CLINICAL FACTORS DETERMINING CURATIVE TUMOR DOSE

ARTHUR JONES, MD, FRCP, DMRT

The dominant factor determining treatment policy, when considering radio- therapy of a neoplastic disorder, is the biologic nature of the tumor process in relation to its spatial configuration. This is also the important factor determin- ing curative tumor dose. With the exception of very small tumors and certain important radiosensitive conditions, it is the effect on normal tissues which de- fines the limits of irradiation and which effectively determines the prescription of dosage. The relationship between dose and volume is basic to this discussion and is considered with particular reference to the integrity of mesenchyme. When comparing the radiosensitivities of tumor and host tissues, i t is important to compare like with like. The ultimate effect on a tumor is measured func- tionally, in terms of suppressing the only function by which the tumour is recognized-its capacity for indefinite proliferation-and reflected in 5- and 10-year cure rates. The effects on normal tissues should therefore be similarly measured in dynamic terms of the final functional state rather than on any transient structural appearance. These features are considered in relation to three different clinical situations: certain radiosensitive tumors, accessible pri- mary tumors of limited sensitivity, and large tumors situated deeply. I t is emphasized that curative treatment requires careful clinical appraisal of all the relevant features in each individual patient. The state of both tumor and host reaction may change significantly during the period of treatment and there is no alternative to continuous clinical observation using all the ancillary aids available.

H E SPECTRUM OF NEOPLASMS CURABLE BY T modern radiotherapy consists mainly of primary tumors, often of epithelial origin. When spread to the regional lymph nodes has occurred the probability of cure is diminished, but may still be substantial-for example, 50yo in carcinoma of the tonsil and 60% in seminoma. Blood stream spread usually pre- cludes cure except in the well-defined in- stances of high sensitivity which must be recognized, such as the pulmonary metastases of seminoma or nephroblastoma. The dom- inant feature determining treatment policy is thus the biologic nature of the tumor pro- cess in relation to its spatial configuration. ‘This is also the important factor determining curative tumor dose.

The biologic nature of the tumor process i17 relation to its sf iatial configuration

The two features are interdependent and in the mind of the clinical radiotherapist

ornew’s Hospital, London. From the Radiotherapeutic Department, St. Barthol-

Received for publication June 13, 1968.

there is a “feedback” of information from the criteria determining the probability of cure in the individual patient to the clinical se- lection of treatment policy for that patient. Therefore, the important first decision is whether treatment shall be initiated with curative intent, for if the chance of cure is remote no one would wish to inflict the radiation reactions often inevitable in curative therapy. On the other hand, we must remem- ber that in certain sites, particularly in the head and neck, the best palliation may follow a frustrated attempt at cure. In this discus- sion of curative tumor dose it is assumed that all the resources of modern radiotherapy, in- cluding mega-voltage methods and compen- sator filter techniques, are available. Dosage is stated as modal dose/overall time (rads/ days) without considering initially any modi- fication by fractionation or radiosensitization.

The idea that for each tumor species there exists a predetermined “tumor lethal dose” is now recognized as a figment of the imag- ination. While we may know the approximate mass of a given tumor of known histologic type, we do not know the proportion of tumor to stroma, and of the tumor cells we do not

759

760 CANCER October 1968 VOl. 22

know how many are potent and how many lack “reproductive integrity” and the capacity for invasion and metastasis. T o this we can add the heterogeneity of cell strains within the tumor, the differences in growth pattern, from whether the tumor is a concentric mass or is made up of autonomous satellites each with its own source of nutrition, and the variations in oxygen tension within each of these loci.

Radiobiologists may wonder how, with so many unknown factors, successful radiother- apy can be achieved at all. T h e reason is that, in the clinical situation, the crucial factor is the relationship of the effect on tumor to that on normal tissues. With the exception of very small tumors and certain important radiosensitive conditions, it is the effect on normal tissues which defines the limits of irradiation and which effectively determines the prescription of dosage.

A fundamental effect in clinical radiother- apy is the relationship between dose and vol- ume; for a given radiation dose, tissue toler- ance is in inverse proportion to the volume irradiated. As this is basic to so much of our work, the mechanisms deserve further study. T h e volume tolerance is made u p of three components: (1) that of the tumor bed or stroma which depends on the integrity of mesenchyme, (2) that of critical organs pres- ent in the irradiated zone, and (3), for very large volumes, the systematic effect.

Limiting effects on Somatic Tissues

L( Mesenchymal Stroma

L Critical Organs

Because of its intimate relationship to the tu- mor cells the stroma will receive the full dose and cannot be physically spared from the brunt of irradiation, and i t is on the recovery of this very mesenchyme that tissue repair later depends. T h e integrity of the blood supply and, in particular, the opportunity for col- lateral circulation are of obvious import in this context. T h e role of the stroma in the control of neoplasia is much debated, but the clinical evidence for its effect is real, for in- stance, in relation to foci of breast adeno- carcinoma. Whatever the quantitative part played by such mechanisms, it is obviously desirable to retain their assistance in aug- menting the direct effect on the tumor.

The question arises: Is there an optimal radiation dose, not linked with the limits of somatic tissue tolerance? T h e most valid data relate to small squamous carcinomas of the mouth treated by radium implantation. Pater- son8 showed that the results for local cure as assessed after 3 years, for single plane im- plants, appeared to indicate 6500 R as being superior to the higher doses of 7000 R or 7500 R. For volume implants, and therefore larger lesions, the results showed an optimum at a higher dose, 6800-7000 R, which were better than those for “over 7000 R”. It is dif- ficult to escape the conclusion that for these relatively small tumors a stromal effect must be acting.

Larger lesions, partly from growth pattern and partly from anoxia, are much less likely to be sterilized, but, again, a stromal factor appears to act in the cure of moderately large tumors deemed incurable on simple cell-sur- viva1 theory.

This is exemplified by a patient with a large carcinoma of the bronchus presenting with superior vena caval obstruction. A 47-year-old woman attended in June 1960 with a 6-week history of swelling of the face and attacks of choking. There was no cough or hemoptysis and only slight dyspnea. Examination re- vealed facial congestion with cyanosis, dilata- tion of both jugular veins and venous con- gestion over the anterior chest wall.

Radiographs of the chest (Fig. IA, B) showed a large mass in the right paramedias stinal area. Its density was confirmed by tomography (Fig. 1C) which showed the lesion extending upwards and forwards into the superior mediastinum, surrounding the upper lobe bronchus and constricting it. Bronchos- copy at another hospital had shown the right main bronchus at the level of the carina to be partly blocked and infiltrated by <growth; the infiltration also extended into the right lateral wall of the trachea.

Biopsy proved the tumor to be an undif- ferentiated oat cell carcinoma of the bronchus. X-ray therapy at 250 kvp by antero-posterior fields (each 16 x 10 cm) gave a midline tumor dose of 3000 R in 42 days. There was excellent clinical and radiologic regression of the lesion.

Six years later (Fig. ID) the chest radio- graph showed only fibrosis of the right upper lobe and the patient remains well and symp- tom-free without evidence of recurrence or metastasis of tumor.

N(I. 1 CURATIVE TUMOR DOSE - Jones 76 1

FIG. 1. A (left), and B (right), Radiographs showing size of tumor mass in oat cell carcinoma of the bronchus causing superior vena caval obstruction in a 47-year-old woman.

'The volume of tumor in this case is esti- matecl at about 180 cc and its mass may be 200 Gnis. While one does not know the pro- portion o f viable tumor to stroma, the tumor

mass must be vastly in excess of that pre- dicted by simple cell-survival theory as being curable by this very modest dose of radiation.

For larger deep lesions such as infiltrating

FIG. 1. C (left), Tomograph showing position of mass surrounding right upper lobe bronchus (same patient as Fig. I A , B). D (right), Radiograph of same patient 6 years after 250 kv x-ray therapy (3000 rads in 42 days). No recurrence.

762 CANCEK October 1968 VOl. 22

carcinoma of the cervix the picture becomes blurred, as the local stromal effects may be difficult to separate clearly from those on critical organs when interpreted purely from cure rates. The ill effects of high-dose irradia- tion on stroma may be shown in another way-the failure to contain irradiated but still viable tumor cells in situ, enabling spread to occur from devitalized tissue. When this happens in tumors infrequently cured (such as bronchial carcinoma), it may be manifest only by decrease in mean survival time.

Failure to deal with residue in curable tumors

Failure to contain Decrease in viable irradiated -*mean survival cells in situ time

Reduction in -% cure rate

The term “supra-lethal dose” effect was adopted by Paterson” to describe the situa- tion in which, following abnormally high radiation dosage, there is poor tumor response -often with central sloughing, leaving an in- durated mass which frequently harbours tu- mor recurrence at a later date. In the normal tissues there is at the same time severe reac- tion, leading to telangiectasia and a trouble- some percentage of necroses. When he further discussed the “supra-lethal dose” effect,7 he stated the principle: “There is in practice an optimum dose which is, for tumours of lim- ited sensitivity, the highest dose compatible with apparent restitution of the normal tis- sues to their usual softness and pliability.”

Paterson’s arguments were derived mainly from consideration of accessible squamous cell tumors, but the terms “softness and pliabil- ity” are of wider import. They imply the integrity of mesenchyme. T h e preservation of the biologic as well as the mechanical func- tions of connective tissue is essential for the fullest exploitation of curative radiotherapy.

The radiation tolerance of most vital struc- tures is now known within broad limits. De- spite refinements of beam directed mega-volt- age therapy, it may be impossible, because of the distribution of tumor, for one or more to be completely protected, and depending on the anatomic level and technique the effect on the proportion of critical organ exposed becomes the determining factor in dosage prescription. It should be noted that the systemic effect of very large volume irradia- tion is (excepting for very short overall treat-

ment periods) usually a manifestation of crit- ical organ effect on hemopoietic tissue.

When comparing the radiosensitivities of tumor and host tissues it is important t o compare like with like. The ultimate effect on a tumor is measured functionally, i.e., in terms of suppressing the only function by which the tumor is recognized-its capacity for indefinite proliferation-and reflected in 5- or 10-year cure rates. Therefore, the ef- fects on normal tissues, e.g., in the thorax, should be similarly measured in dynamic terms of the final functional state rather than on any transient structural appearance.

In determining critical organ dosage it is also important to select the functional criteria with reference to the natural history of the particular neoplasm irradiated. For instance, the incidence of radiation myelopathy of the thoracic spinal cord has been determined for various techniques of treating carcinoma of the bronchus, but the latent period for de- veloping this complication-often 1 to 2 years-is longer than the mean duration of survival of bronchial carcir,oma; to use these data in planning treatment of a tumor com- patible with long survival, such as thymoma or ganglioneuroblastoma, may be quite fal- lacious.

In applying these principles in clinical prac- tice the dominant factors governing curative tumor dose are the nature, size and site of the tumor, the age of the patient and his gen- eral condition. The tumor-bearing volume is related to the tumor mass not only by its present dimensions but by the growth po- tential: the determining factors are the degree of anaplasia, the clinical history of growth and the known behavior of that tumor type for regional spread and metastasis. For a given primary size, the more rapid the growth and the more anaplastic the histologic picture, the larger will be the treated volume; and of course the larger the volume the lower the dosage tolerable.

Age as a factor relates mainly to the ex- tremes of life. In infancy and childhood dos- age is reduced because of the effects on somatic growth and the long period of risk, although volume for volume the systemic ef- fects may be less in childhood. In old age there appears to be an increased immediate tolerance of epithelial surfaces but this may reflect only on impaired ability to react and the later repair processes may be inefficient. The patient’s general condition may in old

No. 4 CURATIVE TUMOR

age be rapidly undermined by mucosal reac- tions and careful observation is necessary par- ticularly if infection (bacterial or fungal) should supervene. The influence of general condition on dosage selection relates inainly to the ability to withstand integral dosage and the effect5 of leukopenia and to overcome any niiicosal reaction involved in curative treat- mmt .

11 inay be of interest to consider these fea- tures in relation to three diffeient clinical sit riations:

1 . Certain radio-sensitive tumors

2. Accessible primary tumors of limited wn5itik ity

3. Large tumors situated deeply

1. Certain Radiosensitive Tumors

The radiosensitivity of a tumor, judged by the rate of change of volume after a given radiation dose, is more a reflection of its growth characteristics and cellular kinetics than of the magnitude of dose required for sterikation. Nevertheless, we recognize a few conditions for which permanent healing is at- tainable by dosage which may be only a frac- tion of the tissue tolerance dose. Such con- ditions a1 e mainly:

(n) Eitabryonal tumors: seminoma and dys- germinonla. Their sensitivity enables cure r a m of 80-907” to be attained by the simul- taneous irradiation of the whole para-aortic lymph node chain and hemipelvis to dosage of 3000 rads in 4 weeks. But most other embryonal tumors require the full exploita- tion of large volume tissue tolerance.

( 2 1 ) Reiiculoendothelial tumors: The inci- dence of multifocal types may render the in- terpretation difficult and these remarks relate to ostensibly localized disease. In lymphoid follicular reticulosis or giant lymphoma 5-year survivals of 46% may be obtained after dos- age of 3000 rads in 4 weeks. Localized lympho- sarcoma of the head and neck may be cured in over 50y0 of cases by dosage of 35004000 rads in 28 days but now we are approaching nearer large-volume tolerance.

The dosage position regarding Hodgkin’s disease has become more complex now that it is recognized that survivals of over 60% at 5 years and over 40y0 at 10 years may be obtained by suitable radiotherapy. As rela- tively resistant instances are met, requiring 3500 rads in 4 weeks for control, the policy

DOSE - Jones 763

is to give this to the primary site and less to the adjacent “prophylactic areas” where de- posits if any are small; these doses are well within the limits of tolerance. But in the notable results obtained by the “mantle” tech- nique of moderately high dosage to extensive areas, the limiting factor becomes large vol- ume tolerance, of both connective and hemo- poietic tissues.

Careful observation during the course of treatment of radio-sensitive tumors may re- veal radical alterations in spatial configura- tion which can be exploited to increase toler- ance. For instance, in thymoma or mediastinal lymphosarconia much more lung protection may be obtained by progressive reduction in field size following rapid shrinkage of the tumor. Similarly, regular radiographs during treatment of the abdomen, following initial lymphangiography, may enable a kidney to be ultimately spared and a higher tumor dose to be attained.

2. Accessible Primary Tumors of Limited Sensitivity

This group includes most squamous cell carcinomas at one end of the scale and soft- tissue sarcomas at the other. With the excep- tion of the small epitheliomas mentioned when discussing stromal response, the limita- tion on dosage is almost always local tissue tolerance. How critical dosage may be is il- lustrated by the studies of Morrison and Deeley5 of carcinoma of the larynx. For Slot- tic tumors, dosage of 5760 rads in 6 weeks gave a local recurrence rate of 34%, but dosage of 6400 to 7000 rads in the same time gave only 11% recurrences. T h e immediate limitation of local tissue tolerance is mesen- chymal rather than epithelial, and i t may be impaired by the effects of the tumor or by extrinsic factors.

Neoplastic invasion of cartilage or bone is an obvious miscreant but the commonest is derangement of the circulation. In fact, im- pairment of the blood supply from any cause is a serious limitation in curative treatment. Important antecedents are previous surgery or radiotherapy. Anemia and impairment of the general condition of the patient act adversely both on tumor response and on tolerance.

Especially for tumors of the mouth and upper air passages, alcoholism has an unto- ward effect, predisposing to unduly early re- action, failure of tumor control and late high- dose effects: possible the effects are mediated

764 CANCER October 1968

by the abnormal capillary dilatation present. Chronic infection, whether syphilitic or other, also reduces tolerance, often by the endarte- ritis produced.

For mesenchymal tumors such as soft-tissue sarcomas the volume to be treated is often large, and as they are of such limited sensi- tivity the radiation dose needs to be high. In- crease in tolerance is obtained by prolonga- tion of treatment time, e.g. 7000 rads in 9 weeks, but, if a whole limb segment has to be irradiated, the later sequelae may be se- rious. Tolerance may be increased if a small corridor of normal tissue can be accurately protected throughout the long course of ra- diotherapy. (Fig. 2A, B)

3. Large Tumors Situated Deeply This common radiotherapeutic situation is

exemplified by intratlioracic tumors. The critical organ of paramount importance is the lung itself. T o revert to the postulate that in comparing radiosensitivity the effects on function should be the main criteria, stud- ies of pulmonary function are more important than any radiologic analysis of fibrosis, be- cause of the peculiar distribution of ventila- tory function within the normal lung. This is least at the apex and gradually increases to- wards the base.9. 10 T h e implications for the radiation tolerance of the lung may be il- lustrated by two examples. In the x-ray ther- apy of mammary carcinoma by antero-poste- rior supraclavicular-axillary fields, a great deal of the upper lobe is irradiated to full tumor dose. Radiologic changes follow, yet untoward clinical sequelae are uncommon. Again, in the

Fic. 2.4. Sparing of medial compartment of upper arm during radiotherapy of fibrosarcoma. Postoper- ative irradiation following extensive surgical resection of recurrent tumor affecting the posterlateral com- partment. Anterior and posterior fields (each 9 x 29 cm) of radio cobalt brams at 110 cm SSD with lead shielding of the medial penumbra. Lesion dose 7000 rads in 62 days. Position of the anterior field.

Vol. 22

FIG. 2B. Appearance of both forearms 21/2 years later showing absence of swelling on the left side. (See legend, Fig. 2A.)

treatment of Pancoast’s syndrome due to su- perior pulmonary S U ~ C U S tumor, the dose for control needs to be high (at least 5000 rads/ 5 weeks) but despite x-ray opacity respiratory complications are rare. It is important not to extrapolate evidence from these examples of dose-time-volume relationship at the apex to other parts of the lung.

In fact, for each thoracic organ the critical radiosensitivity is not a simple function of dose and volume, but in practice is condi- tioned by extrinsic factors. For the lung these are the portion irradiated (particularly whether upper lobe or lower), the basic res- piratory efficiency and the presence and extent of neoplasia within it; for the heart, the pres- ence of juxtapericardial neoplasm predispos- ing to mediastino-pericardial reaction;3 for the spinal cord, the incidence of arterial hyper- tension facilitating progressive mye1opathy;l and for the bone marrow, the extent to which hemopoietic tolerance may have diminished from neoplastic infiltration, chemotherapy or extensive previous irradiation.

When the pattern of response is reviewed

2 0 . 4 CURATIVE TUMOR DOSE - Jones 765

I:IG. 3.4. Wasting of small muscles of left hand in Pan- coast’s tumor of the left su- perior pulmonary sulcus.

i n the light of various radiotherapeutic meth- ods the limiting factors show a transition as we proceed from wide-field to localized tech- niques. For whole thorax irradiation-for pul- monai y metastases-the lung response is nearly always the limitation, at maximal dos- age of 2500 rads in 4 weeks: rarely is hemo- poietic tolerance exceeded if the marrow is previously intact. With medium volume ir- radiation (field area 120 cm2-as for bronchial tumors-the lung response is still the main deterent ,at 4000-5000 rads in 5 weeks, but the tolrrance of the spinal cord now enters the picture at 350011000 rads in 28 days; should the irradiated volume straddle the mediasti- nurn so that the medial segments of both lungs are a t risk, the tolerance is reduced to

not more than 4000 rads in 4 weeks, and should a mediastinal tumor be in contact with the pericardium its response during irradia- tion may prevent further dosage. When strictly localized techniques are employed, the pattern is broken up into the tolerance of particular tissues: the dominant restraining influences become the spinal cord, the medial pleuropulmonary segments, the mediastinal connective tissue, the esophagus and the atrial heart muscle in that order of sensitivity.

Considering the common epithelial tumors within the thorax, from principles already out- lined, oat cell carcinoma of the bronchus will have prescribed for it a lower dose than that for well-differentiated squamous carcinoma- not because it is more readily sterilized, but

FIG. 3B. Radiograph showing Gopacity at left apcx in Pan- coast’s tumor of thc left SLI-

p r i o r pulmonary SLI~CLIS.

766 CANCER October 1968 Vol. 22

simply because of the reduced tolerance of the host tissues. Deeley2 carried out a clinical trial to compare two different dose levels for advanced inoperable bronchial carcinoma. T h e results suggested that mean tumor dosage of 3000 rads gave better survival rates and less morbidity than 4000 rads (each in 4 weeks overall). As there was little difference in the incidence of I esidual growth and of metastases, i t may well be that the different survival was related to the amount of pulmonary fibrosis -an indication of the second type of depres- sion of stromal response already mentioned.

An example of what may be termed “the radiotherapists’s dilemma” is the treatment of Pancoast’s tumor of the superior pulmonary sulcus, illustrated by the following case. A well-built man of 50 presented with intract- able left arm pain and showed clinically left Horner’s syndrome and wasting of the small muscles of the left hand (Fig. 3A, B). Radio- graphs revealed an opacity at the left apes shown histologically to be due to squamous carcinoma of variable differentiation. Follow- ing 15 mev x-ray therapy (lesion dose 5000 rads in 5 weeks) the pain abated and he re- mained well for 3 years. He then became paraplegic from extradural extension of the tumor at the primary level, necessitating laminectomy and x-irradiation.

FIG. 3C. Diagrammatic illus- tration of the dilemma of radio- therapy of Pancoast’s tumor. In- tcrvertebral spread to the spinal cord may occur, but the radia- tion dose for control of niacro- scopic tumor is above the toler- ance of the spinal cord. It is suggested that the canal seg- ment be includcd in the pri- mary irradiation zone but be later protected a t the cord toler- ance of dosngc.

T h e problems are: (1) Pancoast’s syndrome requires high radiation dosage for control; (2) estracliiral spinal extension is a known route of spread, but the dose for primary tumor control is above the tolerance of the spinal cord (Fig. 3C). A way of the “dilemma” may be to include routinely the spinal canal in the initial treatment zone, but to pro- tect the cord later in the course at its toler- ance level; such reduced dosage might be sufficient for “prophylactic” irradiation of small tumor foci. This example brings into focus the considerations which at present de- fine many aspects of clinical radiotherapy.

I t emphasizes that curative treatment re- quires a careful clinical appraisal of all the relevant features in each individual patient. This is a continuing process-the state of both tumor and host reaction may change appreci- ably during the period of treatment, and there is no alternative to continuous clinical obser- vation using all the ancillary aids available. From the investigational point of view, exami- nation of the clinical features determining curative tumor dose also emphasizes the need for continued research into the action of radiation on the somatic elements of what Mitchell4 has so aptly termed that dynamic system of tumor, interwok en normal tissues and the patient as a whoIe.

REFERENCES

1. Asscher, A. W., and Anson, S. G.: Lancet 2: F . Paterson, R.: The Treatment of Malignant Dis- ease by Radium and X-rays. London, E. .4rnold & Co., 1948; pp. 171, 479. 2. Deelcy, T. J.: Cliia. Radiol. 17:?99, 1966.

3. Jones, A., and Wedgwood, J.: Brit. J . Radiol. 31:

4. Mitchell, J. S.: Studies in Radiotherapeutics. Ox-

1343, 1962.

7. - : O p . cit., 2nd ed., 1963; p. 44. 8. - : Brit . J . Radiol. 25:505, 1352.

9. West, J. B.: Postgrad. M e d . J . 44:120, 1968.

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ford. Blackwell Scientific Publications. 1960: D. 3. , I

5. Morrison, R., and Deeley, T. J.: Clin. Radiol. 10. - , and Dollcry, C. T.: J . AfJpl. Physiol. 13:145, 1962. 15:405, 1960.