1111.J. Radiolion
0
Oncology Biol. Phys.. 1976, Vol. 2, pp. 621429.
Pergamon Press.
Printed
in the U.S.A
Original Contribution
FAILURE ANALYSIS OF RADICAL RADIATION THERAPY OF SUPRAGLOTTIC LARYNGEAL CARCINOMA-t JACQUES NIEDERER, M.Sc.,S NIGEL V. HAWKINS, M.D., WALTER D. RIDER, M.D. and JAMES E. TILL, Ph.D. Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M4X lK9, Canada Treatment results for 163 patients with supraglottic laryngeal cancer first treated by radical radiation therapy have been analysed, and an assessment has been made of the benefits to be anticipated as a result of improved methods of management. On the basis of thii assessment, a successful eliiination of tech&al failures of local and regional control would be expected to increase the actuarial S-year survival for all stages from 48% to no more than about 56%. Elimination of not only technical failures but also all other causes of local or regional recurrences would be expected to increase 5-year survival to a maxhnum of about 64%. Effective control of distant metastases could increase the 5-year survival to 71%. Each of these increments in survival is sufficiently small (7-g%) that any improvement would be difficult to demonstrate by a randomized clinical trial. The major factor which emerged from the failure analysis was the ditference in 5year survival between patients who did not die of their laryngeal cancer (71%) and members of a control population with the same age and sex distribution (82%). This difference reflects an increased risk of other diseases in the population not dying of laryngeal cancer. An effective program of primary prevention has the greatest potential for improving survival, and could yield a survival rate markedly superior even to that obtained for a population in which laryngeal cancer has been completely cured. Supraglottic
laryngeal carcinoma,
Radiation
therapy, Failure analysis.
INTRODUCTION
11, 15) have amply demonstrated the importance of such factors as radiation dosage and placement of the radiation field. The purpose of this paper is to utilize the results of failure analysis to assess the expected benefits of possible changes in procedures for management of the disease.
An analysis of causes for treatment failures and of opportunities for alternate approaches to control or prevention is one approach to the assessing of priorities in cancer research and developing strategies for improving treatment. This can only be done in a meaningful way individually for each class of tumor, since the causes of failure for a widely disseminated disease like leukemia will differ from those for a tumor where local control is possible. An example of the latter is laryngeal cancer, where a survey of results from several treatment center? confirmed that clinically detectable distant metastases are relatively infrequent at the time of treatment, and that radical radiotherapy is efficacious for local control of the tumor. The rate of recurrence of supraglottic laryngeal cancer is greater than it is for glottic cancer;18*M*27 for this reason, supraglottic tumors were chosen for detailed analysis. Previous investigations of the reasons for irradiation failure (see, e.g. Refs. 8, 10,
METHODS
AND
MATERIALS
The study was based on results for 215 nonselected patients with a diagnosis of supraglottic laryngeal cancer, who were registered at the Princess Margaret Hospital, Toronto, between 1958 and 1973. Only the 163 patients whose first planned treatment was radical radiaton therapy where cure was intended were included in the present analysis. The remaining 52 were either treated palliatively or by surgery with or without preoperative irradiation. Of the 163 patients, 117 were registered between 1958 and 1971 and the remainder in 1972 and 1973. The latter group (197273) was included for purposes of comparison with the earlier (1958-7 1) results. For the 163 patients included
Wupported in part by the Ontario Cancer Treatment and
DeBoer for the computer program used to calculate
Research Foundation. SPresent address: Centre de RadiothCrapie, HBpital Cantonal de Genkve, Geneva, Switzerland. Acknowledgements-The authors are grateful to Dr. Gerrit
tuarial survival Schweizerische schaften. 621
curves. J.N. held a scholarship Akademie der Medizinischen
acfrom the Wissen-
Radiation Oncology 0 Biology 0 Physics
622
July-August
in the study, all of the diagnoses were confirmed by biopsy. Only one patient was lost to followup before 4 years after completion of radiation therapy. The mean age of the 82 patients who showed no evidence of local recurrence after radical radiation therapy was 60 years; the mean age of the remaining 81 patients who received radical radiation therapy was 63 years. Of the 163 patients, 18 (11%) were female. Classification was done retrospectively by the medical staff of the Princess Margaret Hospital according to the latest TNM classification of the UICC.*’ It was based on the record of clinical examination, including indirect and direct laryngoscopy and, particularly after 1967, tomography. The results are shown in Table 1; 33% of all patients who were treated radically by radiation therapy had clinically positive nodes at the time of first treatment. Of these, 90% were located in the anterior triangle, 7% in the posterior triangle, and 3% in the supraclavicular fossa. Although all patients were treated using *‘Co radiation, treatment policy was not uniform throughout the study period 1958-73. Prior to 1972, a variety of techniques were used, with the total dose usually between 5000 and 6000 rad, but given in different dose fractionation schedules. As a means for comparison of different dose fractions, the concept of equivalent dose (see below) was used. The most frequent equivalent dose used was in the range from 5560 to 6050 rad. After 1972, increased use was made of casts to control beam direction and of larger field sizes. The most frequent equivalent dose used during 197273 remained in the range from 5560 to 6050 rad. Since a variety of doses per fraction and to a lesser extent a variety of total doses were used during the period studied, Ellis’3,4 approach was used to obtain, as a first approximation, a biologically “equivalent for purposes of intercomparison. The dose” equivalent dose (ED) is expressed as the total dose adjusted as if it had been given at a dose-rate of 1OOOrad per week, 5 fractions per week. The equivalent dose is given by the relation:
1977, Volume 2, No. 7 and No. 8
In the analysis of treatment results, the end point used was failure, not status at a point in time. Patients were classified into one of 5 categories: no recurrence, true recurrence, “field problem”, uncertain recurrence and late recurrence, both with regard to the primary site and nodal disease. Tumors (or nodes) which showed no evidence of recurrence after at least 2.5 years were considered to have had no recurrence. As reported previously by Fletcher et al.,7 less than 5% of tumors recur after 2.5 years. Patients without evidence of recurrence but who were lost to follow-up or died of intercurrent disease or for reasons other than their cancer within a time shorter than 2.5 years, were considered uncertain with respect to recurrence. If a recurrence occurred after 4 years, it was considered to be a late recurrence and possible second primary. A “field problem” refers to any situation where a study of the description of the extension of the tumor, the treatment planning, the check films, the treatment record sheet and the anatomo-pathological report of a recurrence gave rise to strong suspicion that a part of the tumor may not have received the prescribed dose. Actuarial survival curves were calculated by the method described by Bradford Hi11.r3 This method involves the assumption that patients who were not followed up would have yielded the same survival curve as those for whom follow-up information was available. Since only 1 of the patients was lost to follow-up within a time shorter than 4 years after the end of treatment, this assumption is unlikely to bias the results. Values for relative survival were based on an estimate of the survival to be expected if the only cause of death were laryngeal cancer, obtained as illustrated graphically in Fig. 3 (see below). The Chi-square test with Yates’ correction for of continuity6 was used for the comparison differences between results. RESULTS AND DISCUSSION Local
control
The results of first treatment by radical irradiation in relation to local local control of the primary tumor are summarized in Table 2. For the period 1958-71, true recurrences were observed for approximately 24% of tumors (all stages). Another 15% showed
ED = 1000(TDF)(7/5)0~16g(200)-o~53* the TDF (Time, Dose and Fractionation Factor) was computed as described by Orton and Ellis.”
Table 1. TNM classification of patients treated by radical irradiation NO 58-71
N,
72-73
58-71
Total
N,
N2
72-73
58-71
72-73
58-71
72-73
58-71
72-73
Tl-T2
49
16
0
0
3
20
20
2
0
3
7
0 1
70
25
18 1.5
4
T3-T4
47
26
Total
74
36
33
6
0
3
10
1
117
46
Failure analysis of radical radiation therapy of supraglottic laryngeal carcinoma 0 J.
Table 2. Results of first treatment
by radical irradiation
Tl-T2 1958-71 1972-73 No recurrence True recurrence Field problem Recurrence uncertain Late recurrence§ Total
6t + 8$
39 14 8 7 2 70
4 0 2 0 20
et
(I/.
623
in relation to local control
T3-T4 1958-71 1972-73 18 14 9 6 0 47
NIEDERER
9?+4$ 9 1 3 0 26
Total 1958-71 1972-73 57 28 17 13 2 117
27 13 1 5 0 46
tNo evidence of recurrence after an average of 28 months. *No evidence or recurrence after an average of 18 months. QIncludes second primaries.
evidence of a “field problem”, i.e. the patients’ records gave rise to strong suspicion that part of the tumor may not have received the prescribed radiation dose (see Methods). Results from the period 1972-73 also are included in Table 2. The major change in treatment policy during this period was an increase in field sizes, with the most frequent fields lying between 70 and 99 cm2 instead of 37 and 69 cm2 in the earlier period. This change in field size corresponded to more frequent use of cast and compensator. As may be seen from Table 2, the frequency of field problems was much smaller in 1972-73 (2%) than in 1958-71 (15%), probably because of increased use of larger field sizes, and the use of controlled beam direction by means of casts as opposed to free set-ups. It seems possible that the variety of radiation dose fractions used could account for some failures of local control. A scattergram of tumor dose versus overall treatment time is shown in Fig. 1. Failures (open circles) tended to be associated with longer treatment times. For more detailed analysis, a method for comparison of different dose fractionation schedules was required. As one approach to this problem,
0. ?? oxp
60000
2 s z % $ 5000-
0
p#q&&m. A
. *
-#P
+!%#@&4M .
F .
4ooo/
0
j
Ax
10
A..
0
0
‘3
=,I
. 0 x
@&“8
0
:0g.
ho
20
o
30 Overall
treatment
,
,
40
50
1
time(days)
Fig. 1. Scattergram of total tumor dose vs overall treatment time, showing local control, 0; true recurrence, 0; field problem, X; recurrence uncertain, A; and late recurrence, 0 (5 fractions/week).
the concept of equivalent dose was applied (see Methods). The overall results obtained for patients who were treated by radical irradiation, broken down by T and N and by category, are presented in Table 3. Although the small number of patients and rather wide range of equivalent doses makes selection of an optimal dose impossible, equivalent doses below 5060 rad appear to be suboptimal. Regional control In addition to failures of local control, failures of regional control of involved lymph nodes must be considered. A summary of results for primary radical radiation therapy to the positive nodes is given in Table 4. For the period 1958-7 1, true recurrences were seen for 4/33 (12%) of the Ni-N2 nodes; 1 of the 4 received an equivalent dose of less than 5060 rad (Table 3). Only 1 of 10 NJ nodes was classified as a non-recurrence. An additional 74 patients who first were treated between 1958 and 1971 were staged No at the time of first treatment. In 8 (11%) positive nodes appeared subsequently outside of the field of irradiation, either during treatment, or in cases were the larynx showed no evidence of recurrence. Of the 8, 6 were Tl-T2 tumors and 2 were T3-T4 tumors. All were considered to have had a “field problem” at the level of the nodes. No nodes developed in the No patients within the field of irradiation. The use of a larger field after 1971 appeared to reduce the frequency of such problems (l/36 or 3% for 1972-73, compared with 11% for 1958-71). Distant metastases None of the population receiving radical radiation therapy had evidence of distant metastases at the time of first treatment. Of the total of 117 patients who first were treated between 1958 and 1971, 9 (8%) developed clinical distant metastases after treatment; 4 patients had metastases in the lungs, 3 in the brain and 2 had multiple metastases. Among 57 patients who showed no recurrences in the larynx or nodes
14 1, 2
2 12 2 2
18
3
1
1
39
1, 2
1 1 2 8 1 2 1
16
Total
N classification 7600
Total
7
1 2 4
2 4 7 1
0
3
13
4 3 6
1, 2 3, 4
4 23 2 9 1
T classification c4050 406OA550 4560-5050 5060-5550 5560-6050 60606550 6560-7050 7060-7550 >7600
3,4
No recurrence 58-71 72-73
1,2
Equivalent dose
4
1 1 2
1, 2
14
1
1 3 2 3 1 3
1,2
7
1
3 1
1
3 1
14
1 2 8 2
3,4 1
Field problem 58-71 72-73
Recurrence uncertain S-71 72-73
0
1, 2
4
2
2
1
1
3
9
5 1 2 1
7
6 1
1, 2
8
1 4 2 1
2
1
1
3
9
2 1 4 1 1
1
1
1, 2
0
0
3
1
1
6
1
2 2 1
1, 2
7
1
1 1 4
0
3
6
1 2 2 1
1
1
1, 2
2
1
1
0
3
3
1 1 1
0
I, 2
2
1
1
0
3
0
0
I, 2
0
I,2
0
3
0
3,4
Late recurrence 58-71 72-73
1,2 3, 4 1, 2 3, 4 1, 2 3, 4 1, 2 3, 4 1, 2 3, 4 1, 2 3, 4
True recurrence 58-71 72-73
33
0 1 4 5 17 2 3 1 0
1, 2
70
10
3 1 0 2 0 5 1 0 0 1
47
72-73
9
0 0 1 4 4 0 0 0 0
1, 2
20
1
3 0 0 0 0 1 0 0 0 0
26
192 3,4 0 0 0 0 5 11 4 5 10 9 1 1 0 0 0 0 0 0
Total 1,2 394 0 1 1 0 4 4 8 7 35 26 5 6 15 3 1 0 1 0
58-71
Table 3. Influence of equivalent dose on the probability of recurrence of laryngeal tumors treated between 1958 and 1973 by radical irradiation
Failure analysis of radical radiation therapy of supraglottic
laryngeal carcinoma
0 J.
NIEDERER
625
et ul
Table 4. Results of radical radiotherapy of positive (palpable) nodes NI-Nz
Total
N3
58-71
72-73
True recurrence
16 4
7 0
:
0 1
Field problem Recurrence uncertain Late recurrence Total
7 6 0 33
1 1 0 9
2 0 0 10
0 0 0 1
No recurrence
58-71
72-73
58-71
72-73
17~
7
11 9 6 0 43
1 1 1 0 10
after initial radiation therapy, 2 (4%) developed clinical distant metastases. Of the remaining 60 patients, 7 developed distant metastases; 5 of these already had received subsequent surgical treatment in the form of laryngectomy prior to the clinical onset of distant metastases. The frequency of occurrence of distant metastases in the group receiving subsequent surgery for true recurrence was 5/33 (15%). The higher frequency of occurrence of clinical metastases in this group probably was a result of their longer survival time rather than any effect of surgery. Subsequent
treatment
For patients who first were treated between 1958 and 1971, subsequent treatment was received by 44/ 117 patients (380/o), either to the larynx or to the nodes or to both. 37 patients received subsequent surgery, 6 radiation and 1 chemotherapy. In all cases subsequent radiation or chemotherapy was unsuccessful. Among the 37 surgical treatments, 1 laryngectomy and 3 laryngectomy plus neck dissections were performed with no subsequent pathological confirmation of malignancy in the larynx. Two of these laryngectomies were performed for recurrence-like situations, and two for pain, necrotic larynx and gross edema. In the 33 subsequent surgical treatments performed for true recurrences, 21 (64%) were successful because no subsequent recurrence was observed. The large majority (90%) of these subsequent treatments were done within 2 years following the end of the first treatment and nearly 50% were done within the first 6 months. Of the 33 patients who received subsequent surgery for true local or regional recurrences, 19 were classified as being subject to “field problems” either with respect to the nodes or to the larynx in their first treatment by radiation. Evaluation
of end results
Figure 2 shows an actuarial survival curve (see Methods) for the population of patients with supraglottic laryngeal carcinoma who did not die of laryngeal cancer (curve A). This population includes
IO’ 0
1
2
Time zfter
8
I IO
’
first treatment(yrs)
Fig. 2. Actuarial survival curves. Curve A: survival curve for patients with supraglottic laryngeal carcinoma first treated by radical radiation therapy in the interval 1958-71, considered to have died of causes unrelated to their malignancy, whether or not evidence of their malignant disease was still present. Curve B: survival curve for a population with the same age and sex distribution, taken from the 1961 Ontario census. Curve C: survival curve for patients who
subsequently died of laryngeal cancer. all patients for whom cancer was considered not to have contributed to the cause of death. For example, for coronary thrombosis or automobile accidents (but not bronchial pneumonia or suicide) it was assumed that cancer was unlikely to be a contributing cause. The median survival time of this population is 9.8 years. Also shown is the survival curve for a normal population having the same age and sex distribution (curve I?). The median survival for this control population is 15 years, that is, 5 years longer than the population having larynx cancer but not dying of it. The shorter life expectancy of the latter group may be a reflection of an increased risk of ill health in this population resulting from such factors as a life style
626
Biology 0 Physics
Radiation Oncology 0
involving heavy cigarette and alcohol consumption.29.30 Also shown in Fig. 2 is a survival curve for patients
first treated by radical radiation therapy in the interval 1958-1971 who subsequently died of laryngeal cancer (curve C). The median survival time of this population is 1.3 years. Figure 3 shows actuarial survival curves for patients with Tl and T2 tumors, T3 and T4 tumors, and all stages, together with the survival curve for patients who did not die of laryngeal cancer (curve A, Fig. 2). Comparison of the former curves with the latter yields an estimate of the relative survival to be expected if the only cause of death were related to their laryngeal cancer, as well as an estimate of the increase in median life expectancy if none of the patients in each group were to die of laryngeal cancer. Results of these comparisons are given in Table 5. For all stages, the 5-year survival rate is about 48%; the estimated relative survival compared with curve A, Fig. 2 is 61% (i.e. 39% die of laryngeal cancer). Successful control of all laryngeal cancers in this group would increase the median life expectancy by 5.4 years. Principal
causes of failures
Two major causes of failures may be termed technical failures and radiobiological failures. The former
July-August 1977, Volume 2, No. 7 and No. 8
Table 5. Summary of evaluation of end results for patients treated between 1958 and 1971
Stage
S-year actuarial survival (%)
Relative survivalt (%)
Increase in median life expectancy (years)
52 42 48 71
68 55 61 100
4.4 7.0 5.4 -
Tl, T2 T3, T4 Overall Other causes4
tFor method of calculation, see text and Fig. 3. *Only for those patients who did not die from laryngeal cancer (see curve A, Fig. 2).
includes incorrect execution of treatment, field problems and suboptimal tumor doses.7X’0Tu The latter results various from unsolved radiobiological problems such as the presence of hypoxic cells.s,‘2.26 Table 6 summarizes the principal causes of technical failures of local and regional control, and their relative frequencies for the population treated by radical irradiation between 1958 and 1971. Approximately 24% of the treatments failed locally in association with either a field problem or a suboptimal dosage. Of the 43 patients with positive nodes, about 40% of recurrences were associated with field problems or an equivalent dose below 5060 rad. Since Wood and Boag** found evidence that the nodes are similar in their response to the primary, this dose probably was suboptimal. At least 11% of the nonpalpable but subclinically positive nodes recurred because of field problems. Technical failures such as errors in dose calculation or the use of the wrong wedge filter were seen in only 2% of the records; such errors were always discovered promptly and corrected, and probably had no significant effect on frequency of recurrence. Between 1958 and 1971 treatments took place exactly as planned in 46% of patients. In the others, one, two or more changes from the planned treatment took place. The type of change was either in the field size or in Table 6. Principal types of failure of local or regional control for patients treated between 1958 and 1971
Type of failure 0
5 Tjme
after
IO first
treatment
(yr5.j
Fig. 3. Actuarial survival curves for patients with supraglottic laryngeal tumors. Curve A: survival curve for patients who did not die of laryngeal cancer (see Fig. 2). The dashed lines represent the extrapolated survival curves used to estimate the relative survival to be expected if laryngeal cancer were the only cause of death (see Table 5).
Field problem, larynx Field problem, non-palpable nodes Field problem, positive nodes Equivalent dose to tumor ~5050 rad Equivalent dose to positive nodes ~5050 rad
Frequency
Percent
Per cent of total cases
17/117
15
15
8174 9143
11 21
7 8
10/117
9
9
8143
19
7
Failure analysis of radical radiation therapy of supraglottic
of
emphysema
and
low
irradiation
No recurrence True recurrence Field problem or uncertain Total Frequency of recurrence+
6 2+1t 1 10
218
Effect of failures
1 2+1t 5 9
213
NIEDERER et (I/.
on 5-year survival
hemoglobin
in patients
levels
treated
of benefits to be anticipated
Low (
0
Oncology Biol. Phys.. 1976, Vol. 2, pp. 621429.
Pergamon Press.
Printed
in the U.S.A
Original Contribution
FAILURE ANALYSIS OF RADICAL RADIATION THERAPY OF SUPRAGLOTTIC LARYNGEAL CARCINOMA-t JACQUES NIEDERER, M.Sc.,S NIGEL V. HAWKINS, M.D., WALTER D. RIDER, M.D. and JAMES E. TILL, Ph.D. Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M4X lK9, Canada Treatment results for 163 patients with supraglottic laryngeal cancer first treated by radical radiation therapy have been analysed, and an assessment has been made of the benefits to be anticipated as a result of improved methods of management. On the basis of thii assessment, a successful eliiination of tech&al failures of local and regional control would be expected to increase the actuarial S-year survival for all stages from 48% to no more than about 56%. Elimination of not only technical failures but also all other causes of local or regional recurrences would be expected to increase 5-year survival to a maxhnum of about 64%. Effective control of distant metastases could increase the 5-year survival to 71%. Each of these increments in survival is sufficiently small (7-g%) that any improvement would be difficult to demonstrate by a randomized clinical trial. The major factor which emerged from the failure analysis was the ditference in 5year survival between patients who did not die of their laryngeal cancer (71%) and members of a control population with the same age and sex distribution (82%). This difference reflects an increased risk of other diseases in the population not dying of laryngeal cancer. An effective program of primary prevention has the greatest potential for improving survival, and could yield a survival rate markedly superior even to that obtained for a population in which laryngeal cancer has been completely cured. Supraglottic
laryngeal carcinoma,
Radiation
therapy, Failure analysis.
INTRODUCTION
11, 15) have amply demonstrated the importance of such factors as radiation dosage and placement of the radiation field. The purpose of this paper is to utilize the results of failure analysis to assess the expected benefits of possible changes in procedures for management of the disease.
An analysis of causes for treatment failures and of opportunities for alternate approaches to control or prevention is one approach to the assessing of priorities in cancer research and developing strategies for improving treatment. This can only be done in a meaningful way individually for each class of tumor, since the causes of failure for a widely disseminated disease like leukemia will differ from those for a tumor where local control is possible. An example of the latter is laryngeal cancer, where a survey of results from several treatment center? confirmed that clinically detectable distant metastases are relatively infrequent at the time of treatment, and that radical radiotherapy is efficacious for local control of the tumor. The rate of recurrence of supraglottic laryngeal cancer is greater than it is for glottic cancer;18*M*27 for this reason, supraglottic tumors were chosen for detailed analysis. Previous investigations of the reasons for irradiation failure (see, e.g. Refs. 8, 10,
METHODS
AND
MATERIALS
The study was based on results for 215 nonselected patients with a diagnosis of supraglottic laryngeal cancer, who were registered at the Princess Margaret Hospital, Toronto, between 1958 and 1973. Only the 163 patients whose first planned treatment was radical radiaton therapy where cure was intended were included in the present analysis. The remaining 52 were either treated palliatively or by surgery with or without preoperative irradiation. Of the 163 patients, 117 were registered between 1958 and 1971 and the remainder in 1972 and 1973. The latter group (197273) was included for purposes of comparison with the earlier (1958-7 1) results. For the 163 patients included
Wupported in part by the Ontario Cancer Treatment and
DeBoer for the computer program used to calculate
Research Foundation. SPresent address: Centre de RadiothCrapie, HBpital Cantonal de Genkve, Geneva, Switzerland. Acknowledgements-The authors are grateful to Dr. Gerrit
tuarial survival Schweizerische schaften. 621
curves. J.N. held a scholarship Akademie der Medizinischen
acfrom the Wissen-
Radiation Oncology 0 Biology 0 Physics
622
July-August
in the study, all of the diagnoses were confirmed by biopsy. Only one patient was lost to followup before 4 years after completion of radiation therapy. The mean age of the 82 patients who showed no evidence of local recurrence after radical radiation therapy was 60 years; the mean age of the remaining 81 patients who received radical radiation therapy was 63 years. Of the 163 patients, 18 (11%) were female. Classification was done retrospectively by the medical staff of the Princess Margaret Hospital according to the latest TNM classification of the UICC.*’ It was based on the record of clinical examination, including indirect and direct laryngoscopy and, particularly after 1967, tomography. The results are shown in Table 1; 33% of all patients who were treated radically by radiation therapy had clinically positive nodes at the time of first treatment. Of these, 90% were located in the anterior triangle, 7% in the posterior triangle, and 3% in the supraclavicular fossa. Although all patients were treated using *‘Co radiation, treatment policy was not uniform throughout the study period 1958-73. Prior to 1972, a variety of techniques were used, with the total dose usually between 5000 and 6000 rad, but given in different dose fractionation schedules. As a means for comparison of different dose fractions, the concept of equivalent dose (see below) was used. The most frequent equivalent dose used was in the range from 5560 to 6050 rad. After 1972, increased use was made of casts to control beam direction and of larger field sizes. The most frequent equivalent dose used during 197273 remained in the range from 5560 to 6050 rad. Since a variety of doses per fraction and to a lesser extent a variety of total doses were used during the period studied, Ellis’3,4 approach was used to obtain, as a first approximation, a biologically “equivalent for purposes of intercomparison. The dose” equivalent dose (ED) is expressed as the total dose adjusted as if it had been given at a dose-rate of 1OOOrad per week, 5 fractions per week. The equivalent dose is given by the relation:
1977, Volume 2, No. 7 and No. 8
In the analysis of treatment results, the end point used was failure, not status at a point in time. Patients were classified into one of 5 categories: no recurrence, true recurrence, “field problem”, uncertain recurrence and late recurrence, both with regard to the primary site and nodal disease. Tumors (or nodes) which showed no evidence of recurrence after at least 2.5 years were considered to have had no recurrence. As reported previously by Fletcher et al.,7 less than 5% of tumors recur after 2.5 years. Patients without evidence of recurrence but who were lost to follow-up or died of intercurrent disease or for reasons other than their cancer within a time shorter than 2.5 years, were considered uncertain with respect to recurrence. If a recurrence occurred after 4 years, it was considered to be a late recurrence and possible second primary. A “field problem” refers to any situation where a study of the description of the extension of the tumor, the treatment planning, the check films, the treatment record sheet and the anatomo-pathological report of a recurrence gave rise to strong suspicion that a part of the tumor may not have received the prescribed dose. Actuarial survival curves were calculated by the method described by Bradford Hi11.r3 This method involves the assumption that patients who were not followed up would have yielded the same survival curve as those for whom follow-up information was available. Since only 1 of the patients was lost to follow-up within a time shorter than 4 years after the end of treatment, this assumption is unlikely to bias the results. Values for relative survival were based on an estimate of the survival to be expected if the only cause of death were laryngeal cancer, obtained as illustrated graphically in Fig. 3 (see below). The Chi-square test with Yates’ correction for of continuity6 was used for the comparison differences between results. RESULTS AND DISCUSSION Local
control
The results of first treatment by radical irradiation in relation to local local control of the primary tumor are summarized in Table 2. For the period 1958-71, true recurrences were observed for approximately 24% of tumors (all stages). Another 15% showed
ED = 1000(TDF)(7/5)0~16g(200)-o~53* the TDF (Time, Dose and Fractionation Factor) was computed as described by Orton and Ellis.”
Table 1. TNM classification of patients treated by radical irradiation NO 58-71
N,
72-73
58-71
Total
N,
N2
72-73
58-71
72-73
58-71
72-73
58-71
72-73
Tl-T2
49
16
0
0
3
20
20
2
0
3
7
0 1
70
25
18 1.5
4
T3-T4
47
26
Total
74
36
33
6
0
3
10
1
117
46
Failure analysis of radical radiation therapy of supraglottic laryngeal carcinoma 0 J.
Table 2. Results of first treatment
by radical irradiation
Tl-T2 1958-71 1972-73 No recurrence True recurrence Field problem Recurrence uncertain Late recurrence§ Total
6t + 8$
39 14 8 7 2 70
4 0 2 0 20
et
(I/.
623
in relation to local control
T3-T4 1958-71 1972-73 18 14 9 6 0 47
NIEDERER
9?+4$ 9 1 3 0 26
Total 1958-71 1972-73 57 28 17 13 2 117
27 13 1 5 0 46
tNo evidence of recurrence after an average of 28 months. *No evidence or recurrence after an average of 18 months. QIncludes second primaries.
evidence of a “field problem”, i.e. the patients’ records gave rise to strong suspicion that part of the tumor may not have received the prescribed radiation dose (see Methods). Results from the period 1972-73 also are included in Table 2. The major change in treatment policy during this period was an increase in field sizes, with the most frequent fields lying between 70 and 99 cm2 instead of 37 and 69 cm2 in the earlier period. This change in field size corresponded to more frequent use of cast and compensator. As may be seen from Table 2, the frequency of field problems was much smaller in 1972-73 (2%) than in 1958-71 (15%), probably because of increased use of larger field sizes, and the use of controlled beam direction by means of casts as opposed to free set-ups. It seems possible that the variety of radiation dose fractions used could account for some failures of local control. A scattergram of tumor dose versus overall treatment time is shown in Fig. 1. Failures (open circles) tended to be associated with longer treatment times. For more detailed analysis, a method for comparison of different dose fractionation schedules was required. As one approach to this problem,
0. ?? oxp
60000
2 s z % $ 5000-
0
p#q&&m. A
. *
-#P
+!%#@&4M .
F .
4ooo/
0
j
Ax
10
A..
0
0
‘3
=,I
. 0 x
@&“8
0
:0g.
ho
20
o
30 Overall
treatment
,
,
40
50
1
time(days)
Fig. 1. Scattergram of total tumor dose vs overall treatment time, showing local control, 0; true recurrence, 0; field problem, X; recurrence uncertain, A; and late recurrence, 0 (5 fractions/week).
the concept of equivalent dose was applied (see Methods). The overall results obtained for patients who were treated by radical irradiation, broken down by T and N and by category, are presented in Table 3. Although the small number of patients and rather wide range of equivalent doses makes selection of an optimal dose impossible, equivalent doses below 5060 rad appear to be suboptimal. Regional control In addition to failures of local control, failures of regional control of involved lymph nodes must be considered. A summary of results for primary radical radiation therapy to the positive nodes is given in Table 4. For the period 1958-7 1, true recurrences were seen for 4/33 (12%) of the Ni-N2 nodes; 1 of the 4 received an equivalent dose of less than 5060 rad (Table 3). Only 1 of 10 NJ nodes was classified as a non-recurrence. An additional 74 patients who first were treated between 1958 and 1971 were staged No at the time of first treatment. In 8 (11%) positive nodes appeared subsequently outside of the field of irradiation, either during treatment, or in cases were the larynx showed no evidence of recurrence. Of the 8, 6 were Tl-T2 tumors and 2 were T3-T4 tumors. All were considered to have had a “field problem” at the level of the nodes. No nodes developed in the No patients within the field of irradiation. The use of a larger field after 1971 appeared to reduce the frequency of such problems (l/36 or 3% for 1972-73, compared with 11% for 1958-71). Distant metastases None of the population receiving radical radiation therapy had evidence of distant metastases at the time of first treatment. Of the total of 117 patients who first were treated between 1958 and 1971, 9 (8%) developed clinical distant metastases after treatment; 4 patients had metastases in the lungs, 3 in the brain and 2 had multiple metastases. Among 57 patients who showed no recurrences in the larynx or nodes
14 1, 2
2 12 2 2
18
3
1
1
39
1, 2
1 1 2 8 1 2 1
16
Total
N classification 7600
Total
7
1 2 4
2 4 7 1
0
3
13
4 3 6
1, 2 3, 4
4 23 2 9 1
T classification c4050 406OA550 4560-5050 5060-5550 5560-6050 60606550 6560-7050 7060-7550 >7600
3,4
No recurrence 58-71 72-73
1,2
Equivalent dose
4
1 1 2
1, 2
14
1
1 3 2 3 1 3
1,2
7
1
3 1
1
3 1
14
1 2 8 2
3,4 1
Field problem 58-71 72-73
Recurrence uncertain S-71 72-73
0
1, 2
4
2
2
1
1
3
9
5 1 2 1
7
6 1
1, 2
8
1 4 2 1
2
1
1
3
9
2 1 4 1 1
1
1
1, 2
0
0
3
1
1
6
1
2 2 1
1, 2
7
1
1 1 4
0
3
6
1 2 2 1
1
1
1, 2
2
1
1
0
3
3
1 1 1
0
I, 2
2
1
1
0
3
0
0
I, 2
0
I,2
0
3
0
3,4
Late recurrence 58-71 72-73
1,2 3, 4 1, 2 3, 4 1, 2 3, 4 1, 2 3, 4 1, 2 3, 4 1, 2 3, 4
True recurrence 58-71 72-73
33
0 1 4 5 17 2 3 1 0
1, 2
70
10
3 1 0 2 0 5 1 0 0 1
47
72-73
9
0 0 1 4 4 0 0 0 0
1, 2
20
1
3 0 0 0 0 1 0 0 0 0
26
192 3,4 0 0 0 0 5 11 4 5 10 9 1 1 0 0 0 0 0 0
Total 1,2 394 0 1 1 0 4 4 8 7 35 26 5 6 15 3 1 0 1 0
58-71
Table 3. Influence of equivalent dose on the probability of recurrence of laryngeal tumors treated between 1958 and 1973 by radical irradiation
Failure analysis of radical radiation therapy of supraglottic
laryngeal carcinoma
0 J.
NIEDERER
625
et ul
Table 4. Results of radical radiotherapy of positive (palpable) nodes NI-Nz
Total
N3
58-71
72-73
True recurrence
16 4
7 0
:
0 1
Field problem Recurrence uncertain Late recurrence Total
7 6 0 33
1 1 0 9
2 0 0 10
0 0 0 1
No recurrence
58-71
72-73
58-71
72-73
17~
7
11 9 6 0 43
1 1 1 0 10
after initial radiation therapy, 2 (4%) developed clinical distant metastases. Of the remaining 60 patients, 7 developed distant metastases; 5 of these already had received subsequent surgical treatment in the form of laryngectomy prior to the clinical onset of distant metastases. The frequency of occurrence of distant metastases in the group receiving subsequent surgery for true recurrence was 5/33 (15%). The higher frequency of occurrence of clinical metastases in this group probably was a result of their longer survival time rather than any effect of surgery. Subsequent
treatment
For patients who first were treated between 1958 and 1971, subsequent treatment was received by 44/ 117 patients (380/o), either to the larynx or to the nodes or to both. 37 patients received subsequent surgery, 6 radiation and 1 chemotherapy. In all cases subsequent radiation or chemotherapy was unsuccessful. Among the 37 surgical treatments, 1 laryngectomy and 3 laryngectomy plus neck dissections were performed with no subsequent pathological confirmation of malignancy in the larynx. Two of these laryngectomies were performed for recurrence-like situations, and two for pain, necrotic larynx and gross edema. In the 33 subsequent surgical treatments performed for true recurrences, 21 (64%) were successful because no subsequent recurrence was observed. The large majority (90%) of these subsequent treatments were done within 2 years following the end of the first treatment and nearly 50% were done within the first 6 months. Of the 33 patients who received subsequent surgery for true local or regional recurrences, 19 were classified as being subject to “field problems” either with respect to the nodes or to the larynx in their first treatment by radiation. Evaluation
of end results
Figure 2 shows an actuarial survival curve (see Methods) for the population of patients with supraglottic laryngeal carcinoma who did not die of laryngeal cancer (curve A). This population includes
IO’ 0
1
2
Time zfter
8
I IO
’
first treatment(yrs)
Fig. 2. Actuarial survival curves. Curve A: survival curve for patients with supraglottic laryngeal carcinoma first treated by radical radiation therapy in the interval 1958-71, considered to have died of causes unrelated to their malignancy, whether or not evidence of their malignant disease was still present. Curve B: survival curve for a population with the same age and sex distribution, taken from the 1961 Ontario census. Curve C: survival curve for patients who
subsequently died of laryngeal cancer. all patients for whom cancer was considered not to have contributed to the cause of death. For example, for coronary thrombosis or automobile accidents (but not bronchial pneumonia or suicide) it was assumed that cancer was unlikely to be a contributing cause. The median survival time of this population is 9.8 years. Also shown is the survival curve for a normal population having the same age and sex distribution (curve I?). The median survival for this control population is 15 years, that is, 5 years longer than the population having larynx cancer but not dying of it. The shorter life expectancy of the latter group may be a reflection of an increased risk of ill health in this population resulting from such factors as a life style
626
Biology 0 Physics
Radiation Oncology 0
involving heavy cigarette and alcohol consumption.29.30 Also shown in Fig. 2 is a survival curve for patients
first treated by radical radiation therapy in the interval 1958-1971 who subsequently died of laryngeal cancer (curve C). The median survival time of this population is 1.3 years. Figure 3 shows actuarial survival curves for patients with Tl and T2 tumors, T3 and T4 tumors, and all stages, together with the survival curve for patients who did not die of laryngeal cancer (curve A, Fig. 2). Comparison of the former curves with the latter yields an estimate of the relative survival to be expected if the only cause of death were related to their laryngeal cancer, as well as an estimate of the increase in median life expectancy if none of the patients in each group were to die of laryngeal cancer. Results of these comparisons are given in Table 5. For all stages, the 5-year survival rate is about 48%; the estimated relative survival compared with curve A, Fig. 2 is 61% (i.e. 39% die of laryngeal cancer). Successful control of all laryngeal cancers in this group would increase the median life expectancy by 5.4 years. Principal
causes of failures
Two major causes of failures may be termed technical failures and radiobiological failures. The former
July-August 1977, Volume 2, No. 7 and No. 8
Table 5. Summary of evaluation of end results for patients treated between 1958 and 1971
Stage
S-year actuarial survival (%)
Relative survivalt (%)
Increase in median life expectancy (years)
52 42 48 71
68 55 61 100
4.4 7.0 5.4 -
Tl, T2 T3, T4 Overall Other causes4
tFor method of calculation, see text and Fig. 3. *Only for those patients who did not die from laryngeal cancer (see curve A, Fig. 2).
includes incorrect execution of treatment, field problems and suboptimal tumor doses.7X’0Tu The latter results various from unsolved radiobiological problems such as the presence of hypoxic cells.s,‘2.26 Table 6 summarizes the principal causes of technical failures of local and regional control, and their relative frequencies for the population treated by radical irradiation between 1958 and 1971. Approximately 24% of the treatments failed locally in association with either a field problem or a suboptimal dosage. Of the 43 patients with positive nodes, about 40% of recurrences were associated with field problems or an equivalent dose below 5060 rad. Since Wood and Boag** found evidence that the nodes are similar in their response to the primary, this dose probably was suboptimal. At least 11% of the nonpalpable but subclinically positive nodes recurred because of field problems. Technical failures such as errors in dose calculation or the use of the wrong wedge filter were seen in only 2% of the records; such errors were always discovered promptly and corrected, and probably had no significant effect on frequency of recurrence. Between 1958 and 1971 treatments took place exactly as planned in 46% of patients. In the others, one, two or more changes from the planned treatment took place. The type of change was either in the field size or in Table 6. Principal types of failure of local or regional control for patients treated between 1958 and 1971
Type of failure 0
5 Tjme
after
IO first
treatment
(yr5.j
Fig. 3. Actuarial survival curves for patients with supraglottic laryngeal tumors. Curve A: survival curve for patients who did not die of laryngeal cancer (see Fig. 2). The dashed lines represent the extrapolated survival curves used to estimate the relative survival to be expected if laryngeal cancer were the only cause of death (see Table 5).
Field problem, larynx Field problem, non-palpable nodes Field problem, positive nodes Equivalent dose to tumor ~5050 rad Equivalent dose to positive nodes ~5050 rad
Frequency
Percent
Per cent of total cases
17/117
15
15
8174 9143
11 21
7 8
10/117
9
9
8143
19
7
Failure analysis of radical radiation therapy of supraglottic
of
emphysema
and
low
irradiation
No recurrence True recurrence Field problem or uncertain Total Frequency of recurrence+
6 2+1t 1 10
218
Effect of failures
1 2+1t 5 9
213
NIEDERER et (I/.
on 5-year survival
hemoglobin
in patients
levels
treated
of benefits to be anticipated
Low (
