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Late results of treatment of cervical carcinoma with CO60 teletherapy and intrauterine radium
Late results of treatment of cervical carcinoma with C0 60 teletherapy and intrauterine radium JAMES F. NOLAN, M.D. Los Angeles, California
I N THE PAsT we have been interested in evaluating the efficacy of megavoltage radiation therapy in the management of carcinoma of the uterine cervix. Preliminary experiences have been reported on the use of conn teletherapy in combination with intracavitary radium."- 4 At the present time we are able to evaluate the late results in patients treated with this modality. A recent retrospective study 5 has been conducted which compared results of treatment of Stage I patients treated during the years 1950-1958, by this technique, with those treated in the previous 5 years by means of i-50 kv. x-rays plus radium. It was thought that late results in such patients would allow for an evaluation of the effectiveness of the external radiation phase of the treatment. In these two sf'ries of patients with early stages of the disease, the incidence of imperceptible pelvic node metastases should be essentially the same, and the local disease should be controllable largely by the intracavitary radium phase of the treatment. The study did reveal a superiority in results for those patients treated with megavoltage therapy. However, it was concluded that the superior physical features of the megavoltage radiation merely allowed for a more uniform technical application of external radiation. With this there was a decrease in the necessity for intense local
radiation. These factors made it possible to deliver a more balanced field of radiation to the local tumor and its fields of extension, which probably accounted for the improved results. The present report is designed to pursue the study further and to evaluate the late results in patients classified as Stage II and Stage III. In the latter group the disease is far advanced, and, although the over-all salvage is slight, the theoretic superiority of megavoltage therapy for the external radiation phase of treatment should be manifest. In the Stage II classification where there i' a wide variation in tumor volume, as well a' the greater incidence of imperceptible nodal metastases, the external radiation phase as well as the intracavitary phase of treatment are equally important. Materials of Stage Ill
For the purposes of this study the patients classified as having League of Nations Stag-e III carcinoma of the uterine cervix at the Los Angeles Tumor Institute were available. In the years 1949 to 1953, 32 such individuals were subjected to treatment by external radiation and intracavitary radium. In the years 1954 to 1958, 26 such patients were treated. The 58 patients in question were classified as to gross extent of the disease by a single examiner, and the incidence of this stage of disease was essentially the same in relation to the per cent of all sta~es of cervical cancer seen during the two periods 1Table I). It is interesting to note that in the earlier vears only one patient was incompletely
From The Los Angeles Tumor Institute. Presented at the Thirty-first Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Santa Barbara, California, Nov. 4-7, 1964.
684
Follow-up results with C0 60 and intrauterine radium
Volume 92 t\umber 5
685
Table I. Carcinoma of the uterine cervix (Stage III), yearly experience CQ6o
450 kv.
Stage III
All stages
%
Year
1949 1950 1951 1952 1953
7 4 6 6 9
43 34 28 42 34
16.3 11.8 21.4 14.3 26.5
1954 1955 1956 1957 1958
Total
32
181
17.7
Year
Table II. Carcinoma of the uterine cerv1x (Stage III), age groups Age group
450 kv.
CQ6o
0-40 +1-50 51-60 60+
3 5 9 10
1 4 11 6
treated, and in the later years 4 patients did not finish the outlined course. This discrepancy may represent a higher proportion of advanced cases who were subjected to palliative therapy only in the latter years. However, for the purposes of comparison of results, only those patients completing the outlined course will be considered in order to achieve a more realistic viewpoint of the value of treatment. It is also noted that in the last years of the early series, 4 individuals were treated primarily with C0 60 plus radium rather than with 450 kv. x-rays plus radium. This variation, too, may represent the use of the theoretically more potent modality in patients with more advanced lesions, but they will be counted in the subsequent comparisons. This, then, leaves 27 patients treated by means of 450 kv. x-rays plus radium, and 22 patients treated with C0 60 plus radium, for evaluation. Another method of evaluating these samples as to the possibility of bias is by comparing the ages of patients at the time of diagnoses. It was noted in the study of Stage I patients that earlier diagnosis brought about by the more general acceptance of the Papanicolaou smear in the later years
Stage III
All stages
%
6 5 5 5 5
35 33 3+ 31 25
17.2 15.2 1+.7 16.1 20.0
26
158
16.5
might be reflected by the inclusion of younger patients in the C0 60 series. This feature is probably not so important in these Stage III patients, since definite symptomatology is usually present in clinically advanced tumors. Consequently, when grouped according to decades, the age distribution of the patients in the two series is essentially the same (Table II). Results of Stage Ill
The results of treatment may be compared from three standpoints. The first may be upon the basis of the 5 year absolute success rate (Table III). This figure includes only those patients who have remained alive without evidence of residual or recurrent disease since the primary treatment. In the earlier 450 kv. plus radium series, only 7 (or 25.9 per cent) of the 27 patients completely treated are so categorized. In the later CO"" plus radium series, only 6 (or 27.2 per cent) of the 22 patients are considered successes at the end of 5 years. These percentage figures are quite low, and the difference between them cannot be considered significant. A second method of comparison is upon the basis of the 5 year absolute survival rate.
Table III. Carcinoma of the uterine cervix (Stage III), 5 year results Grouping Absolute success Absolute survival Actuarial survival
450 kv.
CO"o
25.9 44.4 46.7
27.2 31.8 31.8
686 Nolan
July I, l'l65 ,A:o.tn.
J. Obst.
& Gyii•~C.
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"I 70
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~ 60
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"' "'a.. 0 0::
30 20 10
0 +--+--+--+--+--+--+--+--+--+--+--+--+--·+-~4 0 3 2 4 5 6 7 8 9 10 II 12 13 14 15 YEARS
Fig. 1. Actuarial survival of Stage III carcinoma of the uterine cervix.
This includes those patients known to be surviving after 5 years at risk, despite secondary treatment for residual or recurrent disease. With this comparison, 12 (or 44.4 per cent) of the 27 patients in the early series remained alive 5 years after their primary treatment with 450 kv. x-rays and radium, whereas only 7 (or 31.8 per cent) of the 22 patients treated with C0 60 plus radium survived. There is a difference of some 12.6 per cent in favor of the earlier series. This difference can hardly be called significant by means of the usual mathematical tests, because of the small numbers of patients involved in the comparisons. However, it does indicate that secondary treatment, which was successful in increasing the longevity of 5 of the patients in the early series, may be of some importance. In the transitional years of 1952 to 1955, there was a tendency to re-treat primary orthovoltage failures with megavoltage therapy. In more recent years this has fallen into disfavor because the primary megavoltage therapy is usually carried to a high level of dosage in advanced cases, and the addition of further extensive therapy is prone to distressing complications. Perhaps re-treatment should again be considered within the limits of palliative intent. The third method of comparison is upon the basis of actuarial survival. This conven-
tion JS gammg popularity as a method of reporting cancer results. So-called ''life tables '' 1 arc constructed, which show the per cent of patients surviving in relation to the number actually at risk for each year of follow-up, which allows for the use of as much of the material as is available. When such curves are drawn for these two series in comparison, they are, again, similar, with a rapid fall-off in the first 3 years. After this time there is a small plateau for the 450 kv. group, which probably represents the success of the re-treated patients. There is then a slower diminution in this group similar in slope to the C0" 0 series, which wen' not re-treated. The actuarial survival rate at 5 years is 4.9 per cent higher in the early 450 kv. group than in the later CO'"' series. However, this difference again cannot be considered of significance (Fig. 1•. Comment on Stage Ill
The comparison of late results by all of these methods certainly does not show a favorable effect which may be attributable to megavoltage therapy. Admittedly, the series are small and do not adapt themselves to the conventional mathematical methods of comparison. At best, the results can only be considered as similarly poor. However, as in the case of the Stage I patients, we cannot attribute the ultimate results to the physical
Follow-up results with C0 60 and intrauterine radium
Volume 92 !'\umber 5
2J,000T
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1950
1951
1952
19114
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19511
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IH7
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Fig. 2. Treatment dosage levels of Stage III carcinoma of the uterine cervix.
characteristics of the radiations themselves, without considering the actual techniques used. In all of these patients the external radiation was used in conjunction with intracavitary or interstitial radium. The combined modalities may be expressed conventionally in terms of dose in roentgens and may be normalized to an average over-all treatment time of 6 weeks. When calculated doses to the lateral parametrium (Point B) are plotted, we may consider the ultimate results in relation to what was probably delivered to the anatomic periphery of these advanced tumors. These data are shown in Fig. 2. The calculated doses at Point B for 42 days treatment time are shown for each of these patients in relation to when they were treated throughout the years in question. All of the doses were fairly high for this region, according to the designed treatment plans. Successes and failures are designated. One can see that the few successes are randomly admixed among the failures in the entire group. In the later group the mean doses to the
lateral parametrium are about 1,000 r higher than those in the earlier patients. Certainly, megavoltage therapy allows for the delivery of theoretically "adequate" amounts of radiation to the large volume of tissue involved. However, it is probable that the total dose alone is not the ultimate deciding factor in clinical success or failure in the treatment of patients with advanced disease. In the follow-up of these patients it was noted that many of them failed by reason of distant metastases. This might indicate that the local treatment to the pelvis was sufficient to at least hold the disease in check for some time, or that imperceptible spread beyond the pelvis had occurred before treat_. ment and only became manifest at a later date. Of the patients known to have failed in the 450 kv. plus radium series in 9 years of follow-up, 13 were noted to have local recurrence or residual disease, and 5 showed distant spread only. In the C0 60 plus radium group, 5 showed local disease, and 10 failed because of distant metastases only in 6 years of follow-up.
688
.July I, 196:·,
Nolan
:\m.
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& Cynt•c.
Table IV. Carcinoma of the uterine cervix (Stage II), yearly experience 450 kv. Year
Stage II
All stages
%
1949 1950 1951 1952 1953
16 16 10 13
Total
63
43 3+ 2/l +2 3+ 181
37.2 47.1 35.7 3Ul 23.5 34.8
8
Complications of Stage Ill
One of the features associated with radiation therapy, which is of importance, is the occurrence of complications in the face of tumor control. When megavoltage therapy was first introduced it was feared that the "skin-sparing" feature would allow for the delivery of high doses which would exceed the tolerance of the deeper tissues. It was with this in mind that the first patients subjected to C0 60 teletherapy were treated very conservatively. The occurrence of complications of moderate or major nature were compared in the Stage III patients treated here. In the early 450 kv. plus radium patients there were 25 who exhibited no such complications attributable to their primary treatment. One patient developed a moderate hemorrhagic cystitis and another showed a moderate factitial proctitis. Both of these patients were treated conservatively without surgical interference. In the C0" 0 plus radium group, 19 showed no moderate or major complications. There was one patient who developed moderate cystitis, which was treated conservatively. However, there were 2 patients who developed severe proctitis. Both of these were subjected to colostomy, one temporary and one permanent. Of course, with advanced disease, many of the patients who fail develop fistulas and obstructions in the genitourinary and gastrointestinal organs. Complete long-term tumor control is rare in itself in these cases, so that complications due to treatment alone are hard to assess. However, even with this small experience, it would seem that severe complications are a definite risk of intensive radiation therapy.
I 1
1
'
1954 1955 1956 1957 1958
13 13 13 8 9
35
~3
37.1 39.1
38.2 3+ 31 21.8 25 · - - - - - 36.0 ·----
56
158
Table V. Carcinoma of the uterine cernx (Stage II), age groups
co•o
Age group
450 kv.
0-40 41- 50 51 - 60
5 17 19
8 It 19
60+
22
15
Materials for Stage II
When the Stage II patients are similarly studied, a more significant result should be expected because of the larger number of patients involved and the diversity of tumors in the classification. Table IV shows the distribution of the patients in this stage throughout the same years as before. Tht• total treated by 450 kv. plus radium numbered 63 between 1949 and 1953, and thf' total treated by CO"" plus radium numbered 56 in the years 1954 to 1958. Their per cent occurrence in relation to all patients treated was again quite similar. The age distribution of thesf' two groups was again quite similar except for the patients 61 years of age or over where it was less for the CO"" group. This, however, cannot be considered as indicative of a more favorable sample because this difference was small (Table V). Results of Stage II
The two series were then compared on the three bases of success of treatment as used before (Table VI). The 5 year absolute success rate was calculated at 71.5 per cent for the CO"" plus radium group, and 52.4 per cent for the 450 kv. plus radium group. The difference of 19.1 per cent in favor of the CO';" series was significant at the 3.4
Follow-up results with C0 60 and intrauterine radium
Volume 92 Number 5
689
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IL
20 10 0
2
0
3
4
5
6
7
8
9
10
II
12
13
14
15
YEARS
Fig. 3. Actuarial survival of Stage II carcinoma of the uterine cervix.
Table VI. Carcinoma of the uterine cerv1x (Stage II), 5 year results % Grouping
450 kv.
CQ6o
52.4
71.5 71.5 71.3
Absolute success Absolute survival Actuarial survival
55.6 56.9
per cent confidence level, which can be considered clinically significant. When the 5 year absolute survival rate is used, the per cent figure for the C0 60 group was again 71.5 per cent and the figure for the 450 kv. group raised to 55.6 per cent. This difference of 15.9 per cent in favor of the megavoltage series was calculated to be significant at the 7.2 per cent confidence level, which is above the usually accepted 5 per cent considered significant clinically. Again, when the 5 year actuarial survival rate is shown, the difference in favor of the C:0 60 series is above the 5 per cent level. The curves for actuarial survival when plotted show a more favorable curve for the CO"" series, but essentially the same slope as the earlier group (Fig. 3). Comment on Stage II
It is again necessary to consider these results in relation to the actual doses given before their true significance can be evalu-
ated. Using the same convention of dose in r, normalized to 42 treatment days and calculated both at Point A in the proximal parametrium and Point B in the distal parametrium, the data for each patient are plotted in Fig. 4. As in the case of both the Stage I and Stage III patients, the failures occur at all ranges of dosage, but there was a difference in the amount of radiation actually delivered during this collection of experience. In the previously reported data on the Stage I patients, it was noted that in the earlier years of 1949 to 1951, a greater reliance was placed upon the intracavitary radium phase of treatment than upon the external radiation phase with 450 kv. x-rays. This was reflected in high dosages to the proximal parametrium, which were sometimes associated with clinical failure. Because of this, the local radium treatments were made more uniform by the use of a fixed applicator, and the milligram-hour exposure was somewhat decreased. The effect of these changes can be seen also in the Stage II patients where, in the early years, the Point A doses were high, and in the years immediately before the C0 60 teletherapy became available, they were reduced. During this period, however, the Point B doses were kept at essentially the same level of about 3,500 r.
]ul} l. 1\lh:\ .\m. J. Oh;t, & Cynec
690 Nolan
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2000
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Fig. 4. Treatment dosage levels of Stage 11 carcinoma of the uterine cer;ix.
After the C0 60 apparatus came into use, essentially the same levels of radiation were delivered to both Points A and B in the parametrium, as had been used previously, in order to avoid complications from excessive dosage with this new technique. Early results were evaluated, and, in 1956, the dose of external radiation was arbitrarily raised by 1,000 r tumor dose, which moved the mean dose to the distal parametrium upward. The doses to the proximal parametrium were also increased in this fashion. There is more variation in the Point A dosage in the later years of the C0 60 series, which is attributable to the application of interstitial needles in the Stage liB cases where there is considerable bulky tumor residual in the parametrium after the preliminary external therapy. The Stage IIA lesions with only minimal parametrial extension or primarily vaginal involvement were treated in a fashion similar to the Stage I patients. It is probable that the superior physical characteristics of the megavoltage therapy allow for a greater degree of individualization of technique in the management of
patients in the Stage II group. When the extent of the tumor is minimal, as in Stage I patients, the field of radiation can be held to uniform levels and the dangers of local overdosage can be avoided. vVhen the tumor shows a large gross volume and involves the lateral parametria, levels of radiation can be raised in the areas at risk, but with the calculated risk of overdosage. If the superiority of the late results in the C0 130 series is attributable to the apparatus, it must be through the technique itself. This superiority in adaptability to the individual lesions being treated may be of significance. Complications of Stage II
Again, when complications are considered, the two series may be compared. In the +50 kv. x-ray plus radium group there were 56 patients who showed no major complications. Two patients developed moderate cystitis and 5 patients developed moderate factitial proctitis. All of these were treated conservatively. In the C0" 0 plus radium series, 51 patients showed no major complications. Two patients developed moderatf' cystitis and one developed moderate proc-
Volume 92 J\:umf)('r 5
Follow-up results with (0 60 and intrauterine radium 691
titis, which responded to conservative management. One patient developed severe proctitis, necessitating temporary colostomy. There was one individual who developed a severe late hemorrhagic cystitis, which did not respond to intensive urologic treatment and ultimately caused death. This patient showed no residual tumor but there was a markedly contracted bladder with ureteral scarring and contracture. As in the case of the Stage III patients, designation of true radiation complications with tumor control is difficult, but again it would seem that fears concerning the effects of overirradiation have some basis in fact.
If improved late results are to be attributed to the use of megavoltage rather than orthovoltage therapy, it must be through the adaptability of the apparatus to the clinical problems at hand. Certainly, miraculous cures cannot he expected in the management of far advanced lesions, as in Stage III patients. Nor can one expect perfect results in the treatment of early lesions. There must be features other than the dosage system applied, which may decide the ultimate outcome of therapy. However, the superior characteristics of megavoltage radiations make them a very useful modality within the limitations of our knowledge of the correct principles for the use of radiation therapy.
Comment Summary
A study of 5 year results, such as this, must have shortcomings from a statistical standpoint. Since this is a retrospective clinical evaluation, there are many uncontrollable variables which might affect the results other than the use of one generator or another for the external radiation phase of a combined treatment scheme. Radiation techniques were not applied in a fashion which would explore the limitations and therapeutic parameters of the modalities in question. Each patient was treated individually in relation to previous experiences. Although there is a natural evolution of technical changes in clinical practice, variations in technique were actually emphasized in the present series because several preliminary attempts were made to evaluate results earlier.
A study of patients with Stage II and Stage III carcinoma of the uterine cervix treated with COGo plus radium was carried out. The late results of treatment were compared to similar groups treated in the immediately previous years with 450 kv. x-rays plus radium. In general, the C0 60 plus radium series showed superior end results as in a similar study of Stage I patients. However> the techniques of treatment varied during the years of collection of the patient material. It was considered that the improved results were mediated through improved technical application of the therapy which, in turn, were attributable to some extent to the superior physical characteristics of the external radiation phase of the combined therapy.
REFERENCES 1. Greiss, F. C., Jr., Linton, E. B., Lock, F .. R., and Rhyne, A. L.: AM. J. OBsT. & GYNEC. 90: 703, 1964. 2. Lederman, M.: Brit. J. Radiol. 37: 745, 1964.
5. Nolan, J. F.: Radiation therapy for carcinoma of the cervix, Presented at Fifth National Cancer Conference, Philadelphia, September, 1964. In press.
3. Nolan, J. F., Vidal, AM.
J.
0BST.
J.
A., and Anson,
J.
& GYNEC. 72: 789, 1956.
H.:
4. Nolan, J. ·F., Emmett, J. W., and Anson, J. H.: Am. J. Roent., Rad. Ther., & Nuc. Med. 81: 111, 1959.
1407 South Hope Street Los Angeles, California 90015
692 Nolan
Discussion DR. HENRIKSEN, Los Angeles, California. The errors and weaknesses so common in many simiJar reports, based on the compilation of records or IB:M cards, arc missing, because each case has been examined, evaluated, treated, and followed by one individual. Thus, there is no discrepancy in diagnostic acumen, no differences in int crpretation, and no ambiguity of terminology. It was Confucius who so wisely recognized the dangers inherent in the study and interpretation of many cases, studied by many individuals, when he said, "if the bnguage is not correct, then what is said is not what is meant; if what is said is not what is meant tllC'n what has been done is undone." In other words, it is better not to make a so-called scientific contribution than to try to push the round figures of statistics into the rigid square holes of fact. I cannot disagree with the presented thesis that megavoltage radiation is superior to modalities of far lesser strength. Accruing evidence strongly supports the contention that the supervoltage roentgenotherapy is superior because of its skinsparing effect and better systemic and organ tolerance. However, in assuming a more intolerant approach, it is of great importance that in evaluating the presented cases, one need bear in mind that each case in this series has been managed by an expert. In reviewing a large series of cervical carcinoma cast's, treated by many individuals in many hospitals, it is depressingly evident that too many of these cases were treated by the occasional operator. True, manv of them followed the advice of a so-called or self-admitted consultant, who rarely examined the case. The patient so managed was the potential victim of diagnosis, compounded by errors in treatment, and the end rrsults were often tragic. The proper use of radiation therapy requirt'S close teamwork between the experienced gynecologist and the competent radiotherapist. The gynecologist must have a good knowledge of the potential routes and sites of spread; the radiotherapist must know the potentials of radiation for both good and bad. Dr. Nolan has surreptitiously protected possible points of argument by identifying the pitfalls and loopholes. He has recognized the importance of the anatomic extent of the disease in rt'lation to the prognosis. However, he has failed to accept a statistical windfall due the radiotherapist, u•., the error inherent in our present rough and inadequate methods of esti-
Am.
J.
July I 1%) Ob,t. & c;yn,·c.
mating the clinical extent of the disease. L~ntil bcttPr methods of examination arc evolved. t lw dissemination of the disease from evt·n tl!t~ smallest invasive lesion is !Jased on the l;m of chance. In our cxpericnct~ a so-called Stage 11 will be a III or more in at least ::!5 per cmt of the cases. Owr the past 30-plus yPars it has ht·cn Jtl)" good fortune to closely observe the changes in t h•· management of cervical carcinoma. As a >t udent and later as a house officer I was trained in the usc of radium plus the 250 kv. machitw hy Kelly and Burnam. In the late 1930's l had the opportunity of doing autopsies un c;t.,t•s treated by the so-called ''one million volt 11.~ today. l should like to know if you arc obtaining intravenous urograms in your r;tst·s and, if so, what is your t•xperience concerning strinures of tlw ureters. In sonw cases yon will find that t h·· ureters might be dwnged to resemble sonH~thing likt• Italian macaroni. DR. CEORGE E. Jenn, Los :\ngt•les. California. I would like to ask Dr. l\'olan if he has rak<·n this material and given it anr statistical cla-.sification from the standpoint of tlte grading of lil•' mrnors that he treated. DR. NoJ,\X (Closing). It is the usual practice to grade thr•se tumors histologically, but tlti.' feature ''as not studied in tht• present M·rit'''· Howevcr, in the past we hav" tl<'\'t·r \wen ~1bk to correlate the histologic grade of tlw nunnr with pro_gnosis. Thrrc mar he several reasons for this, one of which is that the grade is usuallv high. \'cry sddom docs on<' se<' a wf'll-differentiatcd tumor by the Broder's classification. An*By invitation.
Volume !l2 Number 5
Follow-up results with C0 60 and intrauterine radium 693
other feature is that the grade probably has less to do with prognosis than does the stage, so that its significance probably is hidden by the stage. Urograms are usually done in the preliminary work-up of these patients. We have found that most ureteral obstructions are due to tumor rather than to radiation itself. An exception to this was the one patient tnentioned \·vho did have bladder difficulty. Other exceptions are in patients who fail the primary radiation treatment
and are subjected to secondary surgical procedure. At the time of autopsy in a patient dying of uremia, it is very common for the pathologist to assume that radiation injury caused the ureteral obstruction. However, when microscopic studies are made, the usual finding is that re· sidual tumor caused the ureteral constriction. I think that the problem, as far as the ureter is concerned, is less one of complication of therapy than of extension of disease.
I N THE PAsT we have been interested in evaluating the efficacy of megavoltage radiation therapy in the management of carcinoma of the uterine cervix. Preliminary experiences have been reported on the use of conn teletherapy in combination with intracavitary radium."- 4 At the present time we are able to evaluate the late results in patients treated with this modality. A recent retrospective study 5 has been conducted which compared results of treatment of Stage I patients treated during the years 1950-1958, by this technique, with those treated in the previous 5 years by means of i-50 kv. x-rays plus radium. It was thought that late results in such patients would allow for an evaluation of the effectiveness of the external radiation phase of the treatment. In these two sf'ries of patients with early stages of the disease, the incidence of imperceptible pelvic node metastases should be essentially the same, and the local disease should be controllable largely by the intracavitary radium phase of the treatment. The study did reveal a superiority in results for those patients treated with megavoltage therapy. However, it was concluded that the superior physical features of the megavoltage radiation merely allowed for a more uniform technical application of external radiation. With this there was a decrease in the necessity for intense local
radiation. These factors made it possible to deliver a more balanced field of radiation to the local tumor and its fields of extension, which probably accounted for the improved results. The present report is designed to pursue the study further and to evaluate the late results in patients classified as Stage II and Stage III. In the latter group the disease is far advanced, and, although the over-all salvage is slight, the theoretic superiority of megavoltage therapy for the external radiation phase of treatment should be manifest. In the Stage II classification where there i' a wide variation in tumor volume, as well a' the greater incidence of imperceptible nodal metastases, the external radiation phase as well as the intracavitary phase of treatment are equally important. Materials of Stage Ill
For the purposes of this study the patients classified as having League of Nations Stag-e III carcinoma of the uterine cervix at the Los Angeles Tumor Institute were available. In the years 1949 to 1953, 32 such individuals were subjected to treatment by external radiation and intracavitary radium. In the years 1954 to 1958, 26 such patients were treated. The 58 patients in question were classified as to gross extent of the disease by a single examiner, and the incidence of this stage of disease was essentially the same in relation to the per cent of all sta~es of cervical cancer seen during the two periods 1Table I). It is interesting to note that in the earlier vears only one patient was incompletely
From The Los Angeles Tumor Institute. Presented at the Thirty-first Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Santa Barbara, California, Nov. 4-7, 1964.
684
Follow-up results with C0 60 and intrauterine radium
Volume 92 t\umber 5
685
Table I. Carcinoma of the uterine cervix (Stage III), yearly experience CQ6o
450 kv.
Stage III
All stages
%
Year
1949 1950 1951 1952 1953
7 4 6 6 9
43 34 28 42 34
16.3 11.8 21.4 14.3 26.5
1954 1955 1956 1957 1958
Total
32
181
17.7
Year
Table II. Carcinoma of the uterine cerv1x (Stage III), age groups Age group
450 kv.
CQ6o
0-40 +1-50 51-60 60+
3 5 9 10
1 4 11 6
treated, and in the later years 4 patients did not finish the outlined course. This discrepancy may represent a higher proportion of advanced cases who were subjected to palliative therapy only in the latter years. However, for the purposes of comparison of results, only those patients completing the outlined course will be considered in order to achieve a more realistic viewpoint of the value of treatment. It is also noted that in the last years of the early series, 4 individuals were treated primarily with C0 60 plus radium rather than with 450 kv. x-rays plus radium. This variation, too, may represent the use of the theoretically more potent modality in patients with more advanced lesions, but they will be counted in the subsequent comparisons. This, then, leaves 27 patients treated by means of 450 kv. x-rays plus radium, and 22 patients treated with C0 60 plus radium, for evaluation. Another method of evaluating these samples as to the possibility of bias is by comparing the ages of patients at the time of diagnoses. It was noted in the study of Stage I patients that earlier diagnosis brought about by the more general acceptance of the Papanicolaou smear in the later years
Stage III
All stages
%
6 5 5 5 5
35 33 3+ 31 25
17.2 15.2 1+.7 16.1 20.0
26
158
16.5
might be reflected by the inclusion of younger patients in the C0 60 series. This feature is probably not so important in these Stage III patients, since definite symptomatology is usually present in clinically advanced tumors. Consequently, when grouped according to decades, the age distribution of the patients in the two series is essentially the same (Table II). Results of Stage Ill
The results of treatment may be compared from three standpoints. The first may be upon the basis of the 5 year absolute success rate (Table III). This figure includes only those patients who have remained alive without evidence of residual or recurrent disease since the primary treatment. In the earlier 450 kv. plus radium series, only 7 (or 25.9 per cent) of the 27 patients completely treated are so categorized. In the later CO"" plus radium series, only 6 (or 27.2 per cent) of the 22 patients are considered successes at the end of 5 years. These percentage figures are quite low, and the difference between them cannot be considered significant. A second method of comparison is upon the basis of the 5 year absolute survival rate.
Table III. Carcinoma of the uterine cervix (Stage III), 5 year results Grouping Absolute success Absolute survival Actuarial survival
450 kv.
CO"o
25.9 44.4 46.7
27.2 31.8 31.8
686 Nolan
July I, l'l65 ,A:o.tn.
J. Obst.
& Gyii•~C.
100~ 90
"I 70
_J
\
~ 60
>
0::
~ 50
1-
z 40
"' "'a.. 0 0::
30 20 10
0 +--+--+--+--+--+--+--+--+--+--+--+--+--·+-~4 0 3 2 4 5 6 7 8 9 10 II 12 13 14 15 YEARS
Fig. 1. Actuarial survival of Stage III carcinoma of the uterine cervix.
This includes those patients known to be surviving after 5 years at risk, despite secondary treatment for residual or recurrent disease. With this comparison, 12 (or 44.4 per cent) of the 27 patients in the early series remained alive 5 years after their primary treatment with 450 kv. x-rays and radium, whereas only 7 (or 31.8 per cent) of the 22 patients treated with C0 60 plus radium survived. There is a difference of some 12.6 per cent in favor of the earlier series. This difference can hardly be called significant by means of the usual mathematical tests, because of the small numbers of patients involved in the comparisons. However, it does indicate that secondary treatment, which was successful in increasing the longevity of 5 of the patients in the early series, may be of some importance. In the transitional years of 1952 to 1955, there was a tendency to re-treat primary orthovoltage failures with megavoltage therapy. In more recent years this has fallen into disfavor because the primary megavoltage therapy is usually carried to a high level of dosage in advanced cases, and the addition of further extensive therapy is prone to distressing complications. Perhaps re-treatment should again be considered within the limits of palliative intent. The third method of comparison is upon the basis of actuarial survival. This conven-
tion JS gammg popularity as a method of reporting cancer results. So-called ''life tables '' 1 arc constructed, which show the per cent of patients surviving in relation to the number actually at risk for each year of follow-up, which allows for the use of as much of the material as is available. When such curves are drawn for these two series in comparison, they are, again, similar, with a rapid fall-off in the first 3 years. After this time there is a small plateau for the 450 kv. group, which probably represents the success of the re-treated patients. There is then a slower diminution in this group similar in slope to the C0" 0 series, which wen' not re-treated. The actuarial survival rate at 5 years is 4.9 per cent higher in the early 450 kv. group than in the later CO'"' series. However, this difference again cannot be considered of significance (Fig. 1•. Comment on Stage Ill
The comparison of late results by all of these methods certainly does not show a favorable effect which may be attributable to megavoltage therapy. Admittedly, the series are small and do not adapt themselves to the conventional mathematical methods of comparison. At best, the results can only be considered as similarly poor. However, as in the case of the Stage I patients, we cannot attribute the ultimate results to the physical
Follow-up results with C0 60 and intrauterine radium
Volume 92 !'\umber 5
2J,000T
687
X
22,00021,000-
zo.ooo..:. 19,000.1. ·---re,vvurj
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16,0001 15,000
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oz "' "'"' _,_ N"'
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.
It
0 01
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2,0001,0000. 1949
1950
1951
1952
19114
1951
19511
1958
IH7
1'188
YEARS
Fig. 2. Treatment dosage levels of Stage III carcinoma of the uterine cervix.
characteristics of the radiations themselves, without considering the actual techniques used. In all of these patients the external radiation was used in conjunction with intracavitary or interstitial radium. The combined modalities may be expressed conventionally in terms of dose in roentgens and may be normalized to an average over-all treatment time of 6 weeks. When calculated doses to the lateral parametrium (Point B) are plotted, we may consider the ultimate results in relation to what was probably delivered to the anatomic periphery of these advanced tumors. These data are shown in Fig. 2. The calculated doses at Point B for 42 days treatment time are shown for each of these patients in relation to when they were treated throughout the years in question. All of the doses were fairly high for this region, according to the designed treatment plans. Successes and failures are designated. One can see that the few successes are randomly admixed among the failures in the entire group. In the later group the mean doses to the
lateral parametrium are about 1,000 r higher than those in the earlier patients. Certainly, megavoltage therapy allows for the delivery of theoretically "adequate" amounts of radiation to the large volume of tissue involved. However, it is probable that the total dose alone is not the ultimate deciding factor in clinical success or failure in the treatment of patients with advanced disease. In the follow-up of these patients it was noted that many of them failed by reason of distant metastases. This might indicate that the local treatment to the pelvis was sufficient to at least hold the disease in check for some time, or that imperceptible spread beyond the pelvis had occurred before treat_. ment and only became manifest at a later date. Of the patients known to have failed in the 450 kv. plus radium series in 9 years of follow-up, 13 were noted to have local recurrence or residual disease, and 5 showed distant spread only. In the C0 60 plus radium group, 5 showed local disease, and 10 failed because of distant metastases only in 6 years of follow-up.
688
.July I, 196:·,
Nolan
:\m.
J. Ob!:.t.
& Cynt•c.
Table IV. Carcinoma of the uterine cervix (Stage II), yearly experience 450 kv. Year
Stage II
All stages
%
1949 1950 1951 1952 1953
16 16 10 13
Total
63
43 3+ 2/l +2 3+ 181
37.2 47.1 35.7 3Ul 23.5 34.8
8
Complications of Stage Ill
One of the features associated with radiation therapy, which is of importance, is the occurrence of complications in the face of tumor control. When megavoltage therapy was first introduced it was feared that the "skin-sparing" feature would allow for the delivery of high doses which would exceed the tolerance of the deeper tissues. It was with this in mind that the first patients subjected to C0 60 teletherapy were treated very conservatively. The occurrence of complications of moderate or major nature were compared in the Stage III patients treated here. In the early 450 kv. plus radium patients there were 25 who exhibited no such complications attributable to their primary treatment. One patient developed a moderate hemorrhagic cystitis and another showed a moderate factitial proctitis. Both of these patients were treated conservatively without surgical interference. In the C0" 0 plus radium group, 19 showed no moderate or major complications. There was one patient who developed moderate cystitis, which was treated conservatively. However, there were 2 patients who developed severe proctitis. Both of these were subjected to colostomy, one temporary and one permanent. Of course, with advanced disease, many of the patients who fail develop fistulas and obstructions in the genitourinary and gastrointestinal organs. Complete long-term tumor control is rare in itself in these cases, so that complications due to treatment alone are hard to assess. However, even with this small experience, it would seem that severe complications are a definite risk of intensive radiation therapy.
I 1
1
'
1954 1955 1956 1957 1958
13 13 13 8 9
35
~3
37.1 39.1
38.2 3+ 31 21.8 25 · - - - - - 36.0 ·----
56
158
Table V. Carcinoma of the uterine cernx (Stage II), age groups
co•o
Age group
450 kv.
0-40 41- 50 51 - 60
5 17 19
8 It 19
60+
22
15
Materials for Stage II
When the Stage II patients are similarly studied, a more significant result should be expected because of the larger number of patients involved and the diversity of tumors in the classification. Table IV shows the distribution of the patients in this stage throughout the same years as before. Tht• total treated by 450 kv. plus radium numbered 63 between 1949 and 1953, and thf' total treated by CO"" plus radium numbered 56 in the years 1954 to 1958. Their per cent occurrence in relation to all patients treated was again quite similar. The age distribution of thesf' two groups was again quite similar except for the patients 61 years of age or over where it was less for the CO"" group. This, however, cannot be considered as indicative of a more favorable sample because this difference was small (Table V). Results of Stage II
The two series were then compared on the three bases of success of treatment as used before (Table VI). The 5 year absolute success rate was calculated at 71.5 per cent for the CO"" plus radium group, and 52.4 per cent for the 450 kv. plus radium group. The difference of 19.1 per cent in favor of the CO';" series was significant at the 3.4
Follow-up results with C0 60 and intrauterine radium
Volume 92 Number 5
689
...J
:!!
>
.,::> 0:
1-
z
40
a::
30
&.J 0 &.J
IL
20 10 0
2
0
3
4
5
6
7
8
9
10
II
12
13
14
15
YEARS
Fig. 3. Actuarial survival of Stage II carcinoma of the uterine cervix.
Table VI. Carcinoma of the uterine cerv1x (Stage II), 5 year results % Grouping
450 kv.
CQ6o
52.4
71.5 71.5 71.3
Absolute success Absolute survival Actuarial survival
55.6 56.9
per cent confidence level, which can be considered clinically significant. When the 5 year absolute survival rate is used, the per cent figure for the C0 60 group was again 71.5 per cent and the figure for the 450 kv. group raised to 55.6 per cent. This difference of 15.9 per cent in favor of the megavoltage series was calculated to be significant at the 7.2 per cent confidence level, which is above the usually accepted 5 per cent considered significant clinically. Again, when the 5 year actuarial survival rate is shown, the difference in favor of the C:0 60 series is above the 5 per cent level. The curves for actuarial survival when plotted show a more favorable curve for the CO"" series, but essentially the same slope as the earlier group (Fig. 3). Comment on Stage II
It is again necessary to consider these results in relation to the actual doses given before their true significance can be evalu-
ated. Using the same convention of dose in r, normalized to 42 treatment days and calculated both at Point A in the proximal parametrium and Point B in the distal parametrium, the data for each patient are plotted in Fig. 4. As in the case of both the Stage I and Stage III patients, the failures occur at all ranges of dosage, but there was a difference in the amount of radiation actually delivered during this collection of experience. In the previously reported data on the Stage I patients, it was noted that in the earlier years of 1949 to 1951, a greater reliance was placed upon the intracavitary radium phase of treatment than upon the external radiation phase with 450 kv. x-rays. This was reflected in high dosages to the proximal parametrium, which were sometimes associated with clinical failure. Because of this, the local radium treatments were made more uniform by the use of a fixed applicator, and the milligram-hour exposure was somewhat decreased. The effect of these changes can be seen also in the Stage II patients where, in the early years, the Point A doses were high, and in the years immediately before the C0 60 teletherapy became available, they were reduced. During this period, however, the Point B doses were kept at essentially the same level of about 3,500 r.
]ul} l. 1\lh:\ .\m. J. Oh;t, & Cynec
690 Nolan
15,000 X
14,000 13,000 12,000
X Ill
~
11,000 10,000
•
~-
9000
Q~ 1000
"'"' 7000 ~~ .Jz
cw ~~ 6000
i-
5000
!
4000
... 0
Q
.
X
N
X. ')(X XX \ llo II X X·
X X
X ,
X X
X M
'1'850
IUO
x.XII!IO ."
X X
X X
'~.,."
• X
•
e
3000
2000
0
1000
YEARS
Fig. 4. Treatment dosage levels of Stage 11 carcinoma of the uterine cer;ix.
After the C0 60 apparatus came into use, essentially the same levels of radiation were delivered to both Points A and B in the parametrium, as had been used previously, in order to avoid complications from excessive dosage with this new technique. Early results were evaluated, and, in 1956, the dose of external radiation was arbitrarily raised by 1,000 r tumor dose, which moved the mean dose to the distal parametrium upward. The doses to the proximal parametrium were also increased in this fashion. There is more variation in the Point A dosage in the later years of the C0 60 series, which is attributable to the application of interstitial needles in the Stage liB cases where there is considerable bulky tumor residual in the parametrium after the preliminary external therapy. The Stage IIA lesions with only minimal parametrial extension or primarily vaginal involvement were treated in a fashion similar to the Stage I patients. It is probable that the superior physical characteristics of the megavoltage therapy allow for a greater degree of individualization of technique in the management of
patients in the Stage II group. When the extent of the tumor is minimal, as in Stage I patients, the field of radiation can be held to uniform levels and the dangers of local overdosage can be avoided. vVhen the tumor shows a large gross volume and involves the lateral parametria, levels of radiation can be raised in the areas at risk, but with the calculated risk of overdosage. If the superiority of the late results in the C0 130 series is attributable to the apparatus, it must be through the technique itself. This superiority in adaptability to the individual lesions being treated may be of significance. Complications of Stage II
Again, when complications are considered, the two series may be compared. In the +50 kv. x-ray plus radium group there were 56 patients who showed no major complications. Two patients developed moderate cystitis and 5 patients developed moderate factitial proctitis. All of these were treated conservatively. In the C0" 0 plus radium series, 51 patients showed no major complications. Two patients developed moderatf' cystitis and one developed moderate proc-
Volume 92 J\:umf)('r 5
Follow-up results with (0 60 and intrauterine radium 691
titis, which responded to conservative management. One patient developed severe proctitis, necessitating temporary colostomy. There was one individual who developed a severe late hemorrhagic cystitis, which did not respond to intensive urologic treatment and ultimately caused death. This patient showed no residual tumor but there was a markedly contracted bladder with ureteral scarring and contracture. As in the case of the Stage III patients, designation of true radiation complications with tumor control is difficult, but again it would seem that fears concerning the effects of overirradiation have some basis in fact.
If improved late results are to be attributed to the use of megavoltage rather than orthovoltage therapy, it must be through the adaptability of the apparatus to the clinical problems at hand. Certainly, miraculous cures cannot he expected in the management of far advanced lesions, as in Stage III patients. Nor can one expect perfect results in the treatment of early lesions. There must be features other than the dosage system applied, which may decide the ultimate outcome of therapy. However, the superior characteristics of megavoltage radiations make them a very useful modality within the limitations of our knowledge of the correct principles for the use of radiation therapy.
Comment Summary
A study of 5 year results, such as this, must have shortcomings from a statistical standpoint. Since this is a retrospective clinical evaluation, there are many uncontrollable variables which might affect the results other than the use of one generator or another for the external radiation phase of a combined treatment scheme. Radiation techniques were not applied in a fashion which would explore the limitations and therapeutic parameters of the modalities in question. Each patient was treated individually in relation to previous experiences. Although there is a natural evolution of technical changes in clinical practice, variations in technique were actually emphasized in the present series because several preliminary attempts were made to evaluate results earlier.
A study of patients with Stage II and Stage III carcinoma of the uterine cervix treated with COGo plus radium was carried out. The late results of treatment were compared to similar groups treated in the immediately previous years with 450 kv. x-rays plus radium. In general, the C0 60 plus radium series showed superior end results as in a similar study of Stage I patients. However> the techniques of treatment varied during the years of collection of the patient material. It was considered that the improved results were mediated through improved technical application of the therapy which, in turn, were attributable to some extent to the superior physical characteristics of the external radiation phase of the combined therapy.
REFERENCES 1. Greiss, F. C., Jr., Linton, E. B., Lock, F .. R., and Rhyne, A. L.: AM. J. OBsT. & GYNEC. 90: 703, 1964. 2. Lederman, M.: Brit. J. Radiol. 37: 745, 1964.
5. Nolan, J. F.: Radiation therapy for carcinoma of the cervix, Presented at Fifth National Cancer Conference, Philadelphia, September, 1964. In press.
3. Nolan, J. F., Vidal, AM.
J.
0BST.
J.
A., and Anson,
J.
& GYNEC. 72: 789, 1956.
H.:
4. Nolan, J. ·F., Emmett, J. W., and Anson, J. H.: Am. J. Roent., Rad. Ther., & Nuc. Med. 81: 111, 1959.
1407 South Hope Street Los Angeles, California 90015
692 Nolan
Discussion DR. HENRIKSEN, Los Angeles, California. The errors and weaknesses so common in many simiJar reports, based on the compilation of records or IB:M cards, arc missing, because each case has been examined, evaluated, treated, and followed by one individual. Thus, there is no discrepancy in diagnostic acumen, no differences in int crpretation, and no ambiguity of terminology. It was Confucius who so wisely recognized the dangers inherent in the study and interpretation of many cases, studied by many individuals, when he said, "if the bnguage is not correct, then what is said is not what is meant; if what is said is not what is meant tllC'n what has been done is undone." In other words, it is better not to make a so-called scientific contribution than to try to push the round figures of statistics into the rigid square holes of fact. I cannot disagree with the presented thesis that megavoltage radiation is superior to modalities of far lesser strength. Accruing evidence strongly supports the contention that the supervoltage roentgenotherapy is superior because of its skinsparing effect and better systemic and organ tolerance. However, in assuming a more intolerant approach, it is of great importance that in evaluating the presented cases, one need bear in mind that each case in this series has been managed by an expert. In reviewing a large series of cervical carcinoma cast's, treated by many individuals in many hospitals, it is depressingly evident that too many of these cases were treated by the occasional operator. True, manv of them followed the advice of a so-called or self-admitted consultant, who rarely examined the case. The patient so managed was the potential victim of diagnosis, compounded by errors in treatment, and the end rrsults were often tragic. The proper use of radiation therapy requirt'S close teamwork between the experienced gynecologist and the competent radiotherapist. The gynecologist must have a good knowledge of the potential routes and sites of spread; the radiotherapist must know the potentials of radiation for both good and bad. Dr. Nolan has surreptitiously protected possible points of argument by identifying the pitfalls and loopholes. He has recognized the importance of the anatomic extent of the disease in rt'lation to the prognosis. However, he has failed to accept a statistical windfall due the radiotherapist, u•., the error inherent in our present rough and inadequate methods of esti-
Am.
J.
July I 1%) Ob,t. & c;yn,·c.
mating the clinical extent of the disease. L~ntil bcttPr methods of examination arc evolved. t lw dissemination of the disease from evt·n tl!t~ smallest invasive lesion is !Jased on the l;m of chance. In our cxpericnct~ a so-called Stage 11 will be a III or more in at least ::!5 per cmt of the cases. Owr the past 30-plus yPars it has ht·cn Jtl)" good fortune to closely observe the changes in t h•· management of cervical carcinoma. As a >t udent and later as a house officer I was trained in the usc of radium plus the 250 kv. machitw hy Kelly and Burnam. In the late 1930's l had the opportunity of doing autopsies un c;t.,t•s treated by the so-called ''one million volt
Volume !l2 Number 5
Follow-up results with C0 60 and intrauterine radium 693
other feature is that the grade probably has less to do with prognosis than does the stage, so that its significance probably is hidden by the stage. Urograms are usually done in the preliminary work-up of these patients. We have found that most ureteral obstructions are due to tumor rather than to radiation itself. An exception to this was the one patient tnentioned \·vho did have bladder difficulty. Other exceptions are in patients who fail the primary radiation treatment
and are subjected to secondary surgical procedure. At the time of autopsy in a patient dying of uremia, it is very common for the pathologist to assume that radiation injury caused the ureteral obstruction. However, when microscopic studies are made, the usual finding is that re· sidual tumor caused the ureteral constriction. I think that the problem, as far as the ureter is concerned, is less one of complication of therapy than of extension of disease.