CORRESPONDENCE

Quality of Life After Prostate Cancer Treatment

To the Editor: I read with considerable interest the recent report by Wei et al1 examining health-related quality of life (HRQOL) after denitive treatment for clinically localized prostate cancer. The authors are to be congratulated for integrating urinary irritative and hormonal domains into a reliable validated HRQOL instrument. I must admit, however, that I am puzzled by the magnitude of urinary HRQOL decrease seen in their patients treated with prostate brachytherapy (PB). In the discussion section, the authors state that the HRQOL they observed after PB is consistent with the limited available patientreported data from other series.1 To support this claim, the authors provide results of the prostate cancer symptom subscale of the Functional Assessment of Cancer Therapy-Prostate and the International Prostate Symptom Score (IPSS) from our prospective series at Wake Forest.2 It is important to point out that the scores they have taken from the Wake Forest experience were obtained from patients 1 to 3 months after PB, when acute urinary symptoms tend to be at their peak. The median time from treatment to questionnaire completion in the Michigan report is 21 months (range, four to 52 months). Two subsequent reports from Wake forest with longer follow-up have observed that the prostate cancer symptom and IPSS scores return to baseline within 12 months of PB.3,4 In short, I am wondering why the Michigan patients nearly 2 years after treatment seem similar to the Wake Forest patients only 3 months after treatment? Two possible explanations for this discrepancy are patient selection and treatment technique. Urinary morbidity after PB has been associated with higher IPSS scores and larger prostate volumes.5 From the beginning of our PB program, patients have been carefully selected for PB. Patients with signicant urinary symptoms (IPSS greater than 12 to 15) or prostate volumes above 45 cc have been discouraged from treatment with PB. Do the authors have any information regarding pretreatment urinary function or prostate volume in men treated with PB? Source loading technique is probably associated with morbidity. Wallner et al6 has reported that urinary morbidity is associated with high urethral doses. The American Brachytherapy Society has recommended a modied peripheral loading technique to reduce high doses in the center of the prostate gland and perhaps reduce urinary morbidity.7 Can the authors provide any information about the source loading technique? Did they use a Quimby method? Were there any constraints on maximum urethral doses? Finally, the authors report that the prescription dose was 160 Gy. Is this dose according to the TG-43 formalism? Is it higher than the 145 Gy recommended by the American Brachytherapy Society? Although it is possible that either of these two explanations can account for the differences in urinary morbidity, without baseline information on HRQOL before treatment, it is impossible to know to what extent any particular treatment is responsible for observed HRQOL decline. As the Michigan group has shown, most evidence to date suggests that there are important differences in sexual, urinary, and bowel HRQOL according to treatment received. This underscores the importance of completing randomized trials in men with clinically localized prostate cancer. For the future, the Expanded Prostate Index Cancer instrument developed by the Michigan group will be an important component of prospective clinical trials examining PB to be

completed by the American College of Surgeons Oncology Group and the Radiation Therapy Oncology Group. W. Robert Lee Wake Forest University School of Medicine Winston Salem, NC

REFERENCES
1. Wei JT, Dunn RL, Sandler HM, et al: Comprehensive comparison of health-related quality of life after contemporary therapies for localized prostate cancer. J Clin Oncol 20:557-566, 2002 2. Lee WR, McQuellon RP, Case LD, et al: Early quality of life assessment in men treated with permanent source interstitial brachytherapy for clinically localized prostate cancer. J Urol 162:403-406, 1999 3. Lee WR, McQuellon RP, Harris-Henderson K, et al: A preliminary analysis of health-related quality of life in the rst year after permanent source interstitial brachytherapy (PIB) for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 46:77-81, 2000 4. Lee WR, Hall MC, McQuellon RP, et al: A prospective qualityof-life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy. Int J Radiat Oncol Biol Phys 51:614-623, 2001 5. Gelblum DY, Potters L, Ashley R, et al: Urinary morbidity following ultrasound-guided transperineal prostate seed implantation. Int J Radiat Oncol Biol Phys 45:59-67, 1999 6. Wallner K, Roy J, Harrison L: Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 32:465-471, 1995 7. Nag S, Beyer D, Friedland J, et al: American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 44:789-799, 1999 In Reply: Dr. Lees letter is greatly appreciated and highlights important caveats to our manuscript. Principal among these is that selection criteria may vary between different institutions, thereby limiting the generalizability of any single institutions experience with early-stage prostate cancer intervention, irrespective of whether the intervention is surgery, external radiation, or brachytherapy. Selection criteria for brachytherapy have undergone evolution since the period (1995 to 1999) when patients described in our cohort were treated, and brachytherapy techniques have been rened as well. It is possible that such improvements may lead to better health-related quality-of-life (HRQOL) outcomes. Baseline function can reect such evolving selection criteria, and therefore, prospective studies such as that reported by Lee et al1,2 provide an important complement to the long-term data reported by cross-sectional studies.3-5 Multi-institutional prospective studies and randomized clinical trials are the rational next step. Toward this goal, the Surgical Prostatectomy Interstitial Radiation Intervention Trial from the American College of Surgeons Oncology Group has been opened and will directly compare outcomes between patients randomized to prostatectomy versus brachytherapy. Trials to randomize subjects between brachytherapy alone versus brachytherapy combined with external radiation are under development by the Radiation Therapy Oncology Group. Perhaps the most relevant and durable

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Journal of Clinical Oncology, Vol 20, No 13 (July 1), 2002: pp 3038-3043 Downloaded from jco.ascopubs.org on August 1, 2011. For personal use only. No other uses without permission. Copyright 2002 American Society of Clinical Oncology. All rights reserved.

CORRESPONDENCE observation from Wei et al5 is that such trials need to evaluate a spectrum of HRQOL domains that should include urinary irritative and hormonal concerns in addition to the previously established domains of urinary incontinence, sexual, and bowel HRQOL.6-7 It should be noted that both the International Prostate Symptom Score (IPSS) and Functional Assessment of Cancer Therapy-Prostate (FACT-P) have limited sensitivity in this regard, and neither instrument was developed or validated for evaluating early-stage prostate cancer HRQOL. We reported IPSS and FACT-P scores only to provide context for our ndings, as evidence suggesting that our observations were not outside of the range of possible expected results. Whether or not the posttherapy IPSS scores we observed (mean IPSS 12.6 at 21 months) are substantially different from those observed by Lee et al2 (IPSS 13.7 at 6 months and 10.2 at 12 months) is debatable. We feel that more important than a comparison of FACT-P or IPSS scores between studies, however, is the recognition that IPSS and FACT-P have very limited utility for comparing HRQOL effects of different early-stage prostate cancer interventions.1 At the time that our subjects received brachytherapy, the utility of baseline IPSS scores as an exclusion criterion for brachytherapy had not been well characterized, and so baseline IPSS score was not used as a selection criterion for therapy. Prostate size was considered, but more than 60 mL was not an absolute contraindication. Higher activity sources were used than we are currently using. In contrast to current planning margins, implants were planned with a wider margin posterior and below the prostate to ensure adequate coverage of the prostatic apex. These elements may have contributed to the observed HRQOL effects, but represented a high quality standard of brachytherapy in 1995 to 1999. Patients were planned with peripheral loading, and the 160-Gy dose was by the prior convention and equivalent to 145 Gy TG-43. Urethral doses were kept below 240 Gy. Martin G. Sanda P. William McLaughlin University of Michigan Medical Center Ann Arbor, MI

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Endocrine Effects of Nonsteroidal Aromatase Inhibitors and Their Clinical Impact
To the Editor: Geisler et al1 have recently published a study that has compared the inuence of letrozole (LTZ) and anastrozole (ANA) on the total-body aromatization and plasma estrogen levels in postmenopausal breast cancer patients. We would like to make some general comments on the study and on clinical impact of these results. ANA and LTZ were given for 6 weeks and, at the end of this period, they were crossed and the patients continued the treatment with the last drug. We are aware that the aim of the study was not clinical; however, we think that the crossing of the drug during the trial was made irrespective of the clinical outcome, and this approach is rather unusual. The sample-size calculation for a cross-over design has not been reported. Generally a cross-over design requires a number of patients lower than a parallel-group design; however, it is unclear why only 12 patients (six in each group) were studied and what hypothesis had to be tested. Furthermore, the study is described as carried out in doubleblind fashion, and LTZ and ANA were given at the standard dosage. It should be interesting to know how the blindness was made. Authors have used a cross-over design.2 This experimental design is seldom used in oncology because it requires that several conditions are satised. In our opinion, the most important conditions are the type of disease and the wash-out between the active periods. Breast cancer is neither a stable nor a chronic disease, and this condition is generally wanted by a cross-over study. Secondly, it is well known that in postmenopausal breast cancer patients the estrogen levels are highly variable (as also demonstrated in the article by the wide condence intervals at baseline), and no data are available demonstrating the behavior of estrogen levels when aromatase inhibitors (AI) are withdrawn. Thus, at the beginning of the second period of the cross, the levels of estrogens could be different from baseline values. In this article, the wash-out was not admitted for obvious ethical and clinical reasons, but this approach could have biased the results in an unpredictable way. No data are available in literature demonstrating that the tumor response is correlated with the estrogen and aromatization suppression induced by AI, although this relationship is intriguing. The correlation between tumor response and estrogen suppression, however, has been investigated and not found.3 Its absence, however, is not surprising, because there is a lot of experimental evidence that breast tumor is induced and sustained by several biologic mechanisms inside and outside the tumor cell (insulin-like growth factor, tumor necrosis factor, and so on), thus the estrogenic stimulus is likely only one out of them. By contrast, there is a clear clinical evidence that moving from formestane (which has a moderate estrogen suppression) to new AIs (which have a high estrogen suppression), the response rate is not dramatically improved, still remaining approximately 30%. Thus, it is still uncertain whether the estrogen suppression is greater and there are more clinical responses and, likewise, if a different potency in estrogen suppression corresponds to a different clinical response. Currently, 11 clinical trials with AI given in adjuvant setting are ongoing, involving thousands of breast cancer patients. Thus, in our opinion, the estrogen and aromatization suppression for comparing AI with each other has a fair clinical interest. Emilio Bajetta Nicoletta Zilembo Medical Oncology B Istituto Nazionale Tumori Ettore Bichisao ITMO Group Milan, Italy

REFERENCES
1. Lee WR, Hall MC, McQuellon RP, et al: A prospective quality of life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy. Int J Radiat Oncol Biol Phys 51:614-623, 2001 2. Lee WR, McQuellon RP, Harris-Henderson K, et al: A preliminary analysis of health-related quality of life in the rst year after permanent source interstitial brachytherapy (PIB) for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 46:77-81, 2000 3. Talcott JA, Clark JC, Stark P, et al: Long-term treatment-related complications of brachytherapy for early prostate cancer: A survey of patients previously treated. J Urol 166:494-499, 2001 4. Davis JW, Kuban DA, Lynch DF, et al: Quality of life after treatment for localized prostate cancer: Differences based on treatment modality. J Urol 166:947-952, 2001 5. Wei JT, Dunn RL, Sandler HM, et al: A comprehensive comparison of health related quality of life following contemporary therapies for localized prostate cancer. J Clin Oncol 20:557-566, 2002 6. Litwin MS, Hays RD, Fink A, et al: Quality-of-life outcomes in men treated for localized prostate cancer [see comments]. JAMA 273:129-135, 1995 7. Wei JT, Dunn RL, Litwin MS, et al: Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality-of-life in men with prostate cancer. Urology 56:899-905, 2000

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REFERENCES
1. Geisler J, Haynes B, Anker G, et al: Inuence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol 20:751-757, 2002 2. Spilker B: Guide to Clinical Trials, Chapter 6. New York, NY, Raven Press, 1991, pp 27-43 3. Bajetta E, Zilembo N, Bichisao E, et al: Tumour response and estrogen suppression in breast cancer patients treated with aromatase inhibitors. Ann Oncol 11:1017-1022, 2000

CORREPONDENCE Bajetta et al cite their observational study, which reported that there was no difference in estrogen suppression between responders and nonresponders to aromatase inhibitors.2 Such an observational study is not appropriate to determine whether greater estrogen suppression can lead to improved efcacy. This requires randomized trials to avoid the numerous potential confounders in an observational study. In their study, Bajetta et al2 reported plasma estrogen suppression varying between 35% and 60% with exemestane. This is less than in our studies, and might be explained by limited assay sensitivity and/or cross-reactions with the steroidal drug or its metabolites.3 It is notable that in three randomized trials comparing different aromatase inhibitors (vorozole v aminoglutethimide,4 letrozole v aminoglutethimide,5 and letrozole v fadrozole6) in each case the thirdgeneration inhibitor, which provided more complete aromatase inhibition, yielded improved outcome in at least one clinical end point. Rose et al7 will present a study comparing anastrozole to letrozole head to head as second-line treatment at this years American Society of Clinical Oncology Annual Meeting. Per E. Lnning Jurgen Geisler Haukeland University Hospital Bergen, Norway Mitch Dowsett Royal Marsden Hospital London, United Kingdom

In Reply: The letter by Bajetta et al raises several issues. First, Bajetta et al consider the treatment interval on each drug regimen (6 weeks) during the study period short. As they correctly stated, the aim of our study was not clinical, and we believe the design was optimal for its pharmacologic end-points. A key goal was to compare the degree of estrogen suppression and aromatase inhibition while avoiding confounding factors. To treat each patient until response evaluation would mean to extend each treatment period to at least 3 months. In addition, we have to assume that for many patients (like those achieving stable disease) a treatment period of 6 months would be required. This would increase the chance of alterations in potential confounding parameters (like body weight). Also, for patients progressing on therapy, it would be ethically questionable to cross them from one nonsteroidal aromatase inhibitor to another compound of the same class when there are no data on the efcacy of this approach. The number of patients was selected on a pragmatic basis. Studies like this are labor-intensive, and it is possible to conduct them in a limited number of patients only. It was apparent to us that if the results from our earlier separate studies with these two compounds were reproduced in this randomized study (as indeed they were) then 12 patients would be adequate. To use more than is necessary would also be ethically inappropriate. Blindness was made with respect to the laboratory analysis (the end points of this study). Each sample was coded (both for the hormone as well as aromatization analysis); the people doing the analysis were unaware of treatment arm until all data were collected. We do not perceive a need for a washout period between the treatments in this circumstance. Both drugs have a half-life of approximately 2 days, indicating there will be no drug leftover after 6 weeks on therapy. The argument that breast cancer is neither a stable nor a chronic disease, and this condition is generally wanted by a cross-over study is, in our opinion, irrelevant to a study of pharmacology in which the disease has no inuence on the biochemical end point. We agree with their argument that estrogen levels in postmenopausal breast cancer patients are highly variable between patients and consider that to be a strong argument favoring our cross-over design. On the other hand, we are somewhat surprised by their argument that no data are available demonstrating the behavior of estrogen levels when aromatase inhibitors (AI) are withdrawn. In the report of the clinical efcacy of exemestane after treatment with nonsteroidal inhibitors by Lonning et al1 (of which E. Bajetta was the second author), it was clearly stated that estrogen levels returned to normal within 4 weeks after termination of treatment with novel nonsteroidal aromatase inhibitors (anastrozole, letrozole, and vorozole). Most importantly, our statistical analysis clearly shows superiority of letrozole by each treatment sequence. We nd their argument that this approach could have biased the results in an unpredictable way to be unsubstantiated.

REFERENCES
1. Lonning PE, Bajetta E, Murray R, et al: Activity of exemestane (Aromasin) in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: A phase II trial. J Clin Oncol 18:2234-2244, 2000 2. Bajetta E, Zilembo N, Bichisao E, et al: Tumor response and estrogen suppression in breast cancer patients treated with aromatase inhibitors. Ann Oncol 11:1017-1022, 2000 3. Lonning PE: Stepwise estrogen suppression manipulating the estrostat. J Steroid Biochem Molec Biol 79:127-132, 2001 4. Bergh J, Bonneterre J, Illiger HJ, et al: Vorozole (Rivizor) versus aminoglutethimide (AG) in the treatment of postmenopausal breast cancer relapsing after tamoxifen. Proc Am Soc Clin Oncol 16:155a, 1997 (abstr 543) 5. Gershanovich M, Chaudri HA, Campos D, et al: Letrozole, a new oral aromatase inhibitor: Randomized trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Ann Oncol 9:639-645, 1998 6. Tominaga T, Morimoto T, Ohashi Y: A pivotal double-blind trial in Japan of an aromatase inhibitor Letrozole (third generation) vs. its predecessor fadrozole hydrochloride (second generation). Japan Letrozole Study Group. Ann Oncol 11:25, 2000 (suppl, O100)

Safety Issues of Soy Phytoestrogens in Breast Cancer Patients

To the Editor: The results of Van Patten et al1 conrmed previous ndings2 that soy phytoestrogens have minimal efcacy for menopausal symptoms in breast cancer patients. However, I am concerned that patients in neither study were apparently informed of the potential stimulatory effects of phytoestrogens on breast tumor.3

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CORRESPONDENCE Similar omission would have raised ethical concerns if pharmaceutical drugs were involved. At concentrations below 10 mol/L, phytoestrogens can stimulate breast tumor growth4-15 and antagonize the antitumor effects of tamoxifen,7,9 particularly in an environment of low endogenous estrogen.3,11 In contrast, phytoestrogens inhibit breast tumor growth and enhance the antitumor effects of tamoxifen at concentrations above 10 mol/L.5,6,8,9,11 In humans, serum phytoestrogen concentrations attained after acute or chronic intake of phytoestrogens were much lower than 10 mol/L.1,16,17 Without long-term human data, cancer risk assessments need to be cautious and assume that substances that promote tumor growth in preclinical studies may pose similar risks clinically.18 Hence, to weigh the potential risks versus benets before using phytoestrogens for unproven indications, breast cancer patients should be informed that phytoestrogens have the potential to stimulate tumor growth. Mario de Lemos Vancouver, British Columbia, Canada

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acid on the growth of breast cancer cell lines. J Cancer Res Clin Oncol 126:448-454, 2000 15. Santell RC, Kieu N, Helferich WG: Genistein inhibits growth of estrogen-independent human breast cancer cells in culture but not in athymic mice. J Nutr 130:1665-1669, 2000 16. King RA, Bursill DB: Plasma and urinary kinetics of the isoavones daidzein and genistein after a single soy meal in humans. Am J Clin Nutr 67:867-872, 1998 17. Lu LJ, Anderson KE, Grady JJ, et al: Decreased ovarian hormones during a soya diet: Implications for breast cancer prevention. Cancer Res 60:4112-4121, 2000 18. National Research Council: Strategies for improving risk assessment: Science and judgment in risk assessment. Washington, DC, National Academy Press, 1994 In Reply: The safety of phytoestrogens in women with breast cancer is controversial, and this issue was specically addressed in the consent form for our study.1 The potential risk was discussed with women. Thirteen eligible women declined randomization as indicated in our article in Figure 1. At least some of these women who declined did so because of their concerns about phytoestrogen risks. At the time the study was designed in 1997, there were limited data on the risk of phytoestrogens, and even today, most studies have been based on the effects of genistein alone rather than soy foods. Additionally, soy foods contain a number of nonhormonal compounds with potential anticancer activity.2,3 Our clinical trial was designed to test the very intervention that many women in our practice were beginning to adopt in the hopes of achieving relief from hot ushes, a complete soy beverage at a dose similar to traditional Asian diets. Furthermore, our intervention with soy was short-term and thus unlikely to pose an important risk, as even with prolonged use of estrogen therapy, the increase in incidence of breast cancer is modest and declines when hormones are stopped.4,5 It remains speculative if a short course of weak phytoestrogens, with no clinical evidence of an estrogenic effect greater than placebo as measured by hot ush relief, would result in a signicant increase in risk of breast cancer. However, we are continuing long-term follow-up of the cohort of women who participated in this study to determine if soy beverage is associated with any excess risk of breast cancer recurrence or second breast primaries. The correspondent and others concerned about breast cancer risks from phytoestrogens are recommended to read a recent review article on the subject.3 The authors of that review conclude, Overall, the data are not impressive that the adult consumption of soy affects the risk of developing breast cancer or that soy consumption affects the survival of breast cancer patients. Cheri L. Van Patten Karen A. Gelmon British Columbia Cancer Agency Vancouver, British Columbia, Canada Ivo A. Olivotto British Columbia Cancer Agency Victoria, British Columbia, Canada

REFERENCES
1. Van Patten CL, Olivotto IA, Chambers GK, et al: Effect of soy phytoestrogens on hot ashes in postmenopausal women with breast cancer: A randomized, controlled clinical trial. J Clin Oncol 20:1449-1455, 2002 2. Quella SK, Loprinzi CL, Barton DL, et al: Evaluation of soy phytoestrogens for the treatment of hot ashes in breast cancer survivors: A North Central Cancer Treatment Group Trial. J Clin Oncol 18:1068-1074, 2000 3. de Lemos ML: Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Ann Pharmacother 35:1118-1121, 2001 4. Sathyamoorthy N, Wang TT, Phang JM: Stimulation of pS2 expression by diet-derived compounds. Cancer Res 54:957-961, 1994 5. Wang TT, Sathyamoorthy N, Phang JM: Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 17:271-275, 1996 6. Dees C, Foster JS, Ahamed S, et al: Dietary estrogens stimulate human breast cells to enter the cell cycle. Environ Health Perspect 105:633-636, 1997 7. Sathyamoorthy N, Wang TT: Differential effects of dietary phyto-oestrogens daidzein and equol on human breast cancer MCF-7 cells. Eur J Cancer 33:2384-2389, 1997 8. Wang C, Kurzer MS: Phytoestrogen concentration determines effects on DNA synthesis in human breast cancer cells. Nutr Cancer 28:236-247, 1997 9. Zava DT, Duwe G: Estrogenic and antiproliferative properties of genistein and other avonoids in human breast cancer cells in vitro. Nutr Cancer 27:31-40, 1997 10. Hsieh CY, Santell RC, Haslam SZ, et al: Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res 58:3833-3838, 1998 11. Wang C, Kurzer MS: Effects of phytoestrogens on DNA synthesis in MCF-7 cells in the presence of estradiol or growth factors. Nutr Cancer 31:90-100, 1998 12. Miodini P, Fioravanti L, Di Fronzo G, et al: The two phytooestrogens genistein and quercetin exert different effects on oestrogen receptor function. Br J Cancer 80:1150-1155, 1999 13. Balabhadrapathruni S, Thomas TJ, Yurkow EJ, et al: Effects of genistein and structurally related phytoestrogens on cell cycle kinetics and apoptosis in MDA-MB-468 human breast cancer cells. Oncol Rep 7:3-12, 2000 14. Nakagawa H, Yamamoto D, Kiyozuka Y, et al: Effects of genistein and synergistic action in combination with eicosapentaenoic

REFERENCES
1. Van Patten CL, Olivotto IA, Chambers K, et al: Effect of soy phytoestrogens on hot ashes in postmenopausal women with breast cancer: A randomized, controlled clinical trial. J Clin Oncol 20:14491455, 2002

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2. Tham DM, Gardner CD, Haskell WL: Potential health benets of dietary phytoestrogens: A review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrin Met 33:2223-2235, 1998 3. Messina MJ, Loprinzi CL: Soy for breast cancer survivors: A critical review of the literature. J Nutr 131:3095S-3108S, 2001 4. Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350:1047-1059, 1997 5. Collaborative Group on Hormonal Factors in Breast Cancer: Breast Cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 347:1713-1727, 1996

CORRESPONDENCE 2. Max GM, Steer CB, Harper P, et al: Unexpected serious toxicity with chemotherapy and anti-angiogenic combinations: Time to take stock! J Clin Oncol 20:l446-1448, 2002 3. Zangari M, Anaissie E, Barlogie B, et al: Increased risk of deep vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 98:l6l4-1615, 200l 4. Zangari M, Siegel E, Barlogie B, et al: Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: Implications for therapy. Blood (in press) 5. Bruns CJ, Solorzano CC, Harbison MT, et al: Blockade of the epidermal growth factor receptor signaling by a novel tyrosin kinase inhibitor leads to apoptosis of endothelial cells and therapy of human of human pancreatic carcinoma. Cancer Res 60:2926-2935, 2000 6. Mailloux A, Grenet K, Bruneel A, et al: Anticancer drugs induce necrosis of human endothelial cells involving both oncosis and apoptosis. Eur J Cell Biol 80:442-449, 200l

Endothelial Dysfunction in AntiangiogenesisAssociated Thrombosis

To the Editor: We read with great interest the recent observation and editorial about thrombosis in patients receiving combination therapy with antiangiogenesis treatment and chemotherapy.1,2 A similar phenomenon occurs when the antiangiogenesis agent thalidomide is used in conjunction with doxorubicin but not with other chemotherapy and not when used alone.3,4 The common feature between the hypercoagulability in each of these regimens is chemotherapy-induced endothelial apoptosis, followed by endothelial-targeted therapy. Gemcitabine causes endothelial cell apoptosis;5 whereas doxorubicin causes necrosis of human endothelial cells through oncosis and apoptosis.6 We propose, therefore, that the common pathogenic factor may be interaction of the antiangiogenesis agent with subendothelium, which becomes exposed only on damage to endothelium. If this is the case, then an alternate pathway to antiangiogenesis may be triggered. We wonder whether the investigators found any evidence of endothelial injury in their patients (eg, signs of capillary leakage), or if laboratory measures of endothelial cell function were performed and could have provided any predictive clues for detecting patients at risk. As antiangiogenesis agents become more widely used, we believe it may be necessary to screen all potential study subjects for endothelial cell function. Many tests are now available, including measurement of circulating endothelial cells, endothelin, von Willebrands factor, and vascular adhesion molecules; these tests may prove useful for predicting risk of thrombosis, for following the effects of antiangiogenesis therapy, and for better understanding the pathophysiology of angiogenesis and thrombosis. Varsha Kaushal Manish Kohli Maurizio Zangari Louis Fink Paulette Mehta University of Arkansas for Medical Sciences Central Arkansas Veterans Healthcare System Little Rock, AR

In Reply: Mehta et al propose an interaction of the antiangiogenesis agent with subendothelium, which occurs after apoptosis of endothelium as a result of the cytostatic agents, in particular gemcitabine, as the common pathogenic pathway of thrombosis in patients receiving combination therapy. We have another hypothesis because gemcitabine alone does not induce apoptosis of endothelial cells.1 Only the tyrosine kinase inhibitor PKI166, which targets the epidermal growth factor receptor, alone and in combination with gemcitabine, does induce endothelial cell apoptosis.1 We hypothesize that endothelial cells become vulnerable during treatment with compounds that interfere with, for instance, vascular endothelial growth factor (VEGF) signaling, because VEGF, among other growth factors, induces the expression of antiapoptotic genes and proteins, such as bcl-2 and survivin.2 Subsequently, endothelial cells become probably procoagulant and in case of apoptosis, blood will be exposed to subendothelium and tissue factor, which is the trigger for activation of the coagulation cascade. It would be of great value to discriminate patients at risk for thrombotic and cardiovascular complications. There are several markers, such as von Willebrands factor and vascular adhesion molecules (although there is a debate ongoing), that have predictive value in determining cardiovascular death, and which in our opinion provide information concerning the condition of the endothelium.3-8 We have determined von Willebrands factor, soluble(s)-E-selectin, and soluble tissue factor in three of our study patients, two of whom developed a thromboembolic event.9 Normal levels of these parameters were found at the start of the treatment but increased signicantly during the rst and second cycle, indicating endothelial cell activation. We agree that it is necessary to screen and monitor endothelial cell parameters during antiangiogenesis therapy, especially when combined with cytotoxic agents. Bart Kuenen Giuseppe Giaccone Vrije Universiteit Medical Center Amsterdam, the Netherlands

REFERENCES
1. Bruns CJ, Solorzano CC, Harbison MT, et al: Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 60:2926-2935, 2000 2. Benjamin LE: The controls of microvascular survival. Cancer Metastasis Rev 19:75-81, 2000

REFERENCES
1. Kuenen BC, Rosen L, Smit EF, et al: Dose nding and pharmacokinetic study of cisplatin, gemcitabine and SU 54l6 in patients with solid tumors. J Clin Oncol 20:l657-1667, 2002

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CORRESPONDENCE 3. Jager A, van Hinsbergh VW, Kostense PJ, et al: von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: The Hoorn Study. Arterioscler Thromb Vasc Biol 19:3071-3078, 1999 4. Blankenberg S, Rupprecht HJ, Bickel C, et al: Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation 104:1336-1342, 2001 5. Malik I, Danesh J, Whincup P, et al: Soluble adhesion molecules and prediction of coronary heart disease: A prospective study and meta-analysis. Lancet 358:971-976, 2001

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6. Ballantyne CM: Soluble adhesion molecules and coronary heart disease. Lancet 359:525, discussion 526-527, 2002 7. Blann AD, Lip GY: Soluble adhesion molecules and coronary heart disease. Lancet 359:525-526, discussion 526-527, 2002 8. Cappuccio FP, Miller MA: Soluble adhesion molecules and coronary heart disease. Lancet 359:526-527, 2002 9. Kuenen BC, Rosen L, Smit EF, et al: Dose-nding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol 20:1657-1667, 2002

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