Adjuvant Thalidomide Research Articles

Paraneoplastic Erythrocytosis: First Manifestation of a Large Hepatocellular Carcinoma Successfully Treated by Radical Liver Resection and Adjuvant Thalidomide

The paraneoplastic syndromes occur in upto 28% of patients with hepatocellular carcinoma (HCC). Among them, erythrocytosis is reported as just 3.9 % of frequency. We describe a 59-year-old male patient with a large HCC in a non-cirrhotic liver presenting with erythrocytosis. Four phlebotomies were performed before radical surgical resection. Extended right hepatectomy was undertaken, proving a unifocal 10.2 X 13 X 6.5 cm, extensively necrotic HCC. There were no postoperative complications, and the patient was discharged on the 6th postoperative day. Adjuvant treatment with thalidomide was indicated for 36 months. We observed a progressive decrease in haemoglobin, haematocrit, EPO, and AFP to normal levels after the surgical procedure. A periodic follow-up with laboratory parameters and CT scan was done for 46 months with no evidence of relapses, until now. This case highlights a rare manifestation of advanced liver cancer; the first documented paraneoplastic erythrocytosis in a large HCC case in Chile was successfully treated by radical liver resection and adjuvant thalidomide.

Adjuvant Thalidomide and Metronomic Chemotherapy for the Treatment of Canine Malignant Mammary Gland Neoplasms.

The aim of the present study was to evaluate a multimodal approach for the treatment of canine malignant mammary gland neoplasms, including surgery, chemotherapy, thalidomide, and metronomic chemotherapy (MC). Fifty-eight female dogs were submitted to four different treatments: surgery; surgery with chemotherapy; surgery with chemotherapy and thalidomide; and surgery with chemotherapy and metronomic chemotherapy and overall survival was evaluated. No statistical difference was found in the proliferative index and microvessel density of primary neoplasms and distant metastases following thalidomide treatment. Diffuse intense inflammatory infiltrate was predominant in primary tumors and diffuse moderate inflammatory infiltrate in metastatic lesions. No statistically significant difference was observed in median survival time (MST) between treatment groups when including all clinical stages (p=0.3177). However, animals diagnosed with distant metastasis treated with surgery and chemotherapy associated with thalidomide or MC presented longer MST when compared to animals treated only with surgery or surgery and chemotherapy (p<0.0001). The proposed multimodal therapy protocols including antiangiogenic and immunomodulatory therapies demonstrated a clinical benefit for patients in advanced clinical stages.

Clinicoradiologic response of neurologic tuberculous mass lesions in children treated with thalidomide.

Neurologic tuberculous pseudoabscesses that clinically progress despite conventional antituberculosis therapy may be responsive to adjuvant thalidomide, a potent tumor necrosis factor-α inhibitor. In this study, the addition of thalidomide provided substantial clinical benefit in the majority of patients, and magnetic resonance imaging evolution of lesions from early-stage "T2 bright" with edema to "T2 black" represented a marker of cure.

Phase II Trial of Adjuvant Oral Thalidomide Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Surface Disease from Colorectal/Appendiceal Cancer

This phase II single-institution trial of adjuvant thalidomide after cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with appendiceal and colorectal malignancies sought to detect an improvement in progression-free survival (PFS) from 7 to 12 months. Eligible patients received CS, HIPEC, and baseline imaging, followed by pretreatment thalidomide counseling. All participants were then started on a 28-day regimen of thalidomide, 100 mg by mouth at bedtime, followed by 200 mg for 4 weeks, followed by 300 mg as the final maintenance dose, as tolerated. Twenty-seven eligible patients (median age 52 years; 52% appendiceal/48% colorectal) were enrolled on this trial and included in the analysis, and 26 were evaluable for response. Eighteen patients demonstrated stable disease on adjuvant thalidomide, while eight showed evidence of progression. Approximately 30% of the patients withdrew due to toxicity. Grade 3/4 toxicities included neurological disorders (16%), nausea (12%), vomiting (8%), and thromboembolism (8%). Median overall survival (OS) and PFS were 43.0 and 9.3 months, respectively, and median follow-up was 40.4 months. Multivariate modeling showed significant improvements in PFS and OS for appendiceal patients and those with R0 or R1 resections. On an intent-to-treat analysis, the PFS of the study group was 9 months. Based on these findings, thalidomide cannot be recommended as adjuvant therapy after CS and HIPEC for gastrointestinal malignancies. Further research is needed to identify active agents in this population.

Tuberculous Meningitis-Related Optic Neuritis: Recovery of Vision With Thalidomide in 4 Consecutive Cases

Blindness is an uncommon but devastating complication of tuberculosis meningitis. The main causes are chronically raised intracranial pressure (hydrocephalus and/or tuberculomas) or direct involvement of the optic chiasm or optic nerves by the basal arachnoiditis (inflammation and/or compression). Antituberculosis therapy combined with corticosteroids and control of intracranial pressure constitutes the mainstay of therapy for tuberculous meningitis. Despite these treatment measures, some patients develop blindness, mainly as a result of progressive optochiasmatic arachnoiditis. This led us to explore the role of adjuvant thalidomide therapy, and we describe the dramatic recovery of vision in 4 consecutive cases. Clinical recovery was accompanied by marked radiological improvement on magnetic resonance imaging (MRI) of the brain.

Primary Epithelioid Angiosarcoma of the Breast Masquerading as Carcinoma

Here we report a case of primary epithelioid angiosarcoma (eas) of the breast occurring in a 30-year-old woman. Following fine-needle asspiration cytology (fnac) and tru-cut biopsy, the patient was initially diagnosed with mammary carcinoma and thereafter underwent modified radical mastectomy. Postoperative histopathologic examination and immunohistochemistry revealed a diagnosis of primary epithelioid angiosarcoma of the breast. The patient received postoperative radiotherapy to the chest wall and was started on adjuvant thalidomide. Preoperatively, eas can be mistaken for carcinoma because it is difficult to appreciate the typical morphology on fnac or tru-cut biopsy. Indeed, this is an area of potential diagnostic error because, nowadays, neoadjuvant therapy is often instituted after core biopsy of a breast mass. This case is being reported not only for its diagnostic difficulty, but also because of its rarity in English literature.

Adjuvant Bortezomib and Dexamethasone Following Risk-Adapted Melphalan and Stem Cell Transplant in Systemic Light-Chain Amyloidosis (AL): A Phase II Study.

Abstract 533 Background:High-dose melphalan (MEL) and autologous stem cell transplant (SCT) induces hematologic and clinical remissions in AL and results in prolonged survival. In a prior phase II study we showed that post-SCT adjuvant thalidomide and dexamethasone improved hematologic responses in 42% of patients, resulting in a 39% strictly defined complete response (sCR) rate at 12 months (mos) post-SCT (BJH 2007;139:224). With a median follow-up of 52 mos, the overall survival of patients on that study is 69%. We now report on an ongoing phase II trial in which we use adjuvant bortezomib and dexamethasone (BD) following risk-adapted SCT. Methods:Patients with newly diagnosed AL involving ≤2 organs were assigned to MEL 100, 140 or 200mg/m2 with SCT, based on age, renal function and cardiac involvement. Responses were assessed at 2-3 mos, 12 mos and 24 mos post-SCT. Patients with persistent clonal plasma cell disease at 2-3 mos post-SCT received adjuvant BD for up to 6 cycles (two 21-day, four 35-day cycles). At 12 mos post-SCT we evaluated hematologic, organ responses and overall survival (OS). Results:Thirty patients have been enrolled with kidney (63%), heart (47%), liver/GI (10%) and peripheral nervous system (10%) involvement, including 38% with two organ-involvement. Three patients were removed from study prior to SCT due to three organ-involvement, co-morbid illness or the development of pulmonary edema while receiving filgrastim for stem cell mobilization; one patient is undergoing stem cell collection. SCT-related 100-day mortality was 12% (3/26), with all deaths occurring in patients with stage II or III cardiac amyloid. With a median follow-up of 20 mos, the one-year OS post-SCT is 83%. One-year OS in patients with cardiac involvement is 50% versus 100% in those without (P < 0.01). In 23 patients evaluable post-SCT, the overall response rate was 52% with 22% sCR. Seventy-four percent (17/23) received adjuvant BD for persistent clonal plasma cell disease. One patient (4%) was ineligible for adjuvant therapy due to thrombocytopenia that developed on immunosuppressive therapy following orthotopic heart transplant. At 12 mos post-SCT, the hematologic response rate in evaluable patients was 95% (18/19) with 74% (14/19) achieving sCR and 58% (11/19) having organ improvement. Ninety-three percent (13/14) of patients who received adjuvant BD and were evaluable at 12 mos post-SCT had improved hematologic responses. Overall, of the 17 patients who received adjuvant BD, 71% of patients experienced grade II-IV toxicity with thrombocytopenia (41%), ≥ grade 2 peripheral neuropathy (35%) and respiratory infection (16%) being most common and one patient with cardiac amyloid experiencing sudden death. Conclusions:In newly diagnosed patients with systemic AL amyloidosis, adjuvant BD following risk-adapted SCT is well-tolerated and effective for eradicating persistent clonal plasma cell disease. At 12 mos post-SCT high overall and unprecedented sCR rates are seen with frequent organ response, demonstrating that this strategy merits further study. Disclosures:Comenzo:Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Recovery of Vision After Adjuvant Thalidomide in a Child With Tuberculous Meningitis and Acute Lymphoblastic Leukemia

A 7-year-old child, on maintenance chemotherapy for acute lymphoblastic leukemia, developed tuberculous meningitis complicated by progressive basal meningeal inflammation and abscess formation, in spite of adequate tuberculosis treatment and adjunctive corticosteriod therapy. The child became blind as a result of involvement of the optic chiasm. After 2 months of adjunctive thalidomide therapy, the child regained vision and cranial magnetic resonance imaging showed marked reduction of the inflammatory changes previously demonstrated. Progression of intracranial tuberculous infection, in spite of a treatment that is generally considered to be adequate, is well recognized. Previous reports of a possible beneficiary role of thalidomide in these cases support an immunological basis. The present case suggests a role for thalidomide in the treatment of blindness due to involvement of the optic chiasm in progressive basal tuberculous meningitis.

Randomized Trial of Adjuvant Thalidomide Versus Observation in Patients With Completely Resected High-Risk Renal Cell Carcinoma

To evaluate the effect of adjuvant thalidomide on recurrence-free survival (RFS) after nephrectomy for high-risk metastatic renal cell carcinoma (RCC). Eligibility criteria for enrollment on this randomized trial included any histologic subtype, T2 (high grade, any N), T3/T4 (any grade, any N), or node-positive (any grade, any T) RCC. We randomized eligible patients to observation or to receive thalidomide 300 mg daily for 24 months. Patients were observed until disease recurrence or death. After we enrolled 46 patients, we stopped the trial at a median follow up of 43.9 months (range, 9.7-74.2 months). Patients on the thalidomide arm had inferior 2- and 3-year probabilities of RFS, compared with controls (47.8% vs 69.3% and 28.7% vs 69.3%, respectively; P = .022). The 2- and 3-year cancer-specific survival was similar for both groups. All observed deaths were attributable to RCC (P = .392). By multivariate analysis, tumor size and grade predicted recurrence (P = .001 and .013) and kidney cancer-specific death (P = .002 and .014). Thalidomide treatment, however, was not an independent predictor of recurrence or cancer-specific mortality. In this small, randomized, controlled trial, adjuvant thalidomide therapy after complete resection of high-risk RCC did not improve the 2- and 3-year RFS rates or cancer-specific death rates.

Managing Systemic Light-Chain Amyloidosis

Amyloidosis is a rare disease in which a specific protein is deposited as aggregated interstitial fibrils that can compromise organ function and lead to death. Immunoglobulin (Ig) light-chain amyloidosis (AL), caused by the monoclonal gammopathy of a plasma cell dyscrasia, is the most common type. A hereditary type is also caused by mutant transthyretin and other proteins. Rarely, a patient with amyloid has both a monoclonal gammopathy and a hereditary protein. In AL, circulating monoclonal Ig light chains can be measured with the free light-chain (FLC) assay and provide a target for therapy to eliminate the underlying plasma cell dyscrasia while supporting the patient's organ function. Amyloid deposits can be resorbed and organ function restored if the amyloid-forming precursor FLC is eliminated. For patients with limited organ involvement, intravenous melphalan in doses from 100 to 200 mg/m2 with autologous stem cell support (SCT) is an effective approach and, when followed at 3 months post-SCT with adjuvant thalidomide and dexamethasone for persistent plasma cell disease, has a 1-year hematologic response rate of 77%. Monthly oral melphalan and dexamethasone for 1 year can also be effective therapy for patients too sick for SCT (67% response rate). Hematologic complete responses are usually durable and result in long-term survival and a variable degree of organ recovery. For patients with advanced cardiac involvement, the prognosis remains guarded even with treatment. Drugs effective in multiple myeloma are usually active in AL, depending on side effects. New agents such as bortezomib and lenalidomide have shown promising activity, and novel antibody-based approaches for imaging amyloid and accelerating removal of deposits are being actively investigated.

Adjuvant thalidomide improves disease specific survival for patients with renal cell carcinoma at high risk for relapse following surgery

14586 Background: Observation is the standard of care for locally advanced renal cell carcinoma (RCC) after surgery. No adjuvant therapy for RCC exists. Thalidomide has shown activity in metastatic RCC. We studied thalidomide in the adjuvant setting for patients with locally advanced RCC. Methods: This phase III trial has enrolled 46 patients to date. All patients underwent resection of all disease. Eligible patients included T2N0M0 grade 3–4, T3a-cN0M0, T4N0M0, TanyN1–2M0, and TanyN0M0 bilateral disease completely resected. All RCC histologies were included. Patients were randomized to observation or thalidomide, 300 mg daily for 2 years. Dose reductions were allowed for toxicity. The primary endpoint was recurrence free survival. Secondary endpoints were disease specific survival and toxicity. Results: Twenty-three patients randomized to thalidomide and 23 were observed. In the thalidomide arm, one patient refused therapy and two stopped within one month due to toxicity. Only 1 patient tolerated therapy for 2 years without dose reduction. With a median follow-up of 18 months, there were 6 recurrences and 5 disease related deaths in the observation arm and 7 recurrences and 2 disease related deaths in the thalidomide arm. Using an intent to treat principle in our multivariate analysis, adjusting for grade, stage, and nodal status, we noted no significant difference in recurrence free survival between observation (mean 31 months; median not reached (NR)) and the thalidomide arm (mean 24.7 months; median NR) (Hazard ratio = 1.04, 95% CI 0.34 to 3.14, p = 0.945). Interestingly, disease specific survival was significantly better in the thalidomide arm (mean 40.1 months; median NR), as compared to the observation arm (mean 37.1 months; median NR) (Hazard ratio = 0.086, 95% CI 0.008 to 0.981, p = 0.048). Conclusions: In this limited experience with surgically resected RCC at high risk for relapse, thalidomide did not impact time to recurrence but significantly improved disease specific survival in the adjuvant setting. Despite this clinical benefit, significant toxicity limited tolerability of the drug. These data suggest that derivatives of thalidomide, with different toxicity profiles, might warrant testing in the adjuvant setting for RCC. No significant financial relationships to disclose.