[CANCER RESEARCH (SUPPL.) 51, 5065s-5073s, September 15, 1991]

Radiation Oncology: Past Achievements and Ongoing Controversies1

James B. Mitchell and Eli Glatstein2

Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland

Abstract

With the development of megavoltage treatment and computerizedtreatment planning the quality and precision of radiation oncology hassteadily improved. Likewise, these developments have contributed tobetter local control for some cancers; however, micrometastatic lesionsbeyond the radiation treatment field and ineffective systemic treatmentsfor many malignancies hamper efforts at the most important oncologicalend point, survival. Major advances in cancer therapy are therefore likelyto come with improved combined modality treatment representing integration of local modalities with the systemic. These advances, in ouropinion, will come from biological developments that address the problems that the modern oncologist faces at the cellular level. The biologicaldevelopments will incorporate modern molecular biology, continued probing for biochemical mechanisms, and an intensified effort to learn moreabout the complexities of human tumor physiology.

Alice laughed, "There is no use trying," she said: "One can'tbelieve impossible things."

"I dare say you haven't had much practice," said the Queen."When 1was your age, I always did it for half an hour a day. Why,

sometimes 1 believed as many as six impossible things beforebreakfast!"

Through the Looking GlassLewis Carroll

Past Accomplishments

The field of radiology is not quite one century old. The useof radiation for the treatment of cancer had its primitive beginnings at the turn of the century. In the first half of the century,treatment empirically improved, and curative treatment developed for seminoma, vocal cord cancer, and cervix cancer. Themajor developments, and indeed the first real revolution, inradiation oncology took place with the midcentury developmentof megavoltage treatment, both 60Co and modern linear accel

erators. With these tools, and their better depth dose distribution, consequent skin sparing and sharper edge falloff, improvements in local control and even curability with acceptablemorbidity occurred for a wide range of localized cancers, including, but by no means limited to, the cervix (1), bladder (2),breast (3), prostate (4), head and neck (5), and a variety oflocally advanced cancers that are generally not cured but stillsuccessfully treated locally [typically in conjunction with surgery: lung (6), rectum (7), and others]. In addition, curativetreatment evolved for lymphoma (8), for Hodgkin's disease (9,

10), and for other surgically inaccessible cancers in the mediastinum. During the second half of this century, a second and lessrecognized revolution took place with computerized treatmentplanning, which superimposes the dose distribution on imagesobtained by computer-assisted tomographic scanning or magnetic resonance-based imaging techniques (11). These techniques have quietly but steadily improved the quality and pre-

1Presented at the Symposium "Discoveries and Opportunities in CancerResearch: A Celebration of the 50th Anniversary of the Journal Cancer Research,"

May 15, 1991, during the 82nd Annual Meeting of the American Association forCancer Research, Houston, TX.

2To whom requests for reprints should addressed, at Radiation OncologyBranch/NCI, Bldg. 10, Room B3-B69, Bethesda, MD 20892.

cisión of radiotherapeutic practice and markedly decreasedradiation morbidities, by identifying "hot spots" in the treat

ment planning early and allowing altered and improved treatment plans to be used. Three-dimensional treatment planningmay further refine this process (12), although such a technological development does not really address any major biologicalissue confronting the modern oncologist. At the same time allthese technical developments have been occurring, there hasbeen a synchronous revolution in medical oncology as well,which offers the opportunity for integration of radiation andmedical oncology in the planning of curative combined modalitytreatment for a wide variety of cancers, such as esophagus (13).

Physics Issues

The history of these improvements in radiation oncology hasbeen predominantly in the sphere of physics. Thus, it is naturalto point to a variety of developments in the physics field, whichmany people view as the future of radiation oncology. Forexample, there's been a rebirth of brachytherapy in radiation

oncology (14). With the advent of megavoltage therapy, brachytherapy had rapidly declined. However, the development ofnewer isotopes, the utilization of afterloading techniques, andthe development of the computer for planning the treatmentand calculating accurately to various points determined by newcomputer-assisted tomographic imaging has resulted in amarked expansion of the utilization of brachytherapy. Indeed,today there are high dose-rate brachytherapy developmentsongoing, which do not address any biological issue, but onlytechnical ones.

Conformational treatment which would allow the technicaldevelopment of improved treatment planning with computerized collimation that would result in a dose distribution conforming to the shape of the cancer is another step forwardwhich many people see as a major improvement (15). It shouldreduce morbidity even further, and because of the improvementin localization of the cancer, one should anticipate some improvement in local control as well. Exactly how much survivalimprovement will be achieved by this kind of technological tourdeforce remains to be seen; likewise, the cost of such improvements must be weighed carefully.

A variety of high linear energy transfer beams have also beenevolving in terms of modern physics for radiation oncology(16). These machines have in some instances (e.g., protons)physical properties that would be optimal and, in some cases,biological properties (e.g., neutrons) which would be optimalfor local treatment. However, they are quite expensive and asTable 1 attempts to show, when one accounts for the cost ofthe construction of a hypothetical heavy ion beam, for housingthe beam, and includes the expenses of running such a machineand maintaining it in terms of "indirect expenses," as well as

the salaries of the appropriate personnel, one must concludethat these machines are fundamentally extremely expensive,accounting only for treatment. The proton units would costmuch less and are economically feasible. However, they canonly be state of the art for approximately two decades and inmost instances would be unable to treat as many as 1000

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Table 1 Cost estimate for a new hypothetical high linear energy' transfertreatment facility: 1991

Cost

Beam constructionBeam housing and physical facilityMaintenance and personnel per annumDuration of "state-of-the-art" facility

Annual throughputCost/patient (radiotherapy only)

$35,000,000$35.000,000$10.000,000

20 yr600 patients/yr

$270.000.000 _12,000 patients'*22'50

patients a year. With the realization of what the Americaneconomy is like in this last decade of the 20th century, of theunwillingness of the public to commit tax dollars in increasedamounts, and of the growing obsession with medical cost containment, it is hard to see how these beams can ever reallyexpect to become standard. The importance of such experimental facilities, of course, remains inestimable.

To summarize, the technical developments that are beinginvestigated at the present time are expensive, and their preciseimprovement on the outcome of patients remains to be seen.

Clinical Issues

Radiation oncologists on the whole have been enthusiasticabout the importance of local control, which is entirely justifiedfrom the view point of symptoms. However, the most importantsingle oncological end point is survival. It is important torecognize that controlled studies in breast (17), lung (18), andrectal (19) cancers have all shown that postoperatively radiationtherapy can markedly improve local control and local symptoms, but rarely does it result in a major improvement insurvival. The presumed explanation for this Pyrrhic paradox isthat the local treatment does not effectively deal with occultmicrometastatic lesions which have typically spread beyond thefield of radiation therapy and that these metastatic lesions, inthe end, determine the long-term success of treatment, in termsof survival. It is precisely for this reason that modern combinedmodality treatment representing integration of local modalitieswith the systemic becomes the most important issue at thepresent time in cancer therapy. If major gains are to be obtainedin the survival of cancer patients, it must come predominantlyfrom improvements in systemic therapy for these micrometastatic lesions. While some might interpret that to mean thatthe future of local treatments will diminish with time, we viewthat as still another paradox of future developments in systemictreatment. As systemic treatments improve gradually in thearea of solid tumors, the importance of local control willincrease, rather than decrease, in the management of thesepatients.

One of the ways in which radiation therapy might be expectedto improve local control is with intraoperative radiation therapy, i.e., the introduction of high doses of electron beam therapyto the tumor bed directly at the time of surgery. One mustacknowledge that this type of treatment requires close interaction between radiation oncology and surgery; everything mustbe anticipated and planned jointly before the surgery. One mustalso acknowledge that this sort of approach violates all principles of fractionation that have evolved with trial and error overthe decades.

At the Radiation Oncology Branch of the National CancerInstitute, we have had ongoing randomized studies for manyyears in the use of intraoperative radiation therapy for upperabdominal neoplasms, namely, pancreatic and gastric carcino

mas, and retroperitoneal sarcomas. With follow-up out to 10years, we have absolutely no suggestion that this kind of treatment improves survival.1 The upper abdominal neoplasms are

particularly difficult challenges to the modern oncologist, andperhaps there will be more positive findings obtained fromstudies that deal with pelvic neoplasms. Again, however, theessential point appears to be that micrometastases and peritoneal seeding make local modalities alone very limited in theirability to deal with these neoplasms from the curative point ofview.

A recent area of investigation has begun in the area offractionation, i.e., the application of varying exposures of radiation over time. Classic experiments in this area began originally with Regaud and his coworkers in Paris, beginning in1919 (20, 21). They showed that spermatogenesis in the ramtestis could be permanently eradicated by the administration ofsuccessive small daily doses of fractionated radiation theapy,whereas a single massive dose had failed to achieve the samebiological end point without severe injury to the overlying skin.Regaud hypothesized (astonishingly for his time) that the testis,which has a very high rate of cell turnover, was analogous inmany aspects to a neoplasm. Using this analogy, he suggestedthat the preferential eradication of spermatogenesis by fractionated radiation therapy indicated that this kind of prolongedtechnique of multiple small exposures should be tried in cancertreatment. He and his colleague, Coutard, applied these techniques of prolonged fractionation to the treatment of patientswith cancers in the head and neck area. Within a few years, theFoundation Curie began to report five-year survival data for avariety of primary cancers of the head and neck region thatwere truly remarkable for that time (22, 23).

A variety of investigators have been evaluating cell survivalcurves and recognizing the linear-quadratic nature of thesecurves. They have hypothesized that advantage could be obtained by using more than one fraction per day, but decreasingthe size of the fraction from the standard 1.8-2.0 Gy used perday (24). This should achieve greater cumulative doses in lesstime without major changes in the frequency of morbidity.Many of these studies are not yet complete, but there is asuggestion that a modest gain in the local control can beachieved by means of multiple fractions per day. Since this kindof work does not require any new equipment, it is consideredresearch that is very economical from the financial point ofview. While the gains are modest, they nonetheless appear tobe significant; therefore, this kind of work has engenderedconsiderable enthusiasm in the radiotherapy community.Again, however, no major impact on survival has yet beenreported.

As noted earlier in this review, combined modality therapyhas considerable theoretical basis by linking treatments that areaimed at the tumor mass with different approaches for occultmicrometastatic disease. The major gains have been thus farachieved in small cell carcinoma of the lung (25) and pediatrieneoplasms (26). At the same time, the results of many effortsin this area have been somewhat disappointing thus far indiseases such as non-oat cell lung cancer. In our opinion, itwould appear as though this kind of treatment has fundamentally sound strategy, but we are still in need of better tools,especially systemically, for eradicating not only the micrometastases of adult carcinomas but also overt métastases.

The major problem at the present time appears to be theneed for better systemic agents to combine with surgery and

3 E. Glatstein, W. Sindelar, and S. A. Rosenberg, unpublished observations.

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radiation therapy. Largely because of this reason, interest hasslowly been building in the area of monoclonal antibodies toneoplasms that could be used for targeting treatment such aschemotherapy or radiation by means of isotopes. A detailedreview of the role of radiolabeled monoclonal antibodies isbeyond the scope of this paper. Nonetheless, the principle is touse antibodies to localize on the surface of the cancer cells.This localization per se will not usually destroy the cells, unlessthere is an associated complement fixation. Using radioisotopesrather than toxins or drugs to arm the antibodies has thepractical advantage that the isotope does not have to be internalized into the cell in order to destroy it; the isotope merelyhas to be in close proximity to the neoplastic cell in order todestroy that cell. The key problem is to link the appropriateisotope to the antibody by conjugating these two together bysome means of chelate or potentially by molecular engineering,without significantly altering the antibody binding capability.There is also an enormous need to improve the antibodies byvarious means to minimize their own immunogenicity whichwill reduce the human antibodies reacting to the murine antibodies that are presently being used. Moreover, there are problems with the antibodies escaping the vascular system, whichphysiologically keeps proteins largely inside the vascular systemin order to maintain osmotic pressure. These problems andothers, dealing with microdosimetry and the alarmingly lowdose rates and low proportion of uptake achievable in tumorsvia antibody isotope delivery, figure to remain critical areas ofinvestigation for radioimmunotherapy for the future.

Biological Developments

It is our opinion that technological developments will beovershadowed in the 21st century by biological developmentsthat address the problems that the modern oncologist faces atthe cellular level. These problems, both biochemical and molecular, will require major scientific research. Quantitative mammalian cell radiobiology did not really begin until Puck andMarcus in 1956 (27). There has been an explosion of information about the ability of the cell to be modified in terms of itssurvival by sensitizers and/or protectors. Why differing humantumor types show diverse inherent sensitivities to radiation andwhy some types of cells repair radiation to a greater extent thanothers is of major importance to both clinicians and experimentalists. Since radiation produces a variety of free radical species,much of the past thinking has centered on characterizing andquantifying intracellular radioprotective species. There are avariety of substances that may be important in this respect:Superoxide dismutase; catalase; GSH4 and GSH-related en

zymes; protein thiols; and a variety of low molecular weightthiol-containing molecules that are present in low concentrations within the cell. These substances should be important inthe detoxification of toxic oxygen-related species that may be

produced by radiation (28, 29). On the other hand, as yet therehas been no direct correlation between GSH levels and cellularradiation sensitivity (30-32).

Sensitizers/Protectors. For many years, radiobiologists havetried to identify substances that sensitize tumor cells to radiation and indeed many agents have been identified. One of thebest radiation sensitizers is clearly oxygen. Hypoxie cells aresignificantly more resistant to radiation than fully oxygenatedcells. Radiobiologists labored many years toward identifying

4The abbreviations used are: GSH, glutatione; SF2, surviving fraction at SF2.

means to sensitize hypoxic cells to radiation. One of the fruitsof their labor was the development of chemical hypoxic cellradiosensitizers which were brought into clinical trials in themid 1970s. The nitroimidazole misonidazole was extensivelystudied in the clinic. Misonidazole did not show dramatic effectsalthough at least one positive study was reported (33). Unfortunately misonidazole exhibited dose-limiting peripheral neuropathy which severely limited its use. Newer sensitizers arereported to have less neurological toxicity while affording equaltumor radiosensitization and are presently being evaluated clinically (34-37). The potential to enhance the effectiveness ofthese agents via GSH depletion in tumor cells by drugs such asbuthionine sulfoximine has been reported (38). Buthioninesulfoximine is just entering Phase I clinical trials as a chemo-sensitizer and will thus be available for future clinical radiosen-sitizer work. Research in this area will continue with development of even more effective sensitizers; however, more emphasis is clearly needed in approaches toward noninvasivelymeasuring oxygen levels (and the extent of hypoxic regions) inhuman tumors. The possibility of measuring oxygen levels inliving tissues by electron paramagnetic resonance was recentlyintroduced (39). The ability to measure oxygen levels in tumorsprior to treatment would give insight as to the importance ofhypoxia in radiation oncology that many have viewed as limiting effective radiation treatment and perhaps serve as a selectivescreen for tumors best served by addition of sensitizers to thetreatment protocol.

Halogenated pyrimidines represent a different type of radi-osensitizer that shows promise in several tumor types thoughtto be incurable with conventional radiotherapy, including massive unresectable sarcomas of the adult type. For the halogen-ated pyrimidines to sensitize, they must be incorporated intothe cellular DNA. In the case of human tumors which have arelatively long cell cycle time this requires several days ofcontinuous drug infusion to achieve adequate replacement.Despite rapid dehalogenation following bolus infusion, studieshave shown that prolonged i.v. infusion is not associated withrapid dehalogenation and that gradually intraarterial concentration can be elevated to a level competitive with thymidinefor dividing cells (40). In vitro studies have demonstrated therelationship between the extent of radiosensitization and theproportion of thymidine replacement (41). These studies areclearly in their infancy, but they represent the beginning of anew era in which radiosensitization appears to be potentiallypractical and beneficial.

A multitude of chemotherapy drugs have been identified asradiation sensitizers (42). Many of these drugs radiosensitizecells maximally when the drug and radiation treatment aregiven simultaneously. There has been considerable (and justified) reluctance in using such protocols in the clinic primarilydue to enhanced normal tissue reactions. While the clinicalexperience of simultaneous chemotherapy/radiation has beensomewhat discouraging this certainly should not curtail research in the area; multiple X-ray fractions per day may represent a ploy to allow for more investigation of simultaneoustreatment (25).

Radioprotectors have thus far been more theoretical thanpractical for use in cancer treatment. Aminothiols were shownto protect against whole body radiation in animals many yearsago. This prompted a large screening effort by the Walter ReedArmy Institute of Research, and the one drug that appeared tohave some promise for clinical application was WR-2721, whichshowed some ability to provide selective radioprotection. To

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date, clinical efficacy of WR-2721 is still in question. Researchcontinues to identify new radioprotectors, but clearly the development of an agent that selectively protects normal tissues asopposed to tumor represents a major challenge. Identificationof molecular/biochemical differences between normal and tumor cells would greatly facilitate this effort.

Combined Hyperthermia/Radiation. Hyperthermia representsanother biological front with direct possibilities in radiationoncology. There is little question that heating cells to temperatures of approximately 43°Cwill markedly enhance the ability

of radiation to destroy those cells (43). The problem is that ithas been difficult technologically to control the heat distributionand to monitor it. Thus, there is presently a fundamentalproblem of suboptimal technology to deliver hyperthermia.There is little question that, as technological improvementsoccur in depositing heat into a three-dimensional volume, witha pulsating blood flow, this kind of treatment will increase inits importance. For the time being, however, it is clearlyinvestigational.

Photodynamic Therapy. Another area of biological importance is photodynamic therapy (44, 45). The use of photosen-sitizers which absorb light at a specific wavelength can beextremely useful. The primary photosensitizer at the presenttime for clinical use is hematoporphyrin derivative. This substance, for reasons which are not entirely clear, appears tolocalize for a longer period of time in tumor cells than innormal tissues which eliminate this substance relatively rapidly.Thus, if the timing of the exposure to light is optimal, one canhave preferential cell killing of tumor cells in vivo with relativelylittle in the way of other reactions. The major problem is thefact that since the light is used in the visible light spectrum(typically from a laser), it does not penetrate human tissue verywell at all, and is only appropriate for tumors up to approximately 5 mm in maximal depth. Even so, this may be veryuseful as an adjunct to other procedures. There is little questionthat this type of treatment is fundamentally a surgical procedure; however, what radiation oncology has to offer this fieldis physics and dosimetry discipline which is critical to thesuccess of this kind of treatment over the long haul. In addition,the potential for development of chemiluminescent substanceswhich could emit light at a wave length compatible with aphotosensitizer could obviate the need for a laser and set thestage for systemic phototherapy in the future.

Tumor and Cellular Resistance and Cross-Resistance. Whysome tumors respond while others do not or why some tumorsappear to become less responsive as treatment progresses arequestions to which many researchers are actively seeking answers. The answers are likely to be complex, but researchdirected in this area will clearly be of priority in the next decade.Managing the critical balance of tumor destruction and preservation of normal tissue is indeed a challenge that hopefullywill resolve as more is learned about the molecular/biochemicalintricacies of normal and tumor cells and the unique physiologyassociated with tumors. Studying one area to the exclusion ofthe other would not seem wise.

Researchers (both clinicians and scientists) dedicated to theimprovement of cancer treatment using both radiation andchemotherapy (and combinations) are directed by individualand collective clinical observations and experience. These findings are taken to the laboratory where both in vitro and in vivomodels are developed to better understand what is observedclinically. While in vitro and in vivo models provide an excellentmeans of studying mechanisms under controlled conditions,

their relevance to the actual situation in humans is alwaysviewed skeptically. Confusion often arises when clinical observations are described using laboratory nomenclature and viceversa. An example is the term "resistance." When clinicians(and some scientists) refer to a tumor as "resistant" to treat

ment, some would interpret this to mean that the cells comprising the tumor are inherently unaffected by the treatment.This may or may not be true. While the inherent sensitivity oftumor cells to a given treatment modality is without questionimportant, it must be appreciated that a variety of factors governtumor physiology and can markedly influence how a tumorresponds to a given treatment. Another, and perhaps moreprecise, description of this situation is that the tumor failed to"respond" (i.e., the tumor does not decrease in size). This term

takes into account both inherent tumor cell sensitivity andtumor physiological factors and more accurately describes whatis seen clinically. Thus, either a tumor is "responsive" or"unresponsive" to treatment. We believe terms such as "resistant" and and its antonym "sensitive" cannot be defined except

in terms of quantitative in vitro survival curve comparisons (46).For example, some human tumors that are "unresponsive"

clinically may, in fact, consist of inherently sensitive tumor cellswhich can be totally destroyed by treatment even though themass may not "shrink," especially when there is a large matrix

or stromal component (41, 47, 48).This simple issue of definitions may seem unimportant and

of little consequence; however, it is often overlooked by bothbasic scientists and clinicians and not infrequently far-reachingclinical decisions or impressions are made on the basis of suchterms. A case in point serving as an example is illustrated inFig. 1. This patient was initially seen at the National CancerInstitute in mid-1978 following trauma to the right knee. This18-year-old male underwent a biopsy that revealed osteogenicsarcoma of the right distal femur. X-rays of the chest showedbilateral pulmonary métastases(Fig. \A). In September 1978,he underwent a median sternotomy, where multiple bilateralmillet seeds were detected, as well as several larger noduleswhich were all resected. However, pulmonary disease regrewrapidly (Fig. IB), and he was begun on adjuvant chemothera-peutic protocols following a disarticulation of the right lowerextremity. He was initially placed on a high dose of methotrex-ate given i.v. over 42 h every 2 weeks but developed progressivedisease. He then progressed despite cisplatin, Adriamycin, 5-azacytidine, and polyinosinic-polycytidylic acid. With multipleobvious pulmonary métastaseshe was begun on a course ICRF-187. With further progression, he was believed to be "resistant"or "refractory" to chemotherapy and was sent for consideration

of radiation therapy to the lungs (Fig. 1C) in July 1979. Itshould be noted that osteogenic sarcoma is considered by manyoncologists to be "radiation resistant" (49). Nonetheless, he

was treated with 15 Gy to both entire lungs in 10 fractions.This treatment was administered in conjunction with i.v. mi-sonidazole, a total of 13.5 g of misonidazole being administeredover 11 days of treatment. The patient's pulmonary disease

stabilized (Fig. ID) and showed no further evidence of growthdespite the fact that pulmonary nodules were still clearly apparent. He continued to be followed until 1982, when there wasan enlarging right perihilar mass, which became obvious onchest X-ray (Fig. IF, arrows). Consideration was raised for aresection, but computer-assisted tomographic scans revealedthat the mass was involving the right ventricle extensively, andit was decided that this could not be resected (Fig. 1(7). Thepatient underwent a second course of radiation therapy to the

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mass, receiving 48 Gy in 2-Gy fractions by isocentric techniques, in 24 fractions over 31 days in conjunction with intravenous bromodeoxyuridine. The mass stabilized; in June 1984he developed subdiaphragmatic disease adjacent to T-9 to T-l 1(Fig. I//, arrow). This manifested itself with a gastrointestinalbleed. He was treated with 60 Gy over 55 days in 30 fractions.Ultimately he had progressive abdominal disease and he diedin December 1984 with a combination of respiratory failureand gastrointestinal bleeding. At autopsy, demonstrable pulmonary lesions showed no histological evidence suggestive ofviability (see Fig. 2).

Several paradoxical points may be derived from this case, (a)The "chemotherapy drug-resistant" pulmonary tumor nodules"responded" (did not continue to increase in size) to radiationplus sensitizer, yet they did not "disappear." Since the nodules

did not go away, did this mean that the tumor (and the cellswithin the tumor) was resistant to radiation? Not at all; in thisparticular case, the tumor cells in the nodules were killed leavingonly a matrix behind, (b) This "radioresistant" tumor (by mostoncologists' standards) was controlled by a low dose of radiation

plus sensitizer treatment for many years, (c) For this patient,previous radiation treatment did not preclude an effective second course of radiation plus sensitizer. It is impressive indeedthat in this particular case, which would generally be deemedinappropriate for consideration of radiation therapy, soundclinical management and radiation treatment added approximately 5 years to this individual's life. Of course, this example

was chosen to illustrate a specific point and surely other examples could be presented where outcomes would be different.The take-home message here is that perhaps the best approachto cancer treatment is one tumor/one patient at a time with anobjective attitude of openness with respect to the selection oftreatment options. Further, just because a tumor does notshrink after treatment doesn't always mean that the cells in the

tumor are resistant.This example was not intended to underplay the importance

of inherent cellular sensitivity to cancer treatment modalitiesand the imperative challenge confronting researchers to betterunderstand how tumor cells defend themselves. Certainly, inherent cellular radiosensitivity must play a significant role inthe treatment of glioblastoma. Enormous doses of radiation tothese tumors have proven ineffective, even for local control.Radiation sensitivities definitely vary among and within tumorcell histologies. Recent radiosensitivity analysis of human tumor cell lines has revealed a relationship between the inherentradiosensitivity as generically expressed as SF2 and the clinicalresponsiveness of the respective tumor type from which the celllines were initiated (50). In general, low SF2 values correlatewith greater clinical responsiveness. There is at best a factor of3 difference between the most "sensitive" and "resistant" tumor

cell types at the SF2 level. A difference of a factor of 3 couldresult in a huge difference in tumor cell kill over a 30-fractioncourse of radiation therapy.

Of particular interest and concern is the issue of cellularresistance. Induced resistance of tumor cells to chemotherapydrugs in vitro is a reality. Usually drug resistance is induced invitro by chronic exposure of cells to increasing concentrationsof drugs with the resultant progeny resistant not only to theinduction drug but also to a variety of other drugs with differentmodes of cell killing. One possible explanation for such resistance might be that the tumor cell membrane is altered so as tonot allow different drugs access to critical targets of cytotoxicitywithin the cell. Kartner and Ling (51) have produced strong

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Fig. 2. A, histologie section of resected pulmonary nodule showing neoplasticcells and malignant osteoid (obtained September 1978 from the patient describedin Fig. 1). B, autopsy photomicrograph; representative section obtained December1984 showing no malignant cells, only inorganic matrix remaining in a space-occupying pulmonary nodule.

evidence that this is the case in an experimental in vitro model.Multidrug-resistant Chinese hamster cells have altered cellmembranes which include increased amounts of a M, 170,000P-glycoprotein (pi70) which appears to "pump" drugs out of

cells, thereby preventing toxicity. Such cell lines which exhibitthe multidrug-resistant phenotype are essentially refractory todrug treatment in that little or no cytotoxicity is observed asthe drug dose is increased. This observation is in sharp contrastto radiation sensitivity of mammalian cells (including humantumor cell lines). While tumor cell lines may exhibit differencesin inherent radiation sensitivity, there are no reports in theliterature of mammalian cells ever becoming totally refractoryto radiation exposure. In one study Chinese hamster cellssurviving 51 fractions of 10 Gy were found to be only 36%more resistant than untreated cells (52). Another study conducted using rodent tumors demonstrated that when cells surviving a dose of radiation sufficient to yield a partial responsewere reevaluated for radiosensitivity they were in fact moresensitive to radiation than untreated cells (53).

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The example in Fig. 1 speaks to the question as to whethercells that are resistant to cytotoxic drugs might also be resistantto radiation. There are clinical situations where a proportionof patients who fail chemotherapy also fail radiation therapy;moreover, there are patients who may fail chemotherapy butrespond to radiation therapy. One potential mechanism asdiscussed above regarding chemotherapy drug resistance can bereadily excluded for radiation resistance; the plasma cell membrane does not pose a barrier to high energy photons. Radiationdose is delivered in an uniform manner to all parts of the cellor tissue being exposed.

One approach to answering the question regarding possibleradioresistance of chemoresistant cells is simply to conduct X-ray survival curve experiments on cell lines which demonstratechemoresistance. Example of such studies are shown in Figs. 3and 4. Fig. 3A shows the X-ray survival curve for the parentalMCF7-WT breast cancer cell line. Fig. 3Ä illustrates themarked resistance to Adriamycin of the MCF7-AdrR cell line(54) compared to parental MCF7-WT cells. As estimated bycomparing the ratio of the 50% inhibitory doses values of thetwo cell lines, MCF7-AdrR were found to be approximately 50-

fold more resistant to Adriamycin than the parental cell line.The radiation dose-response curve for MCF7-AdrR cells isshown in Fig. 3C (the dashed curve is for MCF7-WT cellsredrawn from Fig. 3A). MCF7-AdrR cells were not cross-resistant to X-rays. Fig. 4 shows X-ray and methotrexate sensitivityfor the MCF7-MR100 cells (55). MCF7-MR100 cells wereexquisitely resistant to continuous methotrexate exposure, exhibiting approximately 4 orders of magnitude of resistance (atthe 50% inhibitory dose) compared to MCF7-WT cells. MCF7-MR100 cells were found to be only slightly more resistant toX-rays than MCF7-WT cells as reflected by minor differencesobserved in n and D0 between MCF7-WT and MCF7-MR100cells. It is interesting to note that the patient illustrated in Fig.1 did not respond to either methotrexate or Adriamycin butwas responsive to radiation. This is entirely consistent with thedata presented in Figs. 3 and 4. Similar findings have also beenreported for Chinese hamster cells resistant to Adriamycin (56,57), cisplatin (58), and multidrug-resistant Chinese hamster

cells (30). However, a relatively increased radiation resistancein some (not all) drug-resistant human ovarian tumor cells was

recently reported (31). Cell lines resistant to melphalan andcisplatin were found to be approximately 1.5-fold more resistant(comparing survival at 2 Gy to parental cell lines) to X-rays.The melphalan-resistant cell line had approximately 2.4-foldhigher GSH levels than the parental cell line. GSH depletionrestored the normal radiosensitivity of the melphalan-resistantcell line. In that study it was proposed that increased GSHlevels were responsible for the increased radiation resistance(31). This interpretation differs from that of others who havefound a minimal role for GSH in the radiation response (59,60). GSH levels when modulated within the same cell line overa range of 5-250% of control levels were not found to modifyradiation sensitivity significantly (29, 61). As more drug-resistant cells are evaluated for radiosensitivity, perhaps differencesin the present literature will be resolved; however, what can begeneralized presently is that drug-resistant cells are not necessarily refractory to radiation.

A related consideration is whether radiation treatment mightresult in altered sensitivity to chemotherapy. There are a fewreports where prior radiation exposure resulted in methotrexate(62)- and cisplatin (62)-resistant cells, and more recently it wasshown that multiple fractions of radiation to tumor cells re-

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Fig. 3. Dose-response curves for MCF7-WT and MCFT-Adr" cells exposed toradiation and Adriamycin. A, X-ray survival curve for MCF7-WT cells; differentsymbols represent replicate experiments; B, survival curve for MCF7-WT cells(D, A) and MCF7-AdrR (•,•)cells exposed for l h to different concentrationsof adriamycin; C, X-ray survival curve for MCF7-Adr" cells. , survivalcurve for MCF7-WT cells redrawn from Fig. \A. A, and n for MCF7-WT andMCF7-AdrR cells were 1.25 Gy and 6.0 and 1.49 Gy and 3.4, respectively.

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RADIATION ONCOLOGY

Methotrexate

O

SCD

O>C

10°IO'1IO'2IO'3in-4K:"" \ '"\\'

I•-4

-3-2-101 2) 10 10 10 10 10 10 10

Methotrexate

X-Rays

Bc 10Uo

2 io'1

o10

-2

£(0

10 -J

10 •4

10 12

Dose (Gy)Fig. 4. Dose-response cunes for MCF7-WT and MCF7-MR100 cells (A)

exposed to continuous incubation with different concentrations of methotrexate,MCF7-WT cells P, O) and MCF7-MR100 (•,•);B, X-ray survival curve forMCF7-MR100 cells (n and A, 6.8, 1.37 Gy). , MCF7-WT cells redrawnfrom Fig. ÌA.

suited in the emergence of drug resistance (63). The drugresistance induced by radiation, however, was extremely smallcompared to drug resistance induced by prior drug exposure(63). Certainly in the clinic this could conceivably happen. Itshould be noted that while radiation could lead to changes ininherent cellular sensitivities (as a result of genomic alterations)to subsequent chemotherapy, other possibilities exist. Radiationtreatment could alter the tumor vascular supply, tumor bed,and other physiological determinants that could compromisethe delivery of the drug to the clonogenic tumor cells.

Tumor Physiology

One of the frustrating aspects to all these types of investiga-tional treatment and their biological impact on success inpatients is the remarkable lack of knowledge concerning basictumor physiology. We have precious little knowledge of theamount of any agent that enters an individual tumor and weknow little of its distribution within the three-dimensional

tumor mass. We have no idea how tissue hypoxia has impacton that distribution. Our knowledge of fundamental tumorphysiology is exceedingly primitive. Many times we confuse thepharmacokinetics of drugs in the plasma with basic pharmacology that is taking place within cells. The processes thateliminate and remove tumor cells after their death are virtuallyunknown. It is hard to conceive of what "resistance" means if

we do not have a basic understanding of the limitations on ourtreatment that are set by the tumor physiology itself. Unfortunately, these kinds of experiments are not considered very"sexy"; thus, they represent one of the most neglected areas in

all of oncological research. This surely must change over thenext few years as researchers and oncologists realize that a hostof parameters (both cellular and physiological) may exert barriers to effective cancer treatment. One would hope that ourtreatments in the next century will be dramatically more effective than at present.

"When you say 'hill,'" the Queen interrupted, "I could showyou hills, in comparison with which you'd call that a valley."

"No, I shouldn't," said Alice, surprised into contradicting herat least: "a hill can't be a valley, you know. That would benonsense...."

The Red Queen shook her head. "You may call it 'nonsense' ifyou like," she said, "but I've heard nonsense, compared with whichthat would be as sensible as a dictionary!"

Through the Looking GlassLewis Carroll

Acknowledgments

We thank Dr. Ken Cowan for the MCF7-WT, MCF7-AdrR, andMCF7-MR100 cell lines and Dr. William Travis for the photomicrographs (Fig. 2).

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