Fast neutron radiotherapy for the treatment of carcinoma of the urinary bladder. A review of clinical trials

The major clinical investigation employing fast neutrons in the treatment of invasive bladder cancer are reviewed. Although data suggest that preoperative radiation schedules employing neutrons may result in a greater degree of pathologic downstaging than conventional precystectomy photon regimens, this has not led to an improved survival rate for neutron-treated patients over photon-treated patients. Randomized clinical trials comparing primary neutron irradiation and primary photon irradiation do not disclose an advantage for neutrons over photons as measured by survival rate or freedom from local tumor recurrence. The late complications in normal pelvic tissues following neutron irradiation with low-energy beams exceed those experienced after photon irradiation and have led to an unexpectedly high rate of treatment-related morbidity and mortality. A partial explanation for the toxicity may be attributed to the use of neutron beams with poor depth dose characteristics for the treatment of what is a deep-seated malignancy. An additional explanation is the documented lack of a differential in radioresponsiveness to neutrons between the bladder primary tumor and adjacent normal pelvic tissues.     

Review of the clinical results of fast neutron therapy

The clinical results reported from the different neutron therapy centres are reviewed. Fast neutrons were shown to be useful in the treatment of locally extended inoperable salivary gland tumours (average local control rates 67% for neutrons compared to 28% for photons). For paranasal sinuses and some tumours of the head and neck area, especially extended tumours with large fixed lymph nodes, neutrons could also be of interest. By contrast, the results obtained for brain tumours were, in general, disappointing. Neutrons were shown to be beneficial in the treatment of well differentiated soft tissue sarcomas, as well as to bone- and chondrosarcomas. For locally extended prostatic adenocarcinoma, a RTOG randomized trial gave local control rates of 77% for mixed schedule compared to 31% for photons. Neutrons could be useful also for palliative treatment of melanomas. Further studies are needed in order to evaluate the benefit of fast neutrons for other localizations such as uterine cervix, bladder and rectum. It can be concluded that fast neutrons could be of interest for about 10% of the radiotherapy patients, but it is likely that the new high-energy hospital-based cyclotrons will further extend the indications of neutron therapy. However, patient selection remains one of the main problems and there is a need for development of individual predictive tests.     

Fast Neutron Radiation Therapy: Results of phase III randomized trials in head and neck, lung, and prostate cancers

The results of phase III trials comparing neutrons to photons for head and neck squamous cell cancers, non-small cell lung cancers, and prostate adenocarcinomas are reviewed, with emphasis given to the most recent U.S. National Cancer Institute sponsored randomized clinical studies in which fast neutrons were delivered using modern, hospital-based, high-energy, isocentric-capable cyclotrons. In locally advanced squamous cell head and neck cancers, neutrons showed no convincing advantage over photons. Fast neutron radiotherapy may have provided a therapeutic benefit in selected patients with inoperable non-small cell lung cancers. For locally advanced prostate adenocarcinomas, neutron therapy resulted in significantly superior clinical and histological loco-regional tumor control, which may translate to improved survival with additional follow-up. In general, severe late complications were more frequent with neutrons, especially in patients treated on older physics laboratory-based equipment. Even with modern state-of-the-art neutron generators, careful beam collimation and treatment planning are required to minimize side effects.     

Micronucleus response of human glioblastoma and neuroblastoma cells toward low-LET photon and high-LET p(66)/Be neutron irradiation

The identification of photon resistant tumors that are sensitive to neutrons is still an unresolved problem, and no radiobiological criteria have been developed that could help the selection of patients for neutron therapy. The micronucleus (MN) assay has been evaluated for this purpose in a panel of human glioblastoma and neuroblastoma cell lines spanning a wide range of photon sensitivities defined by mean inactivation doses ([Latin capital letter D with macron above][gamma]) of 1.25-3.21 Gy. We show that the relative biologic effectiveness (RBE) of the p(66)/Be neutrons is significantly correlated with inherent photon sensitivity (r = 0.89, p < 0.01), indicating that the panel of cell lines used is suitable to study the differential biologic response to neutrons and photons. We find that p(66)/Be neutrons are 1.43 to 5.29 times more effective per unit dose in inducing micronuclei than 60Co [gamma]-rays. Surprisingly, cells that are inherently photon resistant tend to show a higher yield of micronuclei following exposure to either photons or neutrons, but no significant correlation could be demonstrated. However, RBE values based on micronucleus yield were found to strongly correlate with RBE values derived from cell survival data (r = 0.91, p < 0.01). It is concluded that although micronucleus yield does not reflect intrinsic sensitivity to either photons or neutrons, the strong correlation between RBE calculated from micronucleus formation and RBE derived from cell survival demonstrates that the micronucleus endpoint has a potential for detecting photon resistant cells that show increased sensitivity to neutrons.     

Transmission measurements in multi-rod arrays: a design study for a multi-rod collimator

The results of transmission measurements for neutrons, cobalt-60 gamma-rays, and 10 and 15 MV photons made with close-packed arrays of tungsten rods are presented. These results indicate that tungsten rod arrays of reasonable thickness can provide for primary or secondary collimation of all these radiation beams. Development work on a collimation system utilizing the multi-rod concept which is capable of producing irregularly shaped fields and suitable for use in photon or neutron radiation therapy is described.     

Treatment with neutrons: hadrontherapy part II: physical basis and clinical experience]

Neutrons have radiobiological characteristics, which differ from those of conventional radiotherapy beams (photons) and which offer a theoretical advantage over photons to fight radioresistance by the differential relative biological effect of them between normal and tumour tissues. Neutron therapy beneficed of great interest between 1975 and 1985. Many of phase III trials were conducted and indications have been definitively deducted of them. After briefly describing the properties of neutron beams, this review discusses the indication of neutron therapy on the basis of the clinical results. Salivary, prostate tumours and sarcomas are the main indications of neutron therapy. In concern to the prostate cancers, other alternative treatments reduce the neutron therapy field. For sarcomas, the lack of randomised trials limits the impact of the interest of neutrons. For other tumours, the ratio benefice/risk of neutron therapy is inferior to these obtained with photons and they could not be considered like classical indications.     

Japanese experience with clinical trials of fast neutrons

Between November, 1975 and November, 1981, 825 patients were treated with 30 MeV (d-Be) neutrons at the National Institute of Radiological Sciences, Chiba. At the Insitute of Medical Science, Tokyo, 302 patients were referred to the Radiation Therapy department and were treated with 16 MeV (d-Be) neutrons. The emphasis of these clinical trials with fast neutrons was placed on the estimation of the effect of fast neutrons for locally advanced cancers or radioresistant cancers, and on evaluation of the rate of complication of normal tissues following irradiation with fast neutrons. Results were evaluated for patients with previously untreated cancer; local control of the tumor was observed in 59.1%. Complications requiring medical care developed in only 32 patients. Patients who had received pre- or postoperative irradiation were excluded from this evaluation. Late reaction of soft tissue seemed to be more severe than that observed with photon beams. The results also suggest that for carcinoma of the larynx, esophagus, uterine cervix, Pancoast's tumor of the lung and osteosarcoma, fast neutrons were considered to be effectively applied in this randomized clinical trial. For carcinoma of the larynx, a fast neutron boost was effectively delivered, although an interstitial implant was necessarily combined with fast neutrons for carcinoma of the tongue. The cumulative survival rate of the patients with carcinoma of the esophagus treated with fast neutrons was 26% compared to the survival rate of 10.5% obtained using photons. This was supported by evidence from the pathological studies that showed that the tumor cells which had deeply invaded into the esophagus were effectively destroyed when fast neutrons were applied. Local recurrence of carcinoma of uterine cervix was 29% and 42% for patients who had received fast neutron therapy and photon beam therapy, respectively. The results also indicate that local control and relief of the symptom related to Pancoast's tumor of the lung seemed to be better with neutrons than with photons. For patients suffering from osteosarcoma, the surgical procedures preserving the function of the leg and arm were studied according to the better local control rate of the tumor following fast neutron beam therapy.     

Evaluation of neutron irradiation of pancreatic cancer. Results of a randomized Radiation Therapy Oncology Group clinical trial

Between 1980-84, the Radiation Therapy Oncology Group conducted a trial in patients with untreated, unresectable localized carcinomas of the pancreas. Patients were randomly chosen to receive either 6,400 cGy with photons, the equivalent dose with a combination of photons and neutrons (mixed-beam irradiation), or neutrons alone. A total of 49 cases were evaluable, of which 23 were treated with photons, 11 with mixed-beam therapy, and 15 with neutrons alone. The median survival time was 5.6 months with neutrons, 7.8 months with mixed-beam radiation, and 8.3 months with photons. The median local control time was 6.7 months with neutrons, 6.5 months with mixed-beam radiation, and 2.6 months with photons. These differences are not statistically significant. Evidence of moderate-to-life-threatening gastrointestinal or hepatic injury was present in three patients treated with neutrons and one patient treated with photons. The causes of this apparent difference are discussed. This study demonstrates there is no evidence to suggest that neutron irradiation, either alone or in combination with photon irradiation, produces better local control or survival rates than photon irradiation.     

Absence of a demonstrable gain factor for neutron beam therapy of epidermoid carcinoma of the head and neck

A comparison of normal tissue and tumor responses in patients treated with the high energy Fermilab neutron beam and conventional photons (Cobalt and 4 MeV X rays), yielded the following parameters. For neutrons the median dose for significant radiation injury in the irradiated tissues was 31 (±2) Gy and the median dose for local control of the tumor was 26 (±2) Gy. The corresponding doses for photons were 90 (±4) Gy for normal tissue injury and 74 (±3) Gy for local control of the tumor. These figures show that the therapeutic ratio is roughly 1.2 for both neutrons and photons. Similarly, the RBE of neutrons relative to photons is about the same for normal tissue tolerance and for tumor control. Under these conditions, there is no demonstrable therapeutic gain factor for neutrons relative to photons. The overall local control rate was the same for both modalities (44%).     

The edinburgh experience of fast neutron therapy

The Edinburgh experience is based on a d(15 + Be neutron beam generated by a compact CS 30 Cyclotron. The facility has an iso-center treatment head providing 240° of rotation. The most important limitation of the beam is its poor penetrating quality. We have compared neutron therapy alone given in 20 daily fractions over four weeks with photon therapy given in the same fractionation schedule. Since clinical studies began in March, 1977, over 500 patients have been treated by fast neutrons. Almost all patients are now admitted to randomly controlled trials. In the head and neck trial conducted in collaboration with colleagues in Amsterdam and Essen,192 patients are available for analysis. Most patients had T3 lesions and about 50% had involved nodes. The cumulative regression rate at six months is similar after neutrons and photons (75%). Later recurrence rates (36%) are also similar. The early radiation morbidity is similar in both groups, but the late reactions are greater after neutrons (15%) than photons (6%). Overall survival is better after photon therapy. A trial of patients with glioblastoma has also shown a better survival after photon therapy. Neutron therapy was associated with demelinization in three of 18 patients. Patients with transitional cell cancer of the bladder have also been the subject of study. Local tumor control was similar (53%) after neutrons and photons. Late radiation morbidity was much greater after neutrons (20%), compared with photons (2%). In a trial of advanced carcinoma of the rectum, the local tumor control was also similar after neutrons and photons (30%), but morbidity was greater after neutrons.Soft tissue sarcomas have shown response rates (37%) that may be expected after photon therapy. Salivary gland tumors have shown a similar experience, although slow growing tumors such as adenoid cystic carcinoma may respond better to neutrons. The response of malignant melanoma also requires further evaluation. No qualitative advantage of neutrons in relation to tumor responses has been determined, while increased late radiation morbidity has been demonstrated following the dose-time schedules used.     

Neutron therapy in cervical cancer: results of a phase III RTOG Study

Between October 1976 and May 1984, 156 patients with locally advanced cervical cancer were entered into a Phase III trial with the participation of five institutions. Patients were randomly assigned to receive photons only (50 Gy in 25 fractions over 5 weeks plus intracavitary applications or external-beam boost) or mixed-beam radiotherapy (2 fractions a week of neutrons, 3 fractions a week of photons to a total RBE-adjusted dose of 50 Gy over 5 weeks plus intracavitary applications or external mixed-beam boost). Only patients with squamous carcinoma of FIGO Stages IIB, III, or IVA with negative para-aortic nodes on lymphangiogram were eligible. Ten patients were excluded from the analysis because of ineligibility or cancellation. Of the 146 patients analyzed, 80 were treated with mixed-beam radiotherapy and 66 with photons. Patients were grouped by stage and institution. The percentage of patients undergoing intracavitary applications was 50% on mixed beam and 75% on photons (p less than 0.01). Tumor clearance was 52% and 72% for mixed beam and photons, respectively (p less than 0.03). Local control at 2 years was 45% for mixed beam and 52% for photons. Median survivals were 1.9 years on mixed beam and 2.3 years on photons. Severe complications occurred in 19% and 11% in mixed beam and photons respectively (p less than 0.13). The inferior outcome with neutron therapy in this study may have resulted from the use of horizontal neutron beams of varying energy and penetration. A new randomized trial using high-energy hospital-based cyclotrons with gantry-mounted beam-delivery systems has recently been activated to evaluate more rigorously the role of fast-neutron therapy for advanced cervical cancer.     

Fast neutron radiotherapy for sarcomas of soft tissue, bone, and cartilage

The basic radiobiological rationale for the use of fast neutron radiotherapy in the treatment of classically radioresistant tumors such as soft tissue sarcomas, osteogenic sarcomas, and chondrosarcomas is reviewed. There are no definitive randomized studies comparing high and low linear energy transfer radiotherapy for these tumor systems, but a review of published series is highly suggestive of a therapeutic advantage for fast neutrons. For soft tissue sarcomas, the local control rate is 53% (158 of 297) with fast neutrons, compared with 38% (49 of 128) with photons/electrons; for osteogenic sarcomas, the local control rate is 55% (40 of 73) with fast neutrons, compared with 21% (15 of 73) with photons/electrons; and for chondrosarcomas, the local control rate is 49% (25 of 51) with fast neutrons, compared with 33% (10 of 30) with photons/electrons. An ongoing clinical trial for these tumors is also described.     

The Effect of Combining Fast Neutron and Photon Irradiation on the Human Osteosarcoma OS-732 Cell Line

OBJECTIVE To determine the lethal effect of combining fast neutron with photon radiation on the OS-732 cell line. METHODS We examined the effect of irradiation by fast neutrons, photons and a mixed beam (fast neutrons plus photons) on the lethality and colony forming ability of the OS-732 cell line at different times. RESULTS Following a single irradiation close, the lethality was markedly strong at 24, 48 and 72 h in the group treated with fast neutrons alone and in the mixed beam group in which there was a high proportion of fast neutrons. CONCLUSION The lethal effect of a fast neutron and mixed beam with a high proportion of fast neutrons on the OS-732 cell line is highly significant. These studies provide guidance for the clinical application of fast neutrons for osteosarcoma treatment.     

Radiothérapie des sarcomes : hadronthérapie,pour qui,pour quoi ?

The radiobiological properties of the hadrons (neutrons, protons, carbon ions) led to their therapeutic use in sarcomas, as a referent therapy or as an alternative to photon therapy. An extensive review of the literature has been conducted to assess the present indications and the perspectives for hadrontherapy. Compared to photons, neutrons are characterized by a higher biological efficiency that is on particular importance for these tumours usually considered as radio-resistant. Neutrons have been considered as a standard therapy for sarcoma’ patients, contra-indicated for surgery or with a definitive R2 resection, but their indications and use have been restricted due to the occurrence of late severe toxicities related to their poor ballistic’ properties. Thanks to their physical properties (Bragg Peak), protons are characterized by a higher conformity index compared to photons (and neutrons) with optimal organs at risk preservation that permits a dose escalation. Protontherapy is to date the standard of care for base of skull, spinal and paraspinal sarcomas. Carbon ions combined both advantages from protons and neutrons. Literature data permits to consider this radiation modality as a referent therapy for unresectable sarcomas. The ongoing diffusions of protons and carbon ions radiotherapy facilities will permit to offer these therapies to more patients and to conduct studies that are warranted to determine their indications and their results.     

Determination of absorbed dose to water for high energy photon and electron beams--comparison of different dosimetry protocols

The determination of absorbed dose to water for high-energy photon and electron beams is performed in Germany according to the dosimetry protocol DIN 6800-2 (1997). At an international level, the main protocols used are the AAPM dosimetry protocol TG-51 (1999) and the IAEA Code of Practice TRS-398 (2000). The present paper systematically compares these three dosimetry protocols, and identifies similarities and differences. The investigations were performed using 4 and 10 MV photon beams, as well as 6, 8, 9, 10, 12 and 14 MeV electron beams. Two cylindrical and two plane-parallel type chambers were used for measurements. In general, the discrepancies among the three protocols were 1.0% for photon beams and 1.6% for electron beams. Comparative measurements in the context of measurement technical control (MTK) with TLD showed a deviation of less than 1.3% between the measurements obtained according to protocols DIN 6800-2 and MTK (exceptions: 4 MV photons with 2.9% and 6 MeV electrons with 2.4%). While only cylindrical chambers were used for photon beams, measurements of electron beams were performed using both cylindrical and plane-parallel chambers (the latter used after a cross-calibration to a cylindrical chamber, as required by the respective dosimetry protocols). Notably, unlike recommended in the corresponding protocols, we found out that cylindrical chambers can be used also for energies from 6 to 10 MeV.     

An interpretation of some biological results obtained in range-modulated negative pion beams

Recent biological data show little change in relative biological effectiveness (RBE) across the peak region of range-modulated pion beams in contrast to previous works which showed increasing RBE with depth. These biological results are shown to be consistent with each other and with previously measured microdosimetric data. The differences are attributed to differences in the lateral spread of the beams. Large lateral distributions result in an increased dose as a result of neutrons emitted in pion “stars,” an effect that is quantified using a high-energy neutron transport code. For a large beam which is of the type used in therapy, the neutron dose is as much as 50% of the total “star” dose and of the high linear energy transfer (LET) dose, this percentage increasing with increasing peak volume. Preliminary measurements are in agreement with the calculated results. The rapid increase in neutron dose with field size should be an important factor in pion treatment planning.     

Responsiveness of experimental prostate carcinoma bone tumors to neutron or photon radiation combined with cytokine therapy

PURPOSE: To improve the outcome of radiotherapy for prostate carcinoma bone tumors, we investigated bone tumor irradiation with photons or neutrons followed by interleukin 2 (IL-2) therapy in a tumor model. METHODS AND MATERIALS: Implantation of PC-3 cells in nude mouse femur cavity induced a bone tumor that progressed to the formation of a palpable tumor, at the hip joint, by Day 20. Established bone tumors were irradiated with photons or neutrons, and a day later, mice were treated with IL-2 therapy for 3 weekly cycles. RESULTS: PC-3 bone tumors responded to radiation with photons or neutrons in a dose-dependent manner. Combination of photon or neutron radiation with IL-2 therapy increased tumor growth delay, compared to that with photons or neutrons alone. Radiation alone or combined with IL-2 significantly increased mouse survival compared to that with IL-2 or no treatment. After combined therapy, a complete inhibition of bone tumor growth was observed in 45% to 50% of the mice. Histologically, the combined therapy resulted in greater tumor destruction associated with fibrosis, new bone formation, and inflammatory infiltrates than that observed with each modality alone. CONCLUSIONS: The efficacy of tumor irradiation with neutrons or photons was enhanced by IL-2 therapy for the treatment of prostate carcinoma bone tumors.     

Fractionated lung irradiation in young pigs with 6.2 MeV neutrons and cobalt-60

Irradiations of the right lung with 6.2 MeV neutrons (38 test animals) and 60Co photons (34 test animals) were made using young pigs. Twenty animals were used as controls. Five fractions were administered in an overall treatment time of 5 or 35 days. The radiogenic pneumopathy was monitored with clinical, radiological and histological investigations, and by determining the hydroxyproline content in the lung tissue. The pneumopathy in pigs given neutrons developed after a shorter latency period and followed a more rapid and serious course than that in animals given gamma rays. While after photons the extension of the overall treatment time from 5 to 35 days led to a measurable but low increase of the ED50 this was not true for neutrons. The relative biological effectiveness (RBE) for the 6.2 MeV neutrons compared with 60Co photons was 4.0 for an overall treatment time of 5 days and 4.1 for 35 days.     

Lead-polystyrene transition zone dosimetry in high-energy photon beams

In order to study the dose enhancement under sheets of lead positioned directly on the skin of patients, parallel-plate ionization chamber measurements in high-energy photon beams (4-15 MV) were performed below a lead-polystyrene interface. The dose in the transition zone can be much higher or lower than in the situation with full buildup of polystyrene. The enhancement of ionization directly beneath the lead-polystyrene interface, compared to the ionization at a reference depth in polystyrene, increases with photon energy and field size. The field size dependence is due to an increase in relative contribution to the energy fluence of low-energy photons scattered in the phantom and for the 4 MV beam also to photons scattered in the head of the accelerator. By adding a thin (100 microns) plastic absorber against the lead, the low-energy and large-angle electrons, which give rise to the enhanced interface dose, can largely be removed. The data indicate that lead as bolus material should only be used with extreme caution.     

Fission reactor neutron sources for neutron capture therapy--a critical review

Summary The status of fission reactor-based neutron beams for neutron capture therapy (NCT) is reviewed critically. Epithermal neutron beams, which are favored for treatment of deep-seated tumors, have been constructed or are under construction at a number of reactors worldwide. Some of the most recently constructed epithermal neutron beams approach the theoretical optimum for beam purity. Of these higher quality beams, at least one is suitable for use in high through-put routine therapy. It is concluded that reactor-based epithermal neutron beams with near optimum characteristics are currently available and more can be constructed at existing reactors. Suitable reactors include relatively low power reactors using the core directly as a source of neutrons or a fission converter if core neutrons are difficult to access. Thermal neutron beams for NCT studies with small animals or for shallow tumor treatments, with near optimum properties have been available at reactors for many years. Additional high quality thermal beams can also be constructed at existing reactors or at new, small reactors. Furthermore, it should be possible to design and construct new low power reactors specifically for NCT, which meet all requirements for routine therapy and which are based on proven and highly safe reactor technology.