Musculoskeletal Symptoms

Many forms of malignancy are associated with musculoskeletal symptoms and these may be due to direct infiltration of bones, joints or muscles. Paraneoplastic syndromes may also involve the musculoskeletal system and several chapters in this book have already dealt with these phenomena. In the last 5 years, it has been noted that musculoskeletal symptoms may develop following combination chemotherapy for various malignancies, particularly breast cancer. Most of these patients were otherwise relatively healthy with no previous history of rheumatic symptoms.

The first report of this syndrome, termed "postchemotherapy rheumatism" by Loprinzi et al. [4], described 8 patients with breast cancer who all underwent postoperative adjuvant chemotherapy. These regimens were all cyclophosphamide based with the addition of either methotrexate and flu-orouracil (CMF), or doxorubicin and fluorouracil (CAF). Two patients also had corticosteroids such as dexamethasone or prednisolone in the regimen. The mean age of these patients was 45 years and all experienced very similar clinical features. Between 2 and 16 months after completing the chemotherapy regimen, these patients experienced generalized myalgia, musculoskeletal aching and polyarthralgia. One patient had symptoms and signs suggestive of synovitis, others had mild peri-articular swelling and another additionally had palmar tenosynovitis and intense morning stiffness. In each case clinical evaluation failed to reveal an overt rheumatological condition. Serologically, one patient had a borderline ANA of 1:40, all were rheumatoid factor negative and the erthryocyte sedimentation rates were all normal. Importantly, bone scans done in 6 out of the 8 patients were normal. On the whole nonsteroidal antiinflammatory agents were ineffective and symptoms generally improved spontaneously after a few months. One patient responded rapidly to a short course of low dose prednisolone.

Loprinzi et al. [4j felt that this syndrome represented a previously undescribed noninflammatory rheumatic disorder that was self-limiting. Although they had no data to support this, they felt that these symptoms could occur in as many as 5% of patients completing a combination chemotherapy regimen for breast cancer. This report produced a brisk correspondence and several further cases of postchemotherapy rheumatism were described [5]. There were further reports of the syndrome occurring after chemotherapy for breast cancer but also following treatment for non-Hodgkin's lymphoma [6, 7] as well as ovarian cancer [8]. A more recent series by Warner et al. [9] describes 23 women with breast cancer who developed postchemotherapy rheumatism bringing the total number of patients in the literature to 46. They described one group of 8 patients in whom there were no preexisting rheumatic symptoms, and a further 15 who had rheumatic complaints prior to chemotherapy but in whom the symptoms markedly worsened or new features appeared. Four patients in the first group developed a polyarthritis and 3 had fibromyalgia after chemotherapy. The most notable patient in the second group was a woman who had autoimmune haemolytic anaemia prior to her breast cancer but who developed systemic lupus erythematosus 15 years after oophorectomy and chemotherapy. The main difference from Loprinzi et al.'s report was that these patients had a poorer outcome with considerable reduction in functional status from the musculoskeletal symptoms that persisted for long periods of time.

The pathogenesis of this postchemotherapy syndrome remains unclear. Various suggestions have included a "steroid withdrawal" effect or a chemotherapy induced menopause [7], However, not all patients received corticosteroids in their chemotherapy regimen and some patients were postmenopausal or male making the latter hypothesis unlikely. One common factor to all the cases so far appears to be the use of cyclophosphamide and its place in combination chemotherapy regimens [8]. However, intravenous cyclophosphamide, often in high doses is used in the treatment of severe connective tissue diseases and this syndrome of arthralgia and myalgia has not been observed. Admittedly, it would be difficult to distinguish arthralgia from cyclophosphamide and that from the underlying connective tissue disease in these patients.

It has been suggested that the importance of the syndrome lies with its early recognition and the avoidance of extensive work-ups for rheumatological diseases and metastatic deposits. However, until the nature of the syndrome becomes clearer, it is unlikely that the need for careful clinical and serological evaluation will be obviated and the possibility of a firm rheumatological diagnosis needs to be considered in each patient.

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