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Shuji Yoshino md, Department of Urology, Japanese Red Cross Hospital Omori, 4-30-11 Chuo, Ota-ku, Tokyo 143-8527, Japan. Email: email@example.com
An 83-year-old man with left renal cell carcinoma (RCC; pT4N0M0) was treated with postoperative combined subcutaneous injection therapy of alpha interferon (IFN-α) and IFN gamma-1a (IFN-γ-1a). Metastasis to the pleura occurred 3 months after surgery. The metastatic lesion grew while the treatment was changed to intramuscular injection of IFN-α-2b due to the presence of severe general malaise, which seemed to be caused by IFN-α and IFN-γ therapy. As melosalgia associated with sciatica was also severe, treatment with meloxicam, which is known as a potent cyclooxigenase-2 inhibitor among commercially available non-steroidal anti-inflammatory drugs, was combined, resulting in significant improvement in activity of daily life, 43.2% decrease in the size of the pleural metastasis and complete regression of retroperitoneal residual tumor.
Generally approved adjuvant therapies for renal cell carcinoma (RCC) include interferon-α (IFN-α), IFN-γ and interleukin-2 (IL-2). However, the response rates of those therapies are only 10–20%.1
In recent years, the effectiveness of non-steroidal anti-inflammatory drugs (NSAID), such as indomethacin, has been studied focusing on their cyclooxigenase-2 (COX-2) inhibiting effects as well as their anti-inflammatory effects. Their antitumor effects, primarily in colon cancer cases, have been recognized.2,3
Here we report our experience with a combined treatment with meloxicam and IFN-α-2b, which resulted in the reduction of pleural metastasis and the disappearance of retroperitoneal residual tumor in a case where the tumor had been progressive despite a combined treatment with IFN-α and IFN-γ-1a.
An 83-year-old patient visited our hospital in November 2000 with the chief complaint of left lateral abdominal pain. Abdominal ultrasonography and computed tomography (CT) revealed an advanced RCC with invasion into the iliopsoas muscle, the spleen and the left renal vein (Fig. 1). A nephrectomy was carried out but the tumor invasion into the iliopsoas muscle was not completely excised. The pathological diagnosis was pT4N0M0, grade 2, alveolar type, mixed subtype. Since we failed to completely excise the tumor, the patient's prognosis was poor. However, the patient had a handicapped child and asked us to save his life at any cost. That is why we initiated combined subcutaneous injection therapy of IFN-α and IFN-γ-1a, although severe side-effects were expected. The therapy was initiated in the second week postoperation. In February 2001, based on worsening of general malaise as well as left hemothorax and metastatic lesion in the left pleura detected by chest X-ray and chest CT scan, the patient was diagnosed with pleural metastasis of RCC and cancerous pleural effusion. Hemothorax was resolved by infusing 10 KE of OK-432 twice while a trocar was indwelled, but the metastasis increased in size. Therefore, we initiated intramuscular injection of IFN-α-2b (3 × 106 IU) twice a week. However, the patient's general malaise worsened in April 2001, and the patient was confined to bed at home, not even being able to take a walk, and growth of the metastatic lesion was revealed by chest X-ray (Fig. 2a).
At this point, treatment with meloxicam 10 mg/day was initiated because: (i) the patient was experiencing spondylosis deformans with pain in the left leg, which was not metastatic when viewed with CT scan; and (ii) meloxicam, an NSAID, demonstrates a strong COX-2 inhibiting effect and therefore might have an antitumor effect. The patient's general malaise was resolved in week 2, and the patient was able to ride a bicycle in week 4, pleural metastasis was reduced by 43.2% on chest X-ray in week 6 (Fig. 2b), and the retroperitoneal residual tumor disappeared on abdominal CT scan in week 8 after initiation of this treatment (Fig. 3a,b).
Immunotherapy, such as IFN or IL-2, is the main treatment for advanced RCC. However, its response rate has not been very satisfactory.1 A clinical trial is required to determine the most effective therapy for advanced RCC.
Cyclooxigenase-1 and COX-2 are key enzymes in the biosynthesis of prostaglandins from arachidonic acid. While COX-1 is expressed constitutively, COX-2 is induced by inflammation and cancers, including collagen disease, and is reported to promote the production of various growth factors in malignant tumors, such as colon cancer and lung cancers. Cyclooxigenase-2 is known to suppress apoptosis, activate angiogenesis of tumors through vascular endothelial growth factor (VEGF) and collagenase type IV and generate immunosupression through prostaglandins. These effects therefore are considered to cause quite a favorable state for the growth of cancer cells. COX-2 inhibitors, through in vitro and in vivo studies, are known to suppress these effects and are therefore expected to act as anti-tumor agents.2–6
It was reported that the selective COX-1 and COX-2 inhibitor indomethacin increases IFN-α stimulation of interferon-stimulated response element (ISRE)-dependent transcription in a dose-dependent manner in CCL13/Chang and HepG2 hepatoma cell lines. The data indicated that indomethacin exerts its effects by synergizing with IFN-α in inducing signal transducers and activators of transcription 1 (STAT1) activation by phosphorylation, without affecting concurrent Jak1 phosphorylation. Additionally, blockade of arachidonic acid metabolism by indomethacin activates a signaling pathway that converges on STAT1 activation to potentiate IFN-α-dependent gene activation. Similar biological modulations probably had occurred in the tumor tissues of our patient.7
Alpha-interferon is known to have an antitumor effect through antiangiogenesis. It was reported that proliferation, angiogenesis and apoptosis play a complex role in the prognosis of patients with RCC. It is suggested that IFN treatment is likely to have an inhibitory effect on the proliferation and angiogenesis of the tumor.8
To our knowledge, no clinical study using combination therapy of IFN-α and a COX-2 inhibitor has previously been reported. The combination of IFN-α and meloxicam might be a novel treatment for RCC because meloxicam is relatively inexpensive and known to have mild side-effects. Additionally, there has been no established therapy against advanced RCC.1 Based on the biological mechanisms of COX-2 inhibitors, they should receive more attention in the future as an option in multimodal treatments for other types of cancers.7