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.

Accelerated radiotherapy for T1 to T2 glottic cancer.

BACKGROUND: Accelerated fractionation radiotherapy (RT) was administered in an attempt to improve the local control rates in patients with T1/T2 N0 glottic cancer. METHODS: Medical charts of 148 consecutive patients who had undergone RT using 2.4 Gray (Gy) once-daily fractionation between July 1999 and April 2007 were reviewed. RESULTS: Of 104 patients with T1 disease treated by RT, 82 received 60 Gy/25 fractions, and the remaining 22 with large tumor volumes and/or slow response to RT received 64.8 Gy/27 fractions. All 44 patients with T2 disease received 64.8 Gy/27 fractions. The 5-year local control and overall survival (OS) rates were 93% and 96%, respectively, in patients with T1 disease, and 77% and 91%, respectively, in patients with T2 disease. No severe acute toxicities were observed, although 2 patients (1%) developed severe late toxicity. CONCLUSION: Accelerated RT for early glottic cancer is feasible, with encouraging local control rates.

Evaluating positional accuracy using megavoltage cone-beam computed tomography for IMRT with head-and-neck cancer.

Accurate dose delivery is essential for the success of intensity-modulated radiation therapy (IMRT) for patients with head-and-neck (HN) cancer. Reproducibility of IMRT dose delivery to HN regions can be critically influenced by treatment-related changes in body contours. Moreover, some set-up margins may not be adaptable to positional uncertainties of HN structures at every treatment. To obtain evidence for appropriate set-up margins in various head and neck areas, we prospectively evaluated positional deviation (δ values) of four bony landmarks (i.e. the clivus and occipital protuberance for the head region, and the mental protuberance and C5 for the neck region) using megavoltage cone-beam computed tomography during a treatment course. Over 800 δ values were analyzed in each translational direction. Positional uncertainties for HN cancer patients undergoing IMRT were evaluated relative to the body mass index. Low positional accuracy was observed for the neck region compared with the head region. For the head region, most of the δ was distributed within ± 5 mm, and use of the current set-up margin was appropriate. However, the δ values for the neck region were within ± 8 mm. Especially for overweight patients, a few millimeters needed to be added to give an adequate set-up margin. For accurate dose delivery to targets and to avoid excess exposure to normal tissues, we recommend that the positional verification process be performed before every treatment.

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.

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.

Impact of early radiological response evaluation on radiotherapeutic outcomes in the patients with nasal cavity and paranasal sinus malignancies.

We analyzed the correlation between primary tumor response within 6 months after radiation therapy (RT) including proton beam therapy (PBT) and progression free survival rate (PFS) in patients with nasal cavity and paranasal sinus malignancies to clarify the impact of early radiological evaluation of treatment response on prognosis. Sixty-five patients treated between January 1998 and December 2008, and whose follow-up duration was more than 2 years were included. The Response Evaluation Criteria in Solid Tumors (version 1.1) was used for the evaluation of treatment. Median age was 59 years (range 21-83 years). Olfactory neuroblastoma (n = 20, 30%) and squamous cell carcinoma (n = 15, 23%) were the major pathological tumor types. The median follow-up duration was 51.6 months. Radiological response evaluation within 6 months after treatment demonstrated that 15% of the patients achieved complete response (CR), and 3-year progression free survival rates of all patients was 49.2%. The 3-year PFS rates according to response for the treatment were 55.6% in the patients with CR and 46.4% in those with non-CR, respectively (P = 0.643). However, the 3-year PFS rates were 80.% in the patients with CR and 10.% in those with non-CR (P = 0.051) in the patients with squamous cell carcinoma (SCC) histology. Radiological response evaluation within 6 months did not have a significant impact on prognosis when analysis included all histology, although early radiological response within 6 months after RT had a borderline significant impact on treatment outcomes for the patients with nasal and paranasal SCC.

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.

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.

Multi-institutional analysis of solitary extramedullary plasmacytoma of the head and neck treated with curative radiotherapy.

PURPOSE: The purpose of this study was to elucidate the efficacy and optimal method of radiotherapy in the management of solitary extramedullary plasmacytoma occurring in the head and neck regions (EMPHN). METHODS AND MATERIALS: Sixty-seven patients (43 male and 24 female) diagnosed with EMPHN between 1983 and 2008 at 23 Japanese institutions were reviewed. The median patient age was 64 years (range, 12-83). The median dose administered was 50 Gy (range, 30-64 Gy). Survival data were calculated by the Kaplan-Meier method. RESULTS: The median follow-up duration was 63 months. Major tumor sites were nasal or paranasal cavities in 36 (54%) patients, oropharynx or nasopharynx in 16 (23%) patients, orbita in 6 (9%) patients, and larynx in 3 (5%) patients. The 5- and 10-year local control rates were 95% and 87%, whereas the 5- and 10-year disease-free survival rates were 56% and 54%, respectively. There were 5 (7.5%), 12 (18%), and 8 (12%) patients who experienced local failure, distant metastasis, and progression to multiple myeloma, respectively. In total, 18 patients died, including 10 (15%) patients who died due to complications from EMPHN. The 5- and 10-year overall survival (OS) rates were 73% and 56%, respectively. Radiotherapy combined with surgery was identified as the lone significant prognostic factor for OS (p = 0.04), whereas age, gender, radiation dose, tumor size, and chemotherapy were not predictive. No patient experienced any severe acute morbidity. CONCLUSIONS: Radiotherapy was quite effective and safe for patients with EMPHN. Radiotherapy combined with surgery produced a better outcome according to survival rates. These findings require confirmation by further studies with larger numbers of patients with EMPHN.

Prospective trial of chemotherapy-enhanced accelerated radiotherapy for larynx preservation in patients with intermediate-volume hypopharyngeal cancer.

BACKGROUND: Altered fractionation radiotherapy (RT) improves locoregional control in head and neck cancer without aggravation of late adverse events. To improve successful larynx-preservation rates in patients with resectable, intermediate-volume hypopharyngeal cancer, a prospective trial of chemotherapy-enhanced accelerated RT was conducted. METHODS: Patients with T2 to T4 hypopharyngeal cancer received 40 Gray (Gy)/4 weeks to the entire neck followed by boost RT administering 30 Gy/2 weeks (1.5 Gy twice-daily fractionation). Cisplatin and 5-fluorouracil were administered concomitantly only during boost RT. RESULTS: Thirty-five patients were enrolled in this study. All patients completed this protocol as planned. After a median follow-up period for surviving patients of 59 months (24-90 months), overall survival and local control rates at 3 years were 91% (95% confidence interval, 81% to 100%), and 88% (79% to 99%), respectively. All surviving patients maintained normalcy of diets. CONCLUSION: This regimen was feasible with encouraging oncological and functional outcomes.

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.

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 beam therapy for unresectable malignancies of the nasal cavity and paranasal sinuses.

PURPOSE: The cure rate for unresectable malignancies of the nasal cavity and paranasal sinuses is low. Because irradiation with proton beams, which are characterized by their rapid fall-off at the distal end of the Bragg peak and sharp lateral penumbra, depending on energy, depth, and delivery, provide better dose distribution than X-ray irradiation, proton beam therapy (PBT) might improve treatment outcomes for conditions located in proximity to risk organs. We retrospectively analyzed the clinical profile of PBT for unresectable malignancies of the nasal cavity and paranasal sinuses. METHODS AND MATERIALS: We reviewed 39 patients in our database fulfilling the following criteria: unresectable malignant tumors of the nasal cavity, paranasal sinuses or skull base; N0M0 disease; and treatment with PBT (>60 GyE) from January 1999 to December 2006. RESULTS: Median patient age was 57 years (range, 22-84 years); 22 of the patients were men and 17 were women. The most frequent primary site was the nasal cavity (n=26, 67%). The local control rates at 6 months and 1 year were 84.6% and 77.0%, respectively. With a median active follow-up of 45.4 months, 3-year progression-free and overall survival were 49.1% and 59.3%, respectively. The most common acute toxicities were mild dermatitis (Grade 2, 33.3%), but no severe toxicity was observed (Grade 3 or greater, 0%). Five patients (12.8%) experienced Grade 3 to 5 late toxicities, and one treatment-related death was reported, caused by cerebrospinal fluid leakage Grade 5 (2.6%). CONCLUSION: These findings suggest that the clinical profile of PBT for unresectable malignancies of the nasal cavity and paranasal sinuses make it is a promising treatment option.

Proton beam therapy as a nonsurgical approach to mucosal melanoma of the head and neck: a pilot study.

PURPOSE: The aim of this pilot study was to assess the clinical benefit of proton beam therapy for mucosal melanoma of the head and neck. METHODS AND MATERIALS: Patients with mucosal melanoma of the head and neck with histologically confirmed malignant melanoma and N0 and M0 disease were enrolled. Proton therapy was delivered three times per week with a planned total dose of 60 Gy equivalents (GyE) in 15 fractions. RESULTS: Fourteen consecutive patients were enrolled from January 2004 through February 2008. Patient characteristics were as follows: median age 73 years old (range, 56 to 79 years); male/female ratio, 7/7; and T stage 1/2/3/4, 3/2/0/9. All patients were able to receive the full dose of proton therapy. The most common acute toxicities were mucositis (grade 3, 21%) and mild dermatitis (grade 3, 0%). As for late toxicity, 2 patients had a unilateral decrease in visual acuity, although blindness did not occur. No treatment-related deaths occurred throughout the study. Initial local control rate was 85.7%, and, with a median follow-up period of 36.7 months, median progression-free survival was 25.1 months, and 3-year overall survival rates were 58.0%. The most frequent site of first failure was cervical lymph nodes (6 patients), followed by local failure in 1 patient and lung metastases in 1 patient. On follow-up, 5 patients died of disease, 4 died due to cachexia caused by distant metastases, and 1 patient by carotid artery perforation cause by lymph nodes metastases. CONCLUSIONS: Proton beam radiotherapy showed promising local control benefits and would benefit from ongoing clinical study.

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.

Dose-volume histogram analysis of the safety of proton beam therapy for unresectable hepatocellular carcinoma.

PURPOSE: To evaluate the safety and efficacy of radiotherapy using proton beam (PRT) for unresectable hepatocellular carcinoma. METHODS AND MATERIALS: Sixty consecutive patients who underwent PRT between May 1999 and July 2007 were analyzed. There were 42 males and 18 females, with a median age of 70 years (48-92 years). All but 1 patient had a single lesion with a median diameter of 45 mm (20-100 mm). Total PRT dose/fractionation was 76-cobalt Gray equivalent (CGE)/20 fractions in 46 patients, 65 CGE/26 fractions in 11 patients, and 60 CGE/10 fractions in 3 patients. The risk of developing proton-induced hepatic insufficiency (PHI) was estimated using dose-volume histograms and an indocyanine-green retention rate at 15 minutes (ICG R15). RESULTS: None of the 20 patients with ICG R15 of less than 20% developed PHI, whereas 6 of 8 patients with ICG R15 values of 50% or higher developed PHI. Among 32 patients whose ICG R15 ranged from 20% to 49.9%, PHI was observed only in patients who had received 30 CGE (V30) to more than 25% of the noncancerous parts of the liver (n = 5) Local progression-free and overall survival rates at 3 years were 90% (95% confidence interval [CI], 80-99%) and 56% (95% CI, 43-69%), respectively. A gastrointestinal toxicity of Grade ≥2 was observed in 3 patients. CONCLUSIONS: ICG R15 and V30 are recommended as useful predictors for the risk of developing PHI, which should be incorporated into multidisciplinary treatment plans for patients with this disease.

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.