The
n e w e ng l a n d j o u r na l
not discuss some adverse reactions of strontium
ranelate. During postmarketing surveillance in
the European Union, cases of a rare hypersensitivity syndrome (referred to as DRESS, or drug
reaction, eosinophilia, and systemic symptoms)
have been reported in patients treated with strontium ranelate, prompting the European Medicines Agency to recommend discontinuation of
its use if a skin reaction develops.1 In addition,
O’Donnell et al., in a post hoc analysis of data
pooled from two randomized, placebo-controlled
trials (with a combined total of 6669 participants),
found that treatment with strontium ranelate was
associated with an increase in the annual incidence of venous thromboembolism (incidence of
2.2% with strontium ranelate vs. 1.5% with placebo; odds ratio, 1.5; 95% confidence interval
[CI], 1.1 to 2.1) and pulmonary embolism (incidence of 0.8% with strontium ranelate vs. 0.4%
with placebo; odds ratio, 1.7; 95% CI, 1.0 to 3.1).2
The potential risks to the vascular system associated with ingestion of 2 g of strontium ranelate
daily need to be further explored and quantified.
Juan F. Sanchez Muñoz-Torrero, M.D., Ph.D.
Jose Zamorano, Ph.D.
Hospital San Pedro Alcantara
Caceres, Spain
[email protected]
No potential conflict of interest relevant to this letter was reported.
1. EMEA recommends changes in the product information for
Protelos/Osseor due to the risk of severe hypersensitivity reactions.
London: European Medicines Agency, November 15, 2007. (http://
www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/
news/2009/11/news_detail_000413.jsp&murl=menus/news_and_
events/news_and_events.jsp&mid=WC0b01ac058004d5c1.)
2. O’Donnell S, Cranney A, Wells GA, Adachi JD, Reginster JY.
Strontium ranelate for preventing and treating postmenopausal
osteoporosis. Cochrane Database Syst Rev 2006;3:CD005326.
The Authors Reply: Panontin et al. note our recommendation concerning calcium intake (total
intake of 1000 to 1200 mg per day including dietary and supplemental sources) and raise a concern
about the safety of calcium supplementation. Although the meta-analysis by Bolland et al. (which
was based in large part on the post hoc analysis
of
m e dic i n e
of a subgroup in the Women’s Health Initiative
[WHI] trial of calcium plus vitamin D supplementation) showed an increased risk of myocardial
infarction with calcium supplementation, with or
without coadministered vitamin D, we point out
that in the WHI Calcium plus Vitamin D Supplementation Trial1 and another meta-analysis2 (also
including data from the overall WHI trial study
population), calcium supplementation, with or without coadministered vitamin D, was not found to
have an effect on the risk of cardiovascular events.
We concur that large, well-designed trials of sufficient duration are needed to accurately quantify
the global health effects of calcium supplementation, with or without coadministered vitamin D.
We thank Muñoz-Torrero and Zamorano for
making us aware of additional potential adverse
effects of strontium ranelate. We agree that the
post hoc analysis by O’Donnell et al. showed an
increased risk of venous thromboembolic events
(including pulmonary embolism) in patients taking 2 g of strontium ranelate daily and that
several cases of DRESS syndrome were identified
in patients taking strontium ranelate in postmarketing surveillance efforts in Europe. Physicians prescribing strontium ranelate should be
aware of these findings, and patients taking this
drug need to be informed of these risks.
Kristine E. Ensrud, M.D., M.P.H.
Veterans Affairs Medical Center
Minneapolis, MN
[email protected]
John T. Schousboe, M.D., Ph.D.
Park Nicollet Health Services
Minneapolis, MN
Since publication of their article, the authors report no further potential conflict of interest.
1. Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplemen-
tation and cardiovascular events. Circulation 2007;115:846-54.
[Erratum, Circulation 2007;115(19):e466.]
2. Wang L, Manson JE, Song Y, Sesso HD. Systematic review:
vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med 2010;152:315-23.
3. The treatment of symptomatic osteoporotic spinal compression fractures: guideline and evidence report. Rosement,
IL: American Academy of Orthopaedic Surgeons, 2010. (http://
www.aaos.org/research/guidelines/SCFguideline.pdf.)
Bending the Cost Curve in Cancer Care
To the Editor: Although we concur with the pro- cologists not prescribe chemotherapy agents
vocative recommendations by Smith and Hillner shown only to increase progression-free survival,
(May 26 issue),1 we would also suggest that on- unless they are accompanied by clinically relevant
674
n engl j med 365;7 nejm.org august 18, 2011
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correspondence
increases in overall survival or health-related quality of life. It is instructive to review the approval
of ixabepilone, which the authors indicate improves
progression-free survival without improving overall survival but also costs more than alternative
therapies. Ixabepilone was approved by the Food
and Drug Administration on October 16, 2007, on
the basis of an open-label trial involving 752 women
with locally advanced or metastatic breast cancer.2
The trial showed an increase in progression-free
survival of 1.6 months among women treated with
ixabepilone and capecitabine as compared with
patients who received capecita­bine alone, but it
also identified significantly more grade 3 or 4
treatment-related neuropathy (21% vs. 0%), fatigue
(9% vs. 3%), and neutropenia (68% vs. 11%).3
Appropriate information about health-related
quality of life was not available to consider in
light of the minimal increase in progression-free
survival and no overall survival benefit. On the
basis of evidence (and lack of evidence) such as
this, why would oncologists choose to prescribe
such a therapy?
Meghan Good
clinical trials,1,2 which currently largely determine standards.
For example, we conducted a study based on
prospective data on 2613 patients at four Melbourne, Australia, hospitals from January 2003
through December 2010. We assessed outcomes
for very elderly patients (median age, 83.4 years)
comprising 17.8% of 471 patients with stage III
colon cancer, with a median follow-up of 4.9 years.
Among the 84 patients who were 80 years of age
or older, the median survival was 2.9 years, the
5-year survival was 26.9%, and 27 of the 46 patients who died (58.7%) did not have cancer recurrence.
Our data show the limited life expectancy of
very elderly patients with stage III colon cancer,
largely because of an excess of deaths not related
to cancer. Given this finding, considering adjuvant chemotherapy for these patients as exceptional rather than routine would seem to be an
acceptable modification of current practice that
would reduce cost, with a minimal effect on
patient survival.
Kathryn Field, M.B., B.S.
Duquesne University
Pittsburgh, PA
Royal Melbourne Hospital
Melbourne, VIC, Australia
Chester B. Good, M.D., M.P.H.
Ian Faragher, M.B., B.S.
Department of Veterans Affairs
Pittsburgh, PA
[email protected]
No potential conflict of interest relevant to this letter was reported.
Western Hospital
Melbourne, VIC, Australia
1. Smith TJ, Hillner BE. Bending the cost curve in cancer care.
N Engl J Med 2011;364:2060-5.
2. Food and Drug Administration. Drug approval package: Ix-
empra (ixabepilone) injection. (http://www.accessdata.fda.gov/
drugsatfda_docs/nda/2007/022065TOC.cfm.)
3. Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus
capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 2007;25:5210-7.
To the Editor: The article by Smith and Hillner
is provocative and timely. However, one critical
area not discussed is the growing financial burden of caring for older patients. Although we
accept that any consideration of restricting treatment on the basis of age alone is uncomfortable
for many clinicians, we feel that a dialogue regarding the value of treating elderly patients
needs to be initiated. Pivotal to this discussion,
however, is the availability and careful analysis
of comprehensive data regarding outcomes in
routine care; this analysis should be used to inform practice along with the subgroup analyses
involving the select older patients enrolled in
Peter Gibbs, M.B., B.S.
Ludwig Institute
Melbourne, VIC, Australia
[email protected]
No potential conflict of interest relevant to this letter was reported.
1. Sargent DJ, Goldberg RM, Jacobson SD, et al. A pooled
analysis of adjuvant chemotherapy for resected colon cancer in
elderly patients. N Engl J Med 2001;345:1091-7.
2. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal
cancer. J Clin Oncol 2006;24:4085-91. [Erratum, J Clin Oncol
2008;26:2925-6.]
The Authors Reply: Good and Good describe
the importance of perspective on value. When we
discuss the benefits and risks of fourth-line chemotherapy with patients with breast cancer, most
opt for treatment. Common comments include
these: they know the outcome without chemotherapy, while their cancer is stable their quality
of life is acceptable, and with good supportive
care the downside of treatment-related toxicity is
less. “After all, Doctor, you have kept me from
being too sick with the last three regimens.” A
n engl j med 365;7 nejm.org august 18, 2011
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Copyright © 2011 Massachusetts Medical Society. All rights reserved.
675
The
n e w e ng l a n d j o u r na l
recent study showed that quality-adjusted time
was actually increased with the ixabepilonecapecitabine combination, despite the toxic effects.1 We know that people facing death from
cancer have a very different perspective, they value
small increments of time even with toxic effects,
and life with treatment is often better than life with
growing symptomatic cancer. That is why these
issues are so hard, they must be considered disease
by disease, and we must have some leeway. Saying
“no” to fourth-line chemotherapy will be difficult
in breast cancer because patients often do have a
clinical benefit.2 That does not apply to patients
with lung cancer, pancreatic cancer, or prostate
cancer. There is no a priori reason why ixabepilone
should cost $6,000 a cycle; it could have an acceptable cost-effectiveness ratio at $2,000 a cycle.3
Field et al. show that only 27% of patients
with stage III colorectal cancer who were 80 years
of age or older were alive at 5 years, and 59%
had died from other causes. Other studies have
shown that the elderly receive about as much
benefit as the nonelderly from adjuvant chemotherapy, with a hazard ratio for death reduced by
50%.4 They show just how small a “drop in the
bucket” adjuvant chemotherapy for the very old
would be — just 3% of patients with colorectal
cancer would receive this treatment. If patients
of
m e dic i n e
are otherwise well enough to receive chemotherapy, we do not think they should be denied just
on the basis of their age.
Meaningful cost control will require tailoring
treatment to patients who can benefit, reducing
the overuse of expensive supportive drugs such
as pegfilgrastim,5 reducing the cost of drugs, and
avoiding unwanted end-of-life hospitalizations.
Thomas J. Smith, M.D.
Bruce E. Hillner, M.D.
Virginia Commonwealth University
Richmond, VA
Since publication of their article, the authors report no further
potential conflict of interest.
1. Corey-Lisle PK, Peck R, Mukhopadhyay P, et al. Q-TWiST
analysis of ixabepilone in combination with capecitabine on
quality of life in patients with metastatic breast cancer. Cancer
2011 May 19 (Epub ahead of print).
2. Dufresne A, Pivot X, Tournigand C, et al. Impact of chemotherapy beyond the first line in patients with metastatic breast
cancer. Breast Cancer Res Treat 2008;107:275-9.
3. Hillner BE, Smith TJ. Efficacy does not necessarily translate to cost effectiveness: a case study in the challenges associated with 21st-century cancer drug pricing. J Clin Oncol 2009;
27:2111-3.
4. Wildes TM, Kallogjeri D, Powers B, et al. The benefit of adjuvant chemotherapy in elderly patients with stage III colorectal
cancer is independent of age and comorbidity. J Geriatr Oncol
2010;1:48-56.
5. Potosky AL, Malin JL, Kim B, et al. Use of colony-stimulating factors with chemotherapy: opportunities for cost savings
and improved outcomes. J Natl Cancer Inst 2011;103:979-82.
The Parathyroid as a Target for Radiation Damage
To the Editor: Exposure to radiation may result
in late adverse effects. Here we describe the consequences of irradiation for the endocrine system, particularly the parathyroid glands, in a cohort of 61 “liquidators,” or cleanup workers, who
participated in the effort to contain the contamination at the Chernobyl nuclear power plant in
Ukraine subsequent to the 1986 explosion. For
these persons, who were among the most heavily
irradiated workers on the site, we conducted annual clinical follow-up for 24 years, until 2009.
For purposes of comparison, we recruited 687
healthy controls in Swabia, Germany, with the
use of a population-based survey; the controls
were followed for the same period of time. Clinical data obtained 14 years after the accident
showed that the radiation exposure had dichotomous effects on levels of parathyroid hormone
(PTH) and that hypercalcemia and nephrolithiasis remained evident. The risk of primary hyper676
parathyroidism in this cohort of workers was
substantial, with an odds ratio of 63.4 (95% confidence interval [CI], 35.7 to 112.5). Elevated PTH
levels were associated with stages 1 and 2 of
acute radiation syndrome.
Twenty-five years after the Chernobyl accident,
the main point of contention is the long-term
effects of the radiation on those who were exposed. In the wake of the accident, a significant
excess in the incidence of thyroid cancer was
observed in children.1 Surprisingly, in this cohort
of liquidators, who were exposed to high local
doses of beta particles and gamma irradiation,2
with whole-body exposure in the range of 0.3 to
8.7 Gy, little effect on the thyroid was detected.
(Clinical outcomes and the results of laboratory
examinations for the cohort are summarized in
Table 1 of the Supplementary Appendix, available
with the full text of this letter at NEJM.org.)
Seven members of the cohort died during follow-
n engl j med 365;7 nejm.org august 18, 2011
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