Chondrosarcoma of the larynx after radiation treatment for vocal cord cancer.

The case of a 57-year-old man with chondrosarcoma of the laryngeal cartilage is presented, occurring 16 years after radiation treatment for squamous cell carcinoma of the right true vocal cord. Chondrosarcoma of the larynx is an uncommon tumor. The location, grade, and time elapsed from initial treatment make it probably that this patient's chondrosarcoma is associated with his prior radiation treatment. However, it is a rare occurrence, this being the second case reported in the literature.

Treatment of sarcomas of the chest wall using intensive combined modality therapy.

As part of two sequential protocols using intensive combined modality treatment in pediatric and adolescent sarcomas, 31 consecutive patients with primary chest wall tumors were treated between November 1977 and March 1986. This group included 13 patients with peripheral neuroepithelioma (Askin's tumor), 11 patients with Ewing's sarcoma, 3 patients with rhabdomyosarcoma, and 4 patients with undifferentiated sarcomas. Following complete work-up, 17 patients presented with localized disease and 14 patients presented with metastases. Patients received intensive combined modality treatment with combination chemotherapy (vincristine, cyclophosphamide, Adriamycin, +/- actinomycin-D and DTIC) and high-dose conventionally fractionated radiation therapy to the primary (55-60 Gy) and non-pulmonary metastases (45-50 Gy). Radiation techniques used for the primary chest wall tumor varied with the clinical presentation. Patients achieving a complete response received either low-dose fractionated TBI (1.5 Gy/0.15 Gy fx/5 weeks) or high-dose TBI (8 Gy/4 Gy fx/2 days) and an intensive cycle of chemotherapy followed by autologous bone marrow transplantation. Twenty-five of 31 patients were judged to have a complete response (including 1 patient with complete resection). With minimum follow-up of 6 months and median follow-up of 36 months from completion of treatment, 14 patients remain disease-free with 2 additional patients alive in second remission after relapse. Patients with localized disease at presentation have improved disease-free survival and overall survival compared to patients with metastases at presentation. All 17 localized patients achieved a CR and 11 are NED compared to 8 of 14 metastatic patients achieving a CR and only 3 are NED. There have been 5 loco-regional recurrences with 3 "in-field" failures and 2 failures in the regional pleura. There were no treatment-related deaths and no clinically significant cases of pneumonitis. To date, 2 patients have significant treatment related morbidity, including 1 patient with scoliosis requiring surgery and 1 patient with acute leukemia developing 42 months after the start of therapy (presently in remission). We conclude that this intensive combined modality therapy results in a high CR rate and good local control with acceptable morbidity. Patients with metastatic disease at presentation remain a therapeutic challenge.

Salvage irradiation of oropharyngeal cancers using iridium 192 wire implants: 5-year results of 70 cases.

Between May 1971 and November 1980, 70 patients with recurrent or new oropharyngeal cancers arising in previously irradiated tissues were treated using iridium 192 afterloading techniques. The actuarial local control was 72% at 2 years and 69% at 5 years. Although local control of the tumor was achieved in the majority of these patients, only 10 patients remained alive at 5 years (14%). Patients with lesions of the faucial arch and posterior pharyngeal wall had the best results; local control was achieved in 100% of these patients. Patients with lesions of the base of tongue and of the glosso-tonsillar sulcus had poorer results; local control was achieved in 61%. Because these results compare favorably with the results of previously published series, we recommend re-irradiation with brachytherapy for recurrent or new malignancies arising in a previously irradiated oropharynx. When the lesion is located in the faucial arch, brachytherapy is the treatment of choice. When the lesion is located in the base of tongue, brachytherapy is a reasonable option.

Diagnosis of pulmonary nodules in the cancer patient: the role for routine culture and an unusual application of the human tumor colony-forming assay.

Many solid tumors that occur in humans tend to metastasize to the lungs. The etiology of pulmonary nodules in cancer patients, therefore, presents a diagnostic problem that can be resolved only by histologic evaluation or resection. We present two cases of cancer patients with preoperative and intraoperative diagnoses of metastatic lung tumors. Tissue culture using the Human Tumor Colony-Forming Assay (HTCFA), a procedure that predicts chemosensitivity patterns of tumors, was employed to successfully diagnose those nodules as fungal infections. In one case, results using the HTCFA were crucial in the identification of the opportunistic organism. These cases stress the importance of routine culture of all pulmonary nodules and present an unusual but noteworthy application of the HTCFA system.

Conservative treatment of breast cancer in Europe: report of the Groupe Européen de Curiethérapie.

These two meetings organised successively to discuss the conservative methods of treatment of breast cancer, made it possible to gather data on a substantial number of patients from an important number of European centers. It is encouraging to note that there is a general consensus among the various European centers concerning the basic principles of treatment and that long years of experience have led to the use of well defined technical protocols which are relatively similar from one center to another. Since serious complications have now become exceptional, we foresee that the conservative treatment of breast cancer will continue to evolve on a technical level as the indications for this approach continue to develop within the overall plan of patient care with the assurance that optimum results may be maintained. However, we must point out that the lack of a unified system of reporting irradiation doses in volumes corresponding to the possible and/or real extension of the tumor remains an obstacle in developing a truly unified attitude in the application of these techniques. Each center defines the radiation dose given by wide field techniques and the dose given by cone-down (boost) techniques in a relatively arbitrary way without true anatomic correlations. These correlations must be found and defined, so that a specified dose has a universal meaning. The role of the surgeon in the successful application of breast conserving techniques is far from negligible. Now that our colleagues who wield the scalpel have begun to gain confidence in the curative powers of irradiation, we may hope that a close collaboration between radiotherapist and surgeon will lead to the application of conservative techniques under optimal conditions in the breast, with the development of minimal tumorectomy and minimal curative cone-down dose; and in the axilla, with the development of axillary dissection limited to the lower border of the pectoralis minor and followed by radiation therapy only if more than two nodes show tumor involvement. However, it is important to point out that while it is possible to use radiation therapy alone to treat breast cancer and conserve the breast at all stages of the development of the disease, it is not possible to use conservative surgical techniques alone as a substitute for adequate irradiation. The development of protocols which routinely apply breast conserving methods in synonymous with the development and routine use of the best radiation therapy techniques. This article presents two separate and complementary studies of two different sets of data presented at two successive meetings.(ABSTRACT TRUNCATED AT 400 WORDS)

Phase I study of ICRF-187 in pediatric cancer patients and comparison of its pharmacokinetics in children and adults.

A phase I study of ICRF-187 as a 2-hour iv infusion daily for 3 days was conducted in 46 evaluable pediatric patients. The maximum tolerated dose was 3500 mg/m2/day X 3 based on changes in hepatic function and coagulation abnormalities encountered when larger dosages were administered. One patient with acute lymphocytic leukemia achieved a complete remission and four cleared the blood of lymphoblasts. No other objective responses were seen. Pharmacokinetic analysis showed that the children had a larger volume of distribution per kilogram of body weight in the central compartment and total body and a more rapid total-body clearance than adults. These parameters can explain only part of the increased tolerance of children to ICRF-187.

Very high dose cyclophosphamide with imidazole carboximide and vincristine sulfate in the treatment of stage IV neuroblastoma.

To address the problem of drug dosage as a limiting factor for successful chemotherapy, seven patients with Stage IV neuroblastoma were treated with very high dose cyclophosphamide with imidazole carboximide (DTIC) and vincristine sulfate in conjunction with intensive supportive care. None of the patients experienced a complete response. The major toxicity was myelosuppression, complicated by significant infections. Toxicity was significantly more severe in this study than in similar regimens using these three drugs at conventional doses. Although the number of patients in this study was small and most had received prior therapy, our data do not support the efficacy of very high dose cyclophosphamide in the treatment of Stage IV neuroblastoma.

Actuarial risk of isolated CNS involvement in Ewing's sarcoma following prophylactic cranial irradiation and intrathecal methotrexate.

Records of 154 patients with Ewing's sarcoma treated at the National Cancer Institute were reviewed to assess the incidence and risk of developing isolated central nervous system (CNS) Ewing's sarcoma. Sixty-two of the 154 patients had received CNS irradiation and intrathecal (i.t.) methotrexate as part of their initial therapy to prevent the occurrence of isolated CNS Ewing's sarcoma. The risk of developing isolated CNS Ewing's sarcoma was greatest within the first two years after diagnosis and was approximately 10%. The overall risk of CNS recurrence in the group of patients receiving CNS treatment was similar to the group receiving no therapy directed to the CNS. The occurrence of isolated CNS involvement was not prevented by the use of CNS irradiation and i.t. methotrexate. Because of a lack of efficacy to the CNS irradiation regimen, current treatment regimens do not include therapy directed to the CNS.

Phase I trial of mitoxantrone in children.

Mitoxantrone was administered as a single iv injection once every 3 weeks to 84 children with advanced acute leukemia and solid tumors in a phase I trial. Dose-limiting granulocytopenia occurred at dosages greater than 18 mg/m2 in children with solid tumors, while hospitalization for febrile episodes occurred in nine of 12 patients with acute leukemia receiving dosages greater than 24 mg/m2. Six children developed evidence of cardiac dysfunction, including three instances of congestive heart failure. No other significant toxicity was noted. Complete responses were seen in one child with neuroblastoma metastatic to bone, one with acute lymphoblastic leukemia, and four with acute nonlymphoblastic leukemia.

Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by tamoxifen and other triparanol analogues.

The effects of the triparanol analogues chlorotrianisene, clomiphene, tamoxifen, 5-[p-(fluoren-9-ylidenemethyl)phenyl]-2-piperidineethanol (MDL 10393), MDL 8917v, nafoxidine, 2-[p-(6-methoxy-2-phenylinden-3-yl)phenoxy]triethylamine (U-11555A), 2-[p-(3,4-dihydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]triethylamine (U-10520A), and nitromifene, as well as triparanol itself, were studied in the P388 murine leukemia cell line and in a doxorubicin-resistant subline (P388/ADR). At noninhibitory concentrations, all the analogues increased the sensitivity of P388/ADR cells to doxorubicin but did not have such an effect on the doxorubicin-sensitive cells. Diethylstilbestrol, deacetylated cyclofenil (F6060), hexestrol, and 17 beta-estradiol did not have such an activity. The effects of tamoxifen on doxorubicin sensitivity of P388/ADR cells could not be reversed by 17 beta-estradiol. Estrogen receptors could not be demonstrated in either cell line. It is therefore suggested that the reversal of the doxorubicin-acquired resistance by the triparanol analogues is unrelated to their estrogenic or antiestrogenic activities. The possible clinical implications of these findings are discussed.

Oxygen radical detoxification enzymes in doxorubicin-sensitive and -resistant P388 murine leukemia cells.

One of the proposed mechanisms for the cytotoxic effects of anthracycline compounds suggests that the effect is mediated through the formation of intracellular superoxide radicals. It is therefore possible that doxorubicin resistance is associated with increased intracellular enzyme capacity to convert these superoxide radicals to inactive metabolites. We have measured the relative activities of superoxide dismutase, glutathione peroxidase, and catalase in P388 mouse leukemia cells and in a doxorubicin-resistant subline. Since oxygen-reactive metabolites also play a role in mediating the cytotoxicity of ionizing radiation, the radiosensitivity of both cell lines was also studied. No significant differences in superoxide dismutase activity between these cell lines was observed, indicating that they have a similar capacity to convert superoxide anion radicals to hydrogen peroxide. P388 cells that are resistant to doxorubicin have 1.5 times the glutathione content and 1.5 times the activity of glutathione peroxidase measured in drug-sensitive P388 cells. However, incubation with 1-chloro-2,4-dinitrobenzene, which covalently binds glutathione, had no effect on the sensitivity of either cell line to doxorubicin. Measured catalase activity in drug-resistant P388 cells was one-third of the activity measured in doxorubicin-sensitive P388 cells. The activity of this enzyme was much higher than that of glutathione peroxidase in terms of H2O2 deactivation in both cell lines. It is therefore unlikely that doxorubicin-resistant P388 cells have an increased ability to detoxify reactive oxygen metabolites when compared to drug-sensitive cells. Doxorubicin-resistant P388 cells were significantly more sensitive to X-irradiation than were drug-sensitive P388 cells. These observations suggest that the difference in catalase activity in these cell lines may be associated with the observed differences in radiosensitivity.

Differences in lipid composition of doxorubicin-sensitive and -resistant P388 cells.

An anthracycline-resistant subline of P388 murine leukemia cells, P388/ADR, has been shown to have an altered total lipid content and composition when compared to the parent line. When specific lipids of the cell lines are compared, it is found that P388/ADR cells contain approximately 3.6 times the amount of triglycerides as P388 cells. Although no differences are noted in the amounts of unesterified cholesterol or total phospholipids in the two cell lines, they do differ in specific phospholipid patterns. P388/ADR cells contain relatively less phosphatidylcholine and more sphingomyelin than drug-sensitive cells. No differences are observed in the content of phosphatidylethanolamine and cardiolipin. The difference in phosphatidylcholine/sphingomyelin ratio (5.57 for ADR-sensitive cells and 3.28 for ADR-resistant cells) may account for the previously observed difference in plasma membrane lipid structural order between these cell lines. Measurements of the relative activity of phosphocholine transferase in the two lines, using the rate of incorporation of 3H-choline into phosphatidylcholine, indicate that lower phosphocholine transferase activity in P388/ADR cells may account for the observed changes in cellular lipid and phospholipid composition.

5'-Nucleotidase activity and arachidonate metabolism in doxorubicin sensitive and resistant P388 cells.

5'-nucleotidase activity, arachidonate metabolism and adenosine uptake were measured in P388 murine leukaemia cells and in a subline resistant to doxorubicin. These membranes related activities were found to be increased in the doxorubicin resistant cell line, compared to the drug sensitive cells. It is suggested that these differences do not play a role in the mechanism of resistance to doxorubicin. Rather they reflect alterations in plasma membrane composition and structure between these cell lines. This study also suggests that the use of decreased 5'-nucleotidase activity as a marker of certain leukaemias should be reviewed with caution. An increase in cell enzyme activity in treated patients may not necessarily indicate a shift toward normal behaviour of these cells, but rather a selection of certain cell subpopulations.

Probenecid inhibition of methotrexate cytotoxicity in mouse L1210 leukemia cells.

The effect of probenecid on methotrexate cytotoxicity has been measured using mouse L1210 leukemia cells in vitro. Cytotoxic effects were measured using a soft agar cloning technique. Cell exposure to varying concentrations of methotrexate at fixed concentrations of probenecid resulted in increased cell survival when compared with exposure to methotrexate alone. Cell exposure to a fixed concentration of methotrexate and varying concentrations of probenecid showed this effect to be dependent on the concentration of probenecid. Intracellular methotrexate concentrations were unchanged by the presence of probenecid. However, there was an effect of probenecid on progression of cells through the cell cycle which would tend to decrease the number of cells susceptible to the cytotoxic effects of methotrexate.

Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by perhexiline maleate.

The effects of perhexiline maleate on growth and drug sensitivity were studied in the P388 murine leukemia cell line and in an anthracycline-resistant subline (P388/ADR). At noninhibitory concentrations, perhexiline maleate markedly increased the sensitivity of P388/ADR cells to doxorubicin but did not have such an effect on anthracycline-sensitive cells. The effects of perhexiline maleate on P388/ADR cells were reversible. Perhexiline maleate also increased the accumulation of another anthracycline, daunorubicin, in P388/ADR cells but did not increase its accumulation in the anthracycline-sensitive cells. Perhexiline maleate did not affect the sensitivity of either cell line to methotrexate or to 6-mercaptopurine. However, its effects on the sensitivity and on drug accumulation of vinblastine, a drug to which P388/ADR cells are cross-resistant, were similar to those observed for the anthracyclines. Although perhexiline maleate has been reported to be a calcium antagonist in other systems, our data do not suggest that this mechanism is involved in its enhancement of the sensitivity of P388/ADR cells to doxorubicin. We suggest instead that this effect might be associated with alterations of cell lipid metabolism induced by perhexiline maleate.

Intensive combined modality therapy including low-dose TBI in high-risk Ewing's Sarcoma Patients.

Twenty-four high-risk Ewing's sarcoma patients were treatedf on an intensive combined modality protocol including low-dose fractionated total body irradiation (TBI) and autologous bone marrow infusion (ABMI). Twenty patients (83%) achieved a complete clinical response to the primary and/or metastatic sites following induction therapy. The median disease-free interval was 18 months, and nine patients remain disease-free with a follow-up of 22 to 72 months. Local failure as a manifestation of initial relapse occurred in only three patients (15%), each having synchronous distant failure. Eight patients failed initially with only distant metastases, usually within 1-2 years following a complete clinical response. Two patients with a single metastasis were again rendered disease-free and remain free from second relapse with 18 and 30 months follow-up. No other relapsed patient was able to be rendered disease-free, and most died of progressive disease within 6 to 12 months of relapse. Two patterns of granulocyte recovery following consolidative therapy (include TBI) and ABMI were recognized. Seventeen patients reached a total granulocyte count of >500 cells/mm3 within 4 weeks of ABMI (early graulocyte recovery), while seven patients required >4 weeks from ABMI (late granulocyte recovery). The time of platelet recovery (>50,000/mm3) was different for the groups with early and late granulocyte recovery (25 days vs. 54 days, p <.001). Six of seven patients with late granulocyte recovery received locl high-dose irratiation to >1/2 pelvis prior to bone marrow storage. Patients with late recovery did not tolerate maintenance chemotherapy. However, there was no difference in disease-free and overall survival, when compaing the groups with early and late granulocyte recovery. We conclude that these high-risk Ewing's sarcoma patients remain a poor-prognosis group in spite of intensive combined modality therapy include low-dose TBI. The control of microscopic systemic disease remains the major challenge to improving the cure rate. A new combined modality protocol with high-dose 'therapeutic' TBI (800 rad/2 fractions) is being used and the protocol design is outlined.

Plasma membrane lipid structural order in doxorubicin-sensitive and -resistant P388 cells.

We have studied the structural order of the lipid phase of plasma membranes from P388 murine leukemia cells and from a Doxorubicin-resistant subline, P388/ADR, using electron spin resonance spectroscopy and fluorescence depolarization measurements. Measurements of the order parameter, S, following incubation of cells from both lines with the N-oxyl-4'-4'-dimethyloxazolidine derivative of 5-ketostearic acid show higher values for the resistant cells at all temperatures where S was measured (4-37 degrees). Fluorescence depolarization measurements following incubation of the cells, or cell fractions, with 1,6-diphenylhexatriene indicate more restricted motion of the probe in resistant cells. These measurements also show increased amounts of cytoplasmic lipid in the resistant cells. The higher degree of structural order in the lipid phase of the plasma membranes of P388/ADR cells and their larger intracellular lipid content may account for the decreased rate of intracellular accumulation of anthracycline drugs (and other compounds) seen in these cells and, in part, for their relative resistance to the cytotoxic effects of these drugs.

Enhancement of doxorubicin and vinblastine sensitivity in anthracycline-resistant P388 cells.

Acquired resistance to doxorubicin in a P388 murine leukemia cell subline was found to be associated with decreased drug accumulation in these cells. We have previously shown that the lipid domain of the plasma membrane in drug-resistant cells is structurally more ordered and has a lower phosphatidylcholine/sphingomyelin ratio. Perhexiline maleate and triparanol both markedly enhance the sensitivity of drug-resistant cells to doxorubicin and vinblastine but do not have an effect on anthracycline-sensitive cells. This enhanced sensitivity is associated with increased drug accumulation. Although perhexiline maleate has been reported to be a calcium antagonist in other systems, our data do not implicate this mechanism in the enhancement of cell sensitivity to doxorubicin. We suggest that this effect might be related to alterations of the cell membrane lipid domain induced by perhexiline maleate and triparanol, which result in decreased structural order of plasma membrane lipids and permit increased drug accumulation.

Extraskeletal Ewing's sarcoma: results of combined modality treatment.

Eleven patients with extraskeletal Ewing's sarcoma (EES) were treated with combined modality therapy at the National Cancer Institute. The diagnosis of EES was reserved for lesions that were identical to Ewing's sarcoma of bone by light and electron microscopy. Diagnostic work-up to rule out a skeletal primary included bone scan, localized views of adjacent bone, and bone tomography. Seven patients presented with an extremity primary and four patients had a truncal primary. No patients had evidence of metastases at presentation. Patients were treated with combined modality therapy consisting of high-dose local irradiation and vincristine, actinomycin D, and cyclophosphamide chemotherapy following a biopsy or local excision. No attempt was made to excise widely the primary tumor mass. Gross tumors generally responded rapidly to the combined modality treatment. Of 11 patients, seven (64%) remain disease free, with a follow-up of three to seven years from completion of therapy. Long-term local control was established in nine of 11 patients (82%). Autopsy findings on two patients with local failure showed no tumor involvement of adjacent bone. Attempts at gross resections by radical surgical procedures do not routinely appear to be necessary in light of the high local control rates with high-dose irradiation.