- Email: [email protected]
Response to Drs. Leibel and Fuks
In1 J Radrorron Onuh~.v B~ol. Phw. Vol. Pnnted in the U S.A. All rights reserved.
24, pp.
387-388
0360.3016/92 $5.00 + .OO Copyright 0 I992 Pergamon Press Ltd.
0 Correspondence
RESPONSE
TO DRS.
LEIBEL
AND FUKS
control, strongly supports Suit’s argument (1) that tumors that fail locally after conventional irradiation do not have established distant metastases at the time of local therapy. Therefore, improvement in primary tumor control (including regional lymphatics) should result in a decreased incidence of distant metastases and higher survival rates. Predictive assays in specific cohorts of patients at high risk for distant metastases are needed to better understand the distinction between metastatic tumor cells and the non-metastatic variants and, therefore, provide data for the selection of candidates for more aggressive initial therapy in a prospective randomized fashion.
To fhe Editor: We greatly appreciate Drs. Leibel and Fuks’ excellent editorial, and we agree with practically all of their comments. It was suggested that a more accurate determination of the annual and cumulative risk of developing distant metastases is obtained by period analysis, with which we concur. This data was presented in Figure 2 (see p. 201, this issue), showing actuarial rate of distant metastasis in each clinical stage by number of patients at each risk period. A table summarizing this data in all patients is included (Table I), showing close agreement with the graphic display. Also, Table 4 (see p. 203, this issue) was modified to show the regression coefficients Leibel and Fuks emphasized Table 2. This issue’s editorial by Leibel and Fuks, along with the review by Suit, H.D., (I) raises a very important, yet unsettled and complex issue, of local failure representing a cause of or a marker for metastatic dissemination. Another hypothesis is that local failure may be a cause of as well as a marker for distant spread. Unfortunately, available information is difficult to interpret. However, the fact that in our analysis, patients with pelvic tumor failure continue to develop distant metastases after the 5th year at a proportionately higher rate than those with tumor Table I. Carcinoma of the uterine cervix annual of distant metastases correlated with pelvic tumor control or failure
M.D. M.D. Radiation Oncology Center Mallinckrodt Institute of Radiology St. Louis. MO 63 I 10 HUMBERTO
CARLOS
Local tumor control
O-l
481933 (5%) 461862 (5%) 261779 (3%) 13/72 I (2%) lo/673 (2%) 91622 (1%) 5/575 (1%) 2/530 (.40/o) l/478 (.20/o) l/442 (.2%) 2/323 (.60/o) l/281 (.4%) O/232 O/183 o/145
1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-10 10-I 1 11-12 12-13 13-14 14-15
HDR VS LDR FOR CA CERVIX: HIGH BIASED REPORTING?
Variable Pelvic tumor control Stage Endometrial extension Histology Volume of disease Age
5 0.0001 IO.0001 0.001 0.06 NS NS
Local failure
pvalue
731278 (26%) 43/155 (28%) I l/82 (13%) I l/58 (19%) 3/38 (8%) 2/33 (6%) l/28 (4%) 3/25 (12%) 2/21 (10%) O/16 (0%) 3/14 (21%) l/11 (9%) l/8 (13%) l/7 (14%) o/4
0.0000 0.0000 0.000 1
Final model regression coefficient (&SE)
I .6845 0.2060 -0.4578 0.0363 -0.2120 -0.0042
f * f f + f
RISK
OR
incidence To fhe Editor: In order to support her contention that HDR brachytherapy for Ca cervix is “high risk,” Dr. Eifel asserts in her Editorial in this issue (5) that, from radiobiological principles, HDR cannot be as good as LDR and that there is no clinical evidence that HDR treatments are effective. Neither of these assertions is correct, as I will now demonstrate.
Radrobiological considerations Dr. Eifel states that HDR is radiobiologically inferior because HDR can only be equivalent to LDR if ‘I. in order to compensate for the loss of dose rate effect . the dose delivered to critical normal tissues in consistently much lower than that to the tumor,” which she states is generally not the case for Ca cervix patients. However, this “loss of doserate effect” can work to the advantage of HDR. Specifically, if the rate of repair of tumor cells exceeds that of cells in late-responding normal tissues, there is a potential gain in therapeutic ratio by replacing LDR therapy, for which there is more opportunity for repair oftumor compared to normal cells during the time of irradiation by HDR, for which there is no repair during each short exposure but full and equal opportunity for repair between fractions. Of course, a certain minimum number of fractions of HDR is necessary before this “radiobiological advantage” is achieved, and Dale (3), using the linear-quadratic model with the dose to normal tissues assumed to be the same as that to the tumor, demonstrated that this minimum number of fractions is of the order of six. If the dose to normal tissues is less than that to the tumor, then less than six fractions are required. However, such an analysis is clearly an oversimplification since “dose” is not a single number for Ca cervix treatments because the dose distribution is highly inhomogeneous. Also, Dale assumed in his calculation that half-times for repair of tumor and normal tissue cells were 0.5h and 1.5h, respectively, for which there is some evidence ( I, 4, 10, 1 I, 12) but also considerable controversy (6). Clearly. the only fair test is to review clinical results.
0.0000 0.0247 0.1886 0.6660 0.0000 0.0001 I .ooOO 0.0000 0.1135 0.0092 0.0368
Table 2. Multivariate analysis for all stages with actuarial distant metastasis rate as endpoint (revision of Table 4) P-value of variables entered into the model
PEREZ,
1. Suit. H. D. Local control and patient survival. Int. J. Radiat. Oncol. Biol. Phys. 23:653-660;1992.
Patients with DM/patients at risk Annual interval
FAGUNDES,
A.
0. I277 0.0309 0.1336 0.0179 0.1788 0.004
Exponent of the regression coefficient
Clinical evidence Dr. Eifel asserts that HDR results cited in the literature and the HDR data from our survey of 56 institutions (9) do not compare favorably with LDR results achieved with careful application of treatment according to Fletcher guidelines. As evidence, she cites the “outstanding results” achieved by the “Groupe des 9,” a consortium of nine French institutions which initiated a cooperative study of Ca cervix LDR “Fletcher-type”
5.3895 I .2287 0.6326 I .0369 0.8090 0.9958 387
24, pp.
387-388
0360.3016/92 $5.00 + .OO Copyright 0 I992 Pergamon Press Ltd.
0 Correspondence
RESPONSE
TO DRS.
LEIBEL
AND FUKS
control, strongly supports Suit’s argument (1) that tumors that fail locally after conventional irradiation do not have established distant metastases at the time of local therapy. Therefore, improvement in primary tumor control (including regional lymphatics) should result in a decreased incidence of distant metastases and higher survival rates. Predictive assays in specific cohorts of patients at high risk for distant metastases are needed to better understand the distinction between metastatic tumor cells and the non-metastatic variants and, therefore, provide data for the selection of candidates for more aggressive initial therapy in a prospective randomized fashion.
To fhe Editor: We greatly appreciate Drs. Leibel and Fuks’ excellent editorial, and we agree with practically all of their comments. It was suggested that a more accurate determination of the annual and cumulative risk of developing distant metastases is obtained by period analysis, with which we concur. This data was presented in Figure 2 (see p. 201, this issue), showing actuarial rate of distant metastasis in each clinical stage by number of patients at each risk period. A table summarizing this data in all patients is included (Table I), showing close agreement with the graphic display. Also, Table 4 (see p. 203, this issue) was modified to show the regression coefficients Leibel and Fuks emphasized Table 2. This issue’s editorial by Leibel and Fuks, along with the review by Suit, H.D., (I) raises a very important, yet unsettled and complex issue, of local failure representing a cause of or a marker for metastatic dissemination. Another hypothesis is that local failure may be a cause of as well as a marker for distant spread. Unfortunately, available information is difficult to interpret. However, the fact that in our analysis, patients with pelvic tumor failure continue to develop distant metastases after the 5th year at a proportionately higher rate than those with tumor Table I. Carcinoma of the uterine cervix annual of distant metastases correlated with pelvic tumor control or failure
M.D. M.D. Radiation Oncology Center Mallinckrodt Institute of Radiology St. Louis. MO 63 I 10 HUMBERTO
CARLOS
Local tumor control
O-l
481933 (5%) 461862 (5%) 261779 (3%) 13/72 I (2%) lo/673 (2%) 91622 (1%) 5/575 (1%) 2/530 (.40/o) l/478 (.20/o) l/442 (.2%) 2/323 (.60/o) l/281 (.4%) O/232 O/183 o/145
1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-10 10-I 1 11-12 12-13 13-14 14-15
HDR VS LDR FOR CA CERVIX: HIGH BIASED REPORTING?
Variable Pelvic tumor control Stage Endometrial extension Histology Volume of disease Age
5 0.0001 IO.0001 0.001 0.06 NS NS
Local failure
pvalue
731278 (26%) 43/155 (28%) I l/82 (13%) I l/58 (19%) 3/38 (8%) 2/33 (6%) l/28 (4%) 3/25 (12%) 2/21 (10%) O/16 (0%) 3/14 (21%) l/11 (9%) l/8 (13%) l/7 (14%) o/4
0.0000 0.0000 0.000 1
Final model regression coefficient (&SE)
I .6845 0.2060 -0.4578 0.0363 -0.2120 -0.0042
f * f f + f
RISK
OR
incidence To fhe Editor: In order to support her contention that HDR brachytherapy for Ca cervix is “high risk,” Dr. Eifel asserts in her Editorial in this issue (5) that, from radiobiological principles, HDR cannot be as good as LDR and that there is no clinical evidence that HDR treatments are effective. Neither of these assertions is correct, as I will now demonstrate.
Radrobiological considerations Dr. Eifel states that HDR is radiobiologically inferior because HDR can only be equivalent to LDR if ‘I. in order to compensate for the loss of dose rate effect . the dose delivered to critical normal tissues in consistently much lower than that to the tumor,” which she states is generally not the case for Ca cervix patients. However, this “loss of doserate effect” can work to the advantage of HDR. Specifically, if the rate of repair of tumor cells exceeds that of cells in late-responding normal tissues, there is a potential gain in therapeutic ratio by replacing LDR therapy, for which there is more opportunity for repair oftumor compared to normal cells during the time of irradiation by HDR, for which there is no repair during each short exposure but full and equal opportunity for repair between fractions. Of course, a certain minimum number of fractions of HDR is necessary before this “radiobiological advantage” is achieved, and Dale (3), using the linear-quadratic model with the dose to normal tissues assumed to be the same as that to the tumor, demonstrated that this minimum number of fractions is of the order of six. If the dose to normal tissues is less than that to the tumor, then less than six fractions are required. However, such an analysis is clearly an oversimplification since “dose” is not a single number for Ca cervix treatments because the dose distribution is highly inhomogeneous. Also, Dale assumed in his calculation that half-times for repair of tumor and normal tissue cells were 0.5h and 1.5h, respectively, for which there is some evidence ( I, 4, 10, 1 I, 12) but also considerable controversy (6). Clearly. the only fair test is to review clinical results.
0.0000 0.0247 0.1886 0.6660 0.0000 0.0001 I .ooOO 0.0000 0.1135 0.0092 0.0368
Table 2. Multivariate analysis for all stages with actuarial distant metastasis rate as endpoint (revision of Table 4) P-value of variables entered into the model
PEREZ,
1. Suit. H. D. Local control and patient survival. Int. J. Radiat. Oncol. Biol. Phys. 23:653-660;1992.
Patients with DM/patients at risk Annual interval
FAGUNDES,
A.
0. I277 0.0309 0.1336 0.0179 0.1788 0.004
Exponent of the regression coefficient
Clinical evidence Dr. Eifel asserts that HDR results cited in the literature and the HDR data from our survey of 56 institutions (9) do not compare favorably with LDR results achieved with careful application of treatment according to Fletcher guidelines. As evidence, she cites the “outstanding results” achieved by the “Groupe des 9,” a consortium of nine French institutions which initiated a cooperative study of Ca cervix LDR “Fletcher-type”
5.3895 I .2287 0.6326 I .0369 0.8090 0.9958 387