Giora M. Mavligit

Treatment of uveal melanoma metastatic to the liver. A review of the M. D. Anderson cancer center experience and prognostic factors

Background. Liver metastasis develops in approximately two‐thirds of patients with recurrent uveal melanoma. Despite therapy, the median survival of those with liver metastasis is 5 to 7 months. The recognition of a grave prognosis associated with liver metastasis has led to evaluation of new modalities of therapy, including the use of regional therapies such as intrahepatic arterial chemotherapy and either embolization or chemoembolization of hepatic metastases. In this study, the results of an institutional experience over the past 2 decades are reviewed and prognostic factors that affect survival from the time the liver metastasis is diagnosed are assessed.

Chemoimmunotherapy of disseminated malignant melanoma with dimethyl triazeno imidazole carboxamide and bacillus calmette--guérin.

Abstract Eighty-nine patients with disseminated malignant melanoma were treated with a combination of dimethyl triazeno imidazole carboxamide (DTIC) administered intravenously and bacillus Calmette–Guerin (BCG) administered by scarification. The results were compared to those in a comparable retrospective group of 111 patients treated with DTIC alone. Metastatic areas regional to BCG immunization showed an augmented response to chemotherapy. Thus, chemoimmunotherapy-treated patients with lymph-node metastasis had a remission rate of 55 per cent compared to one of 18 per cent for patients treated with chemotherapy alone (p = 0.025). The duration of remissions and survival was significantly longer for patients (both nonvisceral and visceral metastases) treated with chemoimmunotherapy than for those treated with chemotherapy alone (p = 0.05, 0.001, respectively). A good prognosis was associated with immunocompetence before treatment or an increase in immunocompetence during treatment. Chemoimmunotherapy was ...

Intracarotid infusion of cis‐diamminedichloroplatinum in the treatment of recurrent malignant brain tumors

Thirty‐five patients with malignant brain tumors (23 with primary brain tumors and 12 with brain metastases) progressing after cranial irradiation chemotherapy received cisplatin, 60 to 120 mg/m2, into the internal carotid artery by a transfemoral approach. Courses of therapy were repeated every 4 weeks. Therapeutic evaluation was performed monthly using the CT scan of the brain and clinical neurologic examination. Thirty patients were evaluable for response. Of 20 evaluable patients with primary malignant brain tumors, 6 responded to therapy and 5 had stable disease. The median time to tumor progression for responding patients was 33 weeks, for stable patients 16 weeks, and 13 weeks for all patients. Five of 10 evaluable patients with brain metastases responded to intracarotid cisplatin, and 2 patients had stable disease. The estimated median time to progression for responding patients was 30+ weeks and 12+ weeks for patients with stable disease. Side effects included seizures in 5 courses, mental agitation and motor restlessness in 1, and transient hemiparesis in 7. One patient may have had a drug‐related death, and one patient appeared to develop encephalopathy after treatment. Five patients had clinical deterioration in vision; in two patients it was bilateral. Intracarotid cisplatin has definite activity in patients with malignant primary brain tumors and in patients with brain metastases. The recommended starting dose for intracarotid cisplatin is 60 to 75 mg/m2. At this dose level side effects are uncommon, but includes the risk of neurologic and retinal toxicity.

The natural history of resectable metastatic melanoma (Stage IVA Melanoma)

One‐hundred‐two patients with malignant melanoma who had distant metastases surgically resected and were judged to be clinically free of disease (M. D. Anderson Stage IVA melanoma) were studied. The median survival for all the patients from time of diagnosis of stage IVA disease was 18 months. The site of the resected metastases did not appear to influence survival, being approximately the same for the brain (15 months), lung (16 months), intraabdominal (18 months), and skin and/or lymph nodes (23 months). The site of the resected metastases also did not influence the median disease‐free interval. Patients who had metastases resected from several organs at the same time had a median survival of 15 months, which was similar to that of patients with one resected site. Patients who were rendered Stage IVA on several occasions by surgical excisions had a median survival of 36 months. Thirty‐five patients received surgery only and 67 patients received adjuvant chemotherapy, immunotherapy, or combined chemoimmunotherapy after surgery. For the group treated with surgery only, the median disease‐free interval and survival from diagnosis of stage IVA disease were 6 months and 16 months, respectively, and for the adjuvant group 6 months and 21 months, respectively. Specifically, by the type of adjuvant therapy, the median disease‐free interval and survival from stage IVA for 23 patients receiving Corynebacterium parvum were 6.9 and 19 months; for 39 patients receiving BCG, eight months and 26 months; for 24 patients receiving BCG + DTIC, eight and 17.4 months; and for all 51 DTIC treated patients 6.3 and 17.8 months, respectively. Patients receiving BCG had a median survival superior to the surgery only group (P = 0.02). An increase in survival was seen predominantly in patients who achieved IVA status more than once and received BCG. Patients with recurrent soft‐tissue metastases appeared to benefit most from BCG in prolonging the disease‐free interval. Only 1/10 treated by surgery alone had a disease‐free interval longer than 1 year, compared with 9/16 who received BCG (P = 0.01). Stage IVA melanoma appears to be distinctly different in prognosis from Stage IVB melanoma and should be classified separately. Patients with recurrent soft‐tissue disease may benefit significantly from treatment with BCG.

Diagnosis of Leukemia or Lymphoma in the Central Nervous System by Beta2-Microglobulin Determination

To detect early relapse in the central nervous systems (CNS) of patients with acute leukemia or lymphoma, we measured levels of beta 2-microglobulin (beta 2 m) in serum and cerebrospinal fluid (CSF). CSF levels were significantly higher in patients with leukemia (P < 0.001) or lymphoma (P < 0.02) with clinical evidence of CNS involvement than in those without this complication. When serum and CSF levels were measured simultaneously, the CSF level of beta 2 m was significantly higher than the serum level in patients with acute leukemia and lymphoma with CNS involvement (P = 0.05), but not in patients without CNS involvement. Serial determination of CSF beta 2 m correlated well with the clinical appearance and disappearance of CNS involvement. These data suggest that serial and simultaneous determination of beta 2 m in serum and CSF may be useful in early diagnosis of CNS involvement and in monitoring intrathecal therapy in patients with acute leukemia or lymphoma.

Percutaneous Hepatic Arterial Infusion (HAI) of Mitomycin C and Floxuridine (FUDR): An Effective Treatment for Metastatic Colorectal Carcinoma in the Liver

The response rate of metastatic colorectal carcinoma confined to the liver to HAI of FUDR alone is at the range of 50% and to mitomycin C by hepatic arterial infusion (HAI) at the range of 35%. Mitomycin C was added to FUDR by continuous infusion and given by HAI to 12 patients with colorectal cancer confined to the liver. Catheters were placed subselectively in the hepatic artery, and infusion continued for five to six days when the catheter was removed. Cycles were repeated every 30 days. Chemotherapy consisted of mitomycin C 15 mg/m2 administered on day 1 followed by FUDR 100 mg/m2 by continuous infusion daily for five days. Response to treatment was evaluated by serial determinations of plasma CEA and by imaging techniques consisting of a computerized tomography, sonography, and radionuclide scanning of liver as well as by angiography. In 2 patients, complete remission was achieved; in 4 patients a 75% and in another 4 patients a 50% decrease in liver metastasis was observed, while 2 patients had stable disease. Thus, a response rate of 83% with a median duration of six to seven months was achieved. The median survival of these patients was 16 months. Eight of the 12 patients have failed previous, i.v. 5‐FU containing regimens. Complications related to 45 treatment cycles were the following: catheter displacement in 11.1%, an intimal tear, usually in the hepatic artery in 4.4%, gastric ulcerations in 5.4%, and septicemia in 2.7% of the cycles. In addition, aneurysmal dilation of the hepatic artery occurred in 4 patients (8.8% of the treatment cycles), all of whom continued treatment. Chemotherapyrelated complications included primarily thrombocytopenia and stomatitis. Mitomycin C + FUDR by hepatic arterial infusion is an effective treatment for colorectal carcinoma metastatic to the liver. The high response rate justifies the adjuvant treatment of Dukes class C colon cancer patients with this treatment.

Human leukocyte interferon to control thrombocytosis in chronic myelogenous leukemia.

Nine patients with refractory chronic myelogenous leukemia and severe symptomatic thrombocytosis (greater than or equal to 1 X 10(6) platelets/mm3) were given partially purified human leukocyte interferon-alpha. A significant decline in platelet counts, from a mean (+/- SE) of 1.71 +/- 0.53 X 10(6)/mm3 to a mean of 0.52 +/- 0.24 X 10(6)/mm3 (p less than 0.01), resulted in all patients. Maintenance of low platelet counts was achieved in two patients for more than 143 and 300 days, respectively. Treatment with human leukocyte interferon-alpha was stopped in the remaining patients because of increases in the leukocyte count, toxicity, or both. Our preliminary observations suggest that human leukocyte interferon-alpha may significantly alleviate progressive thrombocytosis in advanced chronic myelogenous leukemia. Further studies of human leukocyte interferon-alpha and chemotherapeutic agents are indicated.

Phase I‐II trial of percutaneous intra‐arterial Cis‐diamminedichloro platinum (II) for regionally confined malignancy

Forty‐nine patients with regionally confined recurrent malignancy were treated with intra‐arterial cisdiamminedichloro platinum II in a Phase I‐II trial. A safe starting dose of 120 mg/m2 was established. An overall response rate of 45% was noted with significant responses observed among patients with melanoma, sarcoma, breast carcinoma, and neuroblastoma. Side effects included transient renal and bone marrow toxicity as well as neurotoxicity and ototoxicity (6%), the latter usually with residual damage. The rational basis and advantages of treatment with intra‐arterial cis‐platinum are discussed.

THE PALLIATIVE ROLE OF HEPATIC ARTERIAL INFUSION AND ARTERIAL OCCLUSION IN COLORECTAL CARCINOMA METASTATIC TO THE LIVER

Fifty-five patients with metastatic colorectal carcinoma confined to the liver were treated with hepatic arterial infusion of floxuridine and mitomycin C. Tumour response rate was 43.4% and median overall survival was 11 months. Prolonged survival was associated with intentional or inadvertent occlusion of the hepatic artery. The median survival of twenty-four patients with arterial occlusion (15 months) was significantly higher than that of thirty-one patients without arterial occlusion (8 months).

Serial Studies of Immunocompetence of Patients Undergoing Chemotherapy for Acute Leukemia

Immunocompetence was followed serially for 1 yr from the onset of treatment in 55 adult patients with acute leukemia. The tests used were delayed hypersensitivity responses to a battery of five recall antigens (dermatophytin, dermatophytin 0, candida, streptokinase-streptodornase, and mumps) and in vitro lymphocyte blastogenic responses to phytohemagglutinin and streptolysin 0. There was a strong correlation between immunocompetence at the start of treatment and a good prognosis; 32/39 patients who subsequently entered remission were initially immunocompetent compared to 4/15 who failed to enter remission. In the complete remission group there was a decline in competence starting from 2 to 5 mo after the onset of treatment. In those who remained in remission for 1 yr, competence recovered at 6 mo and remained vigorous thereafter. In those who relapsed before 1 yr, the decline in competence occurred 1 mo before relapse and competence continued to decline progressively during the 1 yr follow-up period. These studies suggest that therapeutic approaches which restore immunocompetence or prevent its decline will improve both the remission rate and the remission duration of patients with acute leukemia.