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Small cell carcinoma of the lung developed in a patient with previously diagnosed hairy cell leukemia. Treatment with aggressive chemotherapy resulted in a complete response in both diseases lasting 13 months. Recurrence of the leukemia did not occur. This case demonstrates that hairy cell leukemia may be responsive to combination regimens.
A prospective and randomized trial has been performed in order to evaluate combined modality therapy in patients with astrocytomas grade 3 and 4. Follow-up information is available on 244 patients. One half of the series received radiation therapy twice a week (40.00 Gy/5 weeks), the other half five times a week (50.00 Gy/5 weeks). Misonidazole 1.2 g/m2 was given orally to one half of the patients in the first radiation treatment group 3 1/2 to 4 hours before the treatment. The other half received placebo. The second radiation treatment group was also divided in two halves, one receiving 0.48 g/m2 misonidazole and the other placebo 3 1/2 to 4 hours before radiation. The randomization also included a subdivision of the material into eight groups of which four were given CCNU and four no chemotherapy, beginning 3 months after operation. The dose of CCNU was 120 mg/m2 body surface every 6 weeks. All eight treatment groups showed practically identical periods of median survival, and no statistically significant differences were observed with regard to performance status, side effects, or complications. Another dosage and timing of misonidazole administration in relation to the irradiation schedule, and a consideration of effects of concomitant drugs like dexamethasone and phenytoin are discussed.
Five human small cell carcinoma of the lung (SCCL) cell lines selected from 25 established cultures were grown as three-dimensional spheroid tumor models in either spinner culture or in static, agar-coated multiwells. Volume doubling times for the cell lines were approximately 4.5 days. Decreases in spheroid volumes after exposure to a variety of chemotherapeutic agents were used as indicators of drug activity. To further quantify cell killing in SCCL spheroids by chemotherapeutic agents 24 hours after exposure to drugs, a technique was employed that measured maximum levels of incorporation of 125IUdR after continuous labeling for 48 hours. The results of the use of this assay report for SCCL spheroid responses to various concentrations of doxorubicin hydrochloride, cytosine arabinoside, mechlorethamine hydrochloride, cisplatin, or etoposide. Some evidence for an intertumor heterogeneous response to chemotherapy is presented for some of the drugs tested. This assay was also used to characterize a potentiated cell kill when etoposide is combined with cisplatin and to identify activity by a new compound, diazoacetylcholine iodide (DACI), which was synthesized as an agent targeted for SCCL cells.
Nitrosoureas are alkylating agents that have been associated with the development of a preleukemic syndrome, secondary acute nonlymphocytic leukemia and a variety of acute and delayed toxicities. Nitrosoureas have activity in the treatment of primary malignant brain tumors. The authors report a patient who developed bone marrow myelofibrosis three years following treatment with radiation therapy and oral CCNU. This is the first case of marrow fibrosis associated with the use of a nitrosourea. Bone marrow myelofibrosis may be another delayed treatment effect of this class of drugs.
During the past 10 years, 240 patients with Stage III small cell lung carcinoma (SCLC) were treated with one of five chemotherapy programs plus thoracic irradiation. In addition, prophylactic cranial irradiation was administered concurrently with thoracic irradiation to 194 patients receiving CAML-HC, VCAM, or MOCA. Seventy-two patients had disease confined to the chest (Stage IIIM0), 30 patients had disease in the chest plus ipsilateral supraclavicular nodal involvement (Stage IIIM0SCN+), and 138 patients had distant metastatic disease (Stage IIIM1); the median survivals were 15.2 months, 12.6 months, and 8.4 months, respectively. The overall complete response rate was 30% and the overall response rate (complete and partial) was 76%. The overall response rates by stage were 86% for Stage IIIM0, 90% for Stage IIIM0SCN+, and 67% for Stage IIIM1. Eight patients (3%) were alive and free of disease at 24 months. Due to continued disease relapse in this group (four of eight patients), long-term survivors should not be identified for a minimum of 3.5 years from the time of initial therapy. Prophylactic cranial irradiation (PCI) effectively reduced the incidence of central nervous system (CNS) relapse in patients with a complete response to therapy (44% relapse without PCI versus 13% relapse with PCI, P less than 0.01). More effective chemotherapy is required for the successful treatment and improved long-term survival of patients with SCLC.
Three patients developed the sudden onset of total blindness several months after treatment with oral CCNU and low-dose whole-brain radiation. The anterior visual system was included in the radiation field in all patients. Radiotherapy was given for a frontal-lobe glioblastoma multiforme, for central nervous system prophylaxis in a patient with oat cell carcinoma of the lung, and for a parietal-lobe glioblastoma multiforme. None of the neoplasms involved the anterior visual system. The radiation dose ranged from 3000 to 4650 rad and the oral CCNU dosage from 300 mg to 1050 mg. Patients 1 and 2 also received other chemotherapeutic agents. Patient 3 who was treated only with oral CCNU and cranial irradiation died. At autopsy the brain showed a widely infiltrating residual high-grade glioma as well as patchy coagulative necrosis with swollen axons and dystrophic calcifications. The optic chiasm showed severe demyelination, axonal loss, and hyalinized vessels. Synergism between oral CCNU and radiation may account for the blindness produced.
A total of 306 patients with small cell lung cancer (SCLC) were randomized to receive chemotherapy in a sequential or alternating mode. Sequential chemotherapy consisted of eight cycles of cyclophosphamide, Adriamycin (doxorubicin), and vincristine (CAV) and alternating chemotherapy consisted of three cycles (1, 3, 5) of etoposide, vindesine, and ifosfamide (EVI); three cycles (2, 4, 6) of cisplatin, Adriamycin, and vincristine (PAV); and two cycles (7, 8) of cyclophosphamide, methotrexate, and CCNU (CMC). Responsive patients received prophylactic cranial irradiation after three cycles and chest irradiation after eight cycles of chemotherapy. No maintenance therapy was applied to patients achieving complete remission. Minimum follow-up was 2 years. Of the 302 patients evaluable, overall response rate was 59% in the sequential arm and 70% in the alternating arm. Patients treated with CAV had a complete response rate of 21% in contrast to 36% for those receiving alternating therapy. The median survival for all patients was 9.8 versus 11.3 months, for limited disease 11.1 versus 13.4 months, and for extensive disease 8.9 versus 9.9 months, all in favor of the alternating treatment. Two-year survival rate for all patients was 6% versus 9%, for limited disease 11% versus 14%, and for extensive disease 3% versus 6%, all preferring the alternating treatment mode. Progression-free survival demonstrated a strong correlation to the extent of response irrespective of the treatment regimen applied. Toxicity included 11 lethal and 8 life-threatening complications with a higher frequency in the alternating treatment arm. These results suggest that alternating treatment of SCLC with different drug combinations is more effective than sequential application of CAV.
One hundred consecutive patients with cerebral metastases from malignant melanoma were studied in relation to survival from the time of diagnosis of central nervous system (CNS) involvement, response to treatment, characteristics of their primary lesion, and the course of the disease from initial diagnosis to the development of intracranial tumor. After treatment, clinical and investigational evidence of objective regression of cerebral lesions was demonstrable in ten patients who survived with a median of 11.5 months from diagnosis of CNS involvement. In 11 additional patients, CNS disease remained clinically stable for a median period of 7 months. Median survival for the entire group of 100 patients was 2.5 months. However, eight patients (8%) survived longer than 1 year from the time of diagnosis of cerebral metastases, four of whom (4%) survived longer than 2 years; the longest survivor being disease-free and incomplete neurologic remission at more than 82 months. Patients with malignant melanoma metastatic to the brain should be informed of the therapeutic options available for their disease.
In order to assess the efficacy of high-dose irradiation to the posterior fossa and low-dose irradiation to the spinal axis, we reviewed the results of 60 patients with biopsy-proven medulloblastoma treated at the Joint Center for Radiation Therapy (JCRT) between 1968 and 1984. The 5- and 10-year actuarial survival rates for all patients were 68% and 44%, respectively. The median time to recurrence was 19 months. Extent of surgery, age, and radiation dose to the posterior fossa all were of prognostic value. Complete or subtotal gross resection appeared to be a favorable prognostic indicator compared with biopsy only (P less than 0.05), with a 69% versus 40% actuarial survival rate at 5 years, respectively. Infants 2 years of age or less had a diminished 5-year actuarial survival rate of 48% (P less than 0.05) compared with older age groups. The posterior fossa was the predominant site of recurrence and accounted for 78% of all failures. Local control in the posterior fossa was dose dependent. Seventy-nine percent of the tumors that received 5000 cGy or greater were controlled versus only 33% of the tumors that received less than 5000 cGy (P less than 0.02). There were no supratentorial failures, and there was only one isolated spinal cord failure. There were no solitary spinal failures in 24 patients who received a median dose of only 2400 cGy to the spinal axis. We concluded that low-dose irradiation to the spine and whole brain may be indicated with maintenance of a posterior fossa dose of greater than 5000 cGy.
This article reports a patient with Hodgkin's disease in remission after combined modality therapy who developed metastatic pulmonary osteosarcoma, subsequently found to originate in soft tissue of the mediastinum, within a field irradiated 11 years previously. This patient developed a series of radiotherapy-induced complications in addition to osteosarcoma. Only 16 cases of extraskeletal osteosarcoma after radiation treatment have been reported, none originating in the mediastinum. To the authors' knowledge, this is the first reported case of extraskeletal osteosarcoma occurring in a patient previously treated for Hodgkin's disease and with the sarcoma originating within the irradiated field.
BACKGROUND: Experimental, and more recently, clinical data have suggested the influence of hemostasis in the spread of malignant disease. METHODS: To complete research in this type of coagulation and cancer, a multicentric randomized clinical trial was performed, including 303 patients with small cell lung cancer (SCLC), treated by the addition of aspirin at 1 g/day (a dosage at which aspirin is considered to be a platelet aggregation inhibitor) to combined chemotherapy. RESULTS: Survival was not increased in the aspirin-treated group (P = 0.90). The analysis according to the extent of disease (limited or extensive disease) did not modify that conclusion. CONCLUSIONS: This result does not confirm the hypothesis that, in SCLC, aspirin (a platelet aggregation inhibitor) reduces metastasis formation and local tumor thrombogenesis.
BACKGROUND: Primary central nervous system lymphoma (PCNSL) is the most common brain tumor occurring in patients with acquired immune deficiency syndrome (AIDS). After diagnosis of PCNSL, the median survival time is 2-5 months with treatment with whole brain irradiation (WBI). METHODS: Four (of approximately 40) patients with AIDS and PCNSL seen by the University of California, San Diego (UCSD) Neuro-Oncology service were treated with multimodal therapy, including WBI with hydroxyurea, followed by 3 cycles of procarbazine/lomustine/vincristine (PCV) chemotherapy. RESULTS: Survival after tumor diagnosis ranged from 11 to 16 months, with a median of 13.5 months. CONCLUSION: Selected patients with AIDS and PCNSL may have long survival when treated with multimodal therapy.
We have analyzed the expression of the CDKN1A (p21(CIP1)), CDKN1B (p27(Kip1)), TP53, RB1 and MDM2 proteins and tumor cell proliferation by immunohistochemical staining in 59 cases of metastatic melanoma. The genomic status of the CDKN2A (INK4-ARF, p16/p14(ARF)), CDKN2B (p15) and CDKN2C (p18) genes was determined by PCR-SSCP (single-strand conformation polymorphism) in 46 of these cases. These results were correlated with various clinico-pathological parameters, including the outcome of combined chemoimmunotherapy. We found positive correlations between the expression of CDKN1A and MDM2 (r = 0.5063, P = 0.001), between the expression of CDKN1B and RB1 (r = 0.5026, P = 0.001), and between RB1 expression and tumor cell proliferation (0.5564, P<0.001). Two mutations in the CDKN2A (p16) gene were detected, including a novel base change AAC-->ATC (Asn to Ile) at codon 71, that also changes the codon 85 of the alternative reading frame gene p14(ARF) from CAA to CAT (Gln to His). Homozygous deletion at exon 2 of the CDKN2A (INK4-ARF) gene was detected in six cases. In seven cases, the 540C-->G polymorphism in the 3'UTR of the CDKN2A (p16) gene was found in linkage disequilibrium with the 74C-->A polymorphism in intron 1 of the CDKN2B gene (P < 0.0001). These cases had significantly lower expression of the TP53 protein (P = 0.0032). Both 540C-->G and 580C-->T polymorphisms in the 3'UTR of the CDKN2A (p16) gene were associated with significantly shorter progression time from primary to metastatic disease (P = 0.0071). We conclude, that although none of the analyzed cell cycle regulators could be singled out as a major prognostic factor, G(1)/S checkpoint abnormalities remain one of the most significant factors in the development of malignant melanoma.
BACKGROUND: Combination chemotherapy has been the mainstay of treatment for extensive stage small cell lung cancer (SCLC) over the last 25 years even though it only gives a short prolongation in median survival time. The main goal for these patients, if their survival prognosis is limited, should be adequate palliation with the aim of improving their quality of life. OBJECTIVES: To evaluate the effectiveness of chemotherapy in extensive SCLC compared with best supportive care (BSC) or placebo treatment. SEARCH STRATEGY: Medline (1966-Jan 2003), Embase (1974-Jan 2003), Cancerlit (1993-Jan 2003) and the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, 2002) were searched. In addition experts in the field were contacted to identify further studies not found by electronic searches. SELECTION CRITERIA: Randomised controlled trials in which any chemotherapy treatment was compared with a placebo group or best supportive care in patients with extensive stage SCLC. DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment were undertaken independently by two reviewers and disagreements were resolved by a third author. Additional information on the included studies was obtained from the author of the original studies. MAIN RESULTS: Only two studies (the first published in 1977 and the second in 1982) met the inclusion criteria of the review. A total of 65 patients with extensive disease (33 in the first study and 32 in the second) were randomised to received either placebo treatment or ifosfamide. In the second study a third arm of comparison included ifosfamide plus CCNU. Ifosfamide gave an extra 78.5 days survival (mean survival time) compared with the placebo group. Partial tumour response was greater with the active treatment. Toxicity was only seen in the chemotherapy group. Pooled analysis was not possible because only mean survival time was reported in both studies for patients with extensive disease. REVIEWER'S CONCLUSIONS: Chemotherapeutic treatment prolongs survival in comparison with placebo in patients with advanced SCLC. Nevertheless the impact of chemotherapy on quality of life and in patients with poor prognosis is unknown. Well-designed, controlled trials are needed to further evaluate the risks and benefits of different chemotherapeutic schedules in patients with advanced small cell lung cancer.
Chronic lymphocytic leukemia (CLL) is rarely associated with Hodgkin's disease (HD). We report a case of nodular sclerosis HD in a patient previously diagnosed with CLL. Reed-Sternberg cells were CD15(+) and CD30(+). He was treated with dose-escalated CHOP and at relapse, mitoxantrone, vinblastine, and CCNU (MVC) with partial response to the former and complete response to the latter, although the patient died 15 months later. Data from 88 other similar cases published in the English language were analyzed. Based on the histological and clinical features at the time of transformation, these patients were divided into distinct categories for analysis. Prognosis was found to be poorer in patients with continued active CLL when compared with those with CLL in remission at the time of transformation to HD. It is suggested that these two presentations may derive from different pathogenic mechanisms.
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Recent studies have demonstrated that preoperative and postoperative factors can broadly stratify patients with medulloblastoma/primitive neuroectodermal tumors (MB/PNET) into risk groups. For children with factors that suggest poor outcome after treatment with surgery and radiotherapy, the addition of chemotherapy can improve survival. Since 1983, 26 children with poor-risk posterior fossa MB/PNET have been treated at our institution with craniospinal radiation therapy and adjuvant chemotherapy. Chemotherapy consisted of vincristine during radiotherapy and eight 6-week cycles of vincristine, cis-platinum, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Twenty-five of 26 patients (96%) who have been entered on this protocol remain alive and free of disease at a median of 24 months from diagnosis (range 6 to 50 months). Twenty patients have completed all therapy and are at a median of 32 months from initial diagnosis with no evidence of disease. These patients were compared to a group of children with similar prognostic features treated at our institution between 1975 and 1983. Actuarial disease-free survival was statistically significantly better for protocol patients than for historical control subjects (p less than 0.002). This difference was most marked in patients who had received radiation therapy alone (p less than 0.0003). Actuarial 2-year disease-free survival was 96% for patients on protocol as compared to 59% for historical control patients who had been treated with radiotherapy alone. The chemotherapy given in this protocol was well tolerated. The results of this study, although preliminary, suggest that adjuvant chemotherapy is at least transiently effective in improving the rate of disease-free survival for children with poor-risk MB/PNET.
We treated 3 patients with newly diagnosed aggressive oligodendroglioma with chemotherapy prior to radiotherapy and observed responses. All had residual or progressive tumor following initial surgery. We used a combination called PCV-3 because recurrent anaplastic oligodendroglioma responds predictably to this regimen. Chemotherapy for response induction followed by radiotherapy for consolidation is feasible and effective initial treatment for this tumor.