Milam E. Leavens

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.

Ommaya reservoirs in 387 cancer patients A 15‐year experience

We reviewed records of 387 patients with cancer who had Ommaya reservoirs placed between October 1967 and December 1982. Complications of reservoir placement were reported in 27 patients, including intracranial hemorrhage (5 patients) and reservoir malfunction (15 patients). In 15 of 19 patients with meningitis, the infection was linked to the reservoir. The organism most frequently implicated was Staphylococcus epidermidis. Seizures, leukoencephalopathy, and pericatheter necrosis were seen in 10 patients who had received intraventricular chemotherapy.

Cerebral radiation necrosis following treatment of extracranial malignancies

Nine patients with cerebral radiation necrosis following radiation therapy for extracranial neoplasms were seen at MD Anderson Hospital between 1956 and 1982. The diagnosis was confirmed at autopsy in one case, by surgical intervention in six cases, and strongly suspected based upon CT scan findings and radiation records in two cases. The world literature is reviewed, and diagnostic criteria using the CT scan and radiation doses presented.

Sarcoma metastatic to the brain: results of surgical treatment.

We report on 21 patients surgically treated for intraparenchymal brain metastasis from sarcoma, including six osteosarcomas, four leiomyosarcomas, three malignant fibrous histiocytomas, two alveolar soft-part sarcomas, two Ewings bone sarcomas, one extraskeletal osteosarcoma, one extraskeletal Ewings sarcoma, and two unclassified sarcomas. Median survival after craniotomy was 11.8 months. Patients with a preoperative Karnofsky performance score of > 70 survived for 15.7 versus 6.6 months for those with a Karnofsky performance score < or = 70. Patients. undergoing complete resection survived 14.0 versus 6.2 months for patients undergoing incomplete resection. Patients with evidence of lung metastases at the time of surgery survived 11.8 months, which was similar to the 10.5-month survival for patients with disease limited to the brain. The two patients with alveolar soft-part sarcoma are alive at 16 and 25 months after surgery. We conclude that surgery is effective in treating selected patients with sarcoma metastatic to the brain and that patients with metastasis from alveolar soft-part sarcoma may have a relatively good prognosis if they are surgically treated. The complete removal of all brain metastases and a Karnofsky performance score > 70 are associated with a favorable prognosis, whereas the presence of concurrent lung metastases is not a contraindication to surgery.

Concentrations of vinblastine in human intracerebral tumor and other tissues

SummaryUptake of vinblastine into human cerebrospinal fluid, intracerebral tumor and autopsy tissues was quantitated radiochemically after separating vinblastine from its metabolites by high pressure liquid chromatography. Only low concentrations of vinblastine were found in cerebrospinal fluid from a single patient. A second patient who received a tracer dose of radiolabelled vinblastine prior to surgical resection of an intracerebral tumor had slightly less radioactivity in tumor than in temporalis muscle, but more in tumor than in edematous brain surrounding the tumor. The radioactivity in tumor increased gradually and exceeded concurrent plasma radioactivity by 2 hr after drug administration. A third patient died 4 hr into a planned 24-hr infusion of radiolabeled vinblastine. Highest vinblastine concentrations were found in organs with high blood flow such as kidney and heart. Intermediate concentrations were found in liver and lung, and low concentrations were found in prostate, gastrointestinal tract, spleen, muscle, bladder, and hepatic and lymph node metastases. A fourth patient died one month after receiving radiolabeled vinblastine. Highest concentrations were in liver and next highest concentrations were in intracerebral tumor. Moderately high concentrations were found in pancreas, thyroid, lung, spleen, ovary, kidney, and kidney metastases. Lowest concentrations were found in omental metastases, heart, breast, and brain. Vinblastine concentration decreased with increasing distance into brain from the brain metastases. Thus, vinblastine was not selectively localized in tumors. The concentrations in tumor did not reflect the concentration in the organ in which the tumor was located. There was no indication that uptake into intracerebral tumor was impaired. Cerebrospinal fluid and brain concentrations of vinblastine did not give any indication of the concentration attainable in intracerebral tumor.

Surgical versus Nonsurgical Management of Metastatic Melanoma of the Brain

A retrospective analysis of 80 patients with cerebral metastases from melanoma revealed that 42 patients in whom the metastases were excised experienced a median survival of 5 months, in comparison with a 6-week median survival for 38 patients who were not operated upon. The same survival figures applied when comparing only patients with known Stage 4 disease at the time of diagnosis of the brain metastasis. The surgical mortality rate was 9.5% for the entire series and 5.4% for the 37 patients treated surgically since 1960.

A pilot study of cis-diamminedichloroplatinum and radiation therapy in patients with high grade astrocytomas

SummaryA pilot study was performed combining cis-diamminedichloroplatinum (CDDP) and radiation therapy to treat patients with high-grade astrocytomas. CDDP at a dose of 40 mg/ m2/ week intravenously was given during the course of cranial irradiation. Following irradiation, CDDP was given every three weeks on a schedule of 35–40 mg/ m2/ day for three days until toxicity became unacceptable or until tumor progression occurred. Radiation therapy consisted of 6 000 rads over a seven week period or 5 000 rads followed by an additional 1500 rads to the tumor site. Patients were followed by computerized axial tomography (CT) scan and neurologic examination. Thirty patients were entered onto the study; 22 were considered evaluable. The median survival was 53 weeks and the median time to progression was 21 weeks. Toxicity was generally tolerable; however, ototoxicity may be enhanced by this treatment. CDDP combined with cranial irradiation is tolerable and feasible, although close follow-up is recommended in case CDDP has to be temporarily interrupted.

Intracerebral penetration and tissue distribution of 2,5-diaziridinyl 3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ, NSC-182986)

Abstract[14C]AZQ (2–4 mg/m2, 100–200 mCi) was administered at varying times to five patients undergoing surgical resection of intracerebral tumors. Plasma, cerebrospinal fluid (CSF), edematous brain, and tumor specimens were obtained during surgery and the concentration of AZQ was determined radiochemically and chromatographically. Total [14C]AZQ equivalent concentration in tumor for two patients was determined to be 47.5% and 85% of concurrent plasma concentration which was similar to that found in normal brain (60.4% and 75.5% respectively). Only 18–45% of the total radioactivity in tumor tissue and 30–56% in plasma were accounted for by unchanged AZQ. These findings suggest that AZQ may be metabolized to a certain extent. Tissue samples from various organs were obtained during autopsy in a patient who expired ten days after AZQ administration. The highest AZQ concentration was found in the liver, followed by the kidney. Comparable amounts were found in normal brain and brain tumor (22 ng/ g vs. 31 ng/ g respectively). These results indicate that AZQ penetrates readily into the normal brain and brain tumor with a tendency to persist.

Quinagolide in the Management of Prolactinoma

Objective: This study reports a six year experience with quinagolide (CV205-502) in the treatment of 40 patients with hyperprolactinemia or prolactinoma. Patients and Measurements: Forty patients with hyperprolactinemia were treated with quinagolide (CV 205-502, NorprolacTM) for 2–72 months (mean 31.6 months). The patients ages ranged from 12 to 53 years and 90% were female. Seventeen had no radiologic evidence of tumor; 11 had microadenomas; and 12 had macroadenomas. Results: All patients had a reduction of the serum prolactin following quinagolide therapy with normalization in 82% with no tumor, 73% with microadenomas, and 67% with macroadenomas. Fifty-five percent of microadenoma and 75% of macroadenoma patients had a decrease in tumor size when assessed by a blinded reviewer. Ten of 38 female patients became pregnant while taking quinagolide. The dosage of quinagolide ranged from 75 to 400 μg/day with a median dose of 100μg/day. A comparison of side effects in a subgroup of 35 patients who had taken bromocriptine prior to quinagolide administration showed a greater than 75% reduction in nausea, vomiting, dizziness, and drowsiness during quinagolide administration. Conclusions: We conclude that quinagolide is a safe and effective long-term alternative to bromocriptine therapy, particularly in those individuals with bromocriptine intolerance.