Neutrons and other clinical trials: impossible dreams?

Two papers in this issue deal with neutron treatment.4,7 They reflect the contrary biases of, and animosity between, the Hammersmith and Edinburgh groups. Dr. Catterall and her coauthors are enthusiastic about the clinical efficacy of neutrons for advanced head and neck and breast cancer, whereas Dr. Duncan and his Scottish colleagues are equally determined to concede no advantage. These biases lead Dr. Catterall to pronounce ebulliently that “the results . . . even using a primitive machine and low energy beam . . . were strikingly better than could have been expected from other treatments” and that morbidity “was less than that occurring with chemotherapy regimes combined with radiotherapy or surgery.” Dr. Duncan and his Edinburgh colleagues report results with neutrons that were certainly not worse than generally achieved for head and neck cancer with conventional radiotherapy in the United Kingdom. The local control rate in the neutron arm of their study was better than in the X ray arm and they mention that the improvement may even be understated because of the greater number of enlarged fixed nodes in the neutron series. Nevertheless, they announce that the higher local control rate they obtained with neutrons was not “definitely” better than with photons, and that anyway the improved local control rate was associated with a lower survival rate. One could nitpick about these trials: Dr. Catterall is judicious in selecting her comparisons from the literature (e.g. for morbidity), whereas Dr. Duncan could have argued that the lower survival rate, despite the higher local control rate suggested a poorer performance status or more aggressive tumors among the neutron patients, and that, therefore, the neutron results would be even further improved if the two groups were really equal. One could also take issue with Dr. Duncan’s claim that there was no significant difference between the two randomized groups in the distributions of node stages: 28/38 (74%) in the neutron arm had fixed nodes versus 2 l/4 1 (5 1%) in the photon arm with 24/38 (63%) and 12/41 (29%) being both fixed and larger than 3 cm in the respective series. Although these percentage distributions may not be significantly different from one another in a statistical sense, that is not really the difference whose significance is of concern: clinical experience would suggest that it is unlikely that one can dismiss the distributions as being insignificant to relative treatment outcome, especially when all nodes, regardless of size or fixation, were treated with the same dose, or even with a lower dose if very large. However, rather than becoming involved in the details of the two papers it is more useful to decide what are the main lessons to be learned from the duelling cylotrons at Hammersmith and Edinburgh, as well as from accumulated worldwide clinical and laboratory experience with neutrons. On balance, it is probably true that neutrons are at least as good as megavoltage photons in the treatment of squamous cell carcinomas of the head and neck.3-5~7S9-12~‘4 This conclusion is based on the tumor control and complication frequencies from clinical trials in Britain and America in which inadequate or inappropriate cyclotrons were used to develop neutrons and in which radiotherapists were feeling their way in relative biological darkness. There is some evidence3,12 that salivary gland tumors, and maybe carcinomas of prostate,’ 3 are better treated with neutrons, but improvements in local control in other sites6”’ have not shown an acceptable level of statistical significance. All these results were obtained using cyclotrons with inferior clinical performance characteristics. Our technical demands of machinery and our expectations of treatment are now more realistic than at the outset, and it is generally appreciated that any benefit from neutron therapy will have to be searched for, rather than stumbled upon.