SEVERE HYPOTHYROIDISM AFTER CHEMOTHERAPY AND LOCOREGIONAL IRRADIATION FOR BREAST CANCER

Radiotherapy and Oncology 57 (2000) 103±105

Letter to the Editor SEVERE HYPOTHYROIDISM AFTER CHEMOTHERAPY AND LOCOREGIONAL IRRADIATION FOR BREAST CANCER To the Editor, Thyroid dysfunction can develop following irradiation for Hodgkin's disease and head and neck tumours [2,3,5]. The frequency ranges between 7 and 54% depending on the selection of patients and whether a clinical and/or biological de®nition was used [3,5]. After head and neck tumours treatment, the hypothyroidism risk is signi®cantly increased by high irradiation doses, the association with cervical surgery (including partial thyroidectomy), the absence of mid-line shielding and the duration of therapy [5]. After Hodgkin's disease treatment, risk factors also include the total delivered dose (more than 30 Gy), and high dose per fraction (more than 2.5 Gy per day) [3]. After breast cancer, only a few cases of thyroid dysfunction have been reported [1,4]. Among 80 patients treated by surgery, loco-regional irradiation and three to six cycles of chemotherapy from January 1996 to September 1998, for a pT2-T3-N1 breast cancer, we observed ®ve cases (6.2%) of severe clinical hypothyroidism, which occurred very precociously after the end of this primary treatment for breast cancer. The ®ve cases are described in details in Table 1. The remaining 75 patients did not show any hypothyroidism sign, consequently they did not have usTSH values. It should be noted that among the 80 patients, no thyroid status had been evaluated prior to the breast cancer treatment. Moreover, the ®ve patients who developed hypothyroidism did not have any particular medical history, nor autoimmune diseases. No patients had a signi®cant medical history, nor any autoimmune disease. Three out of the ®ve cases had received neoadjuvant chemotherapy with FEC 100 regimen (5-¯uorouracyl: 500 mg/m 2±Epirubicin:100 mg/m 2±Cyclophosphamide: 500 mg/m 2 with four cycles in two and six in one patient, followed by modi®ed radical mastectomy in one case and lumpectomy 1 axillary dissection (L 1 AD) in two cases. In the other two cases L 1 AD was initially performed, followed by six cycles of FEC 50 and FEC 100, starting loco regional irradiation after the fourth and sixth cycles, respectively. All tumours were in®ltrating ductal carcinoma, with axillary nodes involved and positive

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hormone receptors. The loco-regional irradiation included the chest wall in two cases and the whole breast in three cases. In all cases, due to axillary nodal involvement, internal mammary nodes and supra- and infra-clavicular nodes were treated by a direct ®eld, including both volumes (`Hockey stick'). We used a mixed beam delivering 20 Gy by Cobalt photons and 30 Gy by 9 MeV electrons with an alternate weekly sequence to spare the subjacent heart (at 2 Gy per fraction). Thus, we consider that about 65% of the homolateral thyroid lobe was included in this ®eld. All our patients presented clinical symptoms of hypothyroidism some weeks after the end of the irradiation. The main symptoms were fatigue and a rapid gain in weight, frequently associated with constipation, skin dryness and sensitivity to the cold. No patients showed any cardiac symptoms. The ®rst abnormal dosage of ultra-sensitive thyroid-stimulating hormone (usTSH) was found at 7, 8, 10, 13 and 22 weeks, respectively, following the end of radiotherapy. In all cases, very high levels of usTSH were discovered. Concomitantly, high levels of antimicrosomal antibodies were found, suggesting an auto-immune origin for this disorder. All patients were treated by substitutive exogenous thyroxine, resulting in progressive normalization of their usTSH levels. Four patients are now in remission. Patient no. 2 developed a local recurrence requiring salvage mastectomy and Tamoxifen. These observations suggest a speci®c toxicity with relatively high-dosed chemotherapy containing an anthracyclin in association with loco-regional irradiation delivered at the same time at standard dosage. The most important points are the relatively young age of the patients and the unusual precocity and severity of this hypothyroidism. Indeed, in the literature, this side-effect is more delayed and often only biologically apparent, both after Hodgkin's disease and head and neck cancer [2,3,5]. Furthermore, until now, no evidence of a possible aggravating role for chemotherapy has been clearly found. In another two reports on hypothyroidism after breast cancer treatment [1,4], the time elapsing between irradiation and hypothyroidism was very long and almost all women were menopausal. In the Finnish report, 22 cases of hypothyroidism were described, ®ve with clinical symptoms and 17 detected only by elevated usTSH levels [4]. The volume of thyroid included in the irradiation ®elds is similar to ours. The hypothyroidism, which occurred in these patients, could be due to direct radiation damage to the follicular cells, damage to thyroid vessels or to induction (by partial necrosis of cells?) of an immunolo-

31

35

63

42

47

1

2

3

4

5

T1N1

T3N1

T2N1

T3N1

T2N0

T.N.M

(1) L 1 AD 1 LR Rxt (2) 16 FEC 50 (1) 6 FEC100 (2) L 1 AD (3) LR Rxt (1) 4 FEC 100 (2) L 1 AD (3) LR Rxt (1) 4 FEC 100 (2) M.R.M. (3) LR Rxt (1) L 1 AD 1 LR Rxt (2) 6 FEC 100

Treatment

I.D.C., pN 1 l/15

I.D.C., pN 1 4/10

I.D.C., pN 1 1/19

I.D.C., pN 1 2/10

I.D.C., pN 1 l/29

Histologic features

11-12-97

13-3-97

9-5-97

25-7-96

8-12-95

CT start

31-3-98

15-5-97

11-7-97

13-11-96

22-3-96

CT end

14-4-98

7-7-97

10-9-97

19-1-97

15-2-96

RT start

29-5-98

18-8-97

4-11-97

3-3-97

4-4-96

RT end

20-7-98

13-10-97

23-1-98

13-6-97

20-9-96

Date of discovery

67

169

18

12.9

94.9

T.S.H (1) level

0.40

0.20

1.10

0.66

0.39

FT4 (2) level

2693

4818

18229

711

9093

MIC antibody

a L, lumpectomy; AD, axillary dissection; LR Rxt, loco regional irradiation; M.R.M, modi®ed radical mastectomy; I.D.C, in®ltrating ductal carcinoma; T.S.H, thyroid-stimulating hormone (mU/ml); MIC, microsomial antibody U/ml); FEC, ¯uouracyl±epirubicine±cyclophosphamide; pN 1 , axillary nodal involvement; CT, chemotherapy; RT, radiotherapy; FT4, free thyroxin level (ng/dl); (1), normal value: 0.1±3 mU/l, (2), normal value: 0.78±1.9 ng/dl.

Age

Case

Table 1 Characteristics of the patients a

104 B. Cutuli et al. / Radiotherapy and Oncology 57 (2000) 103±105

B. Cutuli et al. / Radiotherapy and Oncology 57 (2000) 103±105

gic reaction [5]. The very high rate of antimicrosomial antibodies seems to suggest this latter hypothesis, which is similar to the effects observed after treatment by interferon. Even if not clearly physiopathological hypothesis is established, it is questionable whether the abrupt menopause induced by relatively high-dosed chemotherapy can aggravate a latent predisposition toward developing thyroid dysfunction. This point requires further investigation, such as suggested by Shering et al. [6] who investigate the association between thyroid disorders and breast carcinoma. Whatever the case may be, due to recent propensity towards increasing doses in adjuvant and neo-adjuvant chemotherapy and combining this treatment more and more closely with locoregional irradiation in `high risk' breast cancer (e.g. with axillary involved nodes), particular attention should be given to the possible induction of severe thyroid disorders. In the absence of clearly-identi®ed risk factors, we suggest that patients who underwent pre or post-surgical treatment by locoregional radiotherapy and chemotherapy for breast cancer should undergo an initial basic usTSH dosage to be regularly monitored with regular controls of usTSH levels, to precociously detect any `subclinical' hypothyroidism. References [1] Bruning P, Bonfrer J, De Jong-Bakker M, Nooyen W, Burgers M. Primary hypothyroidism in breast cancer patients with irradiated supraclavicular lymph nodes. Br J Cancer 1985;51:659±663. [2] Constine LS. What else don't we know about the late effects of radia-

[3] [4] [5] [6]

105

tion in patients treated for head and neck cancer? Int J Radiat Oncol Biol Phys 1995;31:427±429. Hancock SL, McDougall IR, Constine LS. Thyroid abnormalities after therapeutic external radiation. Int J Radiat Oncol Biol Phys 1995;31:1165±1170. Joensuu H, Vlikari J. Thyroid function after postoperative radiation therapy in patients with breast cancer. Acta Radiol Oncol 1986;25:167±170. Monnier A. Effets tardifs de la radiotheÂrapie externe sur la glande thyroiÈde. Cancer-Radiother 1997;1:717±731. Shering SG, Zbar AP, Moriarty M, Mc Dermott EW, O'Higgins NH, Smyth PP. Thyroid disorders and breast cancer. Eur J Cancer Prev 1996;5:504±506.

Sincerely, Bruno Cutuli a,*, Philippe Quentin a, Jean-Francois Rodier b, Paul Barakat b, Jean-Claude Grob c (Received 3 November 1999; received in revised form 17 January 2000; accepted 8 March 2000) a

Department of Radiotherapy, Paul Strauss Center, 67085 Strasbourg, France b

Department of Surgery, Paul Strauss Center, 67085 Strasbourg, France

c

Department of Nuclear Medicine, Paul Strauss Centre, 67085 Strasbourg, France *Corresponding author. Deparment of Radiotherapy, Polyclinique de Courlancy, 51100 Reims, France. 0167-8140/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167 -8 140(00)00183 -3