Andrew Seidman, Clifford Hudis, and Eric Winer on the Point-Counterpoint on Dosing for Paclitaxel for Ovarian Cancer (11/25/09 issue)

As Co-Chairs of the CALGB Breast Committee and Principal Investigator for the CALBG 9840 trial comparing weekly to every three weekly paclitaxel in metastatic breast cancer,1 we read the Point-Counterpoint in the Nov. 25 issue entitled "Is Dose-Dense Paclitaxel Better than Every-Three-Week Paclitaxel in Ovarian Cancer?" with interest. There are a few significant inaccuracies and errors that we wish to point out.

First, the term dose-density, as used by the authors in the Japanese Oncology Group trial2 and in the title of the OT article is technically incorrect. The trial was not designed to test dose density as both dose size and schedule varied. In contrast, the adjuvant trial CALGB 97413 was such a test since only inter-treatment interval (time) varied while both dose number and size were held constant.

Second, in describing CALGB 9840, Dr. Thigpen was unfortunately wrong when he stated that "the trial used a 2:1 scheme, with twice as many patients assigned to the dose-dense arm," and "when the investigators tried to analyze the trial, they found that there were not enough events in the control arm, so they borrowed 158 patients from the control arm of another trial and added them to the control arm of this trial."

For clarity, and as a matter of record, the facts are as follows:

1. Randomization was 60:40 (3:2) for weekly:every-3-weekly paclitaxel. As an aside, the 2:1 randomization would not necessarily have been problematic; see Ribbon-1 and Ribbon-2 trials, for example.

2. Before commencing enrollment we prospectively planned to incorporate patient data from the 175 mg/m2 every-3-week arm of CALGB 9342.4 This was not an afterthought as alleged but was a protocol prespecified analysis from the outset. This was conceived by our statistician Dr. Donald Berry and approved by the NCI. Indeed, without the 158 patients integrated from CALGB 9342, for which an appropriately adjusted analysis was performed, the C9840 data are compelling on their own (improved PFS of 2 months, p=0.012). There is no chicanery here and we resent the related statement that it was "a disgrace that JCO published it."

Indeed, the CALGB 9840 trial is but a part of a body of evidence demonstrating that weekly paclitaxel outperforms every 3-weekly paclitaxel-in breast cancer.5-8 The combined use of weekly uninterrupted paclitaxel with trastuzumab, as studied in HER2+ MBC in CALGB 9840, provided efficacy and safety data for the use of that approach in the adjuvant setting, one that has proved to be particularly advantageous.9-10 The advantage in breast cancer of weekly scheduling is further supported by the prospective randomized trial E1199 in which this was the best performing arm both compared to higher dose q 3 or either schedule for docetaxel.5 Building on this, of all existing data for taxanes and bevacizumab in MBC, the largest incremental advantage for the addition of bevacizumab has been noted using a foundation of weekly paclitaxel.11

Finally, what proves successful in one type of cancer (e.g., breast) may not prove to be the case for another (e.g., ovarian) vis a vis dose and or scheduling of chemotherapy and Dr. Thigpen surely knows this.

Thank you for the opportunity to provide the facts your readers need to accurately assess this body of work.

ANDREW D. SEIDMAN, MD

Attending Physician

Breast Cancer Medicine Service

Memorial Sloan-Kettering Cancer Center

Professor of Medicine

Weill Medical College of Cornell University

CLIFFORD A. HUDIS, M.D.

Chief, Breast Cancer Medicine Service

Memorial Sloan-Kettering Cancer Center

Professor of Medicine

Weill Medical College of Cornell University

Co-Chair, Breast Committee, CALGB

ERIC P. WINER, M.D.

Chief, Breast Cancer Service

Dana Farber Cancer Institute

Professor of Medicine

Harvard University Medical School

Co-Chair, Breast Committee, CALGB

Simone's OncOpinion: "Professional Careers for 'Old' Guys" (12/10/09 issue)

Loved the piece on "old guys." I can't believe it has happened, but I am now an old guy, too. I have been at M. D. Anderson Cancer Center over 25 years and have had many jobs.

Last year, I went to Capitol Hill as a Robert Wood Johnson Foundation health policy fellow and worked with people less than half my age who could care less that I was a doc. Good for my ego strength (it was challenged as it had not been since internship). I learned a ton, but Capitol Hill is not for me. It's all too partisan for me.

Then, toward the end of my fellowship, the leadership at Anderson needed someone to run our facility in Smithville, Texas, 120 miles from Houston. They had had to make a leadership change and a search had yet to begin. I negotiated a four-day-a-week deal with a day to give to the UT System as a Chancellor's Health Policy Fellow for Executive Vice Chancellor Dr. Kenneth Shine. I spend three nights (four work days) a week away from home in an apartment in Bastrop instead of the seven when I was in DC. This is better. Nicer apartment. Closer to home. Half the price!!

I totally concur with Joe Simone's philosophy. I am so much happier doing this "piece work" than I ever was as a Vice President, I don't know what took me so long. Just as with the situation he described, they'll find a new chair soon and I will be out at Smithville. I have no idea what's next. That used to be a problem. Now it's the solution.

I am not quite ready for the donut hole yet, but Medicare looms just four years away. I am nowhere near ready to quit. I think I am better than ever-just older!!

LEONARD A. ZWELLING, MD, MBA

Robert Wood Johnson Health Policy Fellow and UT Chancellor's Health Fellow for the Executive Vice Chancellor of Health Affairs

Professor of Medicine and Pharmacology

The University of Texas M. D. Anderson Cancer Center

Reply from Dr. Simone:

Great to hear from you about your path to freedom!! Sounds like a series of wise choices and what you wrote might just give some other old guys courage. By the way, my daughter read my column on old guys and gave me a T-shirt imprinted with "Old Guys Rule" on a fancy logo. You can find them at http://oldguysrule.com/catalog/T_Shirts-7-1.html, and the sales apparently help the John Wayne Cancer Foundation.

"Advances in Bone Biology Research Setting Stage for New Cancer Therapies" (11/25/09 issue)

Regarding the article on advances in bone biology research in the Nov. 25 issue: Testosterone is the precursor of estrogen in males and females. Therefore, androgen deprivation for prostate cancer is estrogen deprivation with all the attendant morbidities of postmenopausal females (osteoporosis, increased cardiovascular disease, "hot flash," changes in cognition, and the "metabolic syndrome").

"Osteoporosis" is the reduction in the quantity of bone tissue resulting in bone trabeculae that are scanty, thin, and without osteoclastic resorption (remodeling).

"Osteopenia" is the decreased calcification or density of bone. Bisphosphonates treat osteopenia (demineralization) and improves bone density (bone scans), but does not decrease skeletal events (fractures, bone metastasis) in men treated with androgen deprivation for prostate cancer. Similar results were found in women treated with estrogen deprivation for breast cancer.

The conclusion of the VA Cooperative Urology Group (VACURG III-1988) involving over 4,000 men followed for 30 years, concluded that diethylstilbestrol (DES 1 mg. q.d.) was safe, effective, and better than castration and that DES 1 mg plus castration was no better than DES 1 mg alone as measured by bone scan, acid phosphatase or death of any cause.1 Cox and Crawford (1995) concluded "a 1 mg dose of DES remains a medical alternative to bilateral orchiectomy in the treatment of prostate cancer-i.e., using DES castrate levels of testosterone is not necessary.2

Scherr, Pitts, Vaughan (2002) demonstrated that DES 1mg achieved safe and effective androgen deprivation without osteoporosis.3 Scherr and Pitts (2003) reviewed the nonsteroidal effects of DES (anti-osteoporosis, anti-angiogenic, anti-mitotic, anti-tubulin, anti-atherosclerosis, anti-cognitive decline of androgen deprivation, anti "hot flashes").4,5

These non-steroidal effects explain why DES 1 mg is better than castration and DES 1 mg plus castration is no better than DES alone as measured by bone scan (anti-osteoporosis) acid phosphatase (anti-mitotic, anti-angiogenesis) and death (anti- atherosclerosis).

Therefore, bisphosphonates are unnecessary if androgen/estrogen deprivation without clinical estrogen deprivation is used for hormonal therapy. Males-diethyl-stilbestrol [DES 1 mg] plus/minus tamoxifen 20 q.d. [gynecomastia] plus/minus warfarin 1 mg. p.o. q.o.d. Females-aromatase inhibitor plus tamoxifen 20 mg.). Notice that bisphosphonates treat osteopenia not postmenopausal osteoporosis.

References