Journal of Pain and Symptom Management
Volume 39, Issue 4 , Pages 779-783, April 2010

Paraneoplastic Raynaud's Phenomenon—Good Palliation After a Multidisciplinary Approach

  • Eva K. Schildmann, MD

      Affiliations

    • Department of Hematology, Oncology and Tumor Immunology, Helios Klinikum Berlin-Buch, Berlin, Germany
    • Corresponding Author InformationAddress correspondence to: Eva K. Schildmann, MD, Department of Hematology, Oncology and Tumor Immunology, Robert-Rössle-Klinik, Helios Klinikum Berlin-Buch, Campus Buch, Universitätsmedizin Berlin, Schwanebecker Chaussee 50, 13125 Berlin, Germany.
    • ,
  • Andrew N. Davies, FRCP

      Affiliations

    • Department of Palliative Medicine, Royal Marsden Hospital NHS Foundation Trust, Sutton, Surrey, United Kingdom

Accepted 28 September 2009. published online 04 March 2010.

Article Outline

Abstract 

Paraneoplastic Raynaud's phenomenon is a rare complication of a number of different malignancies (carcinomas, sarcomas, lymphomas, and leukemias). We present a case of paraneoplastic Raynaud's phenomenon in a patient with non-small-cell lung cancer that was associated with significant morbidity, involved a multidisciplinary approach, and eventually responded to a specialized intervention (i.e., iloprost trometamol).

Key Words: Paraneoplastic Raynaud's phenomenon, palliative care, multidisciplinary management, iloprost

 

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Introduction 

Paraneoplastic syndromes have been defined as “pathological conditions that are caused by a cancer but not brought about directly by local infiltration or metastatic spread.”1 They are relatively common, with a reported prevalence of 5%–10% in the general cancer population.1 A number of different paraneoplastic syndromes have been described, including nonspecific constitutional symptoms (e.g., cachexia, fatigue), as well as specific endocrine (e.g., malignant hypercalcemia), hematological (e.g., anemia of chronic disease), neurological (e.g., peripheral neuropathy), renal (e.g., membranous nephropathy), dermatological (e.g., generalized pruritus), and rheumatological (e.g., seronegative polyarthritis) syndromes.1

Raynaud's phenomenon is characterized by episodes of cold-induced pallor and/or cyanosis of the distal portions of the fingers and toes.2 In most (87%) cases,3 the problem is an isolated phenomenon (“primary Raynaud's phenomenon” or “Raynaud's disease”) and represents an exaggerated normal response to cold stimuli.2 In the remaining cases, it is related to an underlying disease (“secondary Raynaud's phenomenon”). Secondary Raynaud's phenomenon can be associated with a variety of conditions but is usually related to the connective tissue diseases (e.g., scleroderma, mixed connective tissue disease).2, 3 However, Raynaud's phenomenon can also be associated with malignant conditions (“paraneoplastic Raynaud's phenomenon”).

We present a case of paraneoplastic Raynaud's phenomenon in a patient with non-small-cell lung cancer. The phenomenon was associated with significant morbidity, and treatment involved a multidisciplinary approach. The patient eventually responded to a specialized intervention (i.e., iloprost trometamol).

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Case Report 

The patient was a 78-year-old man with stage IV non-small-cell lung cancer and no other significant medical history. Initially, he received a course of combination chemotherapy (carboplatin and gemcitabine), but this was discontinued after four cycles because of evidence of progressive disease on radiological imaging. Subsequently, he was treated for ongoing cancer-related chest pain with a course of palliative radiotherapy (20Gy in five fractions). However, the cancer-related chest pain persisted despite the palliative radiotherapy, and the patient was admitted to the palliative care unit for symptom control.

During the admission, eight weeks after the last dose of chemotherapy, the patient described and exhibited the clinical features of Raynaud's phenomenon: when he became cold, his fingers would turn white, then blue, and eventually red. All the fingers were involved, although the fingers of the left hand were more severely affected than those of the right hand. These symptoms had been present for some weeks, had postdated the combination chemotherapy, and were relatively mild in nature. During an attack, the fingers would be uncomfortable, but after the attack, the fingers would return to normal.

The arterial pulses were normal in the arms, and there were no clinical features of connective tissue disease anywhere on the body. Routine laboratory tests were normal, and an antinuclear antibody test was negative. He was reviewed by the surgical team who agreed with the diagnosis of Raynaud's phenomenon and the rheumatology team who agreed with the diagnosis of paraneoplastic Raynaud's phenomenon. At this stage, he was simply advised about keeping warm to attempt to prevent attacks (e.g., wearing gloves).

One week after discharge, he was reviewed in the palliative care clinic. He reported that the Raynaud's phenomenon had become worse. He was experiencing more frequent attacks, and the attacks were more severe in nature. On examination, there was evidence of ischemia of the fingers. The ends of most of the fingers were discolored, and the end of the left fifth finger was necrotic (Fig. 1). At this stage, he was treated with oral nifedipine, which produced limited subjective and objective benefits. Subsequently, he was treated with a temporary interscalene nerve block on the left side, which resulted in some further subjective and objective improvement.

In view of the persistent ischemia of the fingers, it was decided to treat the patient with intravenous iloprost trometamol and also to commence single-agent chemotherapy (docetaxel). Interestingly, there was no evidence of progressive disease on radiological imaging at this time. The iloprost was administered according to the protocol used by the Department of Rheumatology at St. George's Hospital (London). The patient received a titrated dose of iloprost for six hours per day, and five days in total, intravenously; 50mcg iloprost (67mcg iloprost trometamol) was diluted in 250mL of normal saline, with the infusion commenced at 10mL/hour and increased by 10mL/hour every 30minutes (as tolerated).

The iloprost infusion resulted in marked objective improvement in the ischemia of the fingers, associated with a subjective improvement in the cold-related symptoms. The patient died from his cancer two months later, and there was no recurrence of the Raynaud's phenomenon during this time period.

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Discussion 

Raynaud's phenomenon is a relatively common condition, with a reported prevalence of 3%–5% in the general population.2 In contrast, paraneoplastic Raynaud's phenomenon is rare. Indeed, a recent review identified only 33 cases of paraneoplastic Raynaud's syndrome in the medical literature.4 It has been reported in association with a variety of different malignancies, including carcinomas, sarcomas, lymphomas, and leukemias.4 There have been several previous reports of paraneoplastic Raynaud's syndrome in patients with carcinoma of the lung.4, 5, 6, 7, 8, 9 It is often described in the context of locally advanced or disseminated malignant disease.4

Raynaud's phenomenon also has been reported to be a side effect of different chemotherapy agents, particularly bleomycin (either alone or in combination with vinca alkaloids or cisplatin) and cisplatin (in combination with other chemotherapy agents).10 Interestingly, the Medicines and Healthcare Products Regulatory Agency (MHRA) (United Kingdom) have received two reports of Raynaud's phenomenon associated with carboplatin use and five reports of Raynaud's phenomenon associated with gemcitabine usage (MHRA, personal communication). The mechanism for chemotherapy-induced Raynaud's phenomenon is unknown. Raynaud's phenomenon also has been reported as a side effect of biological agents (e.g., interferon)11 and, rarely, radiotherapy treatment.12

The initial clinical features of Raynaud's phenomenon represent vasoconstriction of the digital arteries, precapillary arterioles, and cutaneous arteriovenous shunts, and the subsequent clinical features (rubor during rewarming) represent a reactive vasodilatation of these blood vessels.2 The pathophysiology of Raynaud's phenomenon is not completely understood, but some of the factors involved include increased vasoconstriction, decreased vasodilatation, structural abnormality of small and large vessels, and coagulopathy.13 Raynaud's phenomenon is a heterogeneous condition,2 and the mechanisms involved in primary Raynaud's phenomenon are different from those involved in secondary Raynaud's phenomenon (and also different among the various causes of secondary Raynaud's phenomenon).13 The pathophysiology of paraneoplastic Raynaud's phenomenon is not understood, although it is likely that similar factors to those previously mentioned are involved and that different factors are involved in different patients.4

Primary Raynaud's phenomenon usually presents in childhood/young adulthood and is more common in women than men. It is characterized by intermittent attacks that are precipitated by exposure to cold, although the attacks can also be precipitated by stressful situations.2 The attack may start in one or more fingers, but invariably spreads to all the fingers, and usually involves both hands (and sometimes the feet).2 Initially, the ends of the fingers become white or blue, and these changes may be accompanied by the sensation of coldness, numbness, and/or paresthesia. Subsequently, the ends of the fingers become red, and this change may be accompanied by the sensation of “throbbing” and/or discomfort. The episodes are generally symmetrical in distribution, nonpainful in nature, and not associated with ischemic complications (i.e., ulceration, gangrene).2

The clinical features of secondary Raynaud's phenomenon can be similar to those of primary Raynaud's phenomenon, although it is not unusual for the episodes to be asymmetrical in distribution, painful in nature, and associated with ischemic complications.2, 4, 5, 6, 7, 8, 9, 14 Indeed, the recent review identified 21 cases of gangrene of the fingers secondary to paraneoplastic Raynaud's syndrome.4 Such clinical features, in the absence of evidence of an autoimmune or a vascular disorder, should prompt investigations for an underlying malignancy or for a recurrence of a previously diagnosed malignancy.4, 8 Raynaud's phenomenon may develop at any stage of the cancer, although it is often one of the presenting features of the cancer.4, 14 It may act as a marker of disease activity. Thus, there are reports of improvements in the Raynaud's phenomenon after successful treatment of the underlying cancer.15, 16

It should be noted that patients with persistent cyanosis of the hands and feet that is aggravated by exposure to cold have a condition called acrocyanosis (and not Raynaud's phenomenon). Acrocyanosis can also be associated with malignant disease (paraneoplastic acrocyanosis).4 Its treatment consists of reassurance and advice about avoiding cold exposure; pharmacological interventions are usually not necessary.17

Various treatment strategies have been used in the management of Raynaud's phenomenon.2, 18 Generally, patients should keep themselves warm, particularly their hands and feet. Smoking may aggravate the problem, so patients should be discouraged from smoking. Similarly, vasoconstrictor drugs may worsen the problem, so patients should be switched to alternative therapeutic agents. A number of nonpharmacological treatments have been used in this condition (e.g., biofeedback techniques, acupuncture therapy), although the evidence for most of these interventions is limited.2, 18 Pharmacological treatments are usually reserved for more severe cases of Raynaud's phenomenon.

The mainstay of pharmacological treatment is the calcium channel blocker (e.g., nifedipine). The available evidence suggests that these drugs can reduce the frequency and severity of attacks.19 Other drugs with vasodilating effects have been reported to be effective in this condition (angiotensin II inhibitors, e.g., losartan; selective serotonin reuptake inhibitors, e.g., fluoxetine; angiotensin-converting enzyme inhibitors, e.g., captopril; alpha blockers, e.g., prazosin; nitrates, e.g., topical glyceryl trinitrate), although these are generally reserved for patients who do not respond, or develop intolerable side effects, to calcium channel blockers.18 A variety of new targeted pharmacological treatments are under investigation for the management of Raynaud's phenomenon (phosphodiesterase 5 inhibitors, e.g., sildenafil; endothelin receptor blockers, e.g., bosentan).20 Moreover, a variety of alternative modalities have also been reported to be effective in this condition (e.g., botulinum toxin A, low-level laser therapy).18, 20

In patients with ischemic complications, the recommended options for management include both pharmacological treatment (prostacyclin analogs, e.g., iloprost; phosphodiesterase 5 inhibitors, e.g., sildenafil) and interventional techniques (chemical sympathectomy, surgical sympathectomy).18 Iloprost has been previously reported to be effective in patients with ischemic complications secondary to paraneoplastic Raynaud's phenomenon.4, 15 It has a number of relevant pharmacological actions, including vasodilatation of arterioles, inhibition of platelet aggregation, and stimulation of fibrinolysis (http://emc.medicines.org.uk). Interestingly, the pharmacological actions may be more sustained than suggested by the pharmacokinetic profile (i.e., weeks to months).21

Sympathectomy has occasionally been reported to be effective in patients with ischemic complications secondary to paraneoplastic Raynaud's phenomenon.22 A number of different techniques have been described in the medical literature, including cervicothoracic sympathectomy23 and localized digital sympathectomy.24 It should be noted that certain authors also recommend the use of antiplatelet therapy (e.g., aspirin) and anticoagulant therapy (e.g., heparin) in patients with ischemic complications.2 Some patients will inevitably require surgical debridement or amputation for the necrosis of their fingers and toes.4, 14

As discussed, there are reports of improvements in the Raynaud's phenomenon after successful treatment of the underlying cancer. Thus, treatment of the underlying cancer should always be considered as a therapeutic option in paraneoplastic Raynaud's phenomenon. However, the decision to embark on oncological treatment should always be based on a thorough risk-benefit analysis, particularly when there are a number of alternative therapeutic options.

Finally, it is important to reiterate the multidisciplinary aspects to the management of paraneoplastic Raynaud's phenomenon. Paraneoplastic Raynaud's phenomenon is a rare condition, is a complicated problem, and may require input from a variety of different disciplines. Indeed, our patient was treated by the oncology team, the palliative care team, the acute pain team (for interscalene block), the rheumatology team, and the surgery team. This multidisciplinary input resulted in good palliation of the condition until the death of the patient.

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References 

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PII: S0885-3924(10)00079-5

doi:10.1016/j.jpainsymman.2009.09.006

Journal of Pain and Symptom Management
Volume 39, Issue 4 , Pages 779-783, April 2010

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