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Biomedical subjects

C A Seipp

Publications and source records attributed to C A Seipp.

At least 19 recordsLinked to original sources
PubMed1999

Impact of cytokine administration on the generation of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine.

Patients with metastatic melanoma were immunized with an immunodominant peptide derived from the gp100 melanoma-melanocyte differentiation Ag that was modified to increase binding to HLA-A+0201. A total of 10 of 11 patients who received the g209-2M peptide alone developed precursors reactive with the native g209 peptide, compared with only 5 of 16 patients who received g209-2M peptide plus IL-2 (p2 = 0.005). Peptide reactivity closely correlated with the recognition of HLA-A+0201 melanoma cells (p < 0. 001). The decrease in immune reactivity when peptide was administered with IL-2 appeared specific for the immunizing peptide, since reactivity to an influenza peptide resulting from prior exposure was not affected. Preexisting antitumor precursors did not decrease when peptide plus IL-2 was administered. The administration of GM-CSF or IL-12 also resulted in a decrease in circulating precursors compared with the administration of peptide alone, though not as great a decrease as that seen with IL-2. Immunization with peptide plus IL-2 did, however, appear to have clinical impact since 6 of the 16 patients (38%) that received peptide plus IL-2 had objective cancer regressions. It thus appeared possible that immunization with peptide plus IL-2 resulted in sequestering or apoptotic destruction of newly activated immune cells at the tumor site. These represent the first detailed studies of the impact of immunization with tumor peptides in conjunction with a variety of cytokines in patients with metastatic cancer.

Adult↗
PubMed1999

Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b.

PURPOSE: The combination of chemotherapy with immunotherapeutic agents such as interleukin-2 and interferon alfa-2b has been reported to provide improved treatment results in patients with metastatic melanoma, compared with the use of chemotherapy alone. We have performed a prospective randomized trial in patients with metastatic melanoma, comparing treatment with chemotherapy to treatment with chemoimmunotherapy. PATIENTS AND METHODS: One hundred two patients with metastatic melanoma were prospectively randomized to receive chemotherapy composed of tamoxifen, cisplatin, and dacarbazine or this same chemotherapy followed by interferon alfa-2b and interleukin-2. Objective responses, survival, and toxicity in the two groups were evaluated at a median potential follow-up of 42 months. RESULTS: In 52 patients randomized to receive chemotherapy, there were 14 objective responses (27%), including four complete responses. In 50 patients randomized to receive chemoimmunotherapy, there were 22 objective responses (44%) (P2 = .071), including three complete responses. In both treatment groups, the duration of partial responses was often short, and there was a trend toward a survival advantage for patients receiving chemotherapy alone (P2 = .052; median survival of 15.8 months compared with 10.7 months). Treatment-related toxicities were greater in patients receiving chemoimmunotherapy. CONCLUSION: With the treatment regimens used in this study, the addition of immunotherapy to combination chemotherapy increased toxicity but did not increase survival. The use of combination chemoimmunotherapy regimens is not recommended in the absence of well-designed, prospective, randomized protocols showing the benefit of this treatment strategy.

Adolescent↗
PubMed1998

Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens.

BACKGROUND: The characterization of the genes encoding melanoma-associated antigens MART-1 or gp100, recognized by T cells, has opened new possibilities for the development of immunization strategies for patients with metastatic melanoma. With the use of recombinant adenoviruses expressing either MART-1 or gp100 to immunize patients with metastatic melanoma, we evaluated the safety, immunologic, and potential therapeutic aspects of these immunizations. METHODS: In phase I studies, 54 patients received escalating doses (between 10(7) and 10(11) plaque-forming units) of recombinant adenovirus encoding either MART-1 or gp100 melanoma antigen administered either alone or followed by the administration of interleukin 2 (IL-2). The immunologic impact of these immunizations on the development of cellular and antibody reactivity was assayed. RESULTS: Recombinant adenoviruses expressing MART-1 or gp100 were safely administered. One of 16 patients with metastatic melanoma receiving the recombinant adenovirus MART-1 alone experienced a complete response. Other patients achieved objective responses, but they had received IL-2 along with an adenovirus, and their responses could be attributed to the cytokine. Immunologic assays showed no consistent immunization to the MART-1 or gp100 transgenes expressed by the recombinant adenoviruses. High levels of neutralizing antibody were found in the pretreatment sera of the patients. CONCLUSIONS: High doses of recombinant adenoviruses could be safely administered to cancer patients. High levels of neutralizing antibody present in patients' sera prior to treatment may have impaired the ability of these viruses to immunize patients against melanoma antigens.

Adenoviridae↗
PubMed1998

Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma.

The cloning of the genes encoding cancer antigens has opened new possibilities for the treatment of patients with cancer. In this study, immunodominant peptides from the gp100 melanoma-associated antigen were identified, and a synthetic peptide, designed to increase binding to HLA-A2 molecules, was used as a cancer vaccine to treat patients with metastatic melanoma. On the basis of immunologic assays, 91% of patients could be successfully immunized with this synthetic peptide, and 13 of 31 patients (42%) receiving the peptide vaccine plus IL-2 had objective cancer responses, and four additional patients had mixed or minor responses. Synthetic peptide vaccines based on the genes encoding cancer antigens hold promise for the development of novel cancer immunotherapies.

Adult↗
PubMed1995

The use of polyethylene glycol-modified interleukin-2 (PEG-IL-2) in the treatment of patients with metastatic renal cell carcinoma and melanoma. A phase I study and a randomized prospective study comparing IL-2 alone versus IL-2 combined with PEG-IL-2.

BACKGROUND: Conjugation of polyethylene glycol to recombinant human interleukin-2 (IL-2) results in a compound, polyethylene glycol-modified IL-2 (PEG-IL-2) that retains the in vitro and in vivo activity of IL-2, but exhibits a markedly prolonged circulating half-life. In mice, one dose of PEG-IL-2 results in tumor regression comparable to that achieved with multiple bolus doses of IL-2. Based on these preclinical studies, a Phase I study with PEG-IL-2 was undertaken in patients with metastatic renal cell carcinoma (RCC) and melanoma. Then, to exploit the higher peak levels attained with IL-2 and the improved trough levels of PEG-IL-2, a combination regimen beginning with bolus IL-2 followed by low dose maintenance PEG-IL-2 was devised and tested for efficacy. METHODS: Patients with measurable metastatic melanoma or RCC were entered in a Phase I dose escalation trial of PEG-IL-2 given once a week by intravenous bolus. This trial then was repeated using a twice-a-week schedule. After determining the maximum tolerated dose (MTD) and a safe outpatient regimen for PEG-IL-2, a hybrid regimen combining an initial high dose IL-2 cycle followed by chronic maintenance with weekly PEG-IL-2 was devised. This regimen was compared with a standard regimen consisting of two cycles of high dose unconjugated IL-2 in a randomized prospective clinical trial. RESULTS: When given by intravenous bolus once a week, the MTD of PEG-IL-2 was 12 million IU/m2, with toxicities similar to those of unconjugated IL-2. A twice-a-week schedule was less well tolerated. Of 28 patients given 32 treatment courses at varied dose levels, there were two partial responses and one minor response. A total of 124 patients with metastatic melanoma or RCC were randomized to either standard unconjugated IL-2 therapy or the hybrid regimen. There was no treatment-related mortality in either arm, and the use of PEG-IL-2 resulted in a significant decrease in the need for intensive-care-unit care. The response rates (partial response and complete response) for patients with RCC and melanoma were 19% and 15%, respectively, for IL-2 alone and 17% and 11%, respectively, for the IL-2 and PEG-IL-2 combination. CONCLUSIONS: The combination of high dose IL-2 followed by PEG-IL-2 is a well tolerated regimen with significant activity against RCC and melanoma, but it shows no significant increase in antitumor activity compared with high dose IL-2 alone.

Adult↗
PubMed1995

The hematologic toxicity of interleukin-2 in patients with metastatic melanoma and renal cell carcinoma.

BACKGROUND: High dose interleukin-2 (IL-2) has been found to produce durable antitumor responses in some patients, benefiting most greatly those patients with melanoma and renal cell carcinoma. In this paper, the hematologic toxicity and changes resulting from high dose IL-2 alone administered by intravenous bolus are discussed. METHODS: One hundred ninety-nine consecutive patients treated with high dose IL-2 alone from January 1, 1988 to December 31, 1992 were included in this study. All patients had a diagnosis of metastatic melanoma or metastatic renal cell carcinoma and were treated at the National Cancer Institute (Bethesda, MD). RESULTS: Anemia, requiring erythrocyte transfusions, occurred in 14% of all treatment courses, with a median of two units of erythrocytes transfused. Severe leukopenia ( < 1,000 leukocytes/mm3) was rare (1.5% of all patients) and was not associated with any infectious complications. Severe thrombocytopenia ( < 30,000 platelets/mm3) occurred in 2.2% of all treatment cycles, with two patients experiencing a grade 3 hemorrhage, defined as gross blood loss, and one patient experiencing a grade 4 hemorrhage, defined as a debilitating blood loss. Defects in the coagulation pathway were common: abnormal partial thromboplastin time and prothrombin time values occurred in 64% and 25% of the treatment cycles, respectively. In addition, a mean clearance of 93% of lymphocytes from the peripheral blood was observed within 24 hours after initiating IL-2 therapy. This was followed by rebound lymphocytosis to a mean of 198% of baseline on posttreatment Day 4. There were no treatment-related deaths. CONCLUSIONS: During IL-2 therapy, adverse sequelae of anemia, thrombocytopenia, coagulopathy, and leukopenia were usually mild, transient and rarely limited therapy. A profound decrease in lymphocytes in the peripheral circulation occurred within 24 hours after initiating therapy, with a rebound occurring after stopping IL-2. No specific hematologic parameter was associated significantly with a patient's increased probability of responding to therapy.

Adolescent↗
PubMed1994

Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2.

BACKGROUND: Studies of human tumor-infiltrating lymphocytes (TILs) derived from patients with a variety of histologic types of cancer have demonstrated that cellular immune reactions against established malignancy exist in humans. PURPOSE: We report the results of using autologous TILs plus high-dose bolus interleukin 2 (IL-2), with or without the concomitant administration of cyclophosphamide, in the treatment of 86 consecutive patients with metastatic melanoma. METHODS: From May 1987 through December 1992, 86 patients (38 female and 48 male) with metastatic melanoma were treated (145 courses) with autologous TILs plus high-dose intravenous bolus IL-2 (720,000 IU/kg every 8 hours). TILs plus IL-2 were administered in two cycles separated by approximately 2 weeks. Two treatment cycles constituted one treatment course. Patients received a maximum of 15 doses of IL-2 per cycle given every 8 hours until grade 3 or 4 toxicity was reached that could not easily be reversed by standard supportive measures. All patients received concomitant medications to abrogate some of the side effects of IL-2 administration: acetaminophen (650 mg every 4 hours), indomethacin (50 mg every 8 hours), and ranitidine (150 mg every 12 hours). Fifty-seven of the 86 patients received a single intravenous dose of 25 mg/kg cyclophosphamide approximately 36 hours before receiving the first intravenous infusion of TILs plus IL-2. Six weeks after treatment, all known sites of disease were evaluated. RESULTS: The overall objective response rate in these patients was 34% and was similar in patients receiving TILs and IL-2 alone (31%) or in conjunction with cyclophosphamide (35%). There was no significant difference in the objective response rate in patients whose therapy with high-dose IL-2 had failed (32%) compared with patients not previously treated with IL-2 (34%). The frequency of response to treatment was greater in those patients who were treated with TILs from younger cultures (P = .0001), TILs with shorter doubling times (P = .03), and TILs that exhibited higher lysis against autologous tumor targets (P = .0008). Patients who received TILs generated from subcutaneous tumor deposits had higher response rates (49%) compared with those receiving TILs from lymph nodes (17%; P = .006). There was one treatment-related death due to respiratory insufficiency. CONCLUSIONS: Treatment with TILs and IL-2 with or without cyclophosphamide can result in objective responses in about one third of patients with metastatic melanoma. The side effects of treatment are transient in most patients, and this treatment can be safely administered. These results illustrate the potential value of immune lymphocytes for the treatment of patients with melanoma.

Adolescent↗
PubMed1993

Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer.

BACKGROUND: Treatment using interleukin-2 (IL-2) alone or in conjunction with lymphokine-activated killer (LAK) cells has been shown to mediate disease regression in selected patients with advanced cancer. PURPOSE: This prospective randomized trial was designed to determine whether the administration of LAK cells in conjunction with high-dose IL-2 alters response and survival rates, compared with those for IL-2 alone, in patients with advanced cancer. METHODS: The 181 patients who had metastatic cancer that had failed to respond to standard therapy or who had disease for which no effective therapy existed received treatment with high-dose IL-2 alone or with LAK cells plus IL-2. Both treatment groups were to receive the same dose of IL-2 administered according to the same schedule. IL-2 doses were omitted depending on the tolerance of the patient. Of the 181 patients, 97 had renal cell cancer and 54 had melanoma. RESULTS: Median potential follow-up was 63.2 months. There were 10 complete responses among the 85 assessable patients who received IL-2 plus LAK cells, compared with four among the 79 who received IL-2 alone. There were 14 and 12 partial responses, respectively. Complete response continues in seven patients at 50-66 months. The 36-month actuarial survival with IL-2 plus LAK cells was 31%, compared with 17% with IL-2 alone (two-sided P value [P2] = .089). A trend toward improved survival was seen for patients with melanoma who received IL-2 plus LAK cells, compared with those who received IL-2 alone (24-month survival: 32% versus 15%; 48-month survival: 18% versus 4%; P2 = .064 [corrected]). None of 26 patients with melanoma who received IL-2 alone are alive; five of 28 who received IL-2 plus LAK cells are alive, and three continue in complete response. No difference in survival was seen in patients with renal cell cancer in the two treatment groups. There were six treatment-related deaths (3.3%); three were due to myocardial infarction. Other toxic effects resolved by discontinuation of IL-2. Many toxic effects were related to increased vascular permeability induced by IL-2. CONCLUSIONS: Some patients with metastatic cancer have prolonged remission when they are treated with high-dose IL-2 alone or in conjunction with LAK cells. Our results suggest a trend toward increased survival when IL-2 is given with LAK cells in patients with melanoma, but no trend was observed for patients with renal cell cancer. IMPLICATIONS: As these studies continue, efforts are underway to develop improved immunotherapies using tumor-infiltrating lymphocytes (TIL) and gene-modified TIL.

Adolescent↗
PubMed1989

Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients.

We have administered 1039 courses of high-dose interleukin-2 (IL-2) to 652 cancer patients. Five hundred ninety-six patients had metastatic cancer that either had failed standard effective therapies or had disease for which no standard effective therapy existed, and 56 patients were treated in the absence of evaluable disease in the adjuvant setting. IL-2 was administered either alone (155 patients) or in conjunction with activated immune cells such as lymphokine activated killer (LAK) cells (214 patients) or tumor infiltrating lymphocytes (TIL) (66 patients), with other cytokines such as alpha interferon (a-IFN)(128 patients) or tumor necrosis factor (TNF)(38 patients), with monoclonal antibodies (32 patients), or with the chemotherapeutic agent cyclophosphamide (19 patients). Initial results with the treatment of high-dose IL-2 alone or in conjunction with LAK cells have indicated that objective regressions of cancer can be achieved in 20% to 35% of patients with selected advanced metastatic cancers. Although most responses have been seen in patients with metastatic renal cell cancer, melanoma, colorectal cancer, and non-Hodgkin's lymphoma, many histologic types of cancer have not been treated in significant numbers. These regressions can be durable; of 18 patients achieving a complete response, ten have not experienced recurrence at intervals from 18 to 52 months. Although combinations of IL-2 with TNF do not appear to result in increased responses, there is a suggestion in our initial phase I studies that the combination of a-IFN and IL-2 is more effective than the administration of cytokine alone and this combination deserves further study. Similarly the adoptive transfer of TIL in conjunction with IL-2 also appears to be more effective than the use of IL-2 alone. The toxic side effects in patients treated with high-dose IL-2 are presented and include malaise, nausea and vomiting, hypotension, fluid retention, and organ dysfunction. Treatment-related deaths were seen in 1% of all treatment courses and in 1.5% of patients. These studies demonstrate that a purely immunologic manipulation can mediate the regression of advanced cancers in selected patients and may provide a base for the development of practical, effective biologic treatments for some cancer patients.

Adolescent↗
PubMed1988

Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report.

Lymphocytes extracted from freshly resected melanomas can be expanded in vitro and can often mediate specific lysis of autologous tumor cells but not allogeneic tumor or autologous normal cells. We treated 20 patients with metastatic melanoma by means of adoptive transfer of these tumor-infiltrating lymphocytes and interleukin-2, after the patients had received a single intravenous dose of cyclophosphamide. Objective regression of the cancer was observed in 9 of 15 patients (60 percent) who had not previously been treated with interleukin-2 and in 2 of 5 patients (40 percent) in whom previous therapy with interleukin-2 had failed. Regression of cancer occurred in the lungs, liver, bone, skin, and subcutaneous sites and lasted from 2 to more than 13 months. Toxic effects of interleukin-2 occurred, although the treatment course was short (five days); these side effects were reversible. It appears that in patients with metastatic melanoma, this experimental treatment regimen can produce higher response rates than those achieved with interleukin-2 administered alone or with lymphokine-activated killer cells. It is too early to determine whether this new form of immunotherapy can improve survival, but further trials seem warranted.

Adult↗
PubMed1988

Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study.

Clinical investigations using the adoptive transfer of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) to treat patients with advanced cancer have yielded encouraging results. We have thus sought ways to enhance the effectiveness of adoptive immunotherapy while minimizing its toxic side effects. Murine experiments have identified tumor-infiltrating lymphocytes (TIL) as killer cells more effective than LAK cells and less dependent on adjunctive systemically administered IL-2 to mediate antitumor effects. Accordingly, we performed a pilot protocol to investigate the feasibility and practicality of administering IL-2-expanded TIL to humans with metastatic cancers. Twelve patients, including six with melanoma, four with renal cell carcinoma, one with breast carcinoma, and one with colon carcinoma, were treated with varying doses and combinations of TIL (8.0 X 10(9) to 2.3 X 10(11) cells per patient), IL-2 (10,000 to 100,000 U/kg three times daily to dose-limiting toxicity), and cyclophosphamide (CPM) (up to 50 mg/kg). Two partial responses (PR) to therapy were observed: pulmonary and mediastinal masses regressed in a patient with melanoma, and a lymph node mass regressed in a patient with renal cell carcinoma. One additional patient with breast cancer experienced a partial regression of disease in lymph nodal and cutaneous sites with complete elimination of malignant cells from a pleural effusion, although cutaneous disease recurred at 4 weeks. The toxicities of therapy were similar to those ascribed to IL-2; no toxic effects were directly attributable to TIL infusions. In five of six melanoma patients, TIL demonstrated lytic activity specific for the autologous tumor target in short-term chromium-release assays, distinct from the nonspecific lytic activity characteristic of LAK cells. This study represents an initial attempt to identify and use lymphocyte subsets with enhanced tumoricidal capacity in the adoptive immunotherapy of human malignancies.

Adult↗
PubMed1987

The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells.

STUDY OBJECTIVE: To study the neuropsychiatric manifestations of therapy with interleukin-2 and lymphokine-activated killer cells. DESIGN: Longitudinal survey of consecutive patients who were given the treatment. Each patient was initially interviewed within 5 days before treatment, and a personal and family psychiatric history was obtained during this first session. Cognitive tests and mood self-rating instruments were administered at the beginning and end of interleukin-2 and lymphokine-activated killer cell treatments, before discharge, and at a follow-up visit 2 to 4 weeks after discharge. SETTING: National Cancer Institute inpatient units at the National Institutes of Health. PATIENTS OR OTHER PARTICIPANTS: Sequential samples of 44 patients with metastatic cancer (age range, 28 to 69 years) who were treated systemically with recombinant interleukin-2 combined with autologous lymphokine-activated killer cells between 30 December 1985 and 31 March 1986. MEASUREMENTS AND MAIN RESULTS: Of the 44 patients studied, 15 developed severe behavioral changes that necessitated acute intervention, and 22 patients had severe cognitive changes (all 22 became disoriented and many also had psychometric evidence of cognitive deterioration). The neuropsychiatric side effects were dose and time related, appearing more frequently at the higher dose and almost uniformly at the end of each treatment phase. All 39 patients who were seen at follow-up had a return to their baseline cognitive scores. None of the factors investigated was found to be predictive of the development of neuropsychiatric toxicity. CONCLUSIONS: The development of clinically significant neuropsychiatric changes during the administration of interleukin-2 and lymphokine-activated killer cells was common and may be treatment limiting. A marked latency in the appearance of neuropsychiatric changes after treatment onset was noted in almost all patients. Every patient studied recovered from the neuropsychiatric side effects.

Adult↗
PubMed1987

Limb-sparing surgery for soft tissue sarcomas: wound related morbidity in patients undergoing wide local excision.

When feasible, limb-sparing surgery has become an accepted form of treatment for sarcoma of the extremities. In a review of 100 consecutive cases of local excisions in patients with soft tissue sarcomas, which were performed at the National Cancer Institute, we identified factors associated with the development of wound-related morbidity. The incidence of these wound complications, which include infection, seromas, and skin loss, was 34.4%. Serious complications that necessitated rehospitalization or reoperation occurred in fewer than 10% of the patients. Preoperative factors associated with wound morbidity were patient age greater than 40 years (P2 less than 0.029) and tumor in the lower extremity (P2 less than 0.014). Treatment-related factors associated with morbidity were increased blood loss (p less than 0.01) and an increased volume (p less than 0.006) and duration (p less than 0.002) of wound drainage. The complications significantly delayed the start of adjuvant radiation therapy and lengthened the hospital stay. Measures to prevent these complications are discussed.

Adolescent↗
PubMed1986

Clinical effects and toxicity of interleukin-2 in patients with cancer.

Interleukin-2 (IL-2) is a 15,000 dalton glycoprotein produced naturally by human T-cells during an immune response. IL-2 has been demonstrated to have substantial activity alone or in combination with the adoptive transfer of lymphokine-activated killer cells in murine tumor models. IL-2 derived from both natural (Jurkat human T-cell tumor) and recombinant (Escherichia coli) sources has been studied in Phase I protocols designed to evaluate toxicity in patients with a variety of solid tumors and to ascertain improvement in clinical parameters and immunologic status. A total of 16 patients (7 with acquired immune deficiency syndrome [AIDS] and 9 with non-AIDS malignancies) were treated with Jurkat derived IL-2. The total maximum dose (1.3 X 10(5) U/kg) was limited only by supply of this reagent. A total of 25 patients have been treated with recombinant IL-2 (RIL-2) alone. Dose-limiting toxicity manifested by marked malaise and weight gain was achieved with doses of RIL-2 of 10(6) U/kg as a single bolus or 3000 U/kg/hr. IL-2 could be administered intraperitoneally with similar toxicity. Minimal renal or hepatic toxicity was demonstrated. Hematologic toxicity was limited to mild anemia (25/25), thrombocytopenia (10/25), and marked reversible eosinophilia (15/25). Pronounced weight gain greater than 2 kg (16/25) occurred in most patients, primarily those who received cumulative doses of greater than 1-3 X 10(5) U/kg of IL-2. The weight gain amounted to as much as 10% to 20% of the pretreatment weight over 3 weeks of treatment and limited our ability to give higher doses. Two partial responses (greater than 50% decrease in cross sectional diameters) were seen in two patients with melanoma metastatic to the lung.

Acquired Immunodeficiency Syndrome↗
PubMed1986

High-dose recombinant interleukin 2 in the treatment of patients with disseminated cancer. Responses, treatment-related morbidity, and histologic findings.

Experience with the administration of high doses of interleukin 2 (IL-2) alone is described herein. Ten patients with a variety of malignant disorders unresponsive to conventional treatments were treated with at least 30,000 U/kg of IL-2 by bolus administration three times a day. Patients were treated intravenously or intraperitoneally from four to 21 days in a single course, usually interrupted by a week of recovery. Three of six patients with melanoma experienced an objective regression (greater than 50% decrease in volume); there was no response to treatment in patients with colorectal (0/3) or ovarian (0/1) cancer. Two patients with initial objective regressions who subsequently developed progression were re-treated and one sustained a second partial response. Responses lasted 1, 3, and 7 months without additional treatment. Responses in the three patients with melanoma were in visceral sites (lung, liver, and spleen), as well as cutaneous sites in one patient. Progressive shrinkage of tumors for three to six months after the conclusion of therapy has been noted in two patients. Marked lymphocytic infiltrate was noted in a patient with lesions accessible to repeated biopsies. This study demonstrates that the administration of IL-2 can mediate the regression of established cancer in some patients.

Adolescent↗
PubMed1986

High-grade soft tissue sarcomas of the extremities.

From July 1975 to December 1982, 358 patients were referred to the Surgery Branch of the National Cancer Institute (NCI) with the diagnosis of soft tissue sarcoma of the extremities. Two hundred eleven of these patients presented with resectable, localized high-grade soft-tissue sarcomas and have been included in the present analysis of the management and outcome of patients with high-grade soft tissue sarcomas of the extremity treated at the NCI. One hundred forty-seven of these 211 patients have been included in randomized prospective trials. The remaining 64 patients in this analysis have been followed at the NCI, but were not included in randomized trials because of patient refusal or ineligibility. Tumor size was identified as a highly significant prognostic variable for disease-free and overall survival (P2 = 0.00001 and 0.0081, respectively). Tumor site, histologic type, and microscopic margins of resection were not significant prognostic variables. There was no difference between patients undergoing amputation compared to those undergoing limb-sparing procedures plus postoperative radiotherapy in disease-free or overall survival for all 211 patients in this study (P2 = 0.068 and 0.131, respectively). A significantly greater frequency of local failure among patients treated by local excision was noted compared to patients undergoing amputation (12/128 versus 0/83, P2 = 0.004), but this did not result in decreased overall survival in patients undergoing combined modality limb-sparing procedures. Adjuvant chemotherapy significantly prolonged disease-free survival (P2 = 0.005) for the 124/211 patients treated with adjuvant chemotherapy, although analysis of overall survival did not reveal a significant increase (P2 = 0.10). In a subset of 65 patients included in a prospective randomized trial evaluating the efficacy of adjuvant chemotherapy, a significant improvement in both disease-free (P2 = 0.033) and overall (P2 = 0.055) survival was seen in patients receiving chemotherapy. Sixty-five patients developed recurrent disease (65/211, 31%) and 42 of these patients were rendered disease-free surgically. Survival from the time of first recurrence was significantly prolonged among the 42 patients who were rendered disease-free (median survival, 31 months) compared to those who were not (median survival, 9 months, P2 less than 0.001).

Actuarial Analysis↗
PubMed1986

Prospective study of cardiomyopathy induced by adjuvant doxorubicin therapy in patients with soft-tissue sarcomas.

Since a combination of surgery and adjuvant high-dose doxorubicin therapy can prolong survival in patients with extremity sarcomas, but at the expense of significant cardiomyopathic changes, we prospectively studied the differences in cardiotoxicity in 118 patients with sarcomas treated with high- vs low-dose doxorubicin therapy following surgery. Cardiac function, as assessed by left ventricular ejection fraction (EF), was determined by standard radionuclide angiography during rest and exercise. No patients in this study developed congestive heart failure. While both regimens produced net decreases in EF during rest and exercise, the high-dose doxorubicin regimen resulted in significantly greater declines in EF than the low-dose protocol. Of patients with normal baseline values, a greater percentage of patients receiving the high-dose regimen developed an abnormal EF than did those receiving the low-dose regimen, even after separating younger from older individuals. Thus, treatment-induced cardiomyopathy appears to be a significant clinical problem after both high- and low-dose doxorubicin therapy. The use of the low-dose regimen decreases the magnitude of the cardiomyopathic changes.

Adult↗