Dillman Ro

A Randomized Trial of Induction Chemotherapy plus High-Dose Radiation versus Radiation Alone in Stage III Non-Small-Cell Lung Cancer

BACKGROUND For patients with locally or regionally advanced non-small-cell lung cancer radiation is the standard treatment, but survival remains poor. We therefore conducted a randomized trial to determine whether induction chemotherapy before irradiation improves survival. METHODS All the patients had documented non-small-cell cancer of the lung with Stage III disease established by clinical or surgical staging. Eligibility requirements included excellent performance status, minimal weight loss, and visible disease on radiography. Patients randomly assigned to group 1 received cisplatin (100 mg per square meter of body-surface area given intravenously on days 1 and 29) and vinblastine (5 mg per square meter given intravenously on days 1, 8, 15, 22, and 29) and then began radiation therapy on day 50 (60 Gy over a 6-week period). Patients assigned to group 2 received the same radiation therapy but began it immediately and received no chemotherapy. RESULTS The eligible patients in group 1 (n = 78) and group 2 (n = 77) were comparable in terms of age (median, 60 years), sex, performance status, histologic features, stage of disease, and completeness of radiation therapy. The median survival was greater for those in group 1-13.8 versus 9.7 months (P = 0.0066 by log-rank test). Rates of survival in group 1 were 55 percent after one year, 26 percent after two years, and 23 percent after three years, as compared with 40, 13, and 11 percent, respectively, in group 2. Those in group 1 had a higher incidence of serious infections requiring hospitalization (7 percent, vs. 3 percent in group 2) and severe weight loss (14 percent vs. 6 percent), but there were no treatment-related deaths. CONCLUSIONS In patients with Stage III non-small-cell lung cancer, induction chemotherapy with cisplatin and vinblastine before radiation significantly improves median survival (by about four months) and doubles the number of long-term survivors, as compared with radiation therapy alone. Since three quarters of the patients still die within three years, however, further improvements in systemic and local therapy are needed.

Immunoincompetence in cancer patients. Assessment by in vitro stimulation tests and quantification of lymphocyte subpopulations

The authors performed a variety of lymphocyte‐stimulation tests and quantified several lymphocyte subpopulations in 73 healthy controls and 72 patients with advanced cancer who were no longer receiving anticancer therapy. As a group, cancer patients had fewer lymphocytes and helper cells, but a greater proportion of suppressor cells and Ia+ cells than controls. The ratio of helper to suppressor cells was lower in the cancer group. Uptake of 125I‐uridine was markedly depressed in cancer patients in the face of stimulation with various plant lectins, foreign lymphocytes, and varicella—zoster antigen. There was little correlation between any of the stimulation tests and any of the lymphocyte subpopulation proportions or numbers. The two tests that were most frequently abnormally low among the cancer patients were percent lymphocytes and number of helper cells (81% each). The most frequently abnormal functional assay in patients was pokeweed mitogen stimulation (59%). Three separate statistical methods selected the combination of percent lymphocytes, percent Ia+ cells, percent suppressor cells, number of helper cells, and pokeweed mitogen stimulation as being the best predictors of cancer/immunoincompetent status. This study confirms the breadth of immunoincompetence in advanced cancer patients as defined by in vitro techniques. A smaller battery of tests can be useful in monitoring the immune status of such patients, especially during therapy with proposed immune modulators.

Monoclonal antibodies in the treatment of cancer

Potential uses of monoclonal antibodies in anti-cancer treatment include passive serotherapy, radioisotope conjugates, toxin-linked conjugates, and chemotherapy-monoclonal antibody conjugates. The bases for these applications have been founded in research with heterologous antisera, and in some cases with monoclonal antibodies in animal tumor models. Human trials with passive serotherapy have already begun in both hematopoietic and solid tumor malignancies. Promising results have been reported in cutaneous T cell lymphoma with anti-T cell monoclonal antibody, and in nodular lymphoma with anti-idiotype monoclonal antibody. Radioisotope conjugate work appears promising for imaging in both animals and humans, and this work will lay the foundation for possible therapeutic application of radio-immunotherapy. Toxin-linked conjugates are promising in vitro and may have application in autologous bone marrow transplantation. Research with chemotherapy conjugates is also underway. Preliminary results suggest that murine monoclonal antibodies will be well tolerated clinically except in the setting of circulating cells which bear the target antigen, where rapid infusions may be associated with intolerable side effects. In certain diseases, production of endogenous anti-mouse antibodies may also limit application. Advances in the technology for human-human hybridoma production may help solve some of these problems.

Extensive disease small cell carcinoma of the lung. Trial of non‐cross resistant chemotherapy and consolidation radiotherapy

Twenty‐nine patients with extensive disease, small‐cell carcinoma of the lung, were treated with two cycles of intensive combination chemotherapy: HexaVAC (hexamethylmelamine, vincristine, Adriamycin, cyclophosphamide). Responders received prophylactic cranial radiation (2000 rad/10 fractions) and non cross resistant chemotherapy via a schedule of alternating cycles of CMV (cyclophosphamide, methotrexate, VP‐16–213) and AMV (Adriamycin, methotrexate, VP‐16–213). Whenever a complete response was achieved, consolidation radiotherapy was given to the lung primary (4000 rad/20 fractions, split dose) and abdominal metastases (2000 rad/10 fractions) synchronous with CMV therapy. The complete response rate was 14% with HexaVAC, but increased to 38% during CMV/AMV. Total response rate (complete and partial) was 59% and median survival was 42 weeks. Prophylactic brain radiation prevented clinical relapse in the brain in all 14 patients who received it. However, consolidation radiotherapy failed to prevent clinical relapse in the lung and/or liver, and therapeutic brain radiation (3000 rad) failed to prevent relapse in that site. The simultaneous administration of radiotherapy and chemotherapy was well‐tolerated although two patients with poor performance status died of infectious complications while leukopenic. In spite of the high response rate, durable remissions with prolonged disease free survival were rare. Further evaluation of induction, consolidation, and maintenance modes of therapy are indicated.

Alterations of peripheral blood B‐lymphocyte populations in plasma cell disorders

Peripheral blood lymphocytes of patients with multiple myeloma, macroglobulinemia, and monoclonal gammopathy of uncertain significance were analyzed for B cells, and cells bearing λ light chains and λ light chains on their surfaces. Compared with controls, the number of B cells were decreased in all three groups. Contrary to other reports, the authors found a B‐cell depression of similar magnitude in patients with untreated myeloma and in those with apparently benign monoclonal gammopathy. There was no difference between treated and untreated myeloma patients as a group, or as individuals studied before and after treatment. However, in comparison to control patients, alkylator therapy depressed the leukocyte count, lymphocyte count, and B‐cell number both in the myeloma and in the macroglobulinemia groups. All five patients with previously untreated macroglobulinemia had an increased proportion of circulating lymphocytes with surface light chains of the same type as the M protein. Two patients with IgG myeloma‐like disorders had increased circulating B cells with monoclonal surface light chains. This study supports the concepts that normal B cells are depressed in plasma cell disorders, and that abnormal B cells, which are apparently monoclonal, do circulate in some cases. Our results are compared with other published data.

Applications and limitations of peripheral blood lymphocyte immunoglobulin light chain analysis in the evaluation of non-Hodgkin's lymphoma

Surface immunoglobulin (sIg) light chain analysis of peripheral blood lymphocytes (PBL) from 63 patients with non‐Hodgkins lymphoma (NHL) was performed to determine the ratio of k‐bearing lymphocytes to λ‐bearing lymphocytes (k/λ ratio). In 43% an abnormal k/λ ratio was detected, implying the presence of a malignant clone in the peripheral blood (clonal excess). In 67% of cases with an abnormal k/λ ratio, the absolute lymphocyte count was within normal limits and 20% did not have morphologic bone marrow involvement. Light chain analysis of bone marrow aspirates was performed in three of four patients with a circulating clone and normal bone marrow morphology. All three patients had abnormal bone marrow aspirate k/λ ratios. The presence of a circulating clone was associated with morphologic bone marrow involvement (P < 0.05). Nine patients with documented B‐cell NHL were followed with repeated examinations. The presence of a circulating clone persisted in two patients refractory to therapy and in two patients otherwise believed to be in remission. Conversion to an abnormal k/λ ratio occurred in two patients coincident with the development of new bone marrow involvement and in a third patient prior to the onset of frank leukemia. In three instances, the PBL light chain analyses remained within normal limits in patients with stable lymphadenopathy. The k/λ ratio returned to normal in one patient responding to treatment with a partial remission, and remained within normal limits despite progression of lymphadenopathy in one patient, and local disease recurrence in another patient. These findings suggest that the detection of a circulating clone by sIg light chain analysis may be useful as a noninvasive approach to identify disseminated disease activity unsuspected on the basis of morphologic evaluations, but may not reflect the presence, progression, or recurrence of localized tissue lesions. Cancer 56: 2005‐2010, 1985.

Membranous nephropathy associated with an unusual phenotype of chronic lymphocytic leukemia

The nephrotic syndrome is uncommon in patients with chronic lymphocytic leukemia. When present, the most frequently documented cause is membranous nephropathy, although several other glomerular lesions have also been described. This report describes a patient with chronic lymphocytic leukemia of an unusual surface marker phenotype recently suggested to be associated with an increased incidence of proteinuria. Renal biopsy specimens demonstrated membranous glomerulonephritis. Immunofluorescence staining demonstrated glomerular deposition of IgG and C3, but not the human T‐lymphocyte antigen, T65, which had been found on circulating leukemia cells. Cancer 52:2253‐2255, 1983.

Pharmacokinetics of 111In-labelled monoclonal antibody ZCE-025 and fragments in tumour-bearing mice

Radiolabelled anti-tumor antibodies, their fragments and derivatives hold promise for imaging and therapeutics in oncology. A better understanding of the pharmacokinetcs of these entities is therefore important for clinical applications and management. In the present study, the in vivo behaviour of 111Indium-labelled monoclonal anti-CEA antibody ACE-025 and its F(ab’)2 and Fab’ fragments and a Fab‘ derivative are compared in the nude mouse-human tumour model. The object of the derivative was to improve the tumour uptake of the fragment yet reduce its high renal uptake while continuing to achieve desirable kinetics in the normal tissues. Uptake of the derivative in the tumour was comparable to that of the intact antibody and exceeded that of the underivatized fragments. Moreover, uptake in non-target tissues was lower with the derivative than with the intact entity. The renal uptake of the derivative was dramatically lower than for the fragments. The modelling data strongly suggest that the derivatives will be advantageous for clinical use compared with the underivatized whole antibodies or their fragments.

The use of monoclonal antibodies and flow cytometry to detect peripheral blood and bone marrow involvement of a diffuse, poorly differentiated lymphoma

Using monoclonal antibodies and flow cytometry, we were able to characterize the phenotype of a diffuse, poorly differentiated lymphoma and to isolate subpopulations of cells from the blood and bone marrow that expressed the malignant phenotype even though the patient exhibited no absolute lymphocytosis. Because the circulating clone reacted with the anti-T cell monoclonal antibody T101, we initiated serotherapy with T101 as part of a phase I study. A 10 mg infusion of T101 resulted in the rapid clearance of normal T cells from circulation, but the clone showed evidence of modulation and was not cleared. Twenty-four hours following infusion, all cell populations had returned to pre-treatment levels. Our study suggests that, by using monoclonal antibodies and flow cytometry, blood and bone marrow involvement of a lymphoma can be demonstrated in patients without absolute lymphocytosis, a finding which may influence the staging and treatment of the disease.

Results of Early Trials Using Murine Monoclonal Antibodies as Anticancer Therapy

Abstract We have administered murine monoclonal antibodies (MoAbs) in doses of from 1-50 mg, for 1-10 treatments over a one day to four month time period, to 12 patients with chronic lymphocytic leukemia (CLL), cutaneous T cell lymphoma (CTCL), colorectal carcinoma, and melanoma. In leukemias, a decrease in circulating malignant cells was a reproducible effect of therapy, although durable remissions were not seen. In CLL, the tumor associated antigen (TAA) did not modulate during a two hour infusion of antibody, and CLL cells were decreased as long as serum levels of immunoreactive antibody were detectable. On the other hand, in CTCL, modulation was seen, and a decrease in tumor cells was not sustained in the presence of antibody. Patients with both diseases have tolerated 5-10 courses of treatment over four months without significant complication. Endogenous anti-mouse antibodies are believed to have emerged in the patient with CTCL. Therapeutic and diagnostic efforts with an anti-carcinoembryonic antigen (CEA) MoAb have been hampered by reactivity with mature granulocytes. In_ vivo , there was a decrease in circulating neutrophils associated with fever and chills in three patients, but this complication was transient. Immune complexes were formed in this setting as well. Two different anti-melanoma antibodies have been well tolerated, but clinical research with these agents will be greatly enhanced by using radioisotope-conjugated antibodies to assess distribution and clearance of the MoAb.