Fast neutron radiotherapy for soft tissue and cartilaginous sarcomas at high risk for local recurrence.

PURPOSE: The practice policy at the University of Washington has been to employ fast neutron radiotherapy for soft tissue sarcoma lesions with prognostic features predictive for poor local control. These include gross residual disease/inoperable disease, recurrent disease, and contaminated surgical margins. Cartilaginous sarcomas have also been included in this high-risk group. This report updates and expands our previously described experience with this approach. METHODS AND MATERIALS: Eighty-nine soft tissue sarcoma lesions in 72 patients were treated with neutron radiotherapy in our department between 1984 and 1996. Six patients, each with solitary lesions, were excluded from analysis due to lack of follow-up. Seventy-three percent were treated with fast neutron radiation alone, the rest with a combination of neutrons and photons. Median neutron dose was 18.3 nGy (range 4.8-22). Forty-two patients with solitary lesions were treated with curative intent. Thirty-one patients (including 7 previously treated with neutrons) with 41 lesions were treated with the goal of local palliation. Tumors were predominantly located in the extremity and torso. Thirty of 35 (85%) of curative group patients treated postoperatively had close or positive surgical margins. Thirty-four (82%) lesions treated for palliation were unresectable. Thirty-five patients (53%) were treated at the time of recurrence. Median tumor size at initial presentation was 8.0 cm (range 0.6-29), median treated gross disease size was 5.0 cm (range 1-22), and 46/69 evaluable lesions (67%) were judged to be of intermediate to high histologic grade. Fourteen patients (21%) had chondrosarcomas. RESULTS: Median follow-up was 6 months (range 2-47) and 38 months (range 2-175) for the palliative and curative groups, respectively. Kaplan-Meier estimates were obtained for probability of local relapse-free survival (68%), distant disease-free survival (59%), cause-specific survival (68%), and overall survival (66%) at 4 years for the curatively treated group. For the palliatively treated group, estimated local relapse-free survival at 1 year was 62%. Log-rank analysis of the curative group revealed recurrent disease to be the only risk factor predictive for significantly worse local and distant disease-free survival. Intermediate-/high-grade histology was predictive for inferior overall survival. Effective clinical response was documented for 21/27 (78%) lesions treated palliatively. Ten patients (15%) experienced serious chronic radiation-related complications. All of these patients had clinical situations requiring delivery of high neutron doses and/or large radiotherapy fields. CONCLUSION: Fast neutron radiotherapy is locally effective for soft tissue and cartilaginous sarcomas having well-recognized high-risk features. Results in the palliative setting appear to be particularly encouraging, with neutrons frequently providing significant symptomatic response for gross disease, with minimal serious chronic sequelae. Fast neutron radiotherapy should be considered in patients at high risk for local recurrence in both the curative and palliative settings.

The efficacy of radiotherapy as postoperative treatment for desmoid tumors.

PURPOSE: The purpose of this study was to determine if radiotherapy is a beneficial adjuvant treatment after desmoid tumor resection. METHODS AND MATERIALS: A retrospective analysis was performed on 54 patients who underwent surgery without prior radiation at our institution between 1982 and 1998 to remove a desmoid tumor. Thirty-five patients had adjuvant radiation therapy after surgery, and 19 patients had surgery alone without immediate postoperative radiation. Sixteen of the 35 patients who underwent immediate postoperative radiation treatment had at least one prior resection before reoperation at our institution. Recurrence was defined as radiographic increase in tumor size after treatment. Follow-up interval (mean 39 months) and duration of local control were measured from the date of surgery at our institution. Potential prognostic factors for time to tumor progression were analyzed. RESULTS: Adjuvant treatment with radiation was the only significant prognostic factor for local control. The five-year actuarial local control rate was 81% for the 35 patients who underwent radiation in addition to surgery, compared to 53% for the 19 patients who underwent surgery alone (p = 0.018). For the patients who did not receive adjuvant radiation, only younger age at the time of surgery was associated with increased risk of failure (p = 0.035). Gross or microscopic margin status and number of prior operations were not detected as prognostic for local failure. For patients who did receive postoperative radiation, only abdominal location was associated with increased risk of failure (p = 0.0097). CONCLUSION: Radiation treatment as an adjuvant to surgery improved local control over surgery alone. Multiple operations before adjuvant radiation did not decrease the probability of subsequent tumor control. Radiation should be considered as adjuvant therapy to surgery if repeated surgery for a recurrent tumor would be complicated by a significant risk of morbidity.

Neutron radiotherapy for recurrent pleomorphic adenomas of major salivary glands.

INTRODUCTION: Pleomorphic adenoma is the most common neoplasm arising in the salivary glands. Surgical management is the primary therapeutic modality. With the use of modern surgical techniques, recurrence is infrequent, and facial nerve sparing is the norm. However, for patients with recurrent disease, the risk of further relapses is increased with surgical resection alone, particularly for those patients in whom multiple recurrences have already occurred. The role of adjuvant radiotherapy in this setting remains uncertain. Although neutron radiotherapy is superior to conventional radiotherapy for malignant salivary gland tumors, its role in the treatment of pleomorphic adenomas is less well defined. We report our experience using this modality for high-risk, recurrent pleomorphic adenomas. METHODS: Sixteen patients were treated with neutron radiotherapy for recurrent pleomorphic adenomas of major salivary glands from 1986 through 1993. The median age at diagnosis was 33 years (range, 11-77 years); median age at the time of neutron radiotherapy was 52 years (range, 22-77 years); median number of prior surgical procedures was 3 (range, 1-6); median duration from initial diagnosis to radiotherapy was 14.5 years (range, 3 months-30 years); median follow-up was 83 months (range, 9-144 months). The median period at risk for survivors was 96 months (defined as the interval from completion of neutron radiotherapy to last follow-up). Ten patients had evidence of gross residual disease at the time of treatment as determined by imaging studies, with nine patients having multinodular disease. RESULTS: The 10-year actuarial survival was 79%. One patient died from lung metastases 9 months after treatment; one patient died from a liver tumor of uncertain origin, but the histology could not rule out a metastasis from the previous pleomorphic adenoma; and one patient died from recurrent disease at the base of skull. The 15-year actuarial locoregional control rate was 85%. One of the two patients with locoregional recurrence had a malignant transformation into an adenocarcinoma. No statistical difference in 15-year actuarial survival (75% vs 83%, p =.82) was found comparing patients with gross residual disease vs microscopic residual disease. The actuarial 15-year locoregional control was 76% for patients with gross residual disease vs 100% for those with microscopic disease. The 15-year actuarial risk of RTOG/ESTRO nonaudiologic grade III/IV complications was 21%. No facial nerve injuries were observed as a direct consequence of neutron radiotherapy. CONCLUSIONS: Neutron radiotherapy offers both excellent local control rates and survival rates in patients with multiply recurrent pleomorphic adenomas that are not candidates for surgical resection, even in the presence of gross residual disease. The treatment-related morbidity is acceptable. Malignant transformations and metastases, although uncommon, may be observed in this tumor.

Metastasis to a percutaneous gastrostomy site from head and neck cancer: radiobiologic considerations.

BACKGROUND: The use of percutaneously placed feeding tubes has increased in recent years in an effort to maintain adequate caloric balance in patients receiving combined therapy for head and neck cancers, particularly concurrent radiotherapy and chemotherapy. METHODS: We report a case of a metastasis to a percutaneous endoscopic gastrostomy site occurring in a patient with an advanced tonsillar squamous cell carcinoma and review the published literature regarding this subject. Radiobiologic principles were examined to explain the most likely cause of such metastases. RESULTS: Six cases of percutaneous endoscopic site metastases occurring in patients with head and neck primary tumors have been reported in the literature. The interval from performance of the procedure to development of the metastases ranged from 3 to 16 months. Tumor kinetics suggest that a significant tumor burden (10(5)-10(6) cells) would need to be present at the site to manifest a metastatic lesion in such a short time interval. CONCLUSIONS: The development of metastases at percutaneous endoscopic gastrostomy sites is a relatively uncommon occurrence. Direct tumor implantation by means of instrumentation at the time of the procedure is most likely explanation for such metastases, although hematogenous seeding cannot be completely discounted. Techniques should be used so as not to disrupt the tumor bed, particularly when gross residual disease is present.

The influence of beam energy on the outcome of postoperative radiotherapy in head and neck cancer patients: secondary analysis of RTOG 85-03.

PURPOSE: To determine whether any difference in toxicity or efficacy occurs when head and neck cancer patients are treated postoperatively with (60)C0, 4 MV, or 6 MV photon beam. METHODS AND MATERIALS: This is a secondary analysis of the Intergroup Study 0034. Three hundred ninety-two patients were evaluable for comparison between treatment with (60)C0, 4 MV, or 6 MV photon beam. All patients had advanced but operable squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients were randomized following surgical resection to receive treatment with either postoperative irradiation alone, or postoperative irradiation plus three cycles of cisplatin and 5-fluorouracil. Patients were categorized as having either "low risk" or "high risk" treatment volumes based on whether the surgical margin was 5 mm or less, presence of extra capsular nodal extension, and/or carcinoma in situ at the surgical margins. Low-risk volumes received 50-54 Gy, and high-risk volumes were given 60 Gy. Patients were compared in regards to acute and late radiotherapy toxicities as well as overall survival and loco-regional control according to the beam energy used. RESULTS: One-hundred fifty-seven, 140, and 95 patients were treated by (60)C0, 4 MV, and 6 MV, respectively. No differences were seen in acute or late toxicity among treatment groups. Locoregional control was achieved in 75%, 79%, and 80% of patients treated with (60)C0, 4 MV, or 6 MV (p = 0.61). Patients treated with 6 MV had a higher incidence of ipsilateral neck failure as first event (13%) than patients treated by (60)C0 and 4 MV (9%). This difference was not statistically significant. CONCLUSION: No differences in outcome, acute, or late toxicity were discernible in patients with advanced head and neck cancer treated with (60)C0, 4 MV, or 6 MV. This result should be interpreted with caution as increased incidence, albeit nonsignificant, of ipsilateral neck recurrence was observed in patients treated with 6 MV and the power of the study to detect a statistically significant difference is small.

Treatment of locally advanced adenoid cystic carcinoma of the head and neck with neutron radiotherapy.

PURPOSE: To examine the efficacy of fast neutron radiotherapy for the treatment of locally advanced and/or recurrent adenoid cystic carcinoma of the head and neck and to identify prognostic variables associated with local-regional control and survival. METHODS AND MATERIALS: One hundred fifty-nine patients with nonmetastatic, previously unirradiated, locally advanced, and/or recurrent adenoid cystic carcinoma (ACC) of the head and neck region were treated with fast neutron radiotherapy during the years 1985-1997. One hundred fifty-one patients had either unresectable disease, or gross residual disease (GRD) after an attempted surgical extirpation. Eight patients had microscopic residual disease and were analyzed separately. Sixty-two percent of patients had tumors arising in minor salivary glands, 29% in major salivary glands, and 9% in other sites such as the lacrimal glands, tracheal-bronchial tree, etc. Fifty-five percent of patients were treated for postsurgical recurrent disease and 13% of patients had lymph node involvement at the time of treatment. The median duration of follow-up was 32 months (range 3-142 months). Actuarial curves for survival, cause-specific survival, local-regional control, and the development of distant metastases are presented for times out to 11 years. RESULTS: The 5-year actuarial local-regional tumor control rate for the 151 patients with GRD was 57%; the 5-year actuarial overall survival rate was 72%; and the 5-year actuarial cause-specific survival rate was 77%. Variables associated with decreased local-regional control in the patients with GRD as determined by multivariate analysis included base of skull involvement (p < 0.01) and biopsy only versus an attempted surgical resection prior to treatment (p = 0.03). Patients without these negative factors had an actuarial local-regional control rate of 80% at 5 years. Patients with microscopic residual disease (n = 8) had a 5-year actuarial local-regional control rate of 100%. Base of skull involvement (p < 0.001), lymph node metastases at the time of treatment (p < 0.01), biopsy only prior to neutron radiotherapy (p = 0.03), and recurrent tumors (p = 0.04) were found to be associated with a diminished cause-specific survival as ascertained by multivariate analysis. Patients with base of skull involvement and positive lymph nodes at presentation had an increased rate of the development of distant metastases at 5 years, (p < 0.01 and p < 0.001, respectively). No statistical difference in outcome was observed between major and minor salivary gland sites. CONCLUSIONS: Fast neutron radiotherapy is an effective treatment for locally advanced ACC of the head and neck region with acceptable toxicity. Further improvements in local-regional control are not likely to impact survival until more effective systemic agents are developed to prevent and/or treat distant metastatic disease.

Modification of the University of Washington Neutron Radiotherapy Facility for optimization of neutron capture enhanced fast-neutron therapy.

A modified neutron production target assembly has been developed to provide improved performance of the proton-cyclotron-based neutron radiotherapy facility at the University of Washington for applications involving neutron capture enhanced fast-neutron therapy. The new target produces a neutron beam that yields essentially the same fast-neutron physical depth-dose distribution as is produced by the current UW clinical system, but that also has an increased fraction of BNCT enhancement relative to the total therapeutic dose. The modified target is composed of a 5-millimeter layer of beryllium, followed by a 2.5-millimeter layer of tungsten, with a water-cooled copper backing. Measurements of the free-field neutron spectrum of the beam produced by the new target were performed using activation foils with a direct spectral unfolding technique. Water phantom measurements were performed using a tissue-equivalent ion chamber to characterize the fast-neutron depth-dose curve and sodium activation in soda-lime glass beads to characterize the thermal-neutron flux (and thus the expected neutron capture dose enhancement) as a function of depth. The results of the various measurements were quite consistent with expectations based on the design calculations for the modified target. The spectrum of the neutron beam produced by the new target features an enhanced low-energy flux component relative to the spectrum of the beam produced by the standard UW target. However, it has essentially the same high-energy neutron flux, with a reduced flux component in the mid-range of the energy spectrum. As a result, the measured physical depth-dose curve in a large water phantom has the same shape compared to the case of the standard UW clinical beam, but approximately twice the level of BNCT enhancement per unit background neutron dose at depths of clinical interest. In-vivo clinical testing of BNCT-enhanced fast-neutron therapy for canine lung tumors using the new beam was recently initiated.

Technical advances in radiotherapy of head and neck tumors.

Future teletherapy in head and neck sites will include treatment of additional aggressive base-of-skull tumors, acoustic neuromas, and external ear canal tumors. In addition, protocols are being developed to take advantage of the enhanced precision of stereotaxic and conformal teletherapy to deliver concomitant boosts to gross or residual disease after surgery. These field-in-field boosts permit accelerated, hyperfractionated radiotherapy to be delivered to tumor, while maintaing or decreasing dose to surrounding normal tissues. The improved results of aggressive, accelerated fractionation schedules may be realized with acceptable morbidities through the use of more focused irradiation.

Neutron radiotherapy for the treatment of locally advanced major salivary gland tumors.

BACKGROUND: Malignant salivary gland tumors are rare tumors of the head and neck region. The treatment of these tumors has generally consisted of surgical extirpation, with postoperative radiotherapy improving locoregional control and survival in patients with high risk tumors. Neutron radiotherapy has been found to be more efficacious than conventional radiotherapy in the setting of inoperable or subtotally resected salivary gland tumors. METHODS: One hundred forty-eight patients with malignant salivary tumors of major salivary gland origin were treated at the University of Washington Medical Center with fast neutron radiotherapy between the years 1984 and 1995. One hundred twenty-eight patients were treated with curative intent, and of these, 120 patients had evidence of gross residual disease at the time of treatment. These patients constitute the main analysis of this paper. Of these patients, 19% had recurrent disease, 39% were initially seen with positive lymph nodes, and 11% had previously received full dose conventional radiotherapy. At the time of analysis, the median period at risk of survivors was 26 months. RESULTS: The 5-year actuarial locoregional control rate for all patients with gross tumor treated with curative intent was 59%. A tumor size < or =4 cm was associated with an excellent locoregional control rate (80%), and cause-specific survival (73%) at 5 years compared with patients with larger tumors (35% and 22%, respectively, p<.001 in both cases). On univariate analysis, there appeared to be an advantage in locoregional control for patients with smaller sized tumors (< or =4 cm) who underwent an attempted surgical extirpation. Locoregional control was excellent (100%) in patients having a complete surgical resection of their tumors and undergoing postoperative neutron radiotherapy because of the presence of other high risk factors. Lymph node status at the time of treatment, base of skull involvement, and male sex were associated with the development of distant metastasis, with 52% of node positive patients developing distant metastases by 5 years, compared with 32% of node negative patients (p = .04). CONCLUSIONS: Neutron radiotherapy is an effective form of treatment for patients with high risk, locally advanced tumors of major salivary gland origin. An initial surgical resection appears beneficial in patients for whom such an approach is feasible.

Precisely defining high-risk operable head and neck tumors based on RTOG #85-03 and #88-24: targets for postoperative radiochemotherapy?

BACKGROUND: Local-regional recurrence of disease remains the major obstacle to cure of advanced head and neck cancers. METHODS: This investigation reviewed data derived from Radiation Therapy Oncology Group (RTOG) protocols #85-03 and #88-24 to identify characteristics of tumors that predicted local-regional recurrence of disease following surgery and postoperative radiotherapy (RT). RESULTS: The presence of tumor in two or more lymph nodes, and/or extracapsular spread of nodal disease, and/or microscopic-size tumor involvement of the surgical margins of resection imparts a high risk of local-regional (L-R) relapse. Our data also support the hypothesis that, following surgery, the concurrent addition of chemotherapy (CT) to RT may increase the likelihood of L-R control of disease for patients who have these high-risk characteristics. CONCLUSION: A prospective trial of surgery followed by concurrent RT and CT is warranted for patients who have high-risk characteristics found at surgery.

Fast neutrons in prostatic adenocarcinomas: worldwide clinical experience.

Primary tumor control remains a major problem in the treatment of locally advanced prostate carcinoma. Clinical local failure rates approach 30-40% and may be significantly higher when results of prostatic biopsy or prostate-specific antigen (PSA) levels are considered. The low growth rate and cycling fraction of prostate adenocarcinoma suggest potential therapeutic advantage for the high linear energy transfer (LET) of neutrons. The Radiation Therapy Oncology Group (RTOG) performed a multi-institutional randomized trial (RTOG 77-04) comparing mixed beam (neutron plus photon) irradiation to conventional photon irradiation for the treatment of locally advanced prostate cancer. A subsequent trial by the Neutron Therapy Collaborative Working Group (NTCWG 85-23) compared pure neutron irradiation to standard photon irradiation. Both randomized trials demonstrate significant improvement in locoregional control with neutron irradiation compared to conventional photon irradiation in the treatment of locally advanced prostate carcinoma. To date, only the mixed beam trial has shown a significant survival benefit. Future analysis of the larger NTCWG trial at the 10-year point should confirm whether or not improved locoregional control translates into a survival advantage. These findings have significant implications for all local treatment strategies including dose-escalated conformal photon irradiation, prostate implantation, and neutron radiation. Given the large numbers of patients afflicted with this disease, a positive survival advantage for neutrons or mixed beam therapy would provide a strong incentive for the development of economically feasible clinical neutron facilities.

Boron neutron capture enhanced fast neutron radiotherapy for malignant gliomas and other tumors.

Both fast neutron radiotherapy and boron neutron capture therapy have been investigated as new radiation treatment techniques for patients with malignant gliomas. While each of these techniques individually has shown the potential for pathological eradication of malignant glioma, to date neither has evolved into an accepted, improved method of treatment. We have recently begun a research program investigating the feasibility of combining the benefits of both types of therapy. As a fast neutron beam penetrates tissue some of the particles are degraded to thermal energies. These can be captured by 10B or other suitable isotopes resulting in a highly-localized release of additional energy during a course of fast neutron radiotherapy. In this article we will review the rationale for such an approach, and review the underlying physics as well as in vitro, in vivo, and early human studies testing its feasibility. If appropriate carrier agents can be found that preferentially-localize in tumor cells, this approach ena be applied to many different tumor systems.

The use of neutrons in cancer therapy: a historical perspective through the modern era.

The fields of boron neutron capture therapy (BNCT) and fast neutron radiotherapy are surveyed starting with the early clinical work that began shortly after the discovery of the neutron by Chadwick in 1932. The evolution of each field is described and the current status in regards to accepted clinical indications and ongoing research areas summarized. BNCT remains a research area but a discussion is given of current efforts to design and construct non-reactor-based epithermal neutron sources to deploy this technology to major medical centers if the clinical research proves successful. Fast neutron radiotherapy is a mature field with selected clinical indications for locally advanced salivary gland tumors and inoperable sarcomas of bone and soft tissue. The current status of clinical trials for locally advanced prostate cancer and other tumors is reviewed. Ongoing areas of research in the field of fast neutron radiotherapy are described.

Neutron radiotherapy for adenoid cystic carcinoma of minor salivary glands.

PURPOSE: To examine the efficacy of fast neutron radiotherapy for the treatment of patients with locally advanced, adenoid cystic carcinoma of minor salivary glands and to identify prognostic variables associated with local control, overall survival, and cause specific survival. METHODS AND MATERIALS: Eighty-four patients having adenoid cystic carcinoma of minor salivary glands were treated with fast neutron radiotherapy during the years 1985-1994. All patients had either unresectable disease or gross disease remaining after attempted surgical extirpation. Seventeen patients had previously received conventional radiotherapy and their subsequent treatment fields and doses for neutron radiotherapy were modified for critical sites (brainstem, spinal cord, brain). Although the median doses (tumor maximum and tumor minimum) only varied by < or = 10%, treatment portals were substantially smaller in these patients because of normal tissue complication considerations. Twelve patients (13%) had distant metastases at the time of treatment and were only treated palliatively with smaller treatment portals and lower median tumor doses (< or = 80% of the doses delivered to curatively treated patients). Seventy-two patients were treated with curative intent, with nine of these having recurrent tumors after prior full-dose radiotherapy. The median duration of follow-up at the time of analysis was 31.5 months (range 3-115). Sites of disease and number of patients treated per disease site were as follows: paranasal sinus-31; oral cavity-20; oropharynx-12; nasopharynx-11; trachea-6; and other sites in the head and neck-4. RESULTS: The 5-year actuarial local-regional tumor control rate for all patients treated with curative intent was 47%. Patients without involvement of the cavernous sinus, base of skull, or nasopharynx (51 patients) had a 5-year actuarial local-regional control rate of 59%, whereas local-regional control was significantly lower (15%) for patients with tumors involving these sites (p < 0.005). In the latter cases, normal tissue injury considerations precluded delivery of the full dose to the entire tumor. Patients with no history of prior radiotherapy (63 patients) had an actuarial local control rate of 57% at 5 years compared to 18% for those (9 patients) who had been previously irradiated with conventional photons (p = 0.018). Eliminating the dose-limiting factors of prior radiation therapy and/or high risk sites of involvement, the 5-year actuarial local-regional control rate for these 46 patients was 63%, with an actuarial cause specific survival rate of 79%. Lymph node status was a predictor of distant metastasis: 57% of node positive patients developed distant metastases by 5 years compared to 15% of patients with negative nodes (p < 0.0005), and patients who had nodal involvement developed distant metastases sooner than node negative patients (p < 0.0001). The 5-year actuarial overall survival and cause specific survival for the 72 patients treated with curative intent were 59% and 64%, respectively. CONCLUSIONS: Fast neutron radiotherapy offers high local-regional control and survival rates for patients with locally advanced, unresectable adenoid cystic carcinomas of minor salivary glands. It should be considered as initial primary treatment for these patients, as well as for other patients in whom surgical extirpation would cause considerable morbidity.

Boron neutron capture therapy (BNCT) for high-grade gliomas of the brain: a cautionary note.

PURPOSE/OBJECTIVE: Boron neutron capture therapy (BNCT) is a method of treating high-grade gliomas of the brain that involves incorporating 10B into the tumor using appropriate pharmacological agents and then irradiating the tumor with thermal or epithermal neutron beams. To date, over 120 patients have been treated in this manner by Japanese investigators using a thermal neutron beam from a nuclear reactor. Favorable reports on outcome have motivated considerable current research in BNCT. The purpose of this study is to provide an independent analysis of the Japanese data by identifying the subset of patients from the United States who received this treatment in Japan and comparing their outcomes relative to a matched cohort who received conventional therapy in various Radiation Therapy Oncology Group (RTOG) studies. METHODS AND MATERIALS: The principal referral sources of patients to Japan for BNCT were identified and the names of patients sent for treatment obtained. The treating physicians in Japan were also contacted to see if additional patients from the United States had been treated. Either the patients or their next of kin were contacted, and permission was obtained to retrieve medical records including tumor pathology for central review. Prognostic variables according to an analysis of the RTOG brain tumor database by Curran et al. were determined from these records and used to construct a matched cohort of patients treated conventionally. RESULTS: A total of 14 patients were identified who had traveled to Japan for BNCT treatment between July, 1987 and June, 1994. In the case of one patient (deceased), it was not possible to contact the next of kin. Material was obtained on the other 13 patients and review of the pathology indicated that 1 patient had a central nervous system lymphoma rather than a high-grade glioma. Survival data was analyzed for the other 12 patients on an actuarial basis, and this showed no difference compared to survival data for a matched set of patients constructed according to the classification schema of Curran et al. Median survivals were 10.5 months for both groups; survival at 3 years was 22% for the BNCT group compared to 13% for the conventionally treated group (p = NS). The only long-term survivors in the BNCT group had anaplastic astrocytomas and favorable prognostic criteria (Classes I and II of Curran et al.). The actuarial survival curves for the patients with glioblastoma multiforme (strict histological criteria) who received BNCT and their counterparts who received conventional therapy are virtually superimposable. The respective 2-year survivals are 20 vs. 10% (p = NS). Patterns of failure, toxicity, and analysis of the results according to histology are discussed. CONCLUSIONS: Analysis of patients from the United States who received BNCT treatment in Japan does not support a clinically meaningful improvement in survival attributable to this form of therapy. The implications of this for future BNCT research directions are discussed.

Evolution of the Radiation Therapy Oncology Group clinical trials for head and neck cancer.

During the past 25 years, the Radiation Therapy Oncology Group (RTOG) has played a major role in head and neck cancer clinical research. The major research themes for recent and currently active trials have been: (a) combined modality therapy, (b) altered fractionation radiotherapy, (c) hypoxic cell sensitizers, (d) organ preservation, (e) chemoprevention, and (f) clinical/laboratory correlations. For advanced operable disease, the RTOG showed improved local-regional control with postoperative radiotherapy as compared to preoperative radiotherapy for carcinoma of the supraglottic larynx and hypopharynx. This established the use of surgery followed by postoperative radiotherapy as the standard treatment in subsequent RTOG and Intergroup trials for operable disease. For advanced inoperable disease, the RTOG demonstrated the feasibility of testing altered fractionation radiotherapy in a multiinstitutional clinical trials setting. A Phase III trial comparing hyperfractionation and accelerated fractionation to conventional fractionation is now in progress. Phase I/II combined modality studies established the efficacy of concurrent high-dose cisplatin and radiotherapy in the treatment of advanced disease and provided the basis for further testing in Phase III trials for nasopharyngeal carcinoma, larynx preservation, and high-risk advanced operable disease. Analysis of the extensive RTOG Head and Neck Cancer database established the incidence of second malignancies and their adverse impact on patients whose initial tumors were cured by radiotherapy, and provided the basis for chemoprevention trials. Recursive partitioning analysis identified 6 distinct prognostically homogeneous patient groups based on pretreatment tumor or patient characteristics and/or treatment variables. Retrospective analysis identified tumor p105 antigen density as an independent prognostic indicator in patients irradiated for head and neck cancer. Future trials will continue to focus on the reduction of morbidity and mortality, and improvement of the quality of life of head and neck cancer patients through innovative radiotherapy delivery, multimodality approaches, use of chemical and biological modifiers, and other novel therapies, identification of clinical and biological prognostic indicators, and prevention or diminution of acute morbidity and late complications of the disease and its treatment.

Clinical trials of neutron radiotherapy in the United States.

The development of clinical neutron facilities in the 1980s, capable of delivering high energy neutrons spurred full scale phase III testing of neutron beam radiotherapy in a number of tumors including salivary gland, head and neck, prostate, and non small-cell lung cancer. The Radiation Therapy Oncology Group (RTOG) and the Medical Research Council (MRC) jointly sponsored a randomized trial for the treatment of advanced stage salivary gland tumors comparing neutron to conventional photon and/or electron radiotherapy. Although no improvement in survival was seen, the study demonstrated a striking and statistically significant difference in the local-regional control of unresectable salivary gland tumors (56 vs 17%), favoring neutron beam irradiation. Subsequent clinical trials of neutron beam irradiation were initiated by the Neutron Therapy Collaborative Working Group (NTCWG) sponsored by the National Cancer Institute (NCI). A phase III trial comparing neutron to photon radiotherapy for inoperable regional non-small cell lung cancer showed no overall improvement in survival. However, a statistically significant improvement in survival was observed in the subset of patients with squamous cell histology. The NTCWG trial comparing fast-neutron therapy versus conventional photon irradiation in the treatment of advanced squamous cell carcinomas of the head and neck showed a statistically significant improvement in initial complete response (70 vs 52%) favoring neutrons. However, subsequent failures erased any difference in ultimate local-regional control rates and survival curves were essentially the same in both arms. The randomized study of the NTCWG for locally advanced prostate cancer demonstrated a significant decrease in local-regional failure (11 vs 32%) at 5 years, favoring the neutron arm. Furthermore, biochemical measures of disease control also favored the neutron arm with prostate specific antigen (PSA) levels elevated in 17% of the neutron-treated patients compared to 45% of the photon-treated patients at 5 years. At the 5-year analysis, no significant difference in survival was observed between the two arms; however, longer follow-up is necessary to assess the ultimate impact of improved local-regional control on survival. An analysis of complications in this series revealed the importance of beam shaping and treatment planning capabilities in maintaining long-term sequelae following neutron irradiation at an acceptably low level.

Fast neutron radiotherapy and boron neutron capture therapy: application to a human melanoma test system.

Fast neutron radiotherapy has proven to be an effective form of treatment in a selected subset of tumors (salivary gland tumors, sarcomas, and locally-advanced prostate cancer), but has not proven to be more beneficial than conventional photon irradiation for the majority of tumor types upon which it has been tested. Normal tissue tolerance limits preclude simply further escalating the neutron dose. Boron neutron capture (BNC) provides a way of selectively augmenting the radiation dose to the tumor. This process is described, and cell culture and animal model data reviewed. An irradiation configuration was developed where an enhancement of 2.10(-3) for 1 microgram of 10B per gram of tissue was achieved. This is similar to the enhancement achievable in the center of a 20 x 20 cm field envisioned for future applications such as metastases in the brain. A boron concentration of 50 micrograms per gram of tumor tissue leads to a 10% increase in the delivered physical dose in this scenario. The first human test of BNC enhancement of a fast neutron radiotherapy beam using pharmacologically-acceptable doses of orally-administered, 10B-enriched, L-paraboronophenylalanine is reported. An enhancement of tumor response was demonstrated for a melanoma skin nodule test system. Boron levels achieved in blood, skin, and tumors are presented. Future research plans are discussed.