In: .I Radmm Onroiog? Btol Phn.. 1977. Volume 3, pp. 423-424. Pergamon Press Printed in the U S.A.

0 Conference Summary

BIOLOGY

ERIC HALL, D.Phil. Radiological Research Laboratory, College of Physicians and Surgeons, Columbia University,

630 W. 168th St., New York, NY 10032, U.S.A.

In summarizing the biological research presented at this meeting. certain impressions stand out clearly in one’s mind. It is at once evident that the current status of radiobiology is completely different for the various classes of heavy particles.

Neutrons In a historical context it is impossible to overstate

the importance and far-reaching impact of the radio- biological research that grew out of the vision of L. H. Gray and the efforts concentrated at Hammersmith. It set the stage for an understanding of the factors which are vital to high LET radiotherapy of all kinds, and made possible the current clinical trials.

In many ways our knowledge of tumors is far less complete and satisfactory than of normal tissues. Our friends from The Netherlands, Drs. Barendsen and Broerse shook us all, I believe, by demonstrating such a substantial intrinsic difference in sensitivity between different tumor cells. At a dose of about 100 rad (the daily dose favored by the clinical neu- troneers) the RBE varies from 1.8 to 3.5, a factor of 2 for different tumor types.

Yesterday, in Stan Field’s paper, we were treated to a glimpse of the wealth of knowledge available on neutron radiobiology. We now have a good idea of neutron RBE values for a range of normal tissues, at least for early effects. He emphasized the need for late effect studies in larger animals, where endpoints closer to the human could be studied. This would check whether the correspondence between early and late effects, seen in the mouse foot system, is a general phenomenon.

Janet Rasey pointed out more clearly than I had previously realized how tumor radiobiology has been dominated by the spectre of hypoxic cells; when in practice for most tumors, fractionation makes X-rays so effective that tumor RBE’s are in many cases lower than for some normal tissues. Meanwhile, on empirical grounds and for reasons not really under- stood, mixed fractionation schemes of X-rays and neutrons result in a therapeutic gain factor greater than 1.0, in tumors where there is no gain for neu- trons alone. In short, we don’t know why it works- but it does.

The “slow recovery” process, present with X-rays but not with neutrons, seems now to be established in experimental animals. It suggests that for protracted fractionation regimes, X-rays will lead to a sparing of late fibrosis which would not occur with neutrons. This suggests that short treatment times may be bet- ter with neutrons-a view expressed by Jack Fowler, though for different reasons.

Michael Fry cautioned us to the increasing evidence that neutrons are highly carcinogenic compared with X-rays. The 20 year latency period of most human tumors, and the average age of radiotherapy patients make this an academic consideration in general-but it cannot be ignored if younger patients are considered for treatment.

Rod Withers made an interesting point based on the pig skin experiments. With X-rays, the severity of the late reactions was greater with a small number of large dose fractions. By contrast, for neutrons, the late effects were relatively independent of frac- tionation schedule. Echoing again the view that Jack Fowler expressed some years ago that neutrons are a more “sensible” sort of radiation.

In characteristic fashion Mort Elkind made an eloquent plea for a higher priority to be given to basic studies with neutrons, now that many pragmatic questions have been answered. I must say this is a view I share, since neutron radiobiology is no longer a frontier; the battleground for neutrons has moved to the clinic. Neutroneers are not pioneers-if you get what I mean! Compared with patient treatments al- ready under way, experiments with mice or cells, bacteria or bean-roots, suddenly seem much less interesting and relevant unless basic questions in molecular biology are addressed.

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424 Radiation Oncology ??Biology 0 Physics

Heavy ions The situation with heavy ion radiobiology is quite

different. This is still a frontier, the area of action at the moment. The experiments performed in the past 9 months, reported at this meeting by Drs. Chapman, Leith and Phillips, answer more practical questions than everything done in the previous 9 years. Mainly because they have had a beam at last. Their message is one of good news and bad news. The good news is that relativistic heavy ions all the way from helium to argon have been characterized radiobiologically. The ten- tative conclusion is that argon is already too heavy to be of significant use in radiotherapy and there is little point in pushing to particles of higher and higher z, at least for radiotherapy applications. Carbon or neon may be identified as the optimal ion. The good news is that a dedicated accelerator for, say carbon ions, would not be hopelessly too expensive to build for radiotherapy studies. The bad news is that it now appears certain that no heavy ion, when its Brag8 peak is extended to cover a tumor of realistic dimensions, will ever have an OER that is lower than the 1.6 characteristic of neutrons. We had hoped for miracles, and an ideal OER of unity-but it has not materialized and so to some extent we are disappointed. However, we shouldn’t minimize what we’ve got; with carbon ions we may have a dose distribution close to protons, and an OER like neutrons. Not a bad combination.

In any case, a low OER is no longer a prize worth striving for as it used to be. Where the physicist failed, the chemist has come to the rescue! The electron aIBnic drugs promise that hypoxic cells can be sensitized to a point where they are no longer a problem. Earlier Dr. Fowler, the super-salesman of hypoxic sensitizers, spoke eloquently and per- suasively in their favor. I can’t help feeling that Jack proved to be something of a turncoat as an advocate for Her Majesty’s opposition, because his old love for neutrons showed through. He pointed out in fairness that if X-rays and 0582 are good, then neutrons and 0582 are fantastic! Together they represent a for- midable combination. Earlier, Don Chapman had shown with heavy ions, what we already knew with neutrons, that the residual OER can be further reduced by hypoxic sensitizers. This new generation

of drugs must be regarded as an adjunct-not a competitor for all high-LET radiations, neutrons. pions and heavy ions.

Pions I’m sure we were all delighted to hear that pie in

the sky at Los Alamos has materialized to pions in the target area. In fact little new biological data have become available in the year since last we met. Indeed, the sparsity of data rivals the previous spar- sity of pions themselves! Drs. Raju and Kligerman reviewed the existing data. A final figure for the OER characteristic of a spread out peak at high dose-rate is still not available-but it is unlikely to be far from the guess-timate of 1.8. RBE values in a spread out peak are turning out to be about 25% higher than in the entrance plateau, a small, but useful, biological amplification of the physical peak. A decision seems to have been made to proceed to patient treatment after an absolute minimum of radiobiology, and that at the most pragmatic level. This is perhaps a sensible decision in view of the high stakes at risk, but it doesn’t make life very easy or exciting for conference summarizers.

CONCLUSION When we look back on this conference from the

vantage point of time, and the details begin to blur, what will we remember?

(1) The biological data for pions and heavy ions are scarce and primitive compared with neutrons, and this needs to be rectified.

(2) For the first time, I believe, we are in a position to say with some confidence, that no charged particle, in a practical situation, will have an OER lower than neutrons. We’ve known this for pions all along, now it seems to be true for heavy ions as well.

(3) Hypoxic sensitizers clearly have a place in conjunction with all classes of heavy particles (neu- trons, pions and heavy ions) to take care of the residual OER.

(4) Meanwhile, the extra cost of pions and heavy ions buys a better depth dose distribution-and it remains to be proved clinically if it is worth the price. On the word clinical I’ll end because it isn’t my field!