Sequencing of chemotherapy and radiation therapy

Int. J. Radiation

Oncology

Pergamon

Biol. Phys.. Vol. 28, No. 3, pp. 783-787, 1994 Copyright 0 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0360-3016/94 $6.00 + .OO

??Correspondence

RADIATION AS ADJUNCIWE THERAPY TO CYSTECTOMY FOR BLADDER CANCER: IS THERE A DIFFERENCE FOR BILHARZIAL ASSOCIATION?

tigating, in controlled clinical trials, the adding chemotherapy for the high risk groups. MOHAMED

To the Editor: The article by Reisinger et al. (2) reported elaborately on the survival of bladder cancer patients treated with cystectomy and adjuvant radiotherapy, mainly 4000-4500 cGy postoperatively plus 500 cGy preoperatively. They emphasized on the importance of the use of pathological staging for more accurate comparison of the results of different therapeutic modalities. We previously reported on similar groups of patients treated in a randomized trial for patients with bladder cancer associated with bilharziasis. Although there is a documented clinicopathological differences between bilharzial and non bilharzial bladder cancer, the 5-year survival of the patients in the 2 series, (2, 4) were similar. Table I showed the 5-year disease-free survival for all subgroups in Reisinger et al. (2) and Zaghloul et al. (4) series. This emphasized that there was no effect of the association with bilharziasis when the same treatment was applied (Cystectomy and postoperative radiotherapy) and when reporting on the same pathological stage. The main differences were in the late presentation (probably due to the overlap between cancer signs and symptoms and that of simple bilharziasis), the predominance of squamous variety, the higher male predominance and the younger age at presentation. Moreover, the local pelvic control were excellent in the two series that may confirm the belief that postoperative radiotherapy has a better opportunity and more sure way dealing with the microscopic residuum which may be left after surgery. However, the main disadvantage of adopting postoperative radiotherapy was the high incidence of late gastrointestinal complications that amounted to 37% in Reisinger et a/. series (2) and 36% in Zaghloul et al. series (4) that used the conventional postoperative regimen (5000 cGy in 5 weeks). The multiple daily fractionation (MDF) regimen giving 3750 cGy in 2 weeks in a three daily fractions of 125 cGy led to 10% incidence of chronic enteritis. Such hyperfmctionated regimen with decreasing the dose per fraction decrease the chronic intestinal complication rate nearly to that of cystectomy alone (7-8%) ( 1, 2, 4). The reported discrepancy between the high local pelvic control rates and the moderate 5-year disease-free survival rates proposed the importance of the systemic causes of failure in such patients. In a retrospective study of 358 patients with carcinoma in bilharzial bladder, treated either with radical cystectomy alone, short course preradiooperative radiotherapy (2000 cGy in I week) or postoperative therapy (5000 cGy/5 weeks or 3750 cGy/2 weeks with MDF), the 5-year actuarial incidence of distant metastasis was 23% (5). The independent risk factors that determine distant metastasis, using multivariate analysis, were nodal involvement, pathological stage, and histopathological grade. The adoption of preoperative or postoperative regimens did not influence the actuarial distant metastasis rate (5). This confirmed the finding of Reisinger et al. (2) that preoperative radiotherapy did not decrease or prevent distant metastasis, as dissemination mostly occurred prior to initial therapy and not due to surgical manipulation. The results of the 2 series emphasized the suggestion of Shipley (3) for the need for inves-

Table I. Actuarial

et al. (2)

No. patients

Survival %

Zaghloul

Survival %

Pz (grade 3 and 4)

11

57

-

-

P 3A

12

P3B

10

56 39 50 33

48 79 26 36

64 48 39 14

P4 Node +

7 6

Cancer

Institute,

1. Mathur, V. K.; Krahn, H. P.; Ramsey, E. W. Total cystectomy for bladder cancer. J. Urol. 125:784-786; 198 1. 2. Reisinger, S. A.; Mohiudin, M.; Mulholland, S. G. Combined preand postoperative radiation therapy for bladder cancer-A ten year experience. lnt. J. Radiat. Oncol. Biol. Phys. 24:463-468; 1992. 3. Shipley, W. U. Radiation as adjunctive therapy to cystectomy for bladder cancer. Int. J. Radiat. Oncol. Biol. Phys. 25: 153-I 54; 1993. 4. Zaghloul, M. S.; Awwad, H. K.; Akoush, H. H.; Omar. S.; Soliman, 0.; El-Attar. I. Postoperative radiotherapy of carcinoma in bilharzial bladder: Improved disease free survival through improving local control. Int. J. Radiat. Oncol. Biol. Phys. 23:5 1 l-5 17; 1992. 5. Zaghloul, M. S.; Naggar, M. E.; Halim, A. A.; Kalawy, M. E.; Malt, 0. E.: Gamil, M. Distant metastasis in carcinoma in bilharzial bladder. Int. J. Radiat. Oncol. Biol. Phys. 1993 (in press).

SEQUENCING OF CHEMOTHERAPY RADIATION THERAPY

AND

To the Editor; The article by Buchholz ef al. (2) concluded that, in patients with carcinoma of the breast whose management requires chemotherapy and radiation therapy, in addition to surgery, an adverse effect on survival and local control will result should the radiation program follow that of the systemic chemotherapy. This opinion was based on 105 patients whose disease covered the entire spectrum of breast cancer pathology, namely from Tl NO tumors to T4, inflammatory, Ml (supraclavicular nodes). The patients’ Stage is not stated therefore any comparison to previously published series is not possible. The surgery has varied from biopsy only to lumpectomy to mastectomy. The chemotherapy includes eight different programs. The authors use this mixture to their advantage trying to prove that a unifying truth exists in that no matter how early or advanced a breast cancer is, radiation therapy following chemotherapy is less effective. Unless we were to assume that T 1 NO tumors are biologically similar to T4, inflammatory, or metastatic breast carcinomas, the authors are violating the statistical rules of sampling and their conclusion should be dismissed as wishful thinking. Their conclusion would have been true if they had shown statistically significant differences within each Stage-from I to IV- and then proceeded to publish unifying data. The following additional comment can be made. Disregarding momentarily the patient mixture (Stages I-IV) there are 48 patients who had breast conserving surgery divided into two groups, the early radiation group (26) and the delayed radiation group (22). The actuarial survival at 8 years is 96.2% for the former and 48.3% for the latter group. The standard error on the basis of Figure 5 is 0.1 for the early and 0.3 for the late group. Computing the value ofz to compare the survival difference between the two groups we find it to be I .5 1, therefore, not statistically significant at the 5% level. Computing the z value for local control on the basis of date from Figure 4 we find it to be I, again not statistically significant. Thus, even with the unacceptable mixing of patient populations the authors fail to make their point as far as the lumpectomy patients is concerned. Recht et al. (4) suggested that delay of radiation therapy may increase the potential of local failure. This statement was based on 4 patients of 17 with four or more positive lymph nodes who recurred locally following lumpectomy, chemotherapy, and radiation therapy in sequence. The actuarial recurrence rate was given as 30% at 5 years. In a recent update it is stated that the delayed radio-therapy group contained patients with

et al. (4)

No. patients

systemic

M.D.

Radiotherapy Department, National From El Khalig. Cairo, Egypt

5-year survival in the 2 series

Reisinger

S. ZAGHLOUL,

of adjuvant

783

1. J. Radiation

784

Oncology

0 Biology 0 Physics

heavier lymphatic system burden (3). The reader may assume that this group is not comparable to those receiving early radiotherapy. We have routinely sequenced chemotherapy and radiation therapy for Stage II patients with carcinoma of the breast. In a recent update (l), we find the 5-year actuarial survival rate to be 85% and the adjusted disease specific survival rate to be 90%. Two local recurrences were seen during this period of time. To this date we have not detected any adverse effects resulting from this policy. Issues pertaining to the treatment of carcinoma of the breast Stages I and II have been traditionally separated in the oncologic literature from those dealing with Stages III and IV. Buchholz et al. pay no consideration to staging nor to the statistical process therefore in this reader’s opinion their data are invalid. JOHN ANTONIADES, M.D.

Division of Radiation Oncology Lankenau Hospital Hahnemann University Antoniades, J.; Chen, C.; Gabuzda, T. G.; Gilman, P. B.; Harris, D. T.; et al. Stage II carcinoma of the breast treated in sequence by surgery, chemotherapy and irradiation (Abstr.). Proc. Am. Sot. Clin. Oncol. 12:83; 1993. Buchholz, T. A.; Austin-Seymour, M. M.; Moe, R. E.; Ellis, G. K.; Livingstone, R. B.; et al. Effect of delay in radiation in the combined modality treatment of breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 26123-35; 1993. Harris, J. R.; Recht, A. Sequencing adjuvant chemotherapy and radiotherapy in breast cancer patients. Int. J. Radiat. Oncol. Biol. Phys. 26:183-185; 1993. Recht. A.: Come. , S. E.: Gelman. R. S.: Goldstein. M.: Tishler, S.: et al. Integration of conservative surgery, radiotherapy, and chemotherapy for the treatment of early-stage, node positive breast cancer: Sequencing, timing and outcome. J. Clin. Oncol. 9:1662-1667; 1991.

RESPONSE

TO DOCTOR

ANTONIADES

To fhe Editor: In his letter to the editor, Dr. Antoniades criticizes the statistical interpretations and manner of data presentation used in our article concerning the sequencing of chemdherapy and radiation in breast cancer patients (1). In response, we wish to clarify the specific concerns of Dr. Antoniades, and to show that his criticisms are not justified. In our study, we investigated the effect of timing of chemotherapy and radiation on treatment outcome for both patients with advance stage and early stage disease. Our study was justified by the clinical importance of treatment sequencing in both of these groups of patients. In addition to analyzing the group as a whole, we provided crude and actuarial local control and survival data for patients stratified according to the stage of primary tumor, nodal status, and type of surgical procedure (breast preserving surgery vs mastectomy). Our findings suggested that an extended delay in the initiation of radiation led to an adverse outcome for the group of patients as a whole. Our subgroup analyses revealed that the adverse effect of radiation delay was predominantly seen in the patients with early stage disease treated with a breast conserving surgery. It is true that this subgroup population was not identical to the population studied in the earlier Joint Center of Radiation Therapy (JCRT) report (4). Because all patients treated with chemotherapy and radiation were analyzed in our study, our breast preservation surgery group included 8 patients with Stage I disease (4 in the early radiation group and 4 in the delayed radiation group). However, all 8 of these patients were without histories of local or distant failures, and thereby did not contribute to any of the differences in outcome noted in the breast preservation subgroup. Because of this, we feel that our results in the patients treated with breast preservation surgery are in agreement with the earlier work from the JCRT. Dr. Antoniades’ criticism of our statistical interpretation is likewise unjustified. In our study, comparison of actuarial and survival data were made with a two-sided log rank test (2, 3). This is the appropriate test when comparing local control or survival curves across all points in time, rather than at a single point in time. Comparing actuarial data at a single time point risks misrepresenting an important statistical difference, or stating a difference that does not exist. Using a log rank test, the differences in the local control and survival curves for the early and delayed radiation subgroups treated with breast preserving surgery

Volume

28, Number

3, 1994

achieved statistically significant p values of p = 0.020 and p = 0.007 (1). Even with the restrictive methodology of analyzing only the last point in time on the curve (as used by Dr. Antoniades in his editorial), these differences continue to reach statistically significant p values. Dr. Antoniades was incorrect in his interpretation of the standard error of the curves. The actuarial g-year local control rate for the early radiation group was 100% while the > 4 month local control rate for the delayed radiation aroun was 80.2% (standard error of kO.095). The actuarial Xyear over21 survival rate forihe early radiation group was 96.2% (standard error of ?0.037), while the 84-month overall survival rate for the delayed radiation group was 48.3% (standard error of +O. 174). As we stated in our conclusions, both the earlier JCRT report and our study were retrospective analyses that lack the conclusiveness of a randomized trial. Nonetheless, until the results from such a trial become available, we feel that the retrospective evidence that is currently available suggests that the completion of chemotherapy can be delayed to avoid the : risk of an extended delay in the initiation of radiation. THOMAS A. BUCHHOLZ, M.D. SCOTT E. LANCASTER, M.S. Department of Radiation Oncology,

University of Washington 1959 N.E. Pacific St. Seattle, WA 98 195

RC-08 Medical Center

Buchholz, T. A.; Austin-Seymour, M. M.; Moe, R. E.: Ellis, G. E.; Livingston, R. B.; Pelton, J. G.; Griffin, T. W. Effect of delay in radiation in the combined modality treatment of breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 26( 1):23-35; 1993. Cox, D. R.; Oakes, N. Analysis of survival data. New York, NY: Chapman and Hall; 1988. Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chem. Rep. 5: 163- 170; 1966. Recht, A.; Come, S. E.; Gelman, R. S.; Goldstein, M.; Tishler, S.; Gore, S. M.; Abner, A. L.; Vicini, F. A.; Silver, B.; Connolly, J. L.; Schnitt, S. J.; Coleman, C. N.; Harris, J. R. Integration of conservative surgery, radiotherapy, and chemotherapy for the treatment of earlystage, node-positive breast cancer: sequencing, timing, and outcome. J. Clin. Oncol. 9:1662-1667: 1991.

TO “OPTIMIZATION OF LE’ITER IN RESPONSE RADIATION THERAPY AND THE DEVELOPMENT OF MULTILEAF COLLIMATION” BY ANDERS BRAHME To the Editor: In a recent editorial on the “Optimization of Radiation Therapy and the Development of Multileaf Collimation (l),” Dr. Anders Brahme claimed that the number of radiotherapy beams for optimal dose distributions (assuming optimal beam intensity profiles), will often be 3 to 5, rather than a large number (e.g., continuous rotation delivery), because too many beams “. may cause adverse reactions due to too large irradiated volume.” We would like to point out that this generalization is not supported in the literature, and is indeed contradicted by published examples. We also describe what we see as the radiobiological and physical rationales for being able to deliver a large number of intensity modulated beams for radiotherapy. Webb (10) has published a careful study of computationally optimized dose distributions using varying numbers of intensity-modulated beams. For his irradiation geometry, in which two spherical organs-at-risk are embedded in a larger spherical tumor volume, he showed that the prediction of normal tissue complication probability (NTCP) is kept lowest, for the same tumor control probability (TCP), when a large number of beams is used (2 1 coplanar beams achieved a TCP of 94% at an NTCP of 5%). This is in contrast to much poorer results for three coplanar beams (TCP 19% at an NTCP of 5%). Bortfeld et al. (2) have also remarked‘that, typically, at least 7-9 (coplanar) beams are needed, judging from organ dose-volume histograms, to provide optimal dose distributions. In accord with these results, we argue that radiotherapy optimization using a large number of beams with non-uniform intensity is attractive due to: the physical property of rapid dose falloff on all sides of the target volume (cf. Holmes et al. (5)), combined with the radiobiological principle that, for the same integral dose, spreading lower doses over larger volumes