APOS Clinical E-Mail Update #1
7 August 2003

In this Update:

Are Survivors of Childhood Acute Leukemia or Lymphoma More Apt to be Overweight?

Oeffinger KC, Mertens AC, Sklar CA, Yasui Y, Fears T, Stovall M, Vik TA, Inskip PD, Robison LL. Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the childhood cancer survivor study. J Clin Oncol 2003;21:1359-1365.

Cranial radiotherapy greater than 20 Gy was associated with a higher prevalence of obesity in survivors of childhood acute lymphoblastic leukemia, particularly females treated when they were younger than 4 years old. The odds ratio compared to siblings was 2.59 in females and 1.86 for males.

Because obesity can be a late consequence for children treated for acute lymphoblastic leukemia, Oeffinger et al reviewed retrospectively 1765 participants of the Childhood Cancer Survivor Study who had ALL to 2565 siblings. They looked at the body mass index (BMI) as a guide to obesity (BMI over 30). The risk of obesity was not increased in children treated just with chemotherapy or with cranial radiation doses 10-19 Gy.

Young girls treated with cranial radiation seem also to have a higher risk of neurocognitive impairment, earlier puberty, and a shorter final height.¹ The risk of obesity may be related to growth hormone deficiency or leptin insensitivity.

1. Christie D, Leiper AD, Chessells JM et al. Intellectual performance after presymptomatic cranial radiotherapy for leukaemia: Effects of age and sex. Arch Dis Child 1995;73:136-140.

Nysom K, Holm K, Michaelsen KF, Hertz H, Muller J, Molgaard C. Degree of fatness after treatment of malignant lymphoma in childhood. Med Pediatr Oncol 2003;40:239-243.

In Denmark, Nysom et al studied whole-body percent fat directly in 23 survivors of Hodgkin’s disease and 21 survivors of non-Hodgkin’s lymphoma, a median of 11 years after diagnosis. They used dual energy X-ray absoptiometry (DXA) and the body mass index. They found no difference in the body mass index, but they did find that the whole-body percent fat was increased in the survivors compared to local controls. The excess fatness was seen primarily in those treated for non-Hodgkin’s lymphoma. These patients had a reduced lean body mass.

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Do phytoestrogens from clover treat hot flashes?

Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: The isoflavone clover extract (ICE) study, a randomized controlled trial. JAMA 2003;290:207-214.

For a long time breast cancer survivors, prohibited from taking estrogen replacement to relieve menopausal symptoms, have been most interested in phytoestrogens as an alternative. The most recognized source of phytoestrogens in the diet is soy, but red clover is also a source. Phytoestrogens are polyphenol compounds that bind to estrogen receptors and act as agonists in some tissues and antagonists in others. These researchers evaluated whether either of two dietary supplements could reduce hot flashes in menopausal woman. These patients were not breast cancer survivors but were interested in the alternative since the risks of estrogen replacement have been asserted by the Heart and Estrogen/Progestin Replacement Study.

The researchers compared Promensil (82 mg of total isoflavones per day) with Rimostil (57 mg of total isoflavones per day), both from red clover, with a placebo to see if the frequency of hot flashes decreased. The women were 45 to 60 years old and had become menopausal in the last 3.3 years on average. They had about 8 hot flashes per day. They took the prescription for 12 weeks after a two-week period of placebos. Women who took Promensal but not Rimostil improved more rapidly than the placebo group, but quality of life or mean daily hot flash count did not show a statistically significant difference.

Only a minority of Asian women has hot flashes, and this has been attributed to the soy in their diet. This study excluded women who ate a high quantity of soy or who were vegetarians. Compared to soy, red clover extracts have two added isoflavones, biochanin A and formononetin.

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Do soy, miso soup, and isoflavones reduce breast cancer risk?

Yamamoto S, Sobue T, Kobayashi M, Sasaki S, Tsugane S. Soy, isoflavones, and breast cancer risk in Japan. J Natl Cancer Inst 2003;95:906-913.

Although oncologists have been concerned that phytoestrogens might be estrogen agonists and promote breast cancer in survivors, these researchers have shown that Japanese women who frequently eat miso soup and isoflavones are at less risk of breast cancer. They did a population-based, prospective cohort study in Japan of 21,852 women 40 to 59 years old who filled out a survey in 1990 about consumption of soy products. By 1999, 179 women had developed breast cancer. Consumption of miso soup and isoflavones but not soy foods was inversely related to the risk of breast cancer. This effect was even more significant in post-menopausal women.

The Japanese diet includes dried or green soybeans, fermented soybean paste or miso, soybean curd or tofu, natto or fermented soybeans, okara or tofu lees, soybean sprouts, soymilk, yuba or soy milk skin, soy flour or kinako, and soy sauce. The major components of the isoflavones are genistein, daidzein and their glucosides. These substances have been shown to have an anticarcinogenic effect in hormone-related cancers. Those women who took the equivalent of genistein 25.3 mg/day or who had three or more bowls of miso soup per day had half the risk of breast cancer as the group who ate little. It is not as easy to report the amount of soy in a diet and that may have contributed to the lack of a finding related to soy per se.

This study had the advantage of starting with the general population and using a prospective method. The amount of isoflavone could be distinguished from the amount of soy with a validated questionnaire. Another advantage was the large variation of isoflavone intake in the group studied.

The implication for oncology patients is that treatment with isoflavones may not promote breast tumors and may, in fact, have an anti-estrogenic effect.

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Does paroxetine at low doses prevent hot flashes?

Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes, a randomized controlled trial. JAMA 2003;289:2827-2834.

Building on their work with immediate release paroxetine in breast cancer survivors,1 these researchers studied 165 menopausal women and compared placebo to 12.5 mg and 25 mg paroxetine controlled release over 6 weeks after one week of placebo. On average the hot flash frequency went from 7 to 4 per day in the group on the lower dose. The mean reduction of hot flashes daily was similarly about 3 in the group taking the higher dose. Paroxetine CR was significantly better than placebo. The effect on hot flashes was independent of effects on anxiety or depression. Most in the study were not depressed. The lower dose was better tolerated.

The interesting finding here is that such a low dose of a serotonin reuptake inhibitor was better than placebo. Paroxetine CR 12.5 mg is the equivalent of paroxetine 10 mg immediate release. It reaches steady state in 2 weeks and has an elimination half-life of 15-20 hours, similar to the immediate release formulation.

Other studies in breast cancer survivors have shown the benefit of fluoxetine, venlafaxine,2 and clonidine.3  Fluoxetine 20 mg has shown a modest benefit in a double-blinded, randomized, crossover trial with a four-week evaluation.4  For venlafaxine extended release, 37.5 mg, 75 mg, and 150 mg were evaluated. The reduction of hot flash score was 37% at 75 mg. Adverse events like dry mouth, nausea, constipation were dose related This study of paroxetine does not suggest which drug would be better in the setting of breast cancer patients on an anti-estrogen. Both paroxetine and venlafaxine have a short half-life and some symptoms if discontinued abruptly. Paroxetine is not constipating. The best plan is to tailor the drug choice to the patient.

1. Stearns V, Isaacs C, Rowland J et al. A pilot trial assessing the efficacy of paroxetine hydrochloride in controlling hot flashes in breast cancer survivors. Ann Oncol 2000;11:17-22.
2. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized controlled trial. Lancet 2000;356:2059-2063.
3. Pandya KJ, Raubertas RF, Flynn PJ et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes. Ann Intern Med 2000;132:788-793.
4. Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ et al. Phase III evaluation of fluoxetine for treatment of hot flashes.

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Does treatment for nasopharyngeal carcinoma hurt memory?

Lam LCW, Leung SF, Chan YL. Progress of memory function after radiation therapy in patients with nasopharyngeal carcinoma. J Neuropsychiatry and Clin Neurosci 2003;15:90-97.

Patients who have been treated with radiation for nasopharyngeal carcinoma may show memory deficits, particularly retrieval difficulty, as a result of injury to mesial temporal lobe structures. Radiation treatment is a mainstay of treatment for patients with nasopharyngeal carcinoma. Temporal lobe injury results from the radiation treatment in 1-3% of these patients. Hypodense or cystic lesions are noted on computed tomography as are hyperintense changes in T2-weighted images on magnetic resonance imaging. Researchers in Hong Kong studied the memory function of patients treated for nasopharyngeal carcinoma within two years who were under 60 years old. Of these, 40 had imaging evidence of temporal lobe injury and 20 did not. These were compared to 19 healthy control subjects matched for age and education. In order to learn about the longitudinal course of memory dysfunction, 17 patients were studied after an average of 28 months.

Subtle language deficits may occur after radiation treatment and may be related to injury to mesial temporal structures. Over time verbal memory was better preserved than visual memory. Patients had more trouble with retrieval of memories than with encoding. Patients had lower verbal scores than controls. The studies did not show a difference between the patients with temporal lobe injury on imaging and those who did not have laboratory evidence of injury. The patients who complained about memory difficulties did score worse on verbal learning than those who did not have complaints. These patients were assessed for depression but were not depressed.

The nasopharynx and adjacent regions received at least 66 Gy in fractions of 1.6-2.5 Gy. Eye shields were used to shield the temporal lobe from the anterior photon beam, but the temporal lobe below the pituitary fossa was not shielded. Shielding varied depending on the extent of the tumor. The neuropsychiatric assessment included the Chinese version of the Wechsler Adult Intelligence Scale-Revised verbal subtests, digit and visual spans, and Rey auditory and visual learning tests. An interview about memory complaints was recorded.

This study should remind us to consider neurological deficit as a cause of cognitive complaints in patients who have had radiation treatment above the neck.

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DBG: Donna B. Greenberg, MD, Associate Professor of Psychiatry at Harvard Medical School and Psychiatric Consultant in the Massachusetts General Hospital Cancer Center, Dana Farber Partners Cancer Care