Fruit for thought

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I. J. Radiation Oncology 0 Biology 0 Physlcb M.H., Hendrickson, F.R.: Fast neutron radiotherapy for locally advanced prostate cancer: Results of an R TOG randomized stud) Int. J. Radiat. Oncol. Biol. Phys. 11: 1611-1627, 1985. Maor. M.H.. Gillesuie. B.. Peters. L.J.. Wambersie. K.. Griffin. r.W.; Thorn’=, F.J.:G&ddder, P.: Neutron therapy in’ceriical call cer: Results of a phase II RTOG study. ht. J. Rndiat. Oncol. Biol Phys. 12(l): 99- 100, 1986. Maruyama, Y.: Cf-252 neutron brachytherapy: An advance tar bulky localized cancer therapy. Monograph. Nuclear Sciewe _ilp plications, Section B. London, Halwood. 1984, pp. 677-748. Maruyama, Y., Beach, J.I.., Hazle, J., Ashtari, M., Schroy, C.B Therapeutic dosimetry for Cf-252 neutron brachtherapy of pelvic cancer. Int. J. Radiat. O,tcol. Biol. Phys. 11: 927-935, 1985. Maruyama, Y., Feola, J.M., Beach, J.L.: A tumor/normal tissue advantage for low dose rate neutron brachytherapy. Illr. .! Radiur Oncol. Biol. Phys. 9: 1715-1121, 1983. Maruyama, Y., Kryscio, R., van Nagell, J.R., Yoneda, J.. Donald son, E., Hanson, M., Beach, J.L., Feola, J.M., Martin, A., Parkei. C.: Clinical Trial of “*Cf neutron brachythzrapy vs. conventional radiotherapy for advanced cer vital cancer. Iut. J. Raditrt. One (11 Biol. Phys. 11: 1475-1482, 1985. Maruyama, Y., van Nagell, J.R., Beach, J.L.: Cf-?52 (Ct) neutron brachytherapy (NT): Isodose configuration and local tumor rr sponses. Proc. 8th Int. C’ong.Rad. Rex 1987, p. 3 19. Medical Research Council Neutron Therapy Working Group: ‘y comuarative review of the Hammersmith (1971.-75) and Edit, burgh (1977-82) neutron therapy trials of certain canc?:s ot rhr oral cavity, oropharynx, larynx and hypopharynx. BGt. J. Kmd~ol 59: 429-440.1986. Peters, L.J., Maor, M.H., Laramore. GE., Griffin, T.W., He11 drickson, F.R.: Review of clinic:tl results of fast neutl’on theldpy m the U.S.A. In C’ulifortrizm-252 Brachytherapy ulld Fast Ntiutron Therapy, Maruyama, Y.. et al. (Fds.). London, Haluood. 1986. pp. 243-253 I‘sunemoto, I~., Morita, S., Ar,ii, T., Kusutani. Y.. Kurisu. A Umegaki. Y.: Results of clinical trial with 30 MeV d-Be nrutlolls at NIRS In 1keatrrlerlt oj’Kudic,,.eJi.stuttt C’mwts, M. Abe. K Ss hamato, T.B Phillips (Eds ) N. Holland, Els&er. 1979. pp I I5

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APPLES

AND ORANGES 1N THE PROSTATE: ‘1’0 TIJRP OR NOT TO ‘I’URP?

To the Editor: The recent article by Kuban et al. is the second in a series which attempts to refute the adverse effect oftransurethral reset tion.‘** It is perhaps not surprising that they have not observed the effect we desribed, as once again they have not examined the same sub-group of patients. That sub-group is the intermediate and poorly differentiated Stage C patients treated with external beam therapy.4a5v9*”Not only is the histologic/stage sub-division not examined, but an unknown number ofpatientswere treated with I’25implants (perhaps few intermediate or poorly differentiated Stage C patients). In the current article there were 80 patients with moderate or poorly differentiated Stage C tumors and 43 patients underwent TURP while 37 patients had no TURP. Although these are not large numbers, they may support one view or the other. If the differences are marked, that is, 50% metastasis vs 25% metastasis, they would be different at the .05 level. (Krall, personal communication, November, 1987). Every study that has examined this sub-group has demonstrated an adverse effect of TURP on metastasis and survival.2~4~5*” (Hanks, GE., personal communication, 1988) yet an increase inlocal recurrence has not been a consistent observation in these reports. In contrast, every report not demonstrating a TURP effect has not examined the effected sub-group including a recent report of surgically treated T- 1 and T-2 tumors by Paulson et al.3*6-8*‘ol In Table 4 of Kuban et al.’ they purport to show a significant (p = .04) increase in local recurrence in patients of all stages with poorly differentiated tumors who undergo TURP compared to those who do not underao TURP (42% TURP vs 20% no TURP). Yet in patients with mod&tely differentiated tumors the reverse e&t was ibserved with an increase in local recurrence with no TURP (22% TURP vs 36% no TURP). This was reported as not significant, although the p value for that “reverse effect” group is .08 and perhaps should habe been included as similar values were indicated in Tables 2,3, dud 7 ot Kuban et al,’ Thus, with farily similar levels of significance (.04 vs .08) the data

srptembel

1988, Volume 15, Number 3

ISinternally contradictory regarding the direction of effect of TURP UI rlo 1 URP on local recurrence. Indeed. by combining the intermediatr and poorly differentiated tumors the frequency of local recurrence is essentially identical (3 1% vs 30%). Furthermore, since small number\ were involved in these comparisons, a Chi square test for significant:,, ,hould incorporate a Yates correction for continuity.’ Using the datti tram I’able 4, Kuban et al.,’ the Yates corrected comparison indicati*c. there is no significant increase in local reccurrence for TURP in tnc poorly differentiated tumors or for needle biopsy in the inter mediate oillerentiated tumors (p = .09, .I7 respectively). The thought of an adverse effect of transurethral resection is objz< nonable to some urologists as they feel it implies poor care.” Poor C’IL~ is unplied only if the ‘I‘I.IRP was done for diagnosis lather than to rt’ l~yrr obstruction, and it appears that was the case in 1973 but nul 1~1 lnz same extent in patients diagnosed in 1978.4 I he authors generally get the last word in a discussion of this surl. tierhaps this letter c:fil &rnulate what in the past both curlespondcnt ~3 and discussion ha\< iiigt J Lumparison ofoutcome for the illrovlly cl;tl<~~rli,~t?‘Stage J (‘ patients treated with estenal beam ld1113tll,l.iil:‘<+r\ G.E. HANKS, M.D. Dept. of Radiation Therapy Hospital ofthe University of l’erlrrs)~val~~a Fox Chase (‘ancer Center Central and Shelmire Aves. Philadelphia. PA 19 I 1 1 Armitage, P.: Statistical Method.? i,l Medical Re.seuwh. NY, W11cy &Sons,Pub. 1971,~~. 134. 135. hider, J.S., Haferman, M.D.: Dose tiansul,ethral resection dissrml nate prostatic cancer? proc. RSNA 1984, p. 156. I-owler, J.E., Fisher, H.A.G., Kaiser, D.L., Whitmore, W.F.: Rela tionship of pretreatment transurethr,al resection of the prostate to ,urvival without distant metastases in patients treated with “‘1 unplantation for localized prustatic canLer. Chrrwr53: I 85 7- 186.:. 1984. Hanks, G.E.: Optimizing the radiation treatment and outcome of prostate cancer. Irrr. J. Rudiat. Om~ol. Biol. I’hy.~. 11: 1235 -1243. 1985. Hanks, G.E., Leibel, S.A., Kramer, S.: l he dissemination ofcancel by 1 UR of locally advanced prostate C’IIICCI.J. I’rol. 129: 309 ill, 1983. Hoffman. G.S., Scardino, P.‘l ., C’arlton, C .E.: -1he eflect of1 URP on survival and dissemination ofdiseasein prostatic cancer. /‘/~lc/l .AUA 1983. p. 195. Kuban, D A., El-Mahdi, A.M., Schellhanune~-, P.k..: The effect of I IJRP on prognosis in prostatic car~inama. itif. J. Radial. &ml Biol. ~\&13_1653-1659. 1987. Kuban. D.A.. El-Mahdi. A.M.. Schellhammer. P.F.. Babb. 1 .J I‘he effect of transurethral prostatic resection on the incideilce ot osseous prostatic metastasis. Cancer 56: 96 1- 964, 1985. Leibel, S.A., Hanks, G.E., Kramer, S.: Patterns of care outcome studies: Results of the national practice in adenocarcinoma of the prostate. Int. J. Radiat. Oncol. Biol. Phys. 10: 401-409, 1984. Paulson, D.F., Cox, E.B.: Dose transurethral resection ofthe pros tate promote metastatic disease? J. Ural. 138: 90.-9 1, 1987. Pilepich, M.V., Krall, J.M., Hanks. G.E., Sause, W.T., Baerwald. H., Russ, H.H.. Perez, C.A.. Zinninger, M., Martz. K.L.: Correla,. tion ofpre-treament ?‘URP and Prognosis of patients with Stage C Carcinoma of the prostate treated with definitive radiutherapy-RTOC; Expencnce. Im. J. Ku&at. OrrC,ol.Biol Phyr 13: 195 -199. 1987. FRUIT FOR THOUGH’1 To the Editor: Our recent study regarding the effect of transurethxal resection in patients with prostate cancer suggests that tumor character. istics rather than the surgical procedure it&f may overwhelmingly de. termine ultimate outcome. The most basal issue here seems to be mechanical disruption of tumor cells, launching same into vascular than. nels on the way to future metastatic sites. All patients undergoing this procedure, and therefore with the potential for developing associated tumor cell dissemination, were studied impartially as they have been by multiple authors who have either devoted reports to or included discussIon of TURP ‘,3-‘oThree major treatment modalities, prostatec-

Correspondence o tow, ’ 12’1implantation,4 and external beam irradiation,3*5*6**-‘have now been represented. Depending on the particular report to which one refers, various subgroups have shown statistically significant (z, < .05) evidence of the possible adverse effect of TURF: I&Gowan’i B, and BT(~).~ -. ,_ Hanks’ T1 and T,. MD and PD.’ Fowler’s B.’ Foreman’s C. grade III,’ and %lepich’s’C, Gleason 6110 with no&ml serum acid phosphatase? The only major group omitted is Stage A2, where actual comparison with a NO TURP group is not possible. It would appear that we are dealing not simply with apples and oranges but with peaches, plums, and pears as well. The RTOG study (Pilepich and Hanks et al.) on this topic, containing 494 Stage C patients, shows only a “trend approach(ing) significance” in the Gleason 6-7 (MD) group and no statistical significance in the Gleason 8-10 (PD) category when analyzing the effect of TURP on the incidence of distant metastasis. It is only when these two groups are combined that the resulting comparison to the NO TURP-groip becomes “highly significant”.’ Neither has every study examining a similar group of patients found an adverse effect of TURP, particularly, 55 I externally irradiated Stage C patients reported on by a single institution. ‘O We are not opposed to analyzing Dr. Hanks’ favored subgroup but certainly wonder why the disseminating effect of TURP would only apply to Stage C, MD and PD tumors. What of well-differentiated lesions which we know have the potential to metastasize even without manipulative intervention? Logically, Stage B2, MD and PD neoplasms should also have adequate numbers of cells to free into blood vessels and, in fact, depending on the amount of tumor resected, may even equal Stage C tumors in that regard. Despite suggested statistical manipulations, the local recurrence rate in our patients with poorly-differentiated tumors who had TURP was more than twice that of those patients who did not undergo TURP, p = .04 by Fisher’s Test. According to Fisher and Yates,2 the latter’s correction is used with cell sizes >lOO but ~500, while the former’s statistical test is applied to cell size i 100. Our data also clearly showed that when patients are statified by local tumor control, TURP had no effect on actuarial survival. Finally, these authors do not want nor expect to have the last word on this issue. To quote Pilepich et al., too much remains “unresolved”.’ DEBORAHKUBAN, M.D. ANAS EL-MAHDI, M.D., Sc.D. PAUL SCHELLHAMMER,M.D. Department of Radiation Oncology Department of Urology Eastern Virginia Medical School Norfolk, VA 23507 1. DeLaney, T.F., Shipley, W.U., O’Leary, M.P., Biggs, P.J., Prout, G.R.: Preoperative irradiation, lymphadenectomy, and 12’1implantation for patients with localized carcinoma of the prostate. &t. J. Radiat. &col. Biol. Phys. 12: 1779-1785, 1986. _ 2. Fisher. R.A.. Yates. F.: Statistical Tables for Biolo&al. AmiculPubtural, hnd h&ii& kesearch, 6th edition. I&don, I&&a; lishing. 1963, pp. 4-5,64. 3. Foreman, J.D., Order, S.E., Zinreich, E.S., Lee, D., Wharam, M.D., Mellits, E.D.: The correlation of pretreatment transurethral resection of prostatic cancer with tumor dissemination and diseasefreesurvival. Cancer58: 1770-1778,1986. 4. Fowler. J.E.. Fisher. H.A.. Kaiser. D.L.. Whitmore. W.F.: Relationshib of &treatment &sure&al §ion of the prostate to survival without distant metastasis in patients treated with ‘251-implantation for localized prostatic cancer. Cancer 53: 1857-1863, 1984. 5. Hanks, G.E., Leibel, S., Kramer, S.: The dissemination of cancer by transurethral resection of locally advanced prostate cancer. J. Ural. 129: 309-311, 1983. 6. McGowan, D.G.: The adverse influence of prior tramurethral resection on prognosis in carcinoma of prostate treated bv radiation therapy. ZG. J.-Radiat. Oncol. Biol. Piys. 6: 1121-l 126: 1980. 7. Paulson. D.F.. Cox. E.B.: Does transurethral resection of the orostate promote meta&tic disease? J. Ural. 138: 90-9 1,1987. rm~_ 8. Perez, C.A., Pilepich, M.V., Zivnuska, F.: Tumor control in definitive irradiation of local&d carcinoma of the prostate. Znt.J. Radiat. Oncol. Biol. Phys. 12: 523-531, 1986. 9. Pilepich, M.V., Krall, J.M., Hanks, G.E., Sause, W.T., Baerwald, H., Russ, H.H., Perez, C.A., Zinninger, M., Martz, K.L.: Corrclation of pretreatment transurethral resection and prognosis in pa-

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tients with Stage C carcinoma of the prostate treated with definitive radiotherapy-RTOG experience. Znt.J. Radiat. Oncol. Biol. Phvs 13: 195-199, 1987. 10. Zagars, G.K., Von Eschenbach, A.C., Johnson, D.E., Oswald, M.J.: Stage C adenocarcinoma of the prostate. Cancer 60: 1489 1499,1987.

RESPONSE

TO SEYDEL

To the Editor: Dr. Seydel has kindly pointed to the beneficial aspects of our trial. Whether this indeed represents light at the end of the tunnel or the light from a flash in the pan depends on confirmation at othel institutions and ultimately on a prospective trial. We would like to emphasize that this is an interim report. Further more, to balance the down-toning modifiers he used about toxicity, this is a toxic regimen. As reported in this issue, 65% of patients have white count nadirs below 2000 and nearly three-quarters have acute esopha gitis. Since this analysis, one patient has died of sepsis during induction Most patients are treated as out-patients, but many require relatively brief admissions during febrile episodes or toxic difficulties. Neverthe less, the regimen is tolerable to a wide age range (45-80), but the toxicity seems worse in people over 65 or those with alcoholic histories. It is premature to credit the twice-daily strategy with the success ot this program. We agree that there are biologic rationales that are corn pelling, but other variables interfere with establishing Bid radiotherapy as the reason for this program’s benefit. The Platinum/VP- 16 combina tion is likely to be superior to the chemotherapy used in earlier reports. The timing of both modalities must be considered. Many sequential integrations, that is, chemotherapy followed by radiotherapy or vice versa,are safe but not dramatically effective.’ The concurrent trials recently reported from the CALGB’ and NC12 demonstrate how critical the timing of chemotherapy and radiation are in influencing survival and toxicity. Lastly, our trial used sophisticated, CT-aided treatment planning. Its importance in these results is difficult to sort out at this time. We think the results reported in this issue should stimulate us and others to unravel these variables and design a prospective trial. Presently, the pendulum is swinging. Ten years ago chest radiotherapy was considered too toxic and un-necessary in small cell lung cancer. Now many consider chest radiotherapy to be “standard” because of a plethora of studies showing a small but definite improvement in 2-year sur vival. (One must remember the “facts” said the exact opposite just five years ago!) The difficulty today is deciding what is the standard to corn pare against this new and promising study? The local control end-point of 100% in the responders is perhaps the most impressive point of this study, but again, this must be confirmed. We hope this study brings the light of encouragement to a dlseasc that engendered dark despair a short time ago. ANDREWT. TURRISI, III, M.D. Department of Radiation Oncology Hospital of the University of Pennsylvania Philadelphia, PA 19 104 DONNAJ. GLOVER, M.D. Section of Hematology/Oncology Hospital of the University of Pennsylvania Philadelphia, PA 19 104 BERNARDA. MASON, M.D. Hematology and Oncology The Graduate Hospital Philadelphia, PA 19 146 Bleehen, N.M., Bunn, P.A., Cox, J.D., Dombernowsky, P., Fox, R.M., H&t, H., Joss, R., White, J.E., Wittes, R.E.: The role of radiation therapy in small cell anaplastic carcinoma of the lung. Cancer Treat. Rep. 67: 11-19, 1983: Bunn. P.A.. Lichter. A.S.. Makuch. R.W.. Cohen. M.H.. Veach. S.R., ‘Matthews, M.;., Aiderson, A.J., Ed&n, MI, Glaktein, E.1 Minna, J.D., Ihde, DC.: Chemotherapy alone or chemotherapy with chest radiation therapy in limited stage small cell lung cancer. Annals oflnternal Medicine 106: 655-662, 1987. Perry, M.C., Eaton, W.L., Propert, K.J., Ware, J.H., Zimmer, B., Chahnian, P., Skarin, A., Carey, R.W., Kreisman, H., Faulkner, C., Comis, R., Green, M.R.: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N. Engl. J. Med.316:912-918,1987.