The treatment of osteogenic sarcoma by irradiation

THE TREATMENT OF OSTEOGENIC SARCOMA BY IRRADIATION BRADLEY L. COLEY, M.D., F.A.C.S. NEW YORK OR purposes of comparison of rest&s of treatment of osteogenic sarcoma by various methods we have studied the records of a11 (200) cases treated during the decade from January I, 1923 to January I, 1933 at MemoriaI HospitaI. This paper is concerned with an anaIysis of those cases, 70 in number, treated by irradiation without amputation. This Iist of cases is unseIected and incIudes a11 cases thus treated.

F

DIAGNOSIS

The diagnosis was made by surgica1 biopsy in 21 cases, by autopsy in 5, by aspiration in 8, by punch in 5, and by cIinica1 and characteristic radiographic appearance in 3 I. The histoIogica1 evidence is present, therefore, in 3g of the 70 cases. In 24 of the cases the diagnosis has been confirmed by registration in the Bone Sarcoma Registry. SEX AND

PuImonary metastases were present in 6 cases at the time of first admission and were treated by irradiation in 2 cases, with no effect in one and sIight reIief in the other. Metastases to the Iungs were noted Iater in 25 other cases, the average interva1 being nine months. Eight of these were treated; 6 with no effect and 2 with sIight temporary reIief. Nine cases deveIoped metastases other than in the Iungs. OF LIFE

It has been considered of interest to Iist the surviva1 periods in three separate coIumns; from time of first symptoms, from time of admission to the Bone CIinic, and from time when metastasis was first noted. These periods are recorded for the operabIe and for the inoperabIe cases separateIy. The average duration of Iife is seen to be sIightIy longer in the operabIe than in the inoperabIe cases, despite the fact that the Iongest surviva1 occurred in an inoperabIe case (skuI1).

AGE

OF SYMPTOMS

The shortest was five days; the Iongest four years; the average 5.7 months prior to admission to the cIinic. BONE

METASTASES

DURATION

There were 46 maIes and 24 femaIes. The youngest patient was three years; the oIdest seventy years; the average 32.7 years. There were more than twice as many cases in the second than in any other decade. DURATION

the fibula twice, both operabIe; the OS caIcis once, operabIe. The remaining bones invoIved, aIways inoperabIe were: iIium g, scapuIa 7, rib 2, and cIavicIe, skuI1, ischium, mediastinum, sternum, once each.

CAUSES

OF DEATH

In 48 of the 70 cases the cause of death is stated in the records. In the remainder, it is not known with certainty. PuImonary metastases caused death in 31 cases, whiIe in g it was ascribed to metastases eIsewhere. Of the remaining 8 cases, 5 succumbed to hemorrhage, uIceration of the

INVOLVED

The femur was invoIved in 26 cases: 14 operabIe, 12 inoperabIe; the humerus I I operabIe, I inoperabIe; the 12 times: tibia 6 times: 5 operabIe, I inoperabIe; 43

44

CoIey-Irradiation

American Journal of Surgery

care taken to avoid overIapping of the fieIds. A simiIar method can be used with the radium eIement pack (4 gm.), but we are uncertain as to its superiority to high voItage roentgen ray and it possesses a serious economic disadvantage. We have not had much opportunity to use super voItage (700 kv.) on bone tumors and, during the period covered by this study,

tumor or infection; operation done eIsewhere, hemipIegia and parathyroid tetany each accounted for one death. METHODS

OF

JANUARY. rg3~

IRRADIATION

During the decade covered by this report no singIe standardized technique of irradiation was used. Even at present T.&E DURATION

I OF

LIFE

Shortest

Average

Longest

I

I

I

I

I

I

I

OP.

Inop.

OP.

Inop.

3 mos. 3 mos. 1 mo.

4 mos. 2 mos. 1 mo.

56 mos. 30 mos. 29 mos.

98 mos.

20.8

95 mos. 11 mos.

16. I

I From Istsymptom .................... From admission. ...................... From appearance of metastasis.

........

there is no uniformity of opinion as to the best method of treating these cases. Both radium pack and roentgen ray were used extensiveIy, aIone or combined. InterstitiaI irradiation was empIoyed in onIy one case. There are few cases where its use seems advisabIe. We have cIassified the cases into three groups as regards technique of administration i.e., those receiving a massive dose, of which there were 24; those receiving fractiona1 doses either by roentgen ray or radium pack, of which there were 25 ; and finaIIy a series of 21 cases comprising an uncIassified group where the treatments were given by a wide variety of methods, conforming neither to the massive nor fractiona dose method. It may be stated that as our more recent experience with fractiona dose method has accumuIated we feel it is superior to other methods commonIy in use. By the term “ fractiona dose method ” we mean the giving of smaI1 daiIy doses of 300 r units through a number of portaIs in rotation unti1 approximateIy 3000 r units have been deIivered through each porta1. With such Iarge doses, however, the size of the portaIs must be restricted and great

Inop.

OP.

I g.

mos. mos. mos.

16.2 mos. mos. 3.9 mos.

11.2

onIy 2 cases received such treatment. It is entireIy conceivabIe that by the use of this type of irradiation therapy we may be abIe to improve upon the resuIts hitherto obtained. LIVING

PATIENTS

There are 6 of the 70 patients stiI1 aIive. One of these has radiographic evidence of puImonary metastasis; the remaining 5 are apparentIy free of active disease, but onIy one of these has survived more than five years. It is of interest to note that 4 of these 6 cases are fibrosarcomas ; 2 meduIIary, and 2 periostea1. Another apparentIy represents a primary osteitis fibrosa cystica with secondary deveIopment of an osteogenic sarcoma. In the remaining case, which from radiographic appearance onIy was a scIerosing osteogenic sarcoma, the patient is we11 two and one-fourth years after treatment, but without microscopic confirmation. Toxin treatment was used in 2 of the 6 Iiving patients; it was also used in 24 of the 64 patients known to be dead. Three of the 6 cases of Iiving patients are registered.

NEW SERIES VOL. XXVII,

CAUSES

OF

CoIey-Irradiation

No. I

FAILURE

OF

TREATMENT

ALL

SHOWING

FAVORABLE

CASES

JANUARY

The causes of faiIure of irradiation therapy may be either progress of the IocaI Iesion or puImonary or other metastases or a combination of these causes. Progress of the primary Iesion may occur after an initial response marked by cIinica1, symptomatic and radiographic evidence of improvement; or it may be steadiIy progressive without noticeabIe effect from the treatment; or there may be a Iate reactivation of the process after it has seemed cured or apparentIy quiescent. PuImonary metastases may have antedated irradiation therapy or have occurred during or after treatment. Once metastases have occurred, they may occasionaIIy be heId in check for a time by intensive irradiation, but actua1 cases are few where such restraint has been striking. In most cases IittIe is accompIished and the patient is frequently made more uncomfortable. In some instances where the histoIogica1 sections of the primary tumor showed characteristics that justified the pathoIogist to report radiosensitivity, the puImonary metastases have proved rather responsive to irradiation. RESPONSE

TO

IRRADIATION

We have observed three types of osteogenic sarcoma which have shown favorabIe response to irradiation. a. The highIy ceIIuIar osteogenic sarcoma in young patients, especiaIIy those in which the histoIogic appearance cIoseIy resembIes endothehoma. These have been termed smaI1 round ceII osteogenic sarcoma. Their radiographic appearance may cIosely simuIate endotheIioma. SeveraI such cases have shown remarkabIe improvement and regression under irradiation therapy. b. The periostea1 osteogenic sarcoma with IittIe or no evidence of bone destruction or production, particuIarIy when the primary tumor is smaI1, has responded

Journal

of Surgery

43

TABLE II OSTEOGENIC SARCOMA

BY

IRRADIATION

TYPES

American

TREATED

BY

‘923

I,

IRRADIATION

TO

Total: Operable: Inoperable:

JANUARY

FROM

I,

1933

71 cases. 34 cases.

by Location 13 cases. by Condition 24 cases. Male: 46 cases. Female: 25 cases. Age: Youngest 3 years. Eldest 70 years. Average 32.2 years. Decades ~-IO..................... II-20..................... 2x-30..................... 3x-40..................... 41-50..................... 51-60..................... 61-70..................... Diagnosis by Autopsy........................ Biopsy.......................... Aspiration. Punch.. X-ray..........................

4 22 10 IO 14 7 4 Registered 4

5

IO

21

.

9

I

5

2

31

Total.........................

-

71

7

24

Duration of Symptoms: Shortest 5 days. Longest 4 years. Average 5.7 months. Duration of LiJe in Montbs: Average

--

From I st symptom From admission, From metastasis.

OP.

Inop. Op.

--

__-

-I

3 3

.

4 2 I

I i

Inop

Op.

Inop.

__56 50 29

20.8 16.1

16.2 11.2

9.

3.9

-

Bone Involved: Operable Humerus .... 12 14 Femur. ..... 5 Tibia ....... 2 FibuIa ...... I CaIcaneus ...

Condition Scapula. ..... CIavicIe. .... Humerus. ... Femur. ...... Tibia. ....... Rib .........

InoperabIe Location I 7 SkuII. ........ I Mediastinum .. I 1 1 Sternum ...... 9 12 IIium. ........ I I Ischium. ..... 2

Metastases: On admission.. . . (2 treated; I no e&ct; I sIight reIief) Lungs i Later (Av. int.--9 mos.). . .. (8 treated; 6 no effect; 2 slight relief) 1 Other than Iungs..

6 25 9

Cause of Deatb: PuImonary metastases Other metastases.. Hemorrhage.

UIceration

31 9 2 2

Infection.. Operation.. . . Parathyroid tetany. Hemiplegia. .‘.

. 1 . I . I I

46

American

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CoIey-Irradiation TABLE II (Continued)

TABLE II (Co&rued) I.

E$ects of Treatment:

E&3s of Zrradiatiofl:

-

A. Znoperable Cases ..... ., ................... EarIy Effects: I. Subjective: ReIief of pain. ........................ 2. Objective: Improved function ..................... Decrease in size of tumor. .............. Radiographic decrease in size. ........... Radiographic regeneration, etc. ......... Late Effects: ........................ I. Tumorreceded 2. Tumor remained stationary ............. 3. Tumor continued to grow ............... 4. Later growth of tumor after (a) Apparent cure ..................... (6) EarIy recession. ................... (c) Stationary period. ................. B. Operable Cases ........................... EarIy Effects: I. Subjective: Relief of pain. ........................ 2. Objective: Improved function. .................... Decrease in size of tumor. .............. Radiographic decrease in size. ........... Radiographic regeneration, etc. ......... Late Effects: I. Tumorreceded........................ 2. Tumor remained stationary.. 3. Tumor continued. . . . . . 4. Later growth of tumor after (a) Apparent cure.. . . (b) Early recession. .. (c) Stationary period.. . . . . . . . . . . . . .

37

25 17 17 3 5 3 2 22 I

I

.

34 I 33 20 16 I

15 I

24

. .

9 7 2

. 17 . 7 . IO . 21 13 8

I

inop

7

8

8..

I

I

8

OP

.. I

zoo kv. & Pack and Interstitial inop

I

-----x 36226

OP

-----136316 == 3 8 23 15 3 16 -----3 9 25 5 19 12 5 1748201338

Pack 20

inop OP

o 7 3

1

6

.33312 ------

kv. & Pack

Totals

. IO . 14 . 26 ..

I 511 ------

inop

15

I

------

kv.

33

I....

-----_ . I.... I -----a 2 12IO . .

inop OP

zoo

12

--

----__

OP

.

-

------

inop

kv. & Pack I

ig

Technique:

.

,oo

xm

Used:

.

kv. I

I

A. High VoItage X-ray ...................... (a) 7ooKv .............................. (b) 2ooKv .............................. Radium Pack ............................ :: X-ray and Pack. ......................... ................... (a) 7ooKv.andPack.. .................... (b) 2ooKv.andPack D. X-ray and Pack and InterstitiaI Irradiation.

A. Massive Dose. . (a) InoperabIe.. (6) OperabIe. . B. Fractional Dose.. I. X-ray.. . (a) InoperabIe. (b) OperabIe 2. Radium Pack. (a) InoperabIe. (b) Operable. C. Unclassified.. (a) InoperabIe. (6) OperabIe..

,oo

34

g

Regeneration

----__ OF

8

16 14 3 15

Size Decrease

t-0+-0

OP

NOTE: Two cases omitted; one patient died of tetany after biopsy and the other died folIowing operation performed later in ItaIy. 2. Metbods of Irradiation

Clinical

inop Total..

.

+ = improvement = no effect or improvement o = no record of effect

we11 to combined externa1 and interstitia1 irradiation. Some of these cases may cIoseIy simuIate neurogenic sarcoma cIinicaIIy, radiographicaIIy and even histoIogicaIIy. c. MeduIIary osteogenic fibrosarcoma has seemed to us a Iesion of Iow grade maIignancy without the tendency to earIy metastasis or rapid IocaI progress and hence a form of tumor justifying conservative measures. In one such case the patient is aIive and we11 four and three-fourth years. SUMMARY

Seventy patients with osteogenic sarcoma have been treated by irradiation. Of these, 64 are dead. Of the 6 patients known to be aIive, 4 have fibrosarcomas; one a sarcoma deveIoping on an oId

NEW SERIES VOL.. XXVII.

No. I

CoIey-Irradiation

osteitis fibrosa cystica. The remaining case is by radiographic appearance a scIerosing osteogenic sarcoma, but it Iacks histoIogic confirmation. Of the 6 patients, onIy one has survived more than five years. At present we fee1 that irradiation shouId be offered in preference to amputation 0nIy: I. When of doubtfu1 operability. 2. When the histologic picture suggests definite radiosensitivity. 3. When a smaI1 periostea1 Iesion affords opportunity for combined externa1 and interstitia1 irradiation. 4. In meduIIary osteogenic fibrosarcomas of Iow malignancy. AI1 inoperabIe cases and those in which amputation is refused shouId receive thorough, weII-pIanned irradiation. If improvement is noted, it shouId be an indication for further use of irradiation up to Iimits of skin toIerance. At present we favor proionged treatment by the fractiona1 dose method. With few exceptions our resuIts in the treatment of puImonary metastases have not been encouraging. DISCUSSION

DR. E. A. CODMAN: This paper represents the work of this CIinic for quite a number of years with a carefuI anaIysis of the cases, and ahhough it is a negative paper it is a great contribution to the study of bone sarcoma. Radiation, according to the resuIts which Dr. BradIey CoIey has given us, has had a fair tria1. Dr. Ewing has overseen this work and perhaps he wiI1 be wiIIing to teI1 us his impression of the resuIts. DR. EWING:You have given me this opportunity to express a discordant note. I take an entireIy different point of view. I remember that when the first few patients with tongue cancer were treated by superficia1 radiation we were thriIIed by seeing the regression, the superficia1 heaIing, and the apparent cure of the disease; it then horrified us to see how there was a Iater recurrence and the patients died. Instead of giving up in despair we adopted other methods and said that cancer was a probIem that had to be soIved. Eighty-five per cent of the primary Iesions are cIinicaIIy cured. Now exactIy the

American

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of Surgery

47

same situation, in my opinion, hoIds true of bone tumors. This probIem has not been soIved. Radiation has had a fair tria1. It is a chaIIenge for new points of view, better seIection of cases. Therefore, whiIe I approve entireIy of everything Dr. BradIey CoIey has said, my point of view is quite different. DR. E. A. CODMAN: When Dr. Meyerding read of his cures, his cases probabIy have not been subjected to the fine tooth comb process which Dr. BradIey CoIey and Dr. Higinbotham have subjected theirs to; but stiI1, in the face of what we shouId Iike to have go forth from this meeting about the treatment of bone sarcomas to the genera1 practitioners in this country, we cannot heIp feeIing that the recommendation for amputation is much stronger than it is for radiation. DR. BRADLEY L. COLEY: Dr. Meyerding gave, I think, a sIightIy erroneous impression about my paper. It did not dea1 with preoperative irradiation, but rather with irradiation treatment aIone. I think irradiation has been shown not to have accompIished very much in this group of cases, and I share with Dr. Ewing the hope that our methods of irradiation treatment wiI1 improve in the future and that our seIection of cases wiI1 be better. Dr. Higinbotham can give you some figures on the amputation cases. A word about the pIace of toxin treatment in osteogenic sarcoma. I fee1 that the only rationaIe for using the toxins is foIIowing amputation with the hope that the deveIopment of minute puImonary metastases, which are existent but not demonstrabIe, may be prevented. I question whether every tumor ceI1 that reaches the Iungs Iives and deveIops a metastatic growth; and it may be that toxin treatment in this stage wiI1 upset the equilibrium of the ceI1 and render it non-viabIe. Toxins aIone or toxins combined with irradiation have not given resuIts that wouId warrant their routine use. I agree with Dr. Codman that a comparabIe series of amputated cases, treated both with and without toxins, shouId be compared from a standpoint of the five-year survivals in each group. In endotheIia1 myeIoma, however, the resuIts of treatment with the toxins are often striking and it is my beIief that toxin therapy should be used in conjunction with other methods of treatment (irradiation, amputation) in a11cases.