Lionel Cohen

An update on malignant salivary gland tumors treated with neutrons at fermilab

One hundred and thirteen cases of recurrent and/or unresectable malignant salivary gland tumors, treated with fast neutron therapy at Fermilab between September 1976 and December 1984, are analyzed for local control, sites of failure, and treatment-related morbidity. Sixty-three patients had major and 55 had minor salivary gland tumors. Local control was achieved in 67% of patients with major and 58% of patients with minor salivary gland tumors. In the subgroup of patients with oropharyngeal and oral cavity lesions, 19/24 (80%) had local control. However, only four of 15 patients with maxillary antrum tumors had successful control of their disease. Seventy-four percent of patients with lesions measuring 5 cm or less and 30% of patients with larger lesions had their local disease controlled. Histology did not influence the local control rate. Both observed and adjusted median survival for patients with major salivary gland tumors was 36 months. Disease-free survival was 31 months. Observed and adjusted median survivals for patients with minor salivary gland tumors are 48 and 57 months respectively. Twenty of 86 patients (23%) had major morbidity; this was directly related to the total dose delivered. In the dose range 20-24 Gy the complication rate was 16%. Most of these complications were successfully managed with minimal functional disability. We have concluded that fast neutron irradiation is an appropriate treatment for malignant salivary gland tumors.

Response of pancreatic cancer to local irradiation with high‐energy neutrons

Seventy‐seven patients with locally advanced, nonresectable, biopsy‐proven adenocarcinoma of the pancreas were treated by palliative bypass surgery followed by intensive neutron beam irradiation of the primary tumor site. Three dose levels, under 20, 21 to 23, and 24 to 25 Gy, were studied with the use of a treatment plan that included all known disease within a limited target volume, generally under 21. Symptomatic palliation was achieved in the majority of patients. The median survival time was 6 months. One patient remained alive and well without evidence of tumor 5 years after irradiation. Two were free of tumor at autopsy (one had died of intercurrent disease and one of radiation‐related complications). A common cause of death was metastatic dissemination. Complication rates were dosedependent; life‐threatening complications did not exceed 12% with doses of less than 23 Gy. Autopsies from 19 patients were reviewed. In all, the pancreatic tumor site showed extensive reactive fibrosis. Local control was achieved in two patients, but most had both residual tumor in the pancreas and metastases. Six patients had centrolobular veno‐occlusive liver disease. These patients had all received the higher (22–24 Gy) neutron doses. Six patients had hemorrhagic radiation gastroenteritis. Mild skin atrophy and bone marrow hypoplasia were seen in the irradiated volumes. The kidneys and spinal cord showed no radiation effects. The authors conclude that neutron irradiation can provide a good local response with marked regression and fibrosis of the tumor. This response, coupled with many deaths due to metastases, suggests that combined treatment with neutrons and chemotherapy would be worth exploring.

Response of sarcomas of bone and of soft tissue to neutron beam therapy

A total of 51 patients were treated at Fermilab for sarcoma of bone (25 patients) and soft tissue (26 patients). Neutrons were delivered in twice weekly fractions over 6-7 weeks to total doses between 18 and 26 Gy. Long-term local control (greater than 2 years) was achieved in 24 patients (47%). Overall local control rates were 44% in the bone sarcomas and 50% in the soft tissue tumors. Chondrosarcoma appeared relatively more responsive with 9 out of 16 (56%) controlled, compared to osteogenic sarcoma with 2 out of 9 (22%) controlled. Among the soft tissue tumors, liposarcoma (5/7 controlled) and neurogenic sarcoma (3/3 controlled) appear to be more responsive than other tumors. The overall survival rate was 40% in the entire series. These results are comparable with international experience in neutron therapy of sarcomas of bone and soft tissues. Out of 263 soft tissue sarcomas treated with neutrons only to full dosage throughout the world, 152 (58%) were locally controlled. Similarly out of 74 sarcomas of bone so treated, 44 (60%) were controlled.

CLINICAL EVALUATION OF NEUTRON BEAM THERAPY: CURRENT RESULTS AND PROSPECTS (1983)

Some 9000 patients throughout the world have been treated by some form of neutron beam therapy. These include patients with advanced nonresectable tumors in many different sites treated with a variety of neutron beam generators varying widely in beam energy. Protocols were largely nonrandomized and included both mixed beam studies (neutrons + photons) and neutrons alone in varying doses. In spite of wide variation in equipment, treatment technique, and philosophy, some consistent trends have been identified: (1) in general, the neutron results have been at least as good as those of the photon controls measured in terms of local control, although the incidence of significant side effects have been higher; (2) in none of the randomized studies conducted so far, largely comprising epidermoid carcinomas of the head and neck, has a clear survival advantage for neutrons over photon controls been demonstrated at a statistically significant level; (3) results with mixed beam studies have been uniformly equivocal, with marginally significant differences in favor of the experimental groups compared with the photon controls; (4) adenocarcinomas of the gastrointestinal tract (GI) tract, including tumors of the salivary gland, pancreas, stomach, and bowel, appear to be responsive to high linear energy transfer (LET) radiation; (5) nonepidermoid, radioresistant tumors (sarcoma of bone and soft tissue and melanoma) yield a consistantly high local control rate, with neutron irradiation strikingly superior to those reported with photon therapy; and (6) in the central nervous system, both normal tissues and tumors appear to be exceptionally sensitive to neutron irradiation, therapeutic ratios are small, and the prospect of cure remains remote. It is concluded that neutrons are efficacious for certain specific tumor types, but that essentially new study designs, based on nonrandomized matched case comparisons, will be required to prove the merit of the new modality.

Failure of accelerated neutron therapy to control high grade astrocytomas

Sixty-two patients with high grade malignant astrocytoma were treated with fast neutrons using three different treatment schemes to evaluate the effect of shortening the overall time. Dose and fraction number were kept constant. The total dose was 16-18 neutron Gy delivered in six fractions, weekly for 6 weeks, twice a week over 3-4 weeks, or three times a week over 2 weeks. There were no obvious differences in survival times among the three groups. We conclude that accelerated neutron therapy does not improve survival of patients with grade 3 and 4 astrocytoma.

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%).

Fast neutrons in the treatment of salivary gland tumors

Fast neutrons were used in the management of 30 patients with advanced salivary gland tumors. Twenty-two patients are the subject of this analysis. Neutrons were used as the primary mode of management in only seven patients. The remaining patients either had recurrent disease after surgery and/or radiation, or received post-operative treatment with neutrons. After a minimum follow-up of one year, 66% of the patients are alive with no evidence of disease. Control in the treatment volume is as high as 72%, which suggests a significant improvement in the local control of advanced salivary gland tumors. However, longer periods of observation are necessary for more definitive conclusions.

Pancreatic carcinoma: Results with fast neutron therapy

Abstract Results of therapy in 31 of 50 patients who were treated for advanced pancreatic carcinoma at Fermi National Accelerator Laboratory are presented here. To date, six patients are alive and four are free of disease. Since the main reason for failure was lack of control of primary tumor, the tumor dose has been increased by 15 %. Based on our results, a nationwide study has been launched to assess the effectiveness of neutrons vs. photons in the treatment of locally advanced pancreatic carcinoma.

Tolerance of the human spinal cord to high energy p(66)Be(49) neutrons

The risk of post irradiation myelopathy was evaluated in 76 patients followed for 1-5 years after neutron irradiation of the cervical and thoracic regions. No overt myelopathy was observed. Forty-six patients received doses (central cord dose) in excess of 10 Gy, 9 received doses in excess of 12 Gy, and 5 received doses between 13 and 17 Gy, all without any evidence of spinal cord injury. On careful questioning, a subjective transient neuropathy (a tingling sensation in one extremity) was reported by 6 patients, but this was apparently unrelated to dose. A review of available literature revealed a total of 14 patients with myelopathy, 13 of whom received doses in excess of 13 Gy delivered with relatively low energy neutrons generated by the deuteron + beryllium reaction. It is concluded from these studies that the tolerance limit for the human spinal cord irradiated with high energy [p(66)Be(49)] neutrons is close to 15 Gy, above which the risk of cord injury becomes significant. Central cord doses of 13 Gy or less appear to be well tolerated with little, if any, risk of myelopathy. These conclusions are valid for a treatment time of 4 weeks or more with two or more fractions per week (9 or more fractions). The RBE for the human spinal cord irradiated under the above conditions compared with conventionally fractionated photon therapy does not exceed 4.0.

Re-irradiation of locally recurrent tumors with fast neutrons☆

Forty-six patients with locally recurrent disease were re-irradiated with fast neutrons at Fermilab. All had received prior radical radiation therapy either with or without surgery. Six were palliative. Forty patients treated with curative intent were analyzed for local response, survival, and complications. The overall response rate was 78% (31/40); 50% (20/40) had a complete local response. Ten of 16 patients (63%) with non-epidermoid carcinomas in the head and neck regions had complete response, whereas only nine of twenty patients (45%) with epidermoid carcinomas were complete responders. In a subset of 12 patients with salivary gland type tumors, 10 had a complete response (83%). Two of these 10 patients are alive beyond 5 years. Observed median survival for the forty patients was 9.3 months, and for complete responders 14.4 months. Observed median survival for partial responders was only 7.5 months. Four of six patients treated for palliation had significant subjective improvement. Significant morbidity, Grade III or greater (EORTC/RTOG scale), was seen in only 10 patients (25%), and this was found to depend directly on the total dose delivered. We conclude that neutron beam therapy can be used as a therapeutic modality for patients with recurrent tumors with an acceptable degree of morbidity.