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Biomedical subjects

C N Coleman

Publications and source records attributed to C N Coleman.

At least 127 records · Page 7Linked to original sources
PubMed1988

Radioimmunotherapy with alpha-particle-emitting immunoconjugates.

Alpha particles are energetic short-range ions whose higher linear energy transfer produces extreme cytotoxicity. An alpha-particle-emitting radioimmunoconjugate consisting of a bismuth-212-labeled monoclonal immunoglobulin M specific for the murine T cell/neuroectodermal surface antigen Thy 1.2 was prepared. Analysis in vitro showed that the radioimmunoconjugate was selectively cytotoxic to a Thy 1.2+ EL-4 murine tumor cell line. Approximately three bismuth-212-labeled immunoconjugates per target cell reduced the uptake of [3H]thymidine by the EL-4 target cells to background levels. Mice inoculated intraperitoneally with EL-4 cells were cured of their ascites after intraperitoneal injection of 150 microcuries of the antigen-specific radioimmunoconjugate, suggesting a possible role for such conjugates in intracavitary cancer therapy.

Alpha Particles↗
PubMed1988

Hypoxia in tumors: a paradigm for the approach to biochemical and physiologic heterogeneity.

While the inherent radiosensitivity of tumor cells is likely to affect treatment outcome, the biochemical and physiologic state of the cell may have a major impact. Tumors are likely to be highly heterogeneous for these dynamic properties. Hypoxic cells are radioresistant, requiring two to three times the radiation dose to kill them compared to the same cells in a eu-oxic state. Hypoxia can be of two types: 1) chronic hypoxia, which is diffusion limited, and 2) acute hypoxia, which is perfusion limited. The mechanism of and approaches toward these are different and can serve as a model for other biochemical and physiologic processes that may affect treatment outcome.

Animals↗
PubMed1988

Risk of second cancers after treatment for Hodgkin's disease.

We estimated the risk of second cancers among 1507 patients with Hodgkin's disease treated at Stanford University Medical Center since 1968. Eight-three second cancers occurred more than one year after diagnosis, as compared with 15.9 expected on the basis of rates in the general population (relative risk, 5.2; 95 percent confidence interval, 4.2 to 6.5). The mean (+/- SE) 15-year actuarial risk of all second cancers was 17.6 +/- 3.1 percent, of which 13.2 +/- 3.1 percent was due to solid tumors. The risk of leukemia appeared to reach a plateau level of 3.3 +/- 0.6 percent at 10 years, whereas non-Hodgkin's lymphoma continued to increase, to 1.6 +/- 0.7 percent by the end of the follow-up period. The risk of solid tumors did not vary significantly according to treatment category, with the array of neoplasms resembling that previously observed in populations exposed to radiation and in immunosuppressed groups. The risk of leukemia, although elevated after radiation therapy alone (relative risk, 11; 95 percent confidence interval, 1.2 to 38), was much higher after either adjuvant chemotherapy (relative risk, 117; 95 percent confidence interval, 69 to 185) or chemotherapy alone (relative risk, 130; 95 percent confidence interval, 26 to 380). These data suggest that the risk of solid tumors after therapy for Hodgkin's disease continues to increase with time.

Adolescent↗
PubMed1988

Stage IA and IIA supradiaphragmatic Hodgkin's disease: prognostic factors in surgically staged patients treated with mantle and paraaortic irradiation.

A total of 315 pathologically staged (PS) patients with IA and IIA Hodgkin's disease (HD) were treated with mantle and paraaortic irradiation, and evaluated for freedom-from-first relapse (FFR), survival, prognostic factors, and long-term complications. The 14-year actuarial FFR and survival were 82% and 93%, respectively, with a median follow-up time of 9 years. Mediastinal size was the only factor that predicted for a lower FFR, P less than .001. Forty-nine patients have developed recurrent HD. Thirty-six patients are disease-free following retreatment and only 13 patients have died of HD. Patients with mixed cellularity (MC) histology were more likely to relapse below the diaphragm (11%) as compared with patients with nodular sclerosis (NS) (5.1%) or lymphocyte predominant (LP) (3.6%) histology. These relapses were often associated with bulky pelvic nodal adenopathy and salvage treatment with chemotherapy alone often failed to control recurrent disease. Alternative diagnostic and therapeutic recommendations are presented for these patients. Thyroid abnormalities represented the most common long-term complication with an actuarial risk at 16 years of 37%. Major complications were rare. Mantle and paraaortic irradiation is associated with a high FFR and a low risk of complications and should remain standard treatment for early-stage HD.

Adolescent↗
PubMed1988

Chemical modifiers of cancer treatment.

Chemical modification is a concept in cancer therapy in which the state of tumor cells or normal tissues is modified such that a therapeutic gain can be achieved using conventional therapeutic modalities. Hypoxic zones targeted as cells within them may be radiation resistant, poorly perfused by chemotherapeutic agents, and possibly drug resistant due to hypoxia-related gene amplification. Nitroimidazoles have gained particular attention as chemical modifiers because they can increase the radiation sensitivity of hypoxic cells, are cytotoxic to hypoxic cells, can increase sensitivity to chemotherapeutic agents, and are useful for imaging hypoxic cells. While both radiosensitization and chemosensitization require hypoxia, the mechanism of the enhancement of each of the modalities is different. The 2-nitroimidazole hypoxic sensitizers SR 2508 and Ro-03-8799, which are less toxic than the prototype misonidazole (Miso), are in clinical trials, and dual function molecules that include a hypoxic sensitizer and alkylating function are being developed. The presence of both acutely and chronically hypoxic cells in animal tumors has been demonstrated by new imaging techniques. Oxygen delivery to tumors is being altered by the use of perfluorocarbons, and agents that alter hemoglobin affinity for oxygen. Compounds that are selectively toxic to hypoxic cells are being developed. Nonhypoxic modifiers are also being investigated. Thiol modification, particularly the alteration of glutathione concentration, has complex effects on the cell's biochemistry, in addition to affecting the competition between oxygen and thiol groups for the restoration and fixation of radiation-induced radicals. WR-2721 is being studied as a means of reducing the normal tissue toxicity of radiation and chemotherapy. Increased thiol concentration may be a mechanism of cross-resistance between certain chemotherapeutic agents and radiation.

Antineoplastic Agents↗
PubMed1987

Cardiac disease after mediastinal irradiation for seminoma.

One hundred twenty-four patients with seminoma (119 primary testis, five primary extragonadal) were treated between 1968 and 1984 at the Joint Center for Radiation Therapy. Fifty-seven of the 124 patients were treated with irradiation to the mediastinum as well as to an infradiaphragmatic field. One patient received supradiaphragmatic radiotherapy only. The remaining patients had radiation treatment limited to the infradiaphragmatic field only. Median dose to the mediastinum among the 58 patients was 2400 cGy. Four patients developed heart disease (one fatal myocardial infarction, one uncomplicated myocardial infarction, one constrictive pericarditis resulting in permanent total body anasarca, and one patient requiring aortic valve replacement and coronary artery bypass grafting for atherosclerotic disease) and two died suddenly. The two sudden deaths were thought to be cardiac in origin by the patient's primary physicians. All six complications occurred in the group that received mediastinal irradiation. No cardiac disease was manifested in the group not treated with mediastinal irradiation. This difference in the incidence of cardiac disease between the two groups is statistically significant (two sided, P = 0.019). Neither group had a statistically significant difference in cardiac disease rate from a normal population (Framingham study), although the ratio of observed to expected cardiac disease was 1.97 in the group receiving mediastinal radiation. Further experience from this and other institutions is necessary to confirm this finding.

Adult↗
PubMed1987

Relationship between the neurotoxicity of the hypoxic cell radiosensitizer SR 2508 and the pharmacokinetic profile.

Complete pharmacological data from 71 patients treated on the phase I trial of SR 2508 were analyzed to see if the dose-limiting toxicity of peripheral neuropathy is related to the individual patient's pharmacokinetic profile. In a retrospective analysis, the risk of toxicity was best predicted by using the bivariate model of total drug exposure and the time over which the treatment course was given. Drug exposure [area under the curve (AUC)] for a single treatment was calculated by the integral over time of the serum concentration of SR 2508. Since the AUC was constant during the course of a patient's treatment, the total drug exposure (total-AUC) was estimated by the product of the AUC times the number of drug administrations. While the clinical efficacy of hypoxic cell sensitizers remains to be proven, SR 2508 is better tolerated than its predecessors, misonidazole and desmethylmisonidazole, as three times the amount of SR 2508 can be given. If this model is confirmed in the current phase II and III trials, the probability of developing neuropathy would be predictable for an individual patient from measurements made at the time of the first drug dose, allowing for the adjustment of drug schedule to avoid all but minor toxicity.

Dose-Response Relationship, Drug↗
PubMed1987

Minimal long-term cardiopulmonary dysfunction following treatment for Hodgkin's disease.

UNLABELLED: We studied the long term cardiopulmonary function, at rest and during exercise, of 57 patients who were at least 1 year (mean 5 years) post-treatment for Hodgkin's disease. To establish the maximum degree of dysfunction we studied 40 patients who had extensive intrathoracic disease treated with radiotherapy alone (Exten-X; n = 20) or combined modality therapy (Exten-XC; n = 20). Patients without intrathoracic disease given either prophylactic mantle therapy (Proph-X, n = 10) or no chest irradiation ( CONTROL: n = 7) were used as controls. An abnormal electrocardiogram, by virtue of a conduction defect, was observed in seven patients, six in the Exten-X or Exten-XC groups. Borderline abnormalities including ST-T changes, prolonged QT interval, or axis deviation occurred in 14 patients distributed evenly throughout the groups. Resting mean pulmonary function test values were normal in all treatment groups. Exercise tolerance, as indicated by peak oxygen consumption (VO2), was significantly lower for the Exten-XC group compared to Proph-X (p less than 0.01). However, the mean value of VO2 for group Exten-XC was only 15% below that predicted. Of the 12 patients with abnormally low VO2 (greater than 20% below their predicted value), 11 were in the Exten-X or Exten-XC group with no difference between the two groups. Patients who received radiotherapy to at least one lung field, using either the thin lung block technique or open field irradiation, had significantly lower exercise tolerance than those treated with full thickness blocks (p less than 0.05). Despite these abnormalities only a single patient complained of marked dyspnea. We conclude that extensive treatment to the mantle field, especially when followed by chemotherapy in patients with extensive intrathoracic Hodgkin's disease, can result in minimal cardiopulmonary dysfunction in approximately one-third of patients.

Adolescent↗
PubMed1987

Third-line chemotherapy for resistant Hodgkin's disease with lomustine, etoposide, and methotrexate.

Thirty-two patients with recurrent Hodgkin's disease have been treated with an oral regimen employing lomustine (CCNU, 100 mg/m2 orally on Day 1); etoposide (VP-16, 100 mg/m2 orally on Days 1-3 and 21-23); and methotrexate (30 mg/m2 orally on Days 1, 8, 21, and 28). The regimen was repeated every 6 weeks. Most patients had been treated with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine); 20 had had prior irradiation. Lymph node was the predominant site of disease and the majority of patients had B symptoms. Four patients achieved complete response (13%), with a median duration of 33+ months, and 11 achieved partial response (34%), with a median duration of 5 months, for an overall response rate of 47%. The major toxic effect was severe myelosuppression, which occurred in six patients; there were no treatment-related deaths. This oral regimen was easy to administer in heavily pretreated patients with poor venous access and had minimal toxicity.

Administration, Oral↗
PubMed1986

Phase I trial of the hypoxic cell radiosensitizer SR-2508: the results of the five to six week drug schedule.

Sixty-five patients were entered on the long schedule of the Phase I trial of SR-2508. The planned total doses ranged from 30 to 40.8 g/m2 using various treatment schema including daily, split course, and every-other-day schedules. The individual dose size was 2 g/m2 for 56 patients and 1.7 g/m2 for nine. In contrast to misonidazole and desmethylmisonidazole, more SR-2508 can be administered as the duration of therapy is lengthened. All six patients on the 30 g/m2 step tolerated the drug without toxicity. This total dose was not achievable in the three week schedule. Additionally, a number of patients did not develop neuropathy at a cumulative dose of 40.8 g/m2. Although the analysis is not yet complete, a given patient's drug exposure as measured by their total AUC (mMxhr), defined as the area-under-the-curve of serum concentration of SR-2508 vs. time for a single dose times the number of doses given, is useful in predicting toxicity for that patient. The recommended starting schedule for the Phase II and III trials is 34 g/m2 over a 6 week period (2 g/m2 every other day). A total AUC of approximately 39 mMxhr should be tolerable. The drug regimen must be altered for patients who have a high AUC. Therefore, it is mandatory to have an accurate and rapid pharmacokinetic analysis for each patient. The clinical efficacy of the hypoxic cell sensitizers remains to be proven. However, using the guidelines derived from the Phase I trial, SR-2508 should be a relatively safe drug, producing minor or no toxicity.

Drug Administration Schedule↗
PubMed1986

Treatment of lymphoblastic lymphoma in adults.

Forty-four adult patients with lymphoblastic lymphoma (LBL) were treated according to one of two protocols. Both included (1) induction with cyclophosphamide, doxorubicin, vincristine, prednisone, and L-asparaginase; (2) CNS prophylaxis; and (3) maintenance therapy with methotrexate (MTX) and 6-mercaptopurine. In the second protocol, CNS prophylaxis began earlier than in the first protocol and included cranial irradiation and intrathecal (IT) MTX rather than simultaneous high-dose systemic and IT MTX. The overall response rate was 100% (95% complete). With a 26-month median follow-up, the 1-and 3-year actuarial freedom from relapse (FFR) for the composite patient group was 70% and 56%, respectively. The incidence of CNS relapse was reduced from 31% in the first protocol to 3% in the second protocol (P = .04, Gehan). Patients can be assigned retrospectively to low (n = 19) and high (n = 25) risk prognostic groups, as indicated by a multivariate analysis of pretreatment prognostic factors. High-risk is defined by Ann Arbor stage IV disease with bone marrow or CNS involvement or initial serum lactate dehydrogenase (LDH) concentration of greater than 300 IU/L (normal, less than 200). FFR of low- and high-risk groups at 5 years are 94% and 19%, respectively (P = .0006). Low-risk patients are highly curable using this approach to adult LBL. More intensive treatment for high-risk patients is warranted.

Adult↗
PubMed1986

Combined modality therapy for adults with small noncleaved cell lymphoma (Burkitt's and non-Burkitt's types).

Between June 1979 and June 1984 18 adult patients with small noncleaved cell lymphoma (SNCL) (diffuse undifferentiated lymphoma, Burkitt's and non-Burkitt's types of the Rappaport classification) were treated with high-dose cyclophosphamide, doxorubicin, vincristine, prednisone, midcycle high-dose methotrexate, and intrathecal methotrexate. Early in the course of treatment, hyperfractionated radiotherapy (125 cGy, every two days, for 1,500 to 2,250 centigray [cGy]) was administered to unresected masses greater than 10 cm in their greatest dimension. Chemotherapy was administered every 21 days for six to ten cycles. Treatment was generally well tolerated; however, one patient died of probable tumor lysis syndrome. With a median follow-up of 1.2 years, actuarial survival was 66.8% and relapse-free survival (RFS) was 71.3% for the entire group. All treatment failures and deaths occurred in patients with stage D disease. RFS projected at 2 years was 100% for stages A and AR and 60.6% for stage B, C, and D (P = .13 Gehan). Two-year RFS for patients with stage A, AR, B, or C disease was 100 v 41% for those with stage D disease. Patients with adverse prognostic features (n = 7)--unresected bulk measuring greater than 10 cm, pretreatment serum lactate dehydrogenase (LDH) 500 IU/L (normal, 200) or involvement of CNS or bone marrow--had a projected RFS of 28.6% compared with 100% for those patients without these features (P = .002 Gehan). Too few patients received induction radiotherapy to assert its role in therapy. By using aggressive multiagent therapy, cure can be expected in a high percentage of adults with SNCL. In the subset with adverse prognostic features, more effective therapy is necessary.

Abdominal Neoplasms↗
PubMed1986

Factors predicting survival in adults with stage I and II large-cell lymphoma treated with primary radiation therapy.

The records of 148 consecutive patients with Ann Arbor stage I and II large-cell lymphoma treated with primary radiation therapy with or without adjuvant chemotherapy were analyzed retrospectively for pretreatment prognostic variables and results of treatment. For patients treated with radiation to fields on one side of the diaphragm, the 5 year freedom-from-relapse rate was 25% and the survival rate was 35%, but for those given additional transdiaphragmatic radiation or for those given radiation plus adjuvant chemotherapy, the rates were both approximately 67%. In a multivariate analysis, the only significant pretreatment prognostic variables were the number of sites of involvement and bulk of disease, with relapse as the endpoint. For patients treated with radiation to both sides of the diaphragm or with radiation plus adjuvant chemotherapy, the 5-year freedom-from-relapse rate was 82% for the group with a favorable prognosis (with less than three sites of involvement and a mass size of less than 10 cm) and 55% for those with an unfavorable prognosis.

Actuarial Analysis↗
PubMed1985

Hypoxic cell radiosensitizers: expectations and progress in drug development.

When misonidazole (MISO) was introduced into clinical trials there were great expectations that the cure rate of many tumors would be dramatically increased. The lack of efficacy of MISO discouraged further studies with hypoxic cell sensitizers. In recent years superior sensitizers SR 2508 and RO-03-8799 have been introduced into the clinic. SR 2508 is less neurotoxic than MISO, allowing more than three times the total amount of drug to be administered. Furthermore, based on the analysis of a patient's plasma pharmacokinetic profile, neurotoxicity may be largely avoidable. RO-03-8799 is superior in that it produces a higher sensitizer enhancement ratio than MISO for the same administered dose. Unlike with MISO and SR 2508, the dose of RO-03-8799 that can be administered is limited by acute toxicity with no cumulative toxicity having yet been encountered. The lack of overlapping toxicities of RO-03-8799 and SR 2508 may permit their simultaneous use with radiation thereby further increasing the utility of this class of compounds. Study design has improved and the expected clinical benefit from sensitizers has been clarified. Sensitizers, like particle radiation therapy and hyperthermia will, if successful, effect the rate of local tumor control, but cannot improve the cure rate of patients with preexisting metastatic disease. Taking into account the need to optimize reoxygenation, the various reasons for tumor radioresistance other than hypoxia, and the lower oxygen and sensitizer enhancement ratios at 200 cGy per fraction, it is likely that sensitizers will provide some clinical benefit for patients with selected tumor types. Future trials with sensitizers may not only provide clinical benefit but may help answer the question as to the role of hypoxia in clinical radiotherapy.

Clinical Trials as Topic↗