall survival rate at 2 years was 66% (48% to 84%). CONCLUSION: PRT showed excellent control of the primary tumor, with minimal acute toxicity. Further study is warranted to scrutinize adequate patient selection in order to maximize survival benefit of this promising modality.

Extrahepatic portal vein occlusion without recurrence after pancreaticoduodenectomy and intraoperative radiation therapy.

PURPOSE: Although there are no definitive studies that characterize the survival benefit of intraoperative radiation therapy (IORT), the therapy does not seem to produce significant complication. In our institution, pancreaticoduodenectomy (PD) and IORT are often complicated by the development of extrahepatic portal vein occlusion (EHPO). The aim of this study was to characterize the phenomenon of EHPO after PD and IORT. METHODS AND MATERIALS: Between September 1992 and December 2001, 107 patients received macroscopic curative PD for periampullary disease in our institution. IORT (radiation dose: 20 Gy) was performed in 53 of these patients. Criteria for diagnosis of EHPO were as follows: (1) computerized tomography findings of occlusive extrahepatic portal vein, (2) symptoms of portal hypertension, and (3) confirmation to exclude tumor recurrence from origin of EHPO, because this study examined whether EHPO was a complication of PD and IORT. RESULTS: EHPO was diagnosed in 12 patients. Among patient and operative variables, IORT was the only statistically significant factor associated with a diagnosis of EHPO (p = 0.0052). The median developed time to EHPO and overall survival after surgery in EHPO patients were 358 days and 2,562 days, respectively. Eight patients (67%) with EHPO died during the follow-up period. At 5 years after therapy, EHPO was diagnosed in 67% of survivors who had received IORT. CONCLUSIONS: Patients undergoing IORT and PD have a relatively high incidence of EHPO, and patients who develop postoperative EHPO have poor prognoses.