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SCIENCE & PRACTICE

Biological basis of radiation therapy for cancer

H. RODNEY WITHERS

Radiation oncologists are clinicians who use X rays totreat about one-half of the 25% of the population who willdevelop cancer. X ray treatment for cancer has nothing incommon with diagnostic radiology: the doses given are half amillion times greater than the average dose received by apatient having a chest radiograph. Surprisingly, medicalstudents learn essentially nothing about radiation therapy,even though about,one in ten of them will ultimately receiveit.X ray treatment is directed to the site of the primary

tumour and, commonly, the draining regional lymph nodesits clinical application is more akin to the surgeon’s scalpelthan to a medical oncologist’s cytotoxic drug therapy.However, the basic mode of action of X rays is more likethat of cytotoxic drugs because they kill cells in situ andallow the body to remove them. Radiation therapy involvesthe careful targeting of a cytotoxic agent both to enhancelocal control of the cancer and to limit systemic toxicity; it isusually given over a period of three to eight weeks.

Mechanisms of radiation injuryX-irradiation produces breaks in the DNA. Single-strand

breaks are of little consequence because the cell has efficientmechanisms for repairing them, presumably evolved toprotect us against accumulating injury from environmentalradiation and other toxins. However, if the dose of X rays ishigh enough, two single-strand breaks will be close enoughto one another to cause a double-strand break. Withoutintact templates for their mutual repair, double-strandbreaks may be misrepaired and disrupt the integrity of thechromosome. Chromosomal aberrations do not normallyaffect the survival or function of cells between the time theyare irradiated and the time they attempt to replicatethemselves; cell death usually ensues at the first or earlysubsequent mitotic divisions. Thus, normal tissues andtumours show a radiation response at a rate proportional totheir rate of proliferative turnover. For instance, the mucosaof the respiratory and digestive tract, which is activelyproliferative, develops a detectable reaction within two tothree weeks of first exposure to a course of radiation therapy.Damage to bone marrow may be signalled by a fall in plateletand white cell counts within a few days if large volumes ofthe bone marrow are exposed. Skin reactions are reportedonly rarely with modern, high energy, highly penetratingX ray beams, but when the skin dose is raised intentionallyor unavoidably, desquamation and/or hair loss begin toappear about three weeks after start of treatment. The rate of

appearance of injury depends not only on the proliferativeactivity of "stem", or germinal, cells but also on the lifetimeof the differentiating progeny of these cells. Thus, althoughthe platelet and white-cell count may decrease quickly afterirradiation, anaemia is uncommon because of the slowturnover of mature erythrocytes and the ability of thesurviving erythropoietic precursor cells to compensate forinjury before the effects of radiation injury become obvious.

Slowly proliferating tissues such as connective tissue,kidney, cartilage, bone, lung, and oligodendrocytes respondslowly to X-irradiation with signs of damage only months oryears after exposure.Tumours, like normal tissues, also respond to X-

irradiation at different rates. Tumours with a highproliferative activity and a high rate of cell loss diminish insize quickly whereas more indolent tumours may takemonths. The rate at which a tumour regresses is not areliable index of its radiocurability. Some tumours thatregress quickly may also recur quickly, whereas othertumours may remain detectable for weeks or even monthsafter the end of radiotherapy and yet ultimately disappearand never recur. Therefore, as long as a tumour is regressingafter radiotherapy, biopsy is contraindicated. A positiveresult from a biopsy specimen may lead to unnecessary"salvage" surgery, and repeated biopsies interfere with thehealing of normal tissues.

Why treatment takes so longRadiotherapy is commonly given as a series of equal-sized

doses, usually five times a week for several weeks, a processcalled fractionation. Each daily dose "fraction" kills thesame proportion of cells. For instance, a commonly useddaily dose is 200 centiGray (cGy; previously expressed as200 rad) and, as a reasonable approximation, that dosereduces tumour cell survival to about 50%. A similar dosethe next day will further reduce survival by 50%-ie, to25% of the original population. This equal proportionateeffect results in a logarithmic (geometric) decline in totalsurviving cell number with increase in number of dosefractions.A series of fractionated doses amplifies the therapeutic

differential between normal tissue and tumour for severalreasons, easily remembered as the 4 R’s: Repair of cellularinjury, Repopulation by surviving viable cells,Redistribution within the division cycle, and Reoxygenationof the tumour.

RepairRepair of DNA damage is completed over a few hours,

but the extent of repair is not equal in all tissues. In general,slowly responding normal tissues (eg, connective tissue,kidney, spinal cord) are capable of greater repair than aremalignant tissues. Thus, by spacing dose fractions by atleast 6 h (normally 24 h) the recovery in slowly respondingnormal tissues is relatively greater than that in tumours.Because cell killing is logarithmic rather than linear, thedifference in each day’s effect is amplified exponentially-eg, if the greater repair taking place in critical "target" cellsof a slowly responding normal tissue leads to 60% of them

ADDRESS Department of Radiation Oncology, UCLA MedicalCenter, Los Angeles, California 90024-1714, USA.

Correspondence to Prof H R Withers, MD.

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surviving each dose fraction compared with only 50% of thecancer cells, then, after 30 dose fractions, the relative

survival will be (60/50)30 = 237, a major therapeuticdifferential.

RepopulationRepopulation by surviving cells in proliferative normal

tissues takes place as a homoeostatic response to injury andprovides an important reason for extending treatment overseveral weeks. This regenerative response allows acutelyresponding tissues (eg, mucosa) to tolerate an increased dosegiven to the tumour.Treatment-induced acceleration of growth has also been

identified and quantified in some cancers.2-4 This responseto injury was unexpected since most tumours were thoughtto grow autonomously, although hormone-sensitivetumours were an exception. The mechanisms underlyingthe accelerated regrowth of tumour cells are unknown, justas they are for normal tissues. It seems reasonable to assumethat growth factors are involved, and that their effect may besupplemented by improved vascularisation of residualtumour as it shrinks. Also, like normal tissues, the delaybetween irradiation and a regenerative response, and its rateonce it has begun, may vary widely from tumour to tumour.The rate of repopulation in the average tumour is less thanthat in acutely responding normal tissues, and the differencedetermines the therapeutic advantage for extendingtreatment. However, rapid regeneration is not a factor in thetherapeutic differential between late-responding normaltissues and the tumour; it is therefore desirable to deliver theradiation dose in as short an overall time as is compatiblewith acceptable acute toxicity. Within the framework ofkeeping dose fractions small and limiting the total durationof therapy, the exact pattern of dose fractionation for a givenpatient can vary.

Redistribution within the mitotic cycleCells show large changes in their radiosensitivity as they

progress through the division cycle. Only a small radiationdose to the tumour is necessary to kill preferentially mostcells in the more radiosensitive phases of the division cycle.This selective killing leaves the surviving cell populationpartly "synchronised" in more radioresistant phasesimmediately after each daily dose fraction. By stopping thedose and waiting, say 24 h, one allows cells in radioresistantphases of the division cycle to progress into more

radiosensitive phases. Eventually they will return to beingan asynchronous population because of the wide range ofdivision cycle times in most tumours. A population ofasynchronous cells is more radiosensitive, on average, thanthe population surviving a dose of 200 cGy from which themore radiosensitive cells have just been eliminated. Thisself-sensitising effect of cell-cycle redistribution applies toboth tumours and normal tissues that show acute effectsfrom multi-fraction radiotherapy; it is not, however, afeature of the normal tissues that show only late effects,whose cells are essentially static within the division cycle (ina phase that permits repair). The division cycleredistribution that takes place between successive doses in acourse of radiotherapy enhances the differential effectbetween the critical late-responding normal tissues and thecancer. 5

ReoxygenationWhen solid tumours grow, they often outstrip their blood

supply and acquire areas of hypoxia and necrosis. Hypoxic

cells are two-to-three times as radioresistant as normoxiccells (for radiochemical and not metabolic reasons). Hence,even a small proportion of hypoxic cells could limit

radiocurability of the tumour. When multiple small doses ofX rays are given over a period of days or weeks, the normoxiccells, being more radiosensitive, are killed selectively by eachdose fraction. During the interval between dose fractions,killed normoxic cells are eliminated and the previouslyhypoxic cells gain better access to oxygen.6 This process ofreoxygenation limits the negative effect of hypoxic cells onradiocurability.The notion of fractionating the total radiation dose into

many smaller doses-thereby repeatedly eliminating theradiosensitive subpopulation of cells and allowing survivingradioresistant cells to become sensitive during the interval-thus depends on both cell-cycle redistribution and

reoxygenation.

Dose and tumour control

Some patients abandon their course of radiotherapybefore completion. This outcome is serious because to cure acancer requires killing every cell that is capable of indefiniteproliferation. An inadequate total dose will result in few orno cures. For instance, if 80% of the full dose is given, it willnot achieve an 80% cure rate. If a tumour contained 1010

malignant clonogenic cells capable of indefinite

proliferation, then a dose that was only 80% of that thoughtto be curative would reduce survival by a factor of only about10, 100 (102) malignant cells capable of causing a recurrencewould remain.The relation between dose and the probability of curing

the tumour is shown in the figure.’ There is a threshold dosebelow which no tumours are controlled but above whichcontrol increases steeply. The same curve aoplies to normaltissue injury but, through dose fractionation and otherbiological and physical manoeuvres, it is displaced to theright. The greater the distance between the curves fortumour control and complications, the greater the

therapeutic ratio. The aim of research is to increase theseparation further.The art of clinical radiotherapy practice is to determine

the most appropriate risk-benefit ratio. Major complicationssuch as myelitis must be avoided, but it is not in the bestinterests of patients to choose doses so low that there is norisk of complications.

The relation between X ray dose and outcome of radiotherapy.

At any given dose--eg, A, B, or C-there is a balance between tumourcontrol and complications. The dose prescribed depends on factorsrelating to the tumour, normal tissues, and the whole patient

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Directions and developments

Combined modalities

Each daily fraction of 200 cGy reduces tumour cellsurvival to about 50%. The more tumour cells to be

eradicated, the higher the dose required and the higher therisk of complications. Radiation therapy can eliminate largetumours but it is better at eradicating small tumours andsubclinical tumour deposits. Although surgery is excellentfor removing masses, its therapeutic ratio in subclinicaldisease is usually low. Surgery and radiotherapy are

mutually beneficial, simultaneously increasing thelikelihood of eliminating the loco-regional cancer and

reducing morbidity. There are few sites where a

multidisciplinary approach does not have some place. Inmany settings chemotherapy and radiotherapy can

"consolidate" the cytotoxic achievements of one another;this is well established for lymphomas, leukaemias, andtesticular cancers and holds promise in lung, oesophageal,anal, and rectal cancers.

HyperfractionationReduction of the radiation dose per fraction allows

preferential sparing of late-responding normal tissues’ andenhances self-sensitisation of the tumour through divisioncycle redistribution.5 In clinical trials of hyperfractionation,two fractions of 115-120 cGy per day were given instead ofone fraction of 200 cGy, to deliver a total dose 15-20%higher in the same overall treatment period. Non-randomised studies that showed an advantage8 have nowbeen supported by the results of a randomised prospectivetrial in which patients with moderately advanced cancer ofthe head and neck showed a gain of about 15% in localcontrol rates with no increase in normal tissue sequelae.9

Accelerated treatment

Accelerated repopulation of some human tumours duringtreatment is a recent discovery.24 This process certainlytakes place in head and neck cancer, and there is evidencethat it may occur in cancers of the cervix, bladder, skin, lung,and some lymphomas. Clinical trials are in progress to assessthe value of shortening the duration of treatment; this couldbe achieved in several ways but, to keep the dose per fractionlow, they all involve more than five fractions a week. Somehave incorporated between seven and twenty-one fractionsper week. 111--13Flow cytometry has enabled estimation of the potential

doubling times of tumours accessible to biopsy.13 Thismeasure might provide a method for predicting whichtumours are most likely to "escape" a standard regimenlasting six to eight weeks. Patients could then be selected forentry into an accelerated treatment protocol. The earlyresults of one trial of accelerated treatment suggest that the

greatest improvement in tumour control rates is found inthose tumours with the shortest estimated potentialdoubling times.13

Until recently it was thought that tumours did not havesuch a "homoeostatic" regenerative response and hence theextension of a course of radiation treatment to limit acute

toxicity was a reasonable option. At least as important as anyimprovement attributable to accelerated treatment is theunderstanding that an unnecessarily long treatment

duration could be harmful to patients receiving an otherwisestandard treatment.

Predictive assays

Accurate prediction of the radiation response of a tumourwould allow a more individualised treatment approach.Several tumour variables are being assessed to improve theselection and stratification of patients for particulartreatment regimens, both conventional and experimenta1.14.15Some tumour characteristics that may predict outcome ofradiotherapy are the proportion of cells that survive a dose of2 Gy, the potential doubling time, tumour ploidy, tumourhypoxia, and the degree of expression of oncogenes. Onemust distinguish between those characteristics that predict apoor outcome because of the "natural" biology of the tumourand those that predict responses to treatment. Theyinfluence treatment decisions separately.

Radiosensitisation and radioprotectionX rays damage DNA either directly by ionisation or

indirectly by producing ions in the surrounding water whichthen attack DNA. Most injury is indirect. Oxygen and drugswhose radiochemical reactions resemble oxygen--eg,metronidazole and other newer nitroimidazoles-facilitatethe transfer of free radicals from water to DNA whereasother molecules, such as sulphydryls, "scavenge" radicalsand protect DNA. Attempts have been made to limit theadverse effects of hypoxic cells on tumour response bytreating patients with carbogen in hyperbaric oxygenchambers (95% oxygen, 5% carbon dioxide) or withnitroimidazoles that sensitise hypoxic cells.16

Neutron radiotherapy was another approach that wastried. Hypoxia was known to confer less radioresistance toneutrons since more of their tumoricidal activity depends ondirect DNA damage. However, most tumours reoxygenateefficiently, and the non-selective application of thesemeasures gives little benefit. Although clinical trials ofmethods to eliminate hypoxia should not be abandoned forever, they should be reserved for a time when poorlyreoxygenating tumours can be identified both prospectivelyand with high accuracy. Measurement of oxygen tension in atumour with fine electrodes and detection of radioisotope-labelled metabolites that localise specfically in hypoxic cellsmay prove strong candidates for such strategies. 15The existing sulphydryl-containing radioprotectants are

toxic and have the additional disadvantage that the extent ofnormal tissue protection is difficult to predict. Overdose andcomplications are therefore less predictable than withstandard treatment.

Conclusion

The avenues of investigation in radiation oncology arenumerous: development of better predictive assays,radiolabelling of antibodies for both diagnosis andtreatment, three-dimensional treatment planning and

delivery, stereotactic irradiation to reduce normal tissuedoses, hyperthermia, neutron-capture therapy, protontherapy, and improvements in drug-radiationinteractions.7.14,15,17-19

Radiation therapy has advanced, not only in the

complexity of treatment machines and treatment-planningcomputers but also in the qualitative and quantitativeunderstanding of the biological processes that underlieradiation responses. The manipulation of these

characteristics to increase the therapeutic differentialbetween normal and tumour tissue to provide safer, morecomfortable, and more effective cancer treatment is the goalfor further research.

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REFERENCES

1. Thames HD, Withers HR, Peters LJ, Fletcher GH. Changes in early andlate radiation responses with altered dose fractionation: implications fordose-survival relationships. Int J Radiat Oncol Biol Phys 1982; 8:219-26.

2. Trott K, Kummermehr J. What is known about tumour proliferationrates to choose between accelerated fractionation or hyperfractionation?Radiother Oncol 1985; 3: 1-9.

3. Withers HR, Taylor JMG, Maciejewski B. The hazard of acceleratedtumor clonogen repopulation during radiotherapy. Acta Oncol 1988;27: 131-46.

4. Maciejewski B, Withers HR, Taylor JMG, Hliniak A. Dose fractionationand regeneration in radiotherapy for cancer of the oral cavity andoropharynx: part I: tumour dose-response and repopulation. Int JRadiat Oncol Biol Phys 1989; 16: 831-43.

5. Withers HR. Cell cycle redistribution as a factor in multifractionirradiation. Radiology 1975; 114: 199-202.

6. Kallman RF. The phenomenon of reoxygenation and its implications forfractionated radiotherapy. Radiology 1972; 105: 135-42.

7. Withers HR, Peters LJ. Biologic aspects of radiotherapy. In: FletcherGH, ed. Textbook of Radiotherapy, 3rd ed. Philadelphia, Lea andFebiger, 1980: 103-80.

8. Million RR, Parsons JT. The University of Florida experience with twofractions per day for head and neck cancer. Front Radiat Ther Oncol1988; 22: 79-92.

9. Horiot JC, LeFur R, Nguyen T, et al. Hyperfractionated compared withconventional radiotherapy in oropharyngeal carcinoma: an EORTCrandomized trial. Eur J Cancer 1990; 7: 779-80.

10. Knee R, Field RF, Peters LJ. Concomitant boost radiotherapy foradvanced carcinoma of head and neck. Radiother Oncol 1985; 4: 1-7.

11. Wang CC. Twice daily radiation therapy for head and neck carcinomas.Front Radiat Ther Oncol 1988; 22: 93-98.

12. Saunders MI, Dische S, Hong A, et al. Continuous hyperfractionatedaccelerated radiotherapy in locally advanced carcinoma of the head andneck region. Int J Radiat Oncol Biol Phys 1989; 17: 1287-93.

13. Begg AC, Hofland J, Moonen L, et al. The predictive value of cell kineticmeasurements in a European trial of accelerated fractionation in

advanced head and neck tumours. Int J Radiat Oncol Biol Phys 1990;19: 1449-53.

14. Chapman JD, Peters LJ, Withers HR. Prediction of tumor treatmentresponse. New York: Pergamon Press, 1988.

15. Peters LJ, Brock WA, Chapman JD, et al. Predictive assays for tumorradiocurability. Am J Clin Oncol 1988; 11: 275-87.

16. Brown JM. Sensitizers in radiotherapy. In: Withers HR, Peters LJ, eds.Innovations in radiation oncology. Heidelberg: Springer-Verlag, 1987:247-64.

17. Steel GG, Adams GE, Peckham MJ. The biological basis of

radiotherapy. Amsterdam: Elsevier, 1983.18. Withers HR, Peters LJ. Innovations in radiation oncology. Heidelberg:

Springer-Verlag, 1987.19. Hall EJ. Radiobiology for the radiologist. New York: Lippincott, 1988.

Clinical practice of radiotherapy

Radiotherapy is the most important type of non-surgicaltreatment for patients with common cancers. The

proportion of those treated by radiotherapy at some timeduring their illness has risen steadilyl and is now well over50%. Despite advances in surgical technique, choice andindications for chemotherapy, hormone treatment, andimmunotherapy, radiotherapy remains pre-eminent.Improvements in radiotherapy equipment and techniquehave led to an increasing role for both local treatment and,especially in the past decade, "systemic" therapy in whichmalignant cells are ablated throughout the body.

Advances in techniqueX rays and gamma rays lie at the most energetic end of the

electromagnetic spectrum with a short wavelength and ahigh oscillating frequency. These features explain themolecular ionisation that takes place when such rayspenetrate mammalian cells. As explained by ProfessorWithers in the preceding article, the strategy of the

radiotherapist is to achieve a compromise between

damaging the cancer cell and the normal surrounding hosttissue. Advances in imaging techniques-notably,computed tomography (CT) and magnetic resonance

imaging (MRI)-have aided the radiotherapist in this task.For instance, before CT scanning, a patient with malignant Iglioma who required treatment after craniotomy and partial ’Itumour excision generally needed wide-field irradiationbecause it was impossible to localise the tumour adequately.The dose of radiation was necessarily limited because

high-dose treatment can only be delivered to a restrictedarea. CT scanning enabled radiotherapy to be given moresafely and effectively to patients with low--grade tumours.2Whole-body CT scanning allowed deep tumours to be

localised and MRI has improved the display of brainstem,spinal cord, and pelvis.3To complement improvements in tumour localisation,

advances in the quality and penetrating power of

radiotherapy equipment have resulted in well-localisedradiation beams that can be delivered anywhere in the bodywith homogeneous energy deposition across the tumour anda satisfactory fall-off outside this target volume (table r). Amuch lower dose is given to surrounding sensitive tissueswith, in most cases, almost complete sparing of the skin.Individualised treatment plans, as pointed out by Withers,have become commonplace. Radiation fields can now beshaped by means of shielding blocks, computerisedplanning, and automated tracking techniques to allow evenlarger areas to be treated continuously-eg, pelvic andpara-aortic lymph node field irradiation-with sparing oflocal tissues despite a high dose to the target volume. This"conformal therapy", though not yet fully assessed inrandomised studies, is likely to cause fewer side-effectsin patients who require large-volume irradiation.4

Furthermore, three-dimensional radiotherapy planning andthe creation of a "beam’s eye view" of the tumour and targetarea have permitted both localisation and treatment ofirregular fields that were previously difficult to treat.

Whether these technical advances will translate into

superior survival remains uncertain.There is also renewed interest in brachytherapy, which is

the positioning of sealed radioactive sources close to, or evenwithin, the malignant tissue. Although not new-this

ADDRESS Department of Radiotherapy and Oncology,University College Hospital, Gower Street, London WC1E6AU,UK (Dr J. S. Tobias, MD)