Benefit of continuous treatment for responders with newly diagnosed multiple myeloma in the randomized FIRST trial.

The phase 3, randomized Frontline Investigation of Revlimid and Dexamethasone Versus Standard Thalidomide (FIRST) trial investigating lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) vs melphalan, prednisone and thalidomide for 12 cycles (MPT) and Rd for 18 cycles (Rd18) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) showed that Rd continuous prolonged progression-free survival and overall survival compared with MPT. A subanalysis of the FIRST trial was conducted to determine the benefits of Rd continuous in patients with NDMM based on depth of response. Patients randomized 1:1:1 to Rd continuous, Rd18 or MPT were divided into subgroups based on best response: complete response (CR; n=290), ⩾very good partial response (VGPR; n=679), ⩾partial response (PR; n=1 225) or ⩽stable disease (n=299). Over 13% of patients receiving Rd continuous who achieved ⩾VGPR as best response did so beyond 18 months of treatment. Rd continuous reduced the risk of progression or death by 67%, 51% and 35% vs MPT in patients with CR, ⩾VGPR and ⩾PR, respectively. Similarly, Rd continuous reduced the risk of progression or death by 61%, 54% and 38% vs Rd18 in patients with CR, ⩾VGPR and ⩾PR, respectively. In patients with CR, ⩾VGPR or ⩾PR, 4-year survival rates in the Rd continuous arm (81.1%, 73.1% or 64.6%, respectively) were higher vs MPT (70.8%, 59.8% or 57.2%, respectively) and similar vs Rd18 (76.5%, 67.7% and 62.5%, respectively). Rd continuous improved efficacy outcomes in all responding patients, including those with CR, compared with fixed duration treatment.

Treatment of plasma refractory thrombotic thrombocytopenic purpura with protein A immunoabsorption.

The objective of this study was to assess the effect of protein A immunoabsorption in terms of response rate and toxicities in patients with classical thrombotic thrombocytopenic purpura (TTP) refractory to therapeutic plasma exchange. The study included nine females and one male with a diagnosis of classical TTP treated at multiple university hospital centers with protein A immunoabsorption (PAI) after having failed plasma exchange. The 10 patients had an age range 17-62 years. Prior to PAI, the patients had failed to respond to a mean of 15 (range 6-39) therapeutic plasma exchanges. Three patients had previous episodes of TTP. Evaluation for response to PAI included serial measurements of serum creatinine, lactate dehydrogenase (LDH), hemoglobin, hematocrit, and platelet count before, during, and up to 18 months post-PAI treatment. Seven of 10 study patients had resolution of their TTP. Six of the patients required six or fewer therapeutic PAIs and one required 12 treatments. All responding patients had evidence of improvement by the third PAI treatment. Three patients demonstrated no response to PAI, with two patients expiring from complications of TTP and one patient demonstrating a complete response to a subsequent therapy. No significant toxicity was noted with the use of PAI in this setting. Protein A immunoabsorption in patients with classical TTP refractory to plasma exchange can produce durable complete remissions and warrants comparative studies.

Treatment of cancer chemotherapy-associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome by protein A immunoadsorption of plasma.

BACKGROUND: Chemotherapy-associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (C-TTP/HUS) is a condition involving thrombocytopenia, microangiopathic hemolytic anemia, and progressive renal dysfunction that develops in 2-10% of patients with a history of malignant neoplasms treated with certain chemotherapeutic agents. Pathogenesis of the disease may depend on the following: (1) generation of endothelial lesions in the kidney microvasculature, resulting from drug toxic effects and/or generation of small soluble circulating immune complexes (CIC), and (2) generation of autoantibodies and/or CIC that trigger aggregation and deposition of platelets around the lesions. METHODS: Extracorporeal immunoadsorption treatment of plasma (PROSORBA columns, IMRE Corporation, Seattle, WA) to remove immunoglobulin G and CIC was evaluated in 55 patients for the potential to induce significant clinical benefits (increase in platelet count, decrease in hemolysis, stabilization of renal function) and longer survival. RESULTS: Response to therapy was achieved in 25 of 55 patients examined. Response was associated with an estimated 1-year survival rate of 61%, as compared with an estimated survival rate of only 22% in those who did not respond (P = 0.0001). Patients whose malignant neoplasms were in complete or partial remission at the time of development of C-TTP/HUS had a significantly higher estimated 1-year survival rate (74%) as compared with a historic control group of patients receiving other treatments (22%, P = 0.0161). Clinical responses were correlated with normalization of serum levels of CIC and complement components C3c and C4. There were no side effects associated with 75% of treatments. Immunoadsorption therapy was associated with generally mild to moderate manageable side effects, such as fever, chills, nausea/vomiting, respiratory symptoms, pain, hypertension, and hypotension, which were reported in 25% of procedures. CONCLUSIONS: This multicenter study establishes protein A immunoadsorption as an effective and safe treatment for cancer chemotherapy-associated TTP/HUS, an otherwise fatal disease.

Geriatric oncology.

The rapid increase in persons aged 65 and older will account for 20% of the total United States population by the year 2030. The incidence of malignancy likewise increases with advancing age. These factors are likely to result in an epidemic of geriatric cancer cases. Physicians should become knowledgeable on current issues in geriatric oncology which include: how to appropriately select geriatric patients with malignancies for surgical, medical or radiotherapeutic intervention; age as a bias for treatment selection; toxicities from cancer therapy in the elderly and how they can be modified; cancer screening and prevention measures in the elderly, and the special issues of informed consent and pain control in the geriatric cancer patient.

Experience with protein A-immunoadsorption in treatment-resistant adult immune thrombocytopenic purpura.

Extracorporeal immunoadsorption of plasma to remove IgG and circulating immune complexes (CIC) was evaluated as a therapy for adults with treatment-resistant immune thrombocytopenic purpura (ITP). Seventy-two patients with initial platelet counts less than 50,000/microL who had failed at least two other therapies were studied. They received an average of six treatments of 0.25 to 2.0 L plasma per procedure over a 2- to 3-week period using columns of staphylococcal protein A-silica (PROSORBA immunoadsorption treatment columns; IMRE Corp, Seattle, WA). The treatments caused an acute increase in the platelet count to greater than 100,000/microL in 18 patients and to 50,000 to 100,000/microL in 15 patients. The median time to response was 2 weeks. Responses were transient (less than 1 month duration) in seven of those patients (10%), but no additional relapses were reported over a follow-up period of up to 26 months (mean of 8 months). Clinical responses were associated with significant decreases in specific serum platelet autoantibodies (including anti-glycoprotein IIb/IIIa), platelet-associated Ig, and CIC. Thirty percent of treatments were associated with transient mild to moderate side effects usually presenting as a hypersensitivity-type reaction. Continued administration of failed therapies for ITP, which always included low-dose corticosteroids (less than or equal to 30 mg/d), had no demonstrable influence on the effectiveness of immunoadsorption treatment but did depress the incidence and severity of side effects. The degree of effectiveness of protein A immunoadsorption therapy in patients with treatment-resistant ITP is promising and further controlled studies in this patient population are warranted.

Cisplatin-based chemotherapy in advanced basal and squamous cell carcinomas of the skin: results in 28 patients including 13 patients receiving multimodality therapy.

This study reports the results of cisplatin (CDDP)-based chemotherapy (CT) as sole therapy and as neoadjuvant (NA) therapy in 28 consecutive patients (pts) with advanced basal cell (BC) and squamous cell (SC) cancers of the skin. CT in 24 pts consisted of CDDP 75 mgm/m2 and doxorubicin (Dox) 50 mg/m2 intravenously (IV) every 3 weeks with Dox being omitted in four pts due to severe preexisting cardiac disease. Thirteen of the 28 pts received CT in the NA setting, five before surgery and eight before radiation therapy (RT). Response rates to CT were complete remission (CR) in eight of 28 (28%) pts, partial remission (PR) in 11 of 28 (40%) for an overall response rate of 68%. Thirteen pts received a second treatment modality with five of 13 pts having a CR to CT alone before the second modality and seven converting to CR postsecond modality for a total CR rate of 12 of 13 (92%) in the multimodality group. Duration of responses in the CT-only group ranged from 4 to 82 months; however, only two patients remain in remission in this group. Of the twelve CRs from the multimodality therapy group, 11 of 12 (91%) pts remain in CR with duration of response ranging from 3 to 81 months. Toxicities were manageable, with no toxic deaths and only five pts stopped CT secondary to side effects. This study suggests the combination of CDDP and Dox is highly effective in BC and SC cancers of the skin and by itself can produce long unmaintained remissions, but when combined with a second modality of therapy, it is capable of producing not only long unmaintained CRs but probable cures in the majority of pts.

Cisplatin-associated hemolytic-uremic syndrome. Successful treatment with a staphylococcal protein A column.

Cisplatin-associated hemolytic-uremic syndrome (HUS), an under-reported form of HUS induced by chemotherapy, typically pursues a fulminant and lethal course. We report the cases of two patients with squamous cell carcinoma of the head and neck who developed massive hemolysis, profound thrombocytopenia, and dialysis-dependent renal failure after therapy with cisplatin. Plasma exchange was ineffective in both patients, but plasma perfusion with a staphylococcal protein A column produced a dramatic and permanent response in the second patient. These cases show the importance of considering HUS as a cause of renal failure in such patients who receive cisplatin-based chemotherapy, and support the role of staphylococcal protein A plasma perfusion as treatment for this condition.

Treatable carcinoma of unknown origin.

Carcinoma of unknown histogenesis or primary site is an increasingly recognized syndrome regarded by most physicians as having a grim prognosis. Elaborate evaluations using low yield, and often misleading, radiologic studies focused on identifying primary sites in the lung, liver, pancreas, or gastrointestinal tract offer little benefit to the vast majority of patients. Increasing evidence has accumulated showing that subsets of patients within this broad syndrome exist in whom recognition and proper therapy may result in meaningful prolongation of life or potential cure. In this review, clinical clues and diagnostic aids for identification of nine treatable subsets of patients with the carcinoma of unknown origin (CUO) syndrome are emphasized. Current state-of-the-art treatment for each subset with subsequent end results are stated.

Immune thrombocytopenia purpura: a pilot study of staphylococcal protein A immunomodulation in refractory patients.

Idiopathic thrombocytopenia purpura (ITP) is a primary immune thrombocytopenia that is typically manifested in adults by acute bleeding, severe thrombocytopenia, and normal to increased megakaryocytes in the bone marrow. Labeling studies suggest that most patients with ITP have an IgG antibody directed against the platelet membrane resulting in sequestration in the spleen. Splenectomy and/or corticosteroids remain the mainstay of therapy, with permanent remissions induced in 75% of patients. Despite the use of cyclophosphamide, azathioprine, vincristine, high-dose gamma globulin, and other forms of therapy, less than 50% of refractory patients achieve long-term satisfactory platelet counts. In view of these facts, ten consecutive patients with immune thrombocytopenia, unrelated to human immunodeficiency virus (HIV), received plasma perfusion over a staphylococcal protein A column (PROSORBA column) to evaluate efficacy and toxicity. All patients had an initial platelet count less than 50,000 and had failed corticosteroids. Five patients had also failed splenectomy. Two patients were not splenectomized due to pediatric age, two due to severe coexisting medical conditions, and one due to refusal of operation. Multiple other forms of therapy had also failed in this cohort of patients. Patients received two to ten treatments with the protein A column. All patients are evaluable for response and toxicities. Of the ten patients, results were as follows: complete response in one (platelet count greater than 150,000); partial response in four (platelet count greater than 50,000 and less than 150,000); and no response in five. Duration of responses ranged from 1 to 6 or more months.(ABSTRACT TRUNCATED AT 250 WORDS)

Idiopathic thrombocytopenic purpura in the older adult patient.

Forty adults with idiopathic thrombocytopenic purpura (ITP), aged over 45 years, were seen from March 1954 to December 1983 at the Medical College of Georgia. All patients had bleeding manifestations at presentation. Twenty-one of 40 (52.5%) during the follow-up period had either life-threatening or fatal bleeding episodes. There were no significant differences for the presence of any presenting clinical or laboratory feature for patients who achieved a complete remission compared with those who did not. A complete response to therapy, younger age, higher presenting hemoglobin level, and absence of central nervous system bleeding favorably influenced overall survival. Therapy was ineffective in this age group, with only 12 patients (30%) achieving a permanent complete remission. Fourteen patients (35%) died either from bleeding or from direct complications of therapy. This analysis of ITP in the older adult suggests a disease refractory to therapy that is associated with major morbidity and mortality.

Busulfan-induced hepatitis.

A 61-yr-old man with chronic myelocytic leukemia treated continuously for 8 yr with busulfan presented with fever, abdominal pain, and elevated liver enzymes in a cholestatic pattern. Evaluation of his liver and biliary tract with ultrasound and computerized tomography disclosed no structural abnormality. A percutaneous needle liver biopsy revealed cellular cholestasis with focal liver cell necrosis accompanied by a mild inflammatory infiltrate. Busulfan was discontinued, with subsequent normalization of liver enzymes and resolution of fever. These findings are interpreted as being compatible with busulfan-induced hepatitis.

Idiopathic thrombocytopenic purpura in adults.

Idiopathic thrombocytopenic purpura (ITP) is a primary immune thrombocytopenia that is typically manifested in adults by acute bleeding, severe thrombocytopenia, and normal to increased megakaryocytes in the bone marrow. Labeling studies suggest that most patients with ITP have an IgG antibody directed against the platelet membrane resulting in sequestration in the spleen, and that sequestration in other organs such as the liver bodes a poor prognosis. Splenectomy and/or corticosteroids remain the mainstay of therapy, with permanent remissions induced in 75% of patients. We review alternative forms of therapy such as immunosuppressive agents, high-dose gamma-globulin, and others to enable the practicing physician to select the best treatment for patients refractory to standard therapy. Age appears to influence response to therapy and morbidity, with advancing age imparting a poorer prognosis.

Prostate cancer.

Prostate cancer is the most frequent malignancy in elderly men. Common presentations include asymptomatic prostate nodules, unexplained bone pain or bladder outlet obstruction. Histologic grading clearly influences the prognosis. Either potency-saving subcapsular prostatectomy or radiation therapy is effective in treating localized disease. New prospects for hormonal therapy of metastatic prostate cancer include antiandrogens and gonadotropin-releasing analogs.

High-dose, continuous-infusion cyclophosphamide, cytarabine, vincristine, and prednisone for remission induction in refractory adult acute leukemia.

Fifteen consecutive patients with refractory adult acute leukemia (RAAL) were treated with a combination of high-dose, continuous-infusion cyclophosphamide, cytarabine, vincristine, and prednisone (Hi-COAP). The initial nine patients received cyclophosphamide 350 mg/m2 as a 24-hour intravenous (IV) infusion over 5 days; cytarabine, 100 mg/m2 IV bolus every 12 hours for ten doses; vincristine, 2.0 mg IV bolus on day 1; and prednisone, 100 mg orally for 7 days. The last six patients had the cyclophosphamide infusion lengthened to 7 days, and the cytarabine increased to 14 doses. All patients were evaluable for toxicity and response. Seven patients (47%) obtained a complete remission and six patients (40%) a partial remission. Median duration of all remissions has been 7.0 months with a range of 1 to 32 months. Toxicity has been limited to primarily myelosuppression with no hemorrhagic cystitis, central nervous system (CNS), hepatic, or pulmonary toxicity noted. Gastrointestinal toxicity was mild, with no effect on nutritional status noted. Median duration of complete responders was 8.5 months. Thus, Hi-COAP demonstrates promising efficacy with minimal toxicity in RAAL and warrants further exploration in multiinstitutional trials.

Chemotherapy of basal cell and squamous cell carcinoma of the eyelids and periorbital tissues.

Eight patients, aged 62 to 85 years, with nine instances of histologically proven basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) involving the eyelids and periorbital tissues, were treated with systemic and/or local (iontophoresis) chemotherapy using cisplatin (Platinol) and doxorubicin (Adriamycin). All patients had either refused surgery, would have required extensive procedures, or had medical problems contraindicating surgery. Systemic chemotherapy induced a complete or partial remission in eight of nine lesions. No patient has required maintenance chemotherapy and no significant toxic side effects were encountered. The length of follow-up ranged from 2 to 50 months. Iontophoretic therapy with cisplatin was used to treat five small foci of new, recurrent or persistent tumor(s) in three of these patients and resulted in a partial response in all five lesions. Systemic or local chemotherapy offers an alternative to current standard forms of treatment for BCC and SCC in selected cases.

Neuroendocrine carcinoma of the uterine cervix complicated by pregnancy: case report and review of the literature.

A case report of neuroendocrine carcinoma of the cervix complicating pregnancy is presented. This represents the fourth reported case. Clinical staging was FIGO IB, and treatment consisted of radical surgery and aggressive chemotherapy. Electron microscopy confirmed the diagnosis of neuroendocrine carcinoma. The pregnancy-associated cases and a review of neuroendocrine cervical carcinoma are discussed.

Acute deafness. A complication of high-dose cisplatin.

Acute, profound cisplatin-induced deafness has rarely been reported. Ototoxic reactions to cisplatin in the past have been subclinical, with most hearing loss occurring in the high-frequency range. A patient was treated with ultra-high-dose cisplatin who suffered acute profound deafness. Methods are suggested for preventing similar complications in other patients given cisplatin in high-dose ranges.

Cisplatin and doxorubicin. An effective chemotherapy combination in the treatment of advanced basal cell and squamous carcinoma of the skin.

Eleven patients with advanced basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) of the skin were treated with cis-diamminedichloroplatinum II (cisplatin) and doxorubicin. Seven patients had prior surgery and six of these seven had prior radiation therapy. All patients had an adequate trial of chemotherapy. One patient received a second course of chemotherapy after relapse. Responses were seen in 10 of 12 (87%) of chemotherapy courses, and 5 of 11 patients (46%) have an unmaintained complete remission lasting 2 to 31 months. Toxicity was acceptable and consisted primarily of gastrointestinal side effects. These results indicate the combination of cisplatin and doxorubicin has significant activity in both advanced BCC and SCC of the skin. In addition, a portion of patients treated with the combination achieve a long-term unmaintained disease-free state.