Radioprotective effect of moderate wine consumption in patients with breast carcinoma

Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 5, pp. 1501–1505, 2009 RADIOPROTECTIVE EFFECT OF MODERATE WINE CONSUMPTION IN PATIENTS ALESSIO G. MORGANTI, CINZIA DIGESU`, SIMONA PANUNZI, M.S.,y ANDREA DE GAETANO, M.D.,y GABRIELLA MACCHIA, FRANCESCO DEODATO, M.D.,M. GRAZIA CECE, R.T., MASSIMO CIROCCO, x AUGUSTO DI CASTELNUOVO, M.S.,k LICIA IACOVIELLO, PH.D.,k VINCENZO VALENTINI, M.D.,{ NUMA CELLINI, M.D.,{ AND GIOVANNI DE GAETANO, PH.D.k * Radiotherapy Unit, Department of Oncology, k Research Laboratories, ‘‘John Paul II’’ Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy; y National Research Council, Institute of Systems Analysis and Computer Science, BioMatLab, Rome, Italy; { Department of Radiotherapy, Policlinico Universitario ‘‘Agostino Gemelli,’’ Catholic University, Rome, Italy; z Present address: Department of Radiology, General Hospital ‘‘SS. Annunziata,’’ Cento, Italy; and x Present address: Department of Nuclear Medicine, General Hospital, Grosseto, Italy Purpose: Given the high cost and side effects of radioprotective agents such as amifostine, attention has beenfocused on potentially equally effective but less expensive and toxic natural substances. We evaluated the potentialradioprotective effects of wine in preventing skin toxicity in patients with breast cancer.
Methods and Materials: Before treatment, the medical history and habits of patients were assessed and the infor-mation recorded in their clinical folders. Patients were divided into three groups based on the dose/fractionationscheme used: control group, 60.4 Gy (standard technique); Modulated Accelerated Radiotherapy in Adjuvanttreatment of breast cancer (MARA)-1 protocol group, 44 Gy (concomitant boost to tumoral bed); and MARA-2protocol group, 60 Gy (concomitant boost to tumoral bed). The impact of the following variables on acute skin tox-icity was evaluated by chart review: radiotherapy protocol, planning target volume (PTV), comorbidity (e.g.,hypertension and diabetes), hemoglobin level before therapy, adjuvant hormone therapy, adjuvant chemotherapy,cigarette smoking, and drinking habits.
Results: The study population consisted of 348 patients. More severe skin toxicity was significantly associated withthe radiotherapy protocol (p < 0.001) and median PTV (p = 0.005). In addition, the incidence of acute toxicity ofGrade 2 or greater was higher in patients without alcohol intake (38.4% vs. 22.3%, p = 0.021). The daily amountof alcohol intake also influenced the incidence of skin toxicity, with an incidence of 38.4% in patients with no wineintake, 31.8% in patients drinking half a glass per day, 13.6% in patients drinking one glass per day, and 35.0% inpatients drinking two glasses per day. Multivariate analysis showed that wine intake, PTV, and radiotherapyprotocol were all significantly correlated with acute toxicity.
Conclusions: Our results indicate that wine may have a radioprotective effect; however, prospective studies areneeded to confirm this beneficial effect of wine and its components.
Wine, Radioprotective effect, Breast cancer, Radiotherapy.
genistein, and melatonin, whose radioprotective effects in vitroare well known . These effects have been shown in animal The prevention or cure of radiotherapy-induced side effects studies published in the last 15 years, which have shown that has garnered much interest, as has the discovery and develop- diets rich in vitamins C E , and A plant flavonoids ment of substances and treatments that can protect healthyorgans from the harmful effects of radiation. Several pharma- ; squalene chelates of essential metals (copper, iron, cologic agents have become available for this purpose, the manganese, and zinc) melatonin and chitosan most popular being amifostine . However, these agents all have radioprotective qualities. In humans the protective have several drawbacks, in that they are often very expensive, effects of diets rich in antioxidants against several pathologic they have sometimes severe side effects, and they have the conditions such as cancer, atherosclerosis, stroke, rheumatoid potential to protect tumor cells as well as healthy cells from arthritis, neurodegenerative disorders, and diabetes are well the effects of radiation . Thus attention has been focused known However, a diet that is radioprotective in humans on natural agents, such as the natural antioxidants caffeine, has yet to be identified The possible radioprotective Reprint requests to: Gabriella Macchia, M.D., Radiotherapy Unit, Department of Oncology, Catholic University, Largo A. Gemelli 1, Received July 22, 2008, and in revised form Sept 5, 2008.
86100 Campobasso, Italy. Tel: (+39) 0874-312-259; Fax: (+39) Accepted for publication Oct 1, 2008.
I. J. Radiation Oncology d Biology d Physics effects of diet were first hypothesized by researchers working per day). Patients who reported drinking alcohol less than once in the areas of space travel and military exposure .
Studies of diets for patients receiving radiotherapy havefocused more on the prevention of radiation side effects such as diarrhea and weight loss than on those with a radioprotective We divided patients into three groups based on the dose/fraction- effect . In general, clinical data on possible radioprotective ation scheme. The first group, the control group, was treated with diets in patients undergoing radiotherapy have been unclear a three-dimensional (3D) tangential technique (50.4 Gy, 1.8 Gy/ fraction) with a sequential electron boost (10 Gy, 2.5 Gy/fraction).
It is already known that some wine components have The second group consisted of postmenopausal patients who under-went intensity-modulated radiotherapy, with a 40-Gy dose (2.5 Gy/ radioprotective effects. Polyphenols, in particular, are known fraction) delivered to the planning target volume (PTV)–2 (i.e., to be radioprotective for the immune system and the central whole breast). A concomitant boost (4 Gy, 0.25 Gy/fraction) was de- nervous system and to protect against the carcinogenetic livered to the PTV-1 (i.e., tumor bed) with the 3D technique, photon effects of radiation The tannins that are found in wine beams, and wedge filters. This is known as the MARA-1 protocol.
have been found to protect hairless mice against cutaneous Patients undergoing prophylactic nodal irradiation and patients carcinomas induced by ultraviolet B radiation More with positive or close resection margins were excluded from this recently, in a crossover intervention study involving 6 young treatment. The third group consisted of premenopausal and perime- adult men aged 21 to 26 years, Greenrod et al. tested the nopausal patients who underwent intensity-modulated radiotherapy hypothesis that the nonalcoholic fraction of wine protects to a total dose of 50 Gy (2 Gy/fraction) to the PTV-2 and a 3D against the genome damage induced by oxidative stress.
concomitant boost (0.4 Gy/fraction) to the PTV-1. This is knownas the MARA-2 protocol. In all patients undergoing adjuvant The participants adhered to a low–plant phenolic compound chemotherapy, radiotherapy was started at least 3 weeks after the diet for 48 hours before consuming 300 mL of whole red wine, nonalcoholic red wine, or ethanol on separate occa- All patients underwent a complete clinical examination at least sions 1 week apart. These researchers found that the con- once a week. The daily application of Biafine (OrthoNeutrogena, sumption of nonalcoholic red wine significantly decreased, Skillman, NJ) on the irradiated skin was prescribed for all patients.
by 20%, the gamma radiation–induced deoxyribonucleic Topical steroids were prescribed for patients with Grade 1 to 2 skin acid (DNA) damage at 1 and 2 h after consumption. In con- toxicity. Treatment was interrupted in patients with Grade 3 toxicity trast, alcohol consumption tended to increase the radiation- until the toxicity lessened to Grade 2. Acute skin toxicity was differ- induced genome damage, whereas the consumption of whole entiated according to the site (breast or supraclavicular region).
wine showed only some ability to protect against radiation-induced genome damage. Thus these preliminary data sug- gest that only the nonalcoholic fraction of red wine protects Only skin toxicity on the breast (and not in the nodal areas) was DNA from oxidative damage However, the radioprotec- evaluated in this study. The Radiation Therapy Oncology Group tive effects of wine and its components have not been studied scale was used to evaluate acute toxicity during treatment at in patients undergoing radiotherapy per se.
the weekly clinical examinations and at the first clinical examination In this study we studied wine’s ability to prevent acute 3 weeks after the end of radiotherapy.
Acute toxicity in the three groups (control group, MARA-1 toxicity in patients undergoing radiotherapy after conserva- group, and MARA-2 group) was compared by use of a c2 test.
tive surgery for breast carcinoma. This included examining This test was also used to study the association between acute its potential protective effects in the context of different toxicity and the following variables: comorbidities (hypertension, radiotherapy regimens, adjuvant treatments (i.e., chemother- diabetes), hemoglobin levels at the start of treatment, hormone ther- apy and hormone therapy), and lifestyle habits such as smok- apy (yes or no), adjuvant chemotherapy (yes or no), type of adjuvant ing and alcohol intake. We observed a reduction in both the chemotherapy, smoking and drinking habits, PTV (less than median incidence and severity of skin effects in patients who were value vs. greater than or equal to median value), and age (less than regular wine drinkers compared with those in patients who median value vs. greater than or equal to median value). Variables shown to be significant (p < 0.05) as well as those for which a trendwas seen (p < 0.1) in the c2 analysis were included in a multivariateanalysis done by use of the logistic analysis model. Odds ratios and their confidence intervals were also computed. The reference levelused for the computation of the odds ratio was the level for the Patients consisted of women with breast cancer treated between February 2003 and June 2007 with breast conservation treatmentfollowed by radiotherapy. Patients were identified by a database search. Information on clinical examination findings, blood count, performance status, adjuvant therapies (chemotherapy, hormone Three hundred forty-eight patients met the study criteria.
therapy), and lifestyle habits (cigarette smoking, number of ciga-rettes per day, alcohol consumption) before treatment were obtained Patient characteristics are summarized in . The details in all patients from their clinical charts. At the preoperative evalua- pertaining to the radiotherapy and systemic treatments tion, patients were also asked to describe their daily alcohol intake in performed are summarized in . The overall radiother- terms of both the type and amount of alcohol consumed (i.e., glasses apy treatment time was 6.4 weeks for the control group Radioprotective effect of wine d A. G. MORGANTI et al.
Abbreviation: CMF = cyclophosphamide, methotrexate, and ing only half a glass of wine daily, a 13.6% incidence in (32 fractions), 3.2 weeks for the MARA-1 protocol group patients drinking one glass daily, and a 35% incidence in (16 fractions), and 5 weeks for the MARA-2 protocol group patients drinking two glasses daily. Patients who drank only one glass daily exhibited a significant (p = 0.006)odds ratio. Specifically, their risk of high grades of skin tox- icity was about 75% less than that in nondrinkers.
Univariate analysis showed no significant association A significant odds ratio was also found for the MARA-1 between the incidence of acute skin toxicity and hyperten- protocol group, in that the risk of higher grades of toxicity sion, diabetes, age, cigarette smoking, pretreatment hemoglo- was 65% less in this group than in patients in the control bin level, and administration of adjuvant hormone therapy group (p < 0.001). Furthermore, patients who underwent ad- (data not shown). There was a trend toward a higher juvant chemotherapy had a 1.6 times (p = 0.004) greater risk incidence of skin toxicity in patients undergoing adjuvant of higher grades of toxicity compared with patients who did chemotherapy (When analyzed according to the not. In contrast, the risk in patients receiving anthracyclines type of chemotherapy, the only significant difference found and taxanes (with or without other drugs) was 3.17 (p = was an increase in the incidence of skin toxicity in patients 0.01) times the risk in patients not undergoing chemotherapy.
undergoing treatment with anthracyclines and taxanes (with Multivariate analysis showed that wine intake, PTV or without other drugs) as compared with those not undergo- (evaluated as a continuous variable), and type of radiotherapy ing chemotherapy (p = 0.005). The severity of acute skin protocol were significantly correlated with the grade of acute toxicity was also shown to be significantly correlated with toxicity (categorized as Grade 0–1 vs. 2–3). From this, it the radiotherapy protocol. In particular, patients treated appears that wine intake and the MARA-1 technique confer with the MARA-1 protocol (total dose, 44 Gy) showed protection against acute toxicity ().
a lower toxicity grade than did those in the control group(total dose, 60.4 Gy) and the MARA-2 protocol group (total dose, 60 Gy). Similarly, a PTV higher than the median valuewas associated with a higher grade of toxicity The Our study findings suggest a significant radioprotective incidence of a higher grade of acute toxicity (Grade 2–3) was effect from moderate wine intake. This preliminary observa- also higher in nondrinkers than in drinkers of wine (38.4% vs.
tion was confirmed by a multivariate analysis that included 22.3%, p = 0.021). shows the percentages of patients the PTV, type of chemotherapy, and radiotherapy protocol.
with skin toxicity greater than Grade 1 classified according to Because most studies of diet in patients undergoing radio- the daily amount of wine intake: a 38.4% incidence was therapy have focused on those that lessen side effects rather observed in nondrinkers, a 31.8% incidence in patients drink- than on those that are radioprotective, there is relatively little I. J. Radiation Oncology d Biology d Physics Table 3. Univariate analysis (c2): Acute skin toxicity versus clinical parameters Abbreviations: MARA = Modulated Accelerated Radiotherapy in Adjuvant treatment of breast cancer; PTV = planning target volume.
in the literature on the topic. The study of Greenrod et al.
of wine intake depended upon patient reporting, which can , which examined whether the nonalcoholic fraction of be unreliable. Moreover, we were not able to assess some wine could protect against genome damage induced by oxi- possibly important factors such as the separate effects of dative stress, was the only one we were able to identify in a lit- red and white wine. This is an important consideration, erature search of relevance to our study. As noted earlier, because it appears from the available literature that the anti- these authors found that the consumption of nonalcoholic oxidant properties of red wine may be more significant red wine significantly decreased (i.e., by 20%) the amount than those of white wine. The retrospective design of our of gamma radiation–induced DNA damage at 1 and 2 h after study, our relatively small sample size, and the short-term consumption. In contrast, however, they found that alcohol follow-up are other limitations. Nonetheless, our findings (i.e., ethanol) tended to increase radiation-induced genome do clearly indicate that wine has a radioprotective effect.
damage. In addition, whereas whole wine was protective Further analyses are therefore warranted to elucidate any pos- against radiation-induced genome damage, the decrease in sible effect of regular wine consumption on late radiotherapy damage was less than that seen for nonalcoholic wine. In toxicity. Studies are also needed to verify a possible bimodal our study, in which we retrospectively examined the radio- course (the so-called J curve) of the radioprotective protective effects of whole wine, we could not examine the effect of wine (i.e., a reduced risk for low to moderate effects of the nonalcoholic components. Nonetheless, we still amounts but a relatively increased risk for higher amounts), observed wine to possess a clear radioprotective effect.
which suggests a shift from antioxidant to pro-oxidant One limitation of our study was that our anamnesis ques- effects. This is based on many observations showing that tionnaire in the patients’ charts did not include questions ethanol-induced liver injury may be linked, at least partly, about former drinking behavior, a longstanding concern in to an oxidative stress resulting from increased free radical studies of the health effects of alcohol As a result, our production and/or decreased antioxidant defense. Indeed, group of nondrinkers may have included some who had such oxidative stress has been shown to be restricted not quit drinking, in some cases because of health problems.
only to the liver but also, under some experimental conditions Another limitation of our study was that the quantification of ethanol administration, to extrahepatic tissues, such as thecentral nervous system, the heart, and the testes A prospective intervention study would not be feasible if it involved the possible randomizing of nondrinkers to a wineconsumption group. However, a study of the radioprotectiveeffects of nonalcoholic wine in nondrinkers might be reason-able. A randomized study comparing a compound consistingof the nonalcoholic fraction of wine versus placebo wouldalso be reasonable. In addition, it would be interesting toacquire more in-depth data about the mechanism of actionof alcohol responsible for producing the adverse effects ofionizing radiation. This knowledge would shed light onsome of our results.
Finally, the possible protective effect of wine, which we assessed only in women with breast cancer, should also be Fig. 1. Incidence of skin toxicity grade greater than 1 versus dailywine consumption (Æ 95% confidence intervals).
evaluated in male and female patients with other types of Radioprotective effect of wine d A. G. MORGANTI et al.
Table 4. Multivariate analysis (logistic model): Impact on acute toxicity (Grade 0–1 vs. 2–3) Abbreviations: CI = confidence interval; PTV = planning target volume.
* Control group versus MARA-1 protocol versus MARA-2 protocol.
tumors (e.g., prostate carcinoma) who are undergoing radio- also has the potential to enhance the therapeutic benefit in cancer patients without increasing their risk of serious adverse effects.
In conclusion, if wine can prevent radiotherapy-induced tox- The possibility that particular dietary practices or interventions icity without affecting antitumor efficacy, as we observed, it can reduce radiation-induced toxicity is very intriguing.
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