Radiation Oncology

Programs for the Present and Future

LUTHER W. BRADY. MD,' ARNOLD M. MARKOE, MD. ScD,t GLENN E. SHELINE, PHD. MD,+ NAGALINGAM SUNTHARALINGAM, P H D , ~ AND ROBERT M. SUTHERLAND, PHDI~

Radiation oncology in 1984 continues to make major advances in the multidisciplinary clinical programs. This has been possible by virtue of the radiation oncologist, who is an active participant in these clinical programs. The changing role for the radiation oncologist has dictated a greater participation in the primary management of the patient's disease process and also participation in multidisciplinary research programs.

Cancer 55:2037-2050, 1985.

n 1984 the Amencan Cancer Society estimated that I 870,000 new cases of invasive cancer would be diag- nosed along with 45,000 new cases of carcinoma in s i fu of the uterine cervix. 5000 new cases of carcinoma in situ of the female breast, and 400,000 new cases of nonmelanornatous skin cancer. This would account for 1.320.000 new cases of cancer in the US in 1984.' According to this estimate, 71% of those patients who have invasive cancer would present with disease appar- ently limited to the local region and 29% would have metastases at the time of initial presentation. Of those patients presenting with local regional disease, 56% would be cured of their disease process and 44% would develop recurrent cancer.

In the US, between 50 and 60% of all patients with invasive cancer have radiation therapy as the initial treatment with curative intent, for palliation, or as an adjuvant to surgery and chemotherapy. Approximately

175,000 patients will have recurrent or persistent disease and subsequent radiation therapy for that problem. Therefore, in 1984, about 6 15,000 will need radiation therapy services as a part of their treatment program. The magnitude of this problem will increase progressively as both the population and average age increases.

The results of radiation therapy have improved con- siderably in the last two decades by the wider availability of well-trained radiation oncologists, and by the avail- ability of cobalt 60 (60Co) teletherapy devices and higher energy photon beams from linear accelerators and be- tatrons, many of which are capable of producing electron beams for radiation therapy. These advances have re- sulted in dramatic improvement for cure for patients with Hodgkin's disease, cancers of the cervix, cancers of the endometrium, seminomas, cancers of the larynx, soft tissue sarcomas, efc2 (Table 1).

However, in 1984, radiation therapy remains an

Presented at the American Cancer Society National Conference: Radiation Oncology, Slrn Francisco. California. June 14- 16. 1984.

Supported by Grants Nos. CA 12252. CA 12478 and CCC 75355 by the National Cancer Institute, Department of Health and Human Services. by the Friends of the Radiation Oncology Research Center and by the Alpenn Foundation.

Hylda Cohn/Amencan Cancer Society Professor of Clinical On- cology. Hahnemann University. Philadelphia, Pennsylvania.

t Assistant Professor of Radiation Oncology, Hahnemann University. Philadelphia, Pennsylvania.

Professor of Radiation Oncology, University of California, San Francisco. California.

9: Professor of Radiation Therapy, Thomas Jefferson University. Philadelphia, Pennsylvania.

1) Professor of Radiation Biology and Biophysics. University of Rochester. Rochester. New York.

Address for reprints: Luther W. Brady, MD, Hahnemann University Department of Radiation Oncology and Nuclear Medicine, Mail Stop 200. Broad and Vine Streets, Philadelphia, PA 19102-1 192.

Accepted for publication January 28, 1985.

TABLE 1. Improved Percent of Survival of Several Types of Cancer When Treated With Megavoltage Radiotherapy

Representative

With Kv With hleV Type of cancer x-rays ( 1955) x-rays ( 1970)

Hodgkin's disease Cancer of the cervix Cancer of the prostate Cancer of the nasopharynx Cancer of the bladder Cancer of the ovary Retinoblastoma Seminoma of the testis Embryonal cancer of the testis Cancer of the tonsil

30-35 35-45 5-15

20-25 0-5

15-20 3 0 4 0

20-25 65-70

25-30

70-75 55-65 55-60 45-50 25-35 50-60 80-85 90-95 55-70 40-50

Reprinted with permission from Brady.'

2037

2038 CANCER Muy I Supplrrnenr 1985 VOl. 5 5

TABLE 2. Modification of Radiosensitivity

Increased yield of irreversible radiochemical lesions Oxygen Nitric oxide: organic nitroxides Metronidazole (“Flagyl”): nitrofurans; RO 7-058 High LET particulate radiations

Halogenated pyrimidine analogs (BUdR, K d R , JCdR) Possible potentiation of ECdR by tetrahydrouridine Purine starvation

Inhibition of repair Hyperthermia Chemical inhibitors of single-strand break repair (dactinomycin) High LET particulate radiations

Fractionated radiotherapy timed to mitotic delay Colchicine. vinca alkaloid mitotic spindle poisods

Increased intrinsic sensitivity of target DNA

Partial synchronization in cycle-dependent sensitive states

Differential radioprotection of normal tissues

Reprinted with permission from Brady.’ LET: linear energy transfer.

evolving specialty. It has developed a more effectively defined role in combined modality therapy. This has been associated with a better understanding and appli- cation of biologic and technical developments.2 These include techniques for better tumor localization through improved imaging, computerized treatment planning, the incorporation of computerized tomography infor- mation into treatment planning, and the greater use of radionuclide implants and electron beam therapy. The potential modifiers of radiosensitivity (Table 2 ) are more regularly being investigated as appropriate means for improving the potentials for clinical control of cancer using radiation therapy. Because of the steepness of the dose-response curve for most tumors, modest gains in the therapeutic ratio through dose localization or dose modification are leading to significantly improved local control rates. By virtue of having achieved this, it will be far more important to develop systemic agents that will be effective in eradicating occult metastatic disease using either chemotherapy, immunotherapy, or hor- monal therapy each alone or in combination.

Cancer Cure With Organ Preservation

There has been a resurgence of interest in the appli- cation of definitively administered radiation therapy as

TABLE 3. Cancer of the Breast: Primary Radiation Therapy

Stage 5-yr NED Local failure Distant metastases

I 92% 0 I1 14% 8%

5% 24%

NED no evidence of disease. Brady LW. Personal data. 1984.’

TABLE 4. Primary Radiation Therapy for Breast Cancer

5-yr results 10-yr results

Total Total

(%) survival (%) stage survival (%) (%) .

I 87 91 71 81 11 63 17 40 54

Total 73 83 47 65

Clinical Relapse-free survival Relapse-free survival

Reprinted with permission from Prosnitz el

a primary therapeutic modality as a means of preserving organs intact as compared to previously established techniques of management requiring organ removal. In discussing the potential for cancer cure with organ preservation we shall draw upon experience with breast carcinoma, prostatic carcinoma, and malignant intra- ocular choroidal melanoma for illustration. although other primary sites may also lend themselves to similar concepts of management. In the current practice, the primary treatment for patients with carcinoma of the breast involves multidisciplinary cooperation among surgeons, radiation oncologists, medical oncologists, pa- thologists, and diagnostic radiologists. The optimal use of radiotherapy in breast cancer management requires an understanding of the advantages and limitations of that modality when used alone or in combination with surgery and/or chemotherapy. Many years ago, radiation therapy was suggested as a means for curative manage- ment of breast cancer without necessity of a mastectomy by Keynes3 and Ba~lesse.~ The initial reports indicated that equivalently good survival statistics could be achieved by the utihation of definitively administered radiation therapy when compared with matched cases that had been treated by radical mastectomy. By 1983, more than 16,000 women had been treated definitively by radiation therapy following conservative surgery and the results published, with follow-up periods ranging from 5 to 40 The data apparently substantiate that this approach to treatment gives results that are essentially equivalent to those that can be achieved by radical mastectomy or modified radical mastectomy over the initial 5- and 10-year follow-up periods, that

TABLE 5 . Primary Radiation Therapy in Stage I Breast Cancer ~ ~~

5-yr No. of relapse-free Distant patients survival Local failure metastases

I660 I348 331324 48/323 (8 1.2%) (10.2%) (14.8%)

Reprinted with permission from Brady and Bedwinek.’

No. 9 PROGRESS IN RADIATION ONCOLOGY - BU2d.V Cf Ul . 2039

TABLE 6. Pnmary Radiation Therapy in Stage I1 Breast Cancer

5-yr No. of relapse-free Distant

patients survival Local failure metastases

940 667 8 11595 I14/595 (71%) ( 1 3.6%) (19.2%)

Reprinted with permission from Brady and Bedwinek.’

the breast is cosmetically similar to the normal breast in the majority of patients (more than 90%),24 and that if recurrence does occur, it is generally local and limited to the breast and can be managed by appropriate surgical technique: radical mastectomy or modified rad- ical mastectomy.

To be specific, Table 3 shows that 92% of women treated definitively by radiation therapy for Stage I breast cancer have no evidence of disease (NED) at 5 years after treatment and 74% of women with Stage I1 disease are NED after the same interval. Similar 5-year results are shown in Tables 4 through 9. Tables 4 and 8 through 1 1 also give 10-year follow-up information that show a decline in overall and relapse-free survival from 5-year follow-up information; this decline may continue for as long as 15 years after treatment (Table 9). However, there is clearly no difference between results obtained after definitive radiation therapy follow- ing conservative surgery or after radical or subradical surgery as shown in Tables 8 and 1 1 through 13.

The probability of local recurrence following conser- vative surgery and definitive radiation therapy is in the range of 0% to 14% (Tables 3. 5-7. and 10). with few series reporting higher Table 14 demonstrates that for patients having only locoregional failure in the absence of distant metastatic spread. salvage surgery may be quite successful and survivals at 10 years after primary treatment may approach that of women not having isolated locoregional recurrences. In fact. Mon- tague” has compiled a number of publications in which the survival after salvage surgery for recurrence limited to the treated breast is given in the range of 62% to 85% at 5 years for more than 200 such patients.

The use of definitively administered radiation therapy does not increase the risk of carcinogenesis in the

TABLE 7. Primary Radiation Therapy in Stage 1-11 Breast Cancer

5-yr No. of relapse-free Distant

patients survival Local failure metastases

3156 2492 13411 232 19311232 (79%) ( 10.9%) ( 15.6%)

Reprinted with permission from Brady and Bcdwinek.’

TABLE 8. Five-Year and 10-Year Disease-Free Survival Rates. 1955 through 1980

Radical or Conservation rnoditied radical

suaery mastectomy + irradiation alone -

5-yr 10-yr 5-yr 10-yr

Minimal breast cancer 97% 92% 97% 95% Stage I

TIN0 85% 78% 88% 80% Stage I1

78% 73% 77% 6.5% TIN1 TZNON I

Analysis March, 1983. No statistical significance between any group. Reprinted with permission from Montague.”

contralateral breast as has been substantiated by the data from Montague.” She showed that 30 to 576 (5.2%) of women treated by radical or modified radical mastec- tomy alone developed a malignancy in the second breast as compared with 6 of 3 16 ( 1.9%) of women treated by conservative surgery and irradiation.

It is well accepted that the carcinogenic potential following lowdose radiation appears, paradoxically, to be greater than that following the relatively large thera- peutic doses. Previous studies cited by Harris ef al.zs suggest that the risk of breast cancer is greatest for women exposed to radiation at ages 10 through 19 and decreases thereafter. No increased risk of contralateral breast cancer has been seen with conservative surgery and breast irradiation to date.26

Carcinoma of the prostate gland has, by tradition, been managed by radical prostatectomy, by hormonal manipulation using either estrogen administration or orchiectomy, or by no treatment at all. Table I5 shows the results of the American College of Surgeons National Survey of Prostate Cancer in the US. Clearly, about three fourths of all patients with Stage A through C disease were then receiving noncurative ‘treatment. Table 16 correlates staging of prostatic cancer with selective incidence. About 70%. of all patients presenting with carcinoma of the prostate gland would be candidates

TABLE 9. Cancer of the Breast: Results of Treatment

- Using Radiation Therapy

Survival NED TI. 2 NO TI. 2 NI No. of patients

5 Yr 90% 83% 768 10 yr 75% 71% 247 I5 yr 62% 58% 37

Reprinted with permission from Spitalier el d.” N E D no evidence of d i m .

2040 CANCER May I Sirpplcment 1985 Vol. 55

TABLE 10. Tumorectomy and Radiotherapy: Ten-Year Results

Locoregional Total survival No. of failures

Source patients (percent) Stage Percent

Montague19 21 I 6 1- 78 II- 60

Prosnitz er 01." 279 8 1- 81 II- 54

Calle er 0 1 . ~ I00 I6* I & 11 76 Spitalier e/ a/." 141 20 t I & 11s 81 Pierquin" 152§ 5 I- 80

7 II- 74

Nine patients are alive with no evidence of disease at 10 years after

t Seven-year results. $ Excludes seven patients lost to follow-up. § Eleven patients with no evidence of disease at 10 years after salvage

salvage surgery.

surgery.

TABLE 1 I . Comparison of Surgical and Radiotherapeutic Results at 10 Years

Surgery (Memorial Radiation therapy Hospita1)z' (Fondation Curie)"

No. of Alive No. of Alive Stage patients disease-free patients disease-free

TI. NO. N l a 66 59 (89%) 40 36 (90%) T2. NO. TI. T2 N l b 176 92 (52%) 129 69 (53%) T3. NO. T3. N l b 62 18 (29%) 89 27 (30%)

for definitively administered radiation therapy by inter- stitial implantation techniques or by the use of external beam radiation therapy (clinical stages A-C). Table 17 gives survival at 5-. lo-. and 15-year intervals following radical prostatectomy in a compilation of more than 700 patients. Table 18 shows similarly favorable 5-year survival figures for a compilation of more than 1300 patients treated by definitive radiation therapy. Table

TABLE 12. Three-year and 5-Year Survival of Patients Treated by Implanted Radium Needles (Interstitial Irradiation), With Survival

Rates for a Comparable Contemporary Surgical Series

No. of Group patients

At 3 yr I* 85 I l t 91

I l l $ 74 At 5 yr I* 75

I I t 66 I l l* 60

Net survival

(%)

83.5 51.2 31.4 71.4 29.3 23.6

Comparable surgical

series (%)

79.2 52.3

69.1 30.5

-

- ~~~ ~~ ~~

Disease apparently confined to breast. t Disease apparently confined to breast. $ Disease advanced or inoperable. Reprinted with permission from Keynes.'

TABLE 13. Actuarial 5-Year Survival* in Patients Treated With Halsted Radical Mastectomy or Quadrantectomy Followed by

Dcfinitive Radiation Theraov

Percentage of patients

Quadrantectomy and primary radiation

Halsted therapy

Overall survival 90.1 f 2.5 89.6 f 2.6 Disease-free survival

All patients 83.0 f 2.8 84.6 f 2.8 Patients with negative

Patients with positive nodes 89.9 f 2.4 86.5 f 2.98

lymph nodes 62.0 f 9.0 77.5 f 6.3

Mean f SEM. Reprinted with permission from Veronesi."'

19 shows the 5-year survival after interstitial implantation of the prostate gland. at least as good as for the surgical series at the same time interval after therapy. Longer- term information is not yet available in sufficient num- bers for statistical reliability.

Table 20 gives the relative complication rate associated with radical prostatectomy. external beam radiation therapy, or interstitial therapy. Clearly. the radical sur- gical procedure is associated with an increased risk of impotency and a somewhat increased chance for urinary dysfunction. Therefore, if the survival relationship for comparable stage disease, remains unaltered with in- creasing follow-up time. definitive radiotherapy offers a significant advantage in avoiding potentially embarrassing complications.

The outcome surveys of the Patterns of Care Study have provided useful information on the efficacy of therapy and complication rates. The data is shown for external beam radiation therapy in Table 2 1. Recurrence- free survival is, at 3 years of follow-up. obviously dependent on initial stage of disease. The major com- plication rate over all 617 patients is about 4% to 5%, certainly acceptable for major problems with cystitis. proctitis. and obstructive phenomena.

TABLE 14. Salvage Surgery: Survival With no Evidence of Disease at 10 Years After Primary Radiation Therapy . .

Salvage surgery for proven locoregional failure

Initial stage No. of patients Percent

TI-2 NO MO 21/26 80 TI-2 NI MO 23/44 52 T3 NO-I MO 1@/3 I 32

Kurtz JM. Personal communication."'

\ l l . ' I PROGRESS IN RADIATION ONCO1.OGY - Bradv el a/. 204 1

TABLE 1 5 . Cancer of the Prostate: American College of Surgeons Survey

~.

Stage A 1862 patients I I % curative radiation therapy 11% curative surgery 78% noncurative treatment

25% curative radiation therapy I 1 % curative surgery 64% noncurative treatment

26% curative radiation therapy

74% noncurative treatment

StaEe B 2122 patients

Stage C 1071 patients

0% curative surgery

Rcprintcd hy permission from Murphy ei a/.'"

In an eflort to preserve vision in the patient presenting with choroidal melanoma, there has emerged a treatment Icc.hnique using 6oCo plaques, 12'1 plaques, I9'Ir plaques, atid ruthenium 106 ('06Ru) plaques as a means to deliver adequate radiation therapy dosages to the volume of tumor involving the ~ h o r o i d . ~ ~ . ~ ' Fractionated proton Ixani treatment techniques as well as fractionated helium ion Lams techniques have been used in treatment of choroidal me lan~ma . '~ Results from this treatment have

TABLE 16. Carcinoma of the Prostate: Clinical Staging and Incidence ________

1967Il6 1977"' 1982"' . . ~ ~ _ ~ _ _ _ _ -

15% 5% 30.6%

4090 5090 17.8%

Sr;igc .A - I ncidental tinding < l o % 5% 20.8%

4l-twal r\ ?. -dl fTu.w

Siagc R-Contined to proslatc

H 1 -small. discrete ntdule

R2-large or multiple nodules or areas

Siagc ('-Localized to pcnprostatic area

( ' I -no involve- ment of seminal vrsicles. (70 grn

('?--involvement of srminal vesicles. .70 gni

Stage I)--Melastatic disease 3540-4096 40% 21.5%

I ) I -pelvic node metastases or ureteral obstruc- tion causing hvdronephrosis

I ).!--hone or distant lvrnph node nieIastaces. organ or snft tissue metastases

I !nknown - - 9.3%

TABLE 17. Cancer of the Prostate: Survival After Radical Prostatectomy -

Survival (9) - Type of No. of Source surgery patients 5-yr 10-yr IS-yr

Jewett e/ aL"' Perineal 103 74 50 35 Berlin ei a/."' Perineal I I6 81 57 39 Belt and

SchroederIM Perineal 185 78 5 5 31 Culp and

I62 - 72 54 Meyer"' Perineal Turner and

Belt"' Perineal 76 63 34 10 Kopecky e/

al. Retropuhic 1 3 73 50 - Hudson and

- Howland"' Retropubic 26 92 62

allowed for a major improvement in survival without disease and preserved useful vision for prolonged periods after treatment. Table 22 shows the percent reduction in tumor volume following 6oCo eye plaque therapy of patients having small, medium, or large choroidal mel- anomas. The tumors, on the average, stabilize at about 50% of their pretreatment thickness. Table 23 shows a 97% survival for these patients, most of whom have been followed for longer than 3.5 years. Figure 1 presents a Cox proportional hazards prediction of survival of patients treated for choroidal melanoma by enucleation or by radioactive eyeplaque therapy, the populations normalized with respect to basal diameter and intraocular tumor location. the two most important individual predictive variables. Clearly, 5-year survivals are equiv- alent. Figure 2 shows the decay in useful vision among

TABLE 18. Cancer of the Prostate: Survival After Definitive Radiation Therapy

Results

5-yr No. of Local actuarial

Source patients Stage control survival

Hussey"' I70 B 100% 100% C I 91% 61% c 2 69% 44%

Ray and 430 B 5-yr 71% Bagshaw'16 10-yr 45%

C 5-yr 41% 10-yr 31%

Rangala 128 A 88% I 00% e/ a/."' B 76% 90%

C 76% 78%

Brady 92 A 100% ei al.Iz8 B 83%

C 70%

2042 CANCER A l a y I S i r p p l ~ w i ~ w r 1985 Vol. 5 5

TABLE 19. Cancer of the Prostate: Survival After Interstitial Implantation

5-yr survival No. of

Source patients Stage Overall NED

Hilaris 208 B 86% ri a/.”’ C 70%

Guernero 215 A2 98‘7” 81% n a/.’” B 85% 5 9 6

CI 867~ 64%

Brady 151 A2 I008

Scardino 232 A2 97% 387, el d“’ BI loo? 71%

B2 8 17, 59% CI 867r 46%

el a/ I Z R B 8070

NED: no evidence of disease.

TABLE 20. Complication Rate Associated With DitFerent Modalities of Treatment for Prostatic Cancer

Percent Percent urinary impotence dysfunction

Radical 100% 10%-20‘h dysfunction

External beam 239-479 6%-I 7 7 ~ dysfunction

1’” seeds 71. 12% transient

proslakctom y

radiation with X% incontinence

disturbances. with 3 8 incontinence

Reprinted with permission from Fowler PI ul.’”

the plaqued patients. Although. on the average. vision does slowly deteriorate in the treated eye. this is to be contrasted with the complete and immediate loss of vision in an enucleated eye. Similar results as for eye- plaque therapy are found following helium ion beam external radiotherapy (Table 24) or proton beam external radiotherapy (Table 2 5 ) .

There continues to be major emphasis on the devel- opment of definitively administered radiation therapy alone or after conservative surgery in order to preserve organ function or cosmesis. Many primary tumor sites

TABLE 21. Patterns of Care Study: Outcome Surveys. Carcinoma of the Prostate Definitive External Beam Radiation Therapy Actuanal Analysis of Free of Recurrence and Maior Comolications at 3 Years

No. of Recurrence- Major Staae wtients free cornolications

A 56 85% B 293 7 7 1 C 268 594,

9% 2% 6%

Reprinted with permission from Kramer d a/ . ’33 1982 data.

TABLE 22. Pretreatment and Posttreatment Tumor Dimensions for 100 Posterior Uveal Melanomas Managed by

Cobalt Plaque Radiotherapy

Tumor Pretreatment Posttreatment 46 reduction size mean tumor mean tumor in tumor

category No. dimensions* dimensions* volume

Small 7 7.6 X 6.6 X 2.3 7.1 X 6.1 X 1.0 62.5

Medium 41 9.6 X 8.0 X 4.2 9.4 X 7.8 X 2.7 38.6

Large 52 11.8 X 10.2 X 7.3 10.5 X 9.1 X 4.4 52.0

(115.4 mm’) (43.3 mm’)

(322.6 mm’) (198.0 mm’)

(878.6 mm’) (420.4 mm’)

Base dimensions X thickness in millimeters. Reprinted with permission from Brady cI

may lend themselves to this approach. such as the larynx, the tongue. the tonsils, and the anus.

Diagnostic Oncologic Imaging

Improvements in imaging technology in the last decade have enhanced the ability of the oncologist to diagnose, stage, and evaluate the response of tumors before, during. and after treatment.29 Treatment planning using ad- vanced imaging techniques allows the radiation therapy program to be designed with more confidence.

Magnetic resonance imaging promises to permit dif- ferentiation betwcen normal and tumor tissue by in vivo spectroscopy. metabolic analysis, and tissue character- ization using imaging and paramagnetic compound^.^^.^' Improved spatial resolution over computed tomography imaging may be accomplished by magnetic resonance imaging because of reduced artifacts from surrounding bone. particularly in patients with head and neck cancer.

New opportunities exist for tumor markers or dis- criminators that would allow for earlier detection or for more accurate staging. Monoclonal antibodies promise to open new vistas not only in terms of tumor detection and screening of patients who arc at high risk for the development of cancer but also offer excellent opportu- nities for application to treatment.”

TABLE 23. Mortality Data on 100 Patients With Posterior Uveal Melanoma Managed by Cobalt Plaque Radiotherapy

Mean interval Death Death from plaque from from application to

Tumor size Metastatic all metastatic melanoma category No. melanoma causes melanoma death

Small 7 0 0 0 - Medium 41 1 2 I (2.4%) 14.0 m o Large 52 2 3 2 (3.8%) 9.7 mo

Total I 0 0 3 5 3

Reprinted with permission from Brady el a/.2’

No. 9

1 8 0 E R 90

8 8

N 7 0 T

6 0

5 0 U R 4 8 " 30 I v 2 8

L A 1 8 --

PROGRESS IN RADIATION ONCOLOGY - BrUd?: el a/. 2043

0 Q

8 9 Q

x x ENUCLERTION

o o Co-68 PLAOUE

1 2 3 4 s I > - - Y E A R S -- >

FIG. I . Cox proportional hazards prediction of survival for patients with choroidal melanoma treated by enucleation (N = 137) or by radiorohalt eyeplaque therapy ( N = 97).'"

Digital technology allows for enhanced radiographic image production and interpretation. This would allow for better definition of the true extent of the tu~nor . '~ .~ ' Improved tunior delineation is imperative for support of high precision radiotherapy. These advances obtained through clinical trials are comparing the efficacy and accuracy of existing and proposed technologies.

Predictive Assays of Tumor Radiocurability

From experience accumulated since the discovery of x-rays, radiation oncologists have determined empirically that certain classes of malignancy are more amenable than others to cure using ionizing radiation^.^^ Such experience formed the basis for the earlier traditional classification of tumors as radiosensitive (seminoma and lymphoma). moderately radiosensitive (squamous cell

I . I I T H CI3-t;D PLCIPIJES

GJ ... . . . I .......I .... ...+ .... ...t ...... I... .... t ........ I ......... I ........ t ....... I ..... ..+ .... . . .I . 8 1 2 'j 4 5 6 7 8 9 l W l l l 2

INTERVAL

..f FIG. 2. Decay of visual acuity in 100 patients with choroidal

melanoma treated by radiocobalt plaque therapy. The x-axis is given in successive intervals of 6 months each; the y-axis is the "survival" of useful vision (better than 20/200 corrected)."'

TABLE 24. Local Control in Patients With Choroidal Melanoma

- Treated With Helium Ion Beam

Dose

70 GyEq 80 GyEq

No. of patients 20 5 5 Local failure 4 I Mean follow-up (mo) 30 14

All failures salvaged and with no evidence of disease. Analysis done 1983. Reprinted with permission from Brady er a/."

carcinomas and adenocarcinomas), and radioresistant (sarcomas and melanomas). Within each histologic type and grade, numerous other factors affect radiocurability. These include most notably the tumor size. site of origin. gross morphologic pattern. and potential pattern of spread. However, the goal of predicting radiocurability in individual patients has remained elusive. The ability to accomplish this would not only aid in selecting the appropriate treatment for an individual but would permit testing and application of new treatment strategies to proceed in a rational way. Currently, various tests are being used or are being investigated to predict tumor response: ( I ) in vim or xenograft assays of cellular radiosensitivity: (2) morphologic or biochemical estimates of radiation cell survival and/or repair capability: (3) assessment of tumor oxygenation, (4) measurement of tumor cell kinetics. karyotypes. and ploidy: and ( 5 ) quantitative estimates of tumor cell markers.34

These techniques are being applied in human tumors in prospective clinical trials and in the basic laboratory programs to refine and validate these technologies. After experimental validation of these new techniques. it will be necessary to compare the relative utility of the different assays for different purposes and to weigh the value of each assay against other known prognostic

TABLE 25. Status of Patients From 6 to 89 Months After Proton Beam Therapy of Choroidal Melanoma

Mean NO. of fOllOW-Up Local Distant

patients (mo) Tumor size. control Uncertain metastasis

7 29 Small 7 0 0

65 27 Medium 64 0 I

83 19 Large 81 2 5

13 Extra-large 13 0 1

1 0 x 2

10-15 X 2-5

15 X 5-10

20 x 10

Base diameter X thickness in millimeters. Analysis done March, 1983. Reprinted with permission from Brady el ~ 1 . ~ '

2044 CANCER M N ~ I Sirpplmwnt 1985 VOl . 5 5

TABLE 26. Processes to be Exploited in Maximizing Killing of Tumor Cells

Moditication of initial radiation damage Exploitation by one mndality of cell synchrony induced by another

Reoxygenation after chemotherapy before irradiation Improved drug access after irradiation Reduction in tumor volume by irradiation leading to altered

Debulking of certain tumors by drugs. enabling the use of smaller

modality

proliferation kinetics and greater chemosensitivity of tumor cells

radiation field sizes and higher radiation doses

Reprinted by permission from Withers cr al.”

variables. From these clinical research efforts will emerge the ability to identify the causes of failure of conventional treatment and thus allow specific remedial

Tables 26 and 27 illustrate processes that may be expected to maximize tumor cell kill and improve upon tumor control. These processes enter into the discussions presented below.

Dose Fractionation and Volume Effects

Repair of sublethal and potentially lethal radiation injury, regeneration of surviving cells. and cell cycle recruitment and redistribution during treatment all con- tribute to the response of normal and malignant tissues to fractionated irradiati~n.~’ Clinical trials are currently underway to assess the value of hyperfractionation and/ or shortened overall treatment durations. The data thus far suggest that hyperfractionation offers not only an improvement in the potential for locoregional control but also a diminution in the degree of complication as a consequence of the treatment p r ~ g r a m . ~ ~ - ~ ’

The Radiation Therapy Oncology Group-a national cooperative clinical trial study group working with the National Cancer Institute-has many protocols for as- sessment of various dose fractionation techniques in- volving hyperfractionation, hypofractionation, and ac- celerated fra~tionation.~’

Sensitizers and Protectors

Tumors contain hypoxic cell populations, which limit the potential for tumor control using radiation therapy.43

TABLE 77. Therapeutic Strategies to Improve Tumor Control

Spatial cooperation. using radiation to eradicate local disease and chemotherapy to control metastatic foci

Toxicity independence: using chemotherapy with schedules that minimally enhance radiation-related normal tissue damage

Protection or minimization of toxic effects to normal tissues Enhancement of tumor response

Reprinted with permission from Peters d a/.u

Electron-affinic compounds selectively radiosensitize hypoxic cells and should lead to improvement in local disease control. Many such agents exist, but the agent misonidazole was the first to have been investigated in depth.44 However. the anticipated results from its use have not been realized. Neurotoxicity from the drug occurs at levels below those necessary to obtain adequate radiosensitization. A major effort toward development of more effective and less toxic radiosensitizers has resulted in an analog of misonidazole, SR- 2508.45 This compound is currently in Phase I clinical testing, and is considerably less toxic than misonidazole.

Other approaches to the problem of radiosensitization include the use of agents that deplete the indigenous nonprotein sulfhydryl glutathione from tumors and methods of eliminating or diminishing the undesirable neurotoxic effects of these drugs. Alteration of tumor blood flow. the use of high oxygen-carrying substances such as perfluoro chemicals, and artificial increases in hematocrit levels represent other methods of overcoming tumor h y p ~ x i a . ~ ~

Other means to achieve preferential radiosensitization of tumors compared with surrounding normal tissues is the use of prolonged infusion of pyrimidine analog radiosensitizers such as bromodeoxyuridine or iodo- d e o ~ y u r i d i n e . ~ ~ - ~ ~ The effect of these agents depends on a greater incorporation in the DNA of more rapidly dividing tumor cells than in that of the surrounding normal cells. Initial clinical testing is underway. Prelim- inary analysis indicates benefit from the utilization of these compounds with radiation

The use of radiation protectors that are selectively excluded from tumor cells is an area offering great promise both for radiotherapy as well as for chemother- a ~ y . ~ ’ Currently the agent WR-2721 is in process of Phase 1/11 clinical trial^.^*-^^ The distribution of the radioprotector in normal tissues allows for the delivery of larger radiation dosages to the tumor. with the expectation that greater control of the tumor could be achieved.

Combined Modalities

The combination of radiation therapy with other modalities such as cytotoxic drugs can provide an im- proved therapeutic strategy through the following: ( 1 ) spatial cooperation using radiation to eradicate local disease and cytotoxic drugs to treat metastatic foci: (2) toxicity independence. which requires the identification of chemotherapeutic agents and schedules of adminis- tration that minimally enhance radiation-induced normal tissue damage: and (3) protection of normal tissues for enhancement of tumor response by interaction of the

No. 9 PROGRESS I N RADIATION ONCOLOGY Brud.v et al. 2045

two modalities.6h Clinical protocols combining radiation with drugs (single or multiple) have produced some very encouraging result^."^'" However. little is known about the mechanism of such interactions, and little attention has been given to investigation of optimal sequencing or scheduling. For the short-term studies, the enhance- ment seems most likely to result from the interaction of modalities at the level of the molecular lesions. For the long-term studies, the enhancement appears to be related to cell proliferation kinetic changes and the redistribution of cell sensitivities according to age/response functions.66

Future research work in combined modalities should include the following: ( 1 ) mechanisms of interaction at the cellular and molecular level; (2) normal tissue damage and possible protection; (3) optimizing schedules and regimens: (4) development of appropriate cxperimental models: ( 5 ) significance of tumor cell subpopulations, especially proliferating and nonproliferating compart- ments; and (6) development of technologies to monitor noninvasive metabolic and cytotoxic effects of different therapiesb6

Radiation Therapy and Surgery

Information suggesting that, under certain circum- stances, a combination of radiation therapy and surgery may be superior to either modality alone has been available for many years. Combined therapy has achieved an important increase in local control for patients with carcinoma of the rectum" and endocervical carcinoma of the uterine cervix." The combination of conservative surgery and radiation therapy, designed to preserve anatomy and cosmesis and reduce local failure. has been successful in the treatment of early-stage cancer of the breasts3 and sarcomas of soft tissues in the extremities and torso.R4 Surgery with intraoperative electron beam therapy for locally advanced cancers of the rectosigmoid have produced major improvements in local control rates and strong indications of improved survival.85 However, randomized studies evaluating preoperative and postoperative radiation therapy have been performed for only a few tumor sites and situations. Further studies are needed to identify the situations in which a combi- nation of surgery and radiation therapy would be ben- eficial. Investigations should be initiated for adenocar- cinomas of the stomach. pancreas, and colon; non-oat cell carcinomas of the lung; and squamous cell carci- nomas of the esophagus. For each of these tumor types, the benefit of combined therapy should be determined as a function of stage, histologic type. and grade. as well as the types of surgical therapy. A comparison of the relative value of preoperative versus postoperative therapy should be undertaken only if an advantage has been

shown for one or the other in earlier studies. Likewise, evaluation of altered fractionation schemes should be performed only after preliminary studies have produced positive results. Where preoperative or postoperative treatments have shown benefit in certain head and neck, bladder, and rectal cancers, studies of more convenient regimens and potentially biologically superior strategies. such as multiple fractions per day, should be investigated.

The use of lesser surgical procedures combined with radiotherapy are in the process of being investigated. Under what circumstances will the survival rates be at least as good and the functional results improved com- pared with the more standard and utilized radical surgical procedures? Radical neck dissection vcrsiis limited radical neck dissection with radiation therapy offers one of the opportunities to do a more conservative surgical proce- dure with radiation therapy without compromising the outlook in terms of control. Another area would be evaluation of a sphincter-sparing surgical procedure plus radiation therapy vcrsus a more radical resection for carcinoma of the rectum and anus.

The growing interest in intraoperative radiotherapy requires that this modality be evaluated in a carefully organized fashion to be sure it represents a true advance over the less expensive and simpler implantation tech- niques. There are many institutions in the US at the moment that are proceeding with clinical investigations of intraoperative radiotherapy done with the tumor exposed and local radiation therapy delivered precisely to the tumor confines as identified at the surgical procedure.

Radionuclides for Systemic Oncotherapy

Radionuclides have been used therapeutically for spe- cific clinical situations such as treatment of thyroid cancer, polycythemia Vera, and tumors involving the serosal surfaces for many years. Radioactive colloidal compounds have been used as adjuvants to surgery arid chemotherapy, with emphasis on malignant tumors of the ovary. stomach, and colon. Numerous attempts have also been made to use intra-arterial and intravenously administered radionuclide therapy, primarily for lym- phomas and tumors within the A diverse variety of systemically infused monoclonal and poly- clonal radiolabeled antibodies have been demonstrated to target both primary malignancies and metastatic cancers.88 The science to determine the dose distribution, toxicity. and tumor response following the administration of systemic radioactive agents for therapeutic purposes is in the process of being developed." Dramatic results have been reported by Order d ul. in hepatomas and the lymphomas, particularly Hodgkin's d i s e a ~ e . ~ - ~ ~

2046 CANCER Majp I Siipplcjmcwt 1985 VOl. 5 5

TABLE 28. Effect of Adjuvant Hyperthermia on Response to Irradiation in Human Tumors

Percent of patients with complete response

No. of Source tumors

Radiation Radiation alone + heat

Arcangeli ef al.lY 39

Overgaard'% 22 U et 7

k m er 86 Bede el al.'" 24 Corry el 6

4790 8 5 4 14% 85% 37% 7 7% 33% 80% 090 9% 0% 40%

Total I86 31% 74%

Research in the use of radiolabeled monoclonal and polyclonal antibodies both for diagnostic scanning as well as for antibody therapy are currently being pursued actively with very dramatic results as a consequence of the use of these agents.

The current clinical experience in radiolabeled anti- body therapy has been accomplished through ongoing multi-institutional protocols in the treatment of hepa- toma and Hodgkin's disease. Similar programs need to be initiated and established in other major malignancies such as cancer of the breast, colon and rectum, prostate, bladder, and pancreas. Through its national cooperative clinical trial studies, the Radiation Therapy Oncology Group is pursuing investigations in this area.

Hyperthermia

The rationale for the use of hyperthermia in the treatment of cancer rests on its biologic effects: ( 1 ) heat kills cellsg: (2) cell killing by heat is relatively selective- radioresistant S-phase cell^^'.^*; (3) hypoxic cells are at

TABLE 29. Radiation Therapy for Immunosuppression and Marrow or Organ Transplantation

Total lymphoid irradiation Renal transplant Bone marrow transplantation Rheumatoid arthritis Refractory diabetic nephropathy Refractory lupus nephritis Heart transplantation Systemic lupus erythernatosus

Bone marrow transplantation Total body irradiation

Leukemia Lymphomas Congenital hematopoietic disorders Immunodeficiency syndromes Solid tumors with it predilection for marrow involvement

Reprinted with permission from Botnick el a/.''"

least as sensitive as euoxic cells: (4) nutritionally deprived acidotic cells are heat-sensitive: and ( 5 ) heat interacts synergistically with ionizing radiation and certain che- motherapeutic d r ~ g s . ~ ~ - ' ~ ' Table 28 gives a review of the results of clinical studies from multiple institutions. Clearly, adjuvant hyperthermia has efficacy in the treat- ment of cancer. When used alone, the effectiveness of hyperthermia is limited.lo2 Hyperthermia plus radiation therapy is far more effective than the same doses of radiation given alone. However, the doses of radiation that have been used in these studies were usually sub- optimal.

The Radiation Therapy Oncology Group and the National Cancer Institute contract group are currently pursuing clinical hyperthermia efforts to broaden the knowlege gained from laboratory research and from clinical trials. Welldesigned Phase 11 trials exploiting heating techniques are in process to set the stage for the appropriate Phase 111 clinical studies. The current studies are directed also toward the establishment of the best instrumentation for use in clinical trials and the devel- opment of reliable thermography techniques. Additional research is in process to develop a rationale for combining chemotherapeutic agents with hyperthermia. to investi- gate normal tissue damage (especially late effects), to explore thermal tolerance and temperature manipulation, to study the sequencing of hyperthermia with other modalities. and to evaluate the impact of environmental manipulations of vascular and metabolic properties of tumors.

Radiation Therapy for Immune Supression

Total body irradiation and total lymphoid irradiation are methods of using ionizing radiation to induce im- munosuppression. Table 29 shows the known and po- tential uses of immunosuppressive radiotherapy.

Total body irradiation has been used mainly in prep aration for bone marrow transplantation in patients with hematopoietic disease such as leukemia and aplastic

Total lymphoid irradiation is a form of partial body irradiation and may be of benefit in the treatment of autoimmune disease such as rheumatoid arthritis and in organ tran~plantation.'~'-' I I Although there have been numerous reports regarding the use of total body irradiation and total lymphoid irradiation, neither technique has been systematically evaluated for efficacy relative to other treatment modalities, normal tissue tolerances, optimal dose or timing, or for the best combination with chemotherapeutic agents. These studies are curiently underway.

Clinical investigation of the value of total lymphoid irradiation in rheumatoid arthritis and in systemic lupus

No. 9 PROGRESS IN RADIATION ONCOLOGY a &UdJJ et a/. 2047

erythematosus is in the process of evaluation as are other techniques to evaluate its application in other autoimmune disorders such as multiple sclerosis. Like- wise, the use of total lymphoid irradiation for cardiac”’ and renal transplantation’05*’” has been suggested and is in the process of being evaluated. These suggestions are based on evidence from laboratory investigations with animal models and characterization of these mech- anisms leading to transplantation tolerance in animals.

Conclusions

Radiation therapy has made major contributions to the improved quality of care for the cancer patient. This quality improvement has derived not only from a greater understanding of the natural history of the disease process but also from a more critical evaluation of the results of clinical treatment. Clinical radiation therapy now stands on a firm foundation of basic understanding of ionizing radiations and their effect on tissue and the biology of that effect in normal tissues and tumor. This explosive growth of knowledge relative to radiation therapy physics, clinical treatment planning, and utili- zation of computers in radiation oncology, as well as basic information in radiation biology and how it might be implemented in clinical situations, is well known. The data at this point illustrate how the major and important applications of basic physics and biologic data in clinical practice are beginning to significantly change the potential for long-term cure in cancer, with associated diminished potentials for complications. The implementation of research trials in general clinical practice offers major potential opportunities toward improving the expectation of cure for many cancers that were not cured in the past.

Continued clinical investigation is necessary to doc- ument the value of these new clinical techniques in cancer management. Major cooperation among various clinical centers allows for accession of the number of patients needed to unambiguously evaluate the efficacy of each of the techniques and to substantiate the conclu- sions indicated by the pilot study. This is a program carried out particularly through the aegis of the Radiation Therapy Oncology Group, where each institution has a sophisticated and innovative array of facilities, resources, and qualified personnel.

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