PURPOSE:It is recommended that patients with breast cancer who present with mammographically detected microcalcification should undergo postlumpectomy mammogram with magnification views to ensure adequate removal of all clinically demonstrable disease. The value of postlumpectomy mammogram has not been adequately examined in the literature. This report aims to quantify the value of such a study.MATERIALS AND METHODS:Retrospective review identified 90 breast cancer patients referred to our department between 1992 and 1997 who met all of the following criteria: (1) patients were considered for breast conserving management; (2) patients had suspicious microcalcifications on diagnostic mammograms; (3) the mammographic lesions were thought to be removed entirely on postexcision specimen radiographs; (4) surgical excisions were thought to be adequate on the basis of a review of the histologic pathology reports; and (5) postlumpectomy mammograms with magnification views were obtained. Fifty patients had invasive adenocarcinoma and 40 patients had ductal carcinoma in situ. The margins of last resection were clear, close, or focally involved in 70, 13, and seven patients, respectively. Patient records were reviewed to determine whether postlumpectomy mammograms demonstrated residual microcalcifications.RESULTS:Sixteen patients (17%) were found to have residual microcalcifications on postlumpectomy mammograms. Twelve patients underwent either local re-excision (seven patients) or simple mastectomy (five patients). Re-excision was not performed in four patients. Residual malignant cells were found in eight patients (67% of the re-excision group and 9% of the whole group). Six of these patients had their tumors initially resected with clear margins and the remaining two patients had their tumors initially resected with close margins.CONCLUSIONS:Postlumpectomy mammograms with magnification views detected residual clinical disease in a significant proportion of patients. Our result supports the routine use of this test, even when satisfactory postexcision specimen radiographs and adequate lumpectomy resection margins are obtained. This finding is particularly true for patients with ductal carcinoma in situ.
The measurement of the effect of cisplatin on DNA has become feasible with the development of antibodies against DNA adducts. In a phase II dose escalation trial with concomitant radiotherapy and daily cisplatin in lung cancer, we found that patients with high DNA adduct levels measured in the buccal mucosa had a much higher survival rate than patients with a low or undetectable amount of cisplatin-DNA adducts. The use of this assay may therefore allow the selection of individual patients for concomitant treatment with cisplatin and radiotherapy, as has been shown to be effective in randomized trials in patients with lung, head and neck, and cervix malignancies. To predict the response to radiation treatment, assays have been developed for tumor growth potential by measuring the labeling index after intravenous injection of IdUrd or by estimating cyclin D1 expression. Intrinsic radiation sensitivity of human tumors can be estimated by conventional techniques, which are probably too slow or cumbersome for routine use, or with more rapid assays, such as those for chromosome damage with fluorescent probes. These assays should be able to guide us in the adaptation of the individual radiation doses that should be applied and to select patients for an accelerated or hyperfractionated regimen. Pretreatment levels of apoptosis may also be helpful in predicting treatment outcome, although the data so far show inconsistent results. A better understanding of the signal transduction pathways involved in radiation-induced apoptosis may help in the design of studies aimed at modulating the apoptotic response, thereby increasing cell kill. We have recently shown that alkyllysophospholipids, which inhibit mitogenic signaling, induce apoptosis in a variety of tumor cell lines. In combination with ionizing radiation, these compounds cause an enhancement of apoptotic cell kill. This type of a signaling-based intervention could form the basis for new therapeutic strategies. The role of hormonal therapy in breast cancer patients, both in an adjuvant setting and for the treatment of disseminated disease, is becoming increasingly important. The development of a functional assay for the estrogen receptor (ER-FASAY), based on a yeast growth assay, provides a better way than the classical immunohistochemistry assay of estimating abnormal function of the receptor in tumors. These assays are simply examples, illustrating how clinicians could improve the therapeutic outcome for their patients by implementing knowledge obtained in the laboratory in clinical decision making. With further optimization of these assays, this holds the promise for the future that the treatment for each patient can be tailored rationally to the biology of the individual.
PURPOSE:The development of an effective antitumor immune response is compromised in patients with renal cell carcinoma. Despite significant infiltration by T lymphocytes into renal tumors, no detectable induction of gene expression is associated with the generation of an antitumor immune response. Tumor-induced down-regulation of interleukin (IL)-2 expression may contribute to the impaired development of the T cell-mediated antitumor immune response. Within renal tumors, there is no detectable expression of IL-2 or the IL-2 receptor alpha chain, and only low levels of interferon gamma (IFN-gamma) mRNA are detected. Products in the tumor environment may suppress the expression of these genes, thus inhibiting production of type 1 helper T cell cytokines.METHODS:Peripheral blood lymphocytes obtained from healthy volunteers were exposed to supernatants from renal cell carcinoma explants, and the immunologic consequences of this were assessed using a variety of molecular assays.RESULTS:Soluble products from renal tumor explants can inhibit the production of IL-2 and IFN-gamma by peripheral blood lymphocytes and can suppress T-cell proliferation. Soluble products from renal cell carcinoma explants appear to block the nuclear translocation of nuclear factor kappa B (NFkappaB) proteins p50 and RelA without affecting cytoplasmic levels of these proteins. In some experiments, a reduction in the nuclear translocation of other transcription factors involved in IL-2 gene expression, including nuclear factor of activated T cells and accessory protein-1, was observed. Gangliosides isolated from tumor supernatants blocked the production of IL-2 and IFN-gamma in response to ionomycin plus phorbol myristate acetate stimulation. These gangliosides also inhibited stimulus-dependent activation and nuclear accumulation of NFkappaB. Coculture experiments demonstrated that renal cell carcinoma lines known to express gangliosides could inhibit the activation of NFkappaB in normal T cells and the Jurkat T-cell line. Supernatants from renal cell carcinoma explants and renal cell carcinoma cell lines can also suppress the proliferation of normal T cells, thus reproducing another defect observed in tumor-infiltrating lymphocytes. Supernatants from renal cell carcinoma tumors also appear to inhibit signaling through the IL-2 receptor. Although tumor supernatants had little effect on IL-2 receptor (alpha, beta or gamma) expression, they did block expression of JAK3, a key kinase involved in signaling through the IL-2 receptor pathway. Moreover, downstream events in IL-2 receptor signaling linked to JAK3 were impaired in T cells treated with tumor supernatants.CONCLUSION:These findings suggest that soluble products from renal tumors may suppress T-cell responses by blocking both IL-2 production and normal IL-2 receptor signaling.
PURPOSE:Recent randomized controlled trials have shown that tamoxifen and raloxifene may prevent invasive breast cancer. This decision analysis study compares the outcomes of chemoprevention with tamoxifen, raloxifene, or oral contraceptives with the outcomes of prophylactic surgery among women with high-risk BRCA1/2 mutations.PATIENTS AND METHODS:We used a simulated cohort of 30-year-old women who tested positive for BRCA1/2 mutations and constructed a Markov model with Monte Carlo simulations, incorporating cumulative breast and ovarian cancer incidence rates from the literature and survival figures from SEER data. We assumed that prophylactic surgery reduces ovarian cancer risk by 45% and breast cancer risk by 90%, that tamoxifen reduces invasive breast cancer risk by 49%, and that raloxifene has similar efficacy and safety in premenopausal and postmenopausal women. We used data obtained from high-risk women by a time trade-off questionnaire to calculate quality-adjusted life-years. We based our cost estimates for hospital and ambulatory care on Health Care Financing Administration payments, the SEER-HCFA database, and the Pharmacy Fundamental Reference.RESULTS:In our model, a 30-year-old BRCA1/2+ woman could prolong survival by 0.9 years (95% probability interval, 0.4-1.2 years) by having bilateral oophorectomy, 3.4 years (2.7-3.7 years) by having bilateral mastectomy, and 4.3 years (3.6-4.6 years) by having both procedures instead of surveillance alone. Chemoprevention with tamoxifen and raloxifene increased survival by 1.6 years (1.0-2.1 years) and 2.2 years (1.3-2.8 years), respectively. Chemoprevention yielded more quality-adjusted life-years than did prophylactic surgery, even when treatment was delayed to age 40 or 50 years. All these procedures were cost-effective or cost-saving compared with surveillance alone.DISCUSSION:Our model suggests that although surgery may yield more substantial survival and cost benefits, quality of life issues may make chemoprevention a more attractive option for young women at high genetic risk.
PURPOSE:The drastic increase in the incidence of non-Hodgkin's lymphoma in patients infected with HIV-1 is testimony to the fact that our immune system is critical for the prevention of certain malignancies. Preclinical and clinical studies were conducted to (1) gain further insight into defects in immunity that can lead to malignant transformation and (2) determine if certain immune deficiencies could be corrected by cytokines delivered at doses that result in near-physiologic concentrations in vivo.METHODS:We have used the severe combined immune deficient mouse engrafted with human peripheral blood leukocytes from healthy individuals who are seropositive for the Epstein-Barr virus to study the spontaneous development of malignant Epstein-Barr virus-positive human B-cell lymphoproliferative disorder.RESULTS:We have demonstrated in this model that, in the absence of CD4+ T cells, cytokine replacement with low-dose interleukin (IL)-2 therapy can prevent Epstein-Barr virus-positive human B-cell lymphoproliferative disorder by interacting with mouse natural killer and human CD8+ T cells. We review our clinical experience with administration of low-dose IL-2 therapy in patients with HIV-1-related cancer, noting minimal toxicity and significant immune modulation. We provide evidence that this therapy can favorably alter the type 1 cytokine profile in vivo in these patients, and improve the cellular response to infectious insults in vitro.CONCLUSION:Early clinical studies with low-dose IL-2 therapy in patients with HIV-1-related lymphoma suggest that this therapy may have a role in the prevention and treatment of this disease.
PURPOSEThe purpose of this study was to explore the effect of concurrent intra-arterial infusion of platinum drugs in patients with stage III or IV uterine cervical cancer treated with radical radiation therapy.PATIENTS AND METHODSThirty-three patients with advanced (stage IIIA, 2; IIIB, 28; IVA, 3) uterine cervical squamous cell carcinoma were randomized into a concurrent intra-arterial infusion of platinum drugs with radiation therapy (IAPRT) group (18 patients) and a radiation therapy alone group (15 patients). After altering intrapelvic blood flow by embolization of the superior and inferior gluteal arteries under pelvic angiography, intra-arterial infusion of platinum drug through catheters inserted into both internal iliac arteries was performed concurrently with radiation therapy. One-shot infusion of cisplatin (100 mg/m2) twice with a 2- to 3-week interval was performed in eight patients, weekly infusion of carboplatin (100 mg/m2) via a reservoir five to six times was performed in four patients, and daily shot of cisplatin (10 mg/body) or 21 days via a reservoir was performed in six patients. Radiation therapy consisted of external-beam irradiation of 50 Gy/25 fractions/5 weeks for the whole pelvis with midline block after 30 Gy and intracavitary high-dose-rate brachytherapy using tandem and ovoids of 24 Gy/4 fractions/4 weeks to point A.RESULTSThe local complete response rate of the IAPRT group was 94% and was significantly higher than that of the radiation therapy group (67%). There were no significant differences in local response in the three drug delivery methods. Two- and 5-year overall survival rates were 54.5% and 44.4% in the IAPRT group, and 74.5% and 50.0% in the radiation therapy group, respectively. There was no significant difference between the two groups. In the IAPRT group, grade 3 or 4 acute bowel complications were seen in 33% of patients, grade 3 or 4 late bowel complications were seen 44%, and grade 3 or 4 myelosuppression was seen in 33%, and these complications were seen more in the IAPRT group than in the radiation therapy group and caused death in some patients.CONCLUSIONSIAPRT had a better local response than radiation therapy but showed no proof of control over recurrence and had a poorer survival than radiation therapy. There were many local recurrences and distant metastases, contrary to the better first response of the IAPRT group over the radiation therapy group. Complications of the IAPRT group were very severe and made the patient's performance status and prognosis worse than in the radiation therapy group. We need to design some methods to decrease these complications to make use of the good local response acquired with IAPRT. Furthermore, we should re-examine the indication of IAPRT in patients with a large tumor because local recurrence and distant metastasis would be inevitable.
PURPOSE:The median survival for patients with metastatic renal cell carcinoma (mRCC) is generally < 1 year. Immunotherapy with high-dose recombinant interleukin (IL)-2 has been reported to produce objective responses in approximately 15% of treated patients and is associated with durable complete responses and prolonged survival in responding patients. The impact of IL-2 therapy on survival of metastatic renal cell carcinoma patients has begun to emerge, based on long-term follow-up data from large databases. Combinations of IL-2 and interferon alfa (IFN-alpha) have also been intensively investigated in mRCC.PATIENTS AND METHODS:Between 1987 and 1990, 281 mRCC patients were treated with continuous infusion IL-2 in three European multinational, single-arm phase II trials. Long-term treatment outcomes for these patients were analyzed, and the results are presented here. The results of a large, randomized French cooperative group trial (the Cancer Renal Cytokine [CRECY] study) that enrolled 425 patients between 1991 and 1995 are also summarized. Patients on this trial were randomized to treatment with IL-2 alone, IFN-alpha alone, or the combination.RESULTS:Among patients included in the 281-patient database, the objective response rate was 15%. Median survival was 10 months; 41% of patients were alive at 1 year, 22% were alive at 2 years, and 8% were alive at 5 years. Among patients with a complete or partial response, 60% and 18% were alive at 5 years, respectively. No clinical factors were predictive for response or survival; however, no patient with a high endogenous IL-6 level at diagnosis responded to IL-2 therapy. The CRECY trial demonstrated that the combination of IL-2 and IFN-alpha induced a significantly higher response rate (P < 0.01) and significantly improved 1-year event-free survival (P = 0.01) compared with either agent alone, but overall survival was not significantly different between the three treatment groups.CONCLUSION:The European experience suggests that the 5-year survival rate for metastatic renal cell carcinoma patients treated with high-dose continuous infusion IL-2 therapy is approximately 8% and that the majority of the therapeutic benefit is restricted to patients achieving a complete response. Therefore, given the toxicity, candidates for IL-2 therapy should be carefully selected. The combination of IL-2 and IFN-alpha does not appear to provide additional survival benefit. Efforts to further improve therapeutic outcome for patients with metastatic renal cell carcinoma should focus on understanding the underlying mechanisms of cytokine-induced tumor regression.
PURPOSE:Interferon-alfa, 2'-deoxycoformycin, and 2-chlorodeoxy-adenosine (2-CdA) are effective in the management of patients with hairy cell leukemia. These agents produce remissions in most patients, but relapses occur with all three drugs. The optimal means to follow patients for relapse after treatment has not been determined.METHODS:We retrospectively examined serial serum soluble interleukin-2 receptor levels (sIL-2R) and absolute granulocyte counts in eight patients with relapsed hairy cell leukemia. All were treated with 2-CdA at the time of relapse. Serum samples were available at 3- to 6-month intervals from 5 to 9 years before relapse and 2-CdA treatmentRESULTS:sIL-2R levels increase only in patients who go on to relapse. sIL-2R levels doubled a mean of 17.1 months (range, 4-36 months) before absolute granulocyte count decreased by 50%.DISCUSSION:Demonstration of a rising serum sIL-2R level in patients with hairy cell leukemia identified those with an increased risk of relapse who need more frequent observation than patients who maintain a stable sIL-2R level. Early intervention may ameliorate the toxicity of salvage therapy because disease-related neutropenia may be anticipated.
PURPOSESix of the most active chemotherapy agents in small cell lung cancer were administered sequentially in a weekly fashion in an attempt to optimize the dose and the number of agents received over a 12-week period. The purpose of this study was to estimate the efficacy and to characterize the toxicity of this approach.PATIENTS AND METHODSThirty-six patients with extensive-stage small cell lung cancer received weekly treatments with cisplatin and etoposide (weeks 1, 5, and 11), cyclophosphamide (weeks 2, 7, and 10), vincristine (weeks 2, 4, 7, 8, 10, and 12), methotrexate (weeks 3, 6, and 9), and doxorubicin (weeks 4, 8, and 12). Patients achieving a partial response received a second 12-week course. Patients achieving a complete response received prophylactic cranial radiation.RESULTSTwenty-nine of the 36 patients completed the initial 12-week program over a median of 16 weeks. Hematologic toxicity was most prominent, with two deaths from sepsis and 31 patients having grade 3 or 4 neutropenia The overall response rate was 85%, with 33% of patients achieving a complete response. The median survival was 10.5 months, and the median time to progression was 8.2 months.DISCUSSIONThis 12-week program, consisting of administration of six active agents for small cell lung cancer, caused significant myelosuppression that resulted in significant treatment delays and dose reductions. Although a high response rate was achieved, the median overall survival of 10.5 months was not significantly longer than expected from other standard two- to three-drug regimens.
OBJECTIVE:The purpose of this study was to determine the impact of final pathologic margin status on breast relapse-free survival, distant metastasis-free survival, and overall survival in patients undergoing conservative surgery and radiation therapy for invasive breast cancer.MATERIALS AND METHODS:Between January 1970 and December 1990, 984 patients underwent conservative surgery and radiation therapy at our institution as treatment for invasive breast cancer. After lumpectomy, patients were given radiation therapy to the intact breast with or without treatment to regional nodes with the routine use of electron boost to a total median tumor bed dose of 64 Gy. Pathology reports were available for review in 871 patients. Re-excision was carried out in 294 of these patients. For this analysis, patients were divided into four groups based on final pathologic margin status: negative (n = 278), dose (typically within 2 mm, n = 47), positive (n = 55), or indeterminate (n = 491).RESULTS:There were no significant differences between the groups with respect to age, histology, estrogen and progesterone receptor status, tumor location, or total radiation dose. Patients with negative margins were more likely than those with positive margins to have T1 mammographically detected lesions, to have negative nodal status, and to have undergone re-excision. Patients with positive margins were more likely to receive adjuvant chemotherapy or hormone therapy (P = 0.001). As of July 1998, with a median follow-up of 13 years, the median breast relapse-free survival, distant metastasis-free survival, and overall survival rates at 10 years for the entire cohort of patients were 86%, 81%, and 76%, respectively. Breast relapse-free survival at 10 years was 98% for patients with negative margins versus 98% for those with close margins versus 83% for those with positive margins versus 82% for those with indeterminate margins. There were no significant differences in breast relapse-free survival between patients with negative and dose margins or between patients with positive and indeterminate margins. Although the negative margin status also conferred an overall survival and distant metastasis-free survival advantage, this difference is confounded by the earlier stage of disease in these patients, and margin status did not influence overall survival in multivariate analysis.CONCLUSION:In patients undergoing conservative management of breast cancer, negative margin status significantly improves breast relapse-free survival. Close margins appear equivalent to negative margins, and indeterminate margins appear equivalent to positive margins. Adjuvant chemotherapy or hormone therapy did not counteract the adverse impact of positive margin status. Re-excision to obtain dear surgical margins is recommended, even if a radiation boost or adjuvant systemic therapy is planned.
PURPOSE:To update response duration and survival data for patients with metastatic renal cell carcinoma treated with high-dose interleukin (IL)-2.PATIENTS AND METHODS:Two hundred fifty-five assessable patients were entered onto seven phase II clinical trials. Recombinant IL-2 600,000 or 720,000 IU/kg was administered by 15-minute intravenous infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximal support. A second, identical cycle of treatment was scheduled following 5 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. All data were updated as of December 1998, with report forms completed by the clinical investigators. These data had last been updated as part of the Food and Drug Administration reporting requirements in 1996.RESULTS:Objective responses previously have been reported in 37 of 255 patients (15%) with 17 complete responses (7%) and 20 partial responses (8%). These data remain unchanged from previous reports. Median response duration for all objective responders remains unchanged at 54 months, but the range now extends from 3 to > 131 months. Median duration for all complete responses has not yet been reached, but was at least 80 months (range, 7- > 131 mo) at the time of this analysis. Median duration for all partial responses remains 20 months (range, 3- > 126 mo). Median survival time for all 255 patients remains 16.3 months, with 10% to 20% of patients estimated to be alive 5 to 10 years after treatment with high-dose IL-2.CONCLUSION:With prolonged follow-up, treatment with high-dose recombinant IL-2 remains extremely effective for a subset of patients with metastatic renal cell carcinoma.
PURPOSE Recombinant interleukin (IL)-2 administration can mediate regression of solid tumors in patients with melanoma and renal cell carcinoma. A better understanding of the mechanisms of IL-2-mediated antitumor effects has led to the investigation of novel immunotherapeutic approaches. The rationale for these immunotherapeutic approaches and the results of preliminary clinical studies are presented. PATIENTS AND METHODS The therapeutic potential of dendritic cells and the role of FLT3 ligand, a potent hematopoietic growth factor, was investigated in a variety of preclinical models. In addition, a clinical study with autologous dendritic cells pulsed with synthetic melanoma peptides derived from the MART1/ Melan A, gp100, and tyrosinase proteins was conducted. Twenty-eight human leukocyte antigen (HLA)-A2+ melanoma patients received an average of 106 dendritic cells a week for 4 weeks. RESULTS In a murine liver metastases model, FLT3 ligand administration alone or in combination with IL-12 or IL-2 had significant antitumor effects and resulted in significant infiltration of the tumor border by lymphocytes and dendritic cells, which was associated with an increased number of apoptotic figures. Administration of melanoma peptide-pulsed dendritic cells to 28 patients with advanced metastatic melanoma produced a complete response in two patients and a partial response in one. Significant infiltration of T cells and dendritic cells into melanoma lesions was observed. CONCLUSION These studies confirm the feasibility of immunotherapeutic approaches using dendritic cells and FLT3 ligand and demonstrate their potential antitumor activity. These approaches may be effective for patients with metastatic melanoma and other solid tumors and will likely be used to improve the efficacy of IL-2-based immunotherapy.
PURPOSE:Locoregional administration of interleukin (IL)-2, which acts physiologically as a local hormone, is an effective therapeutic modality. Diverse preclinical and clinical models have described methods of administration that expose tumor tissues to continuously high levels of cytokines. Regional administration of IL-2 that does not raise intravascular IL-2 levels induces local and systemic immunomodulation and produces objective local tumor responses. Most importantly, regional therapy is much less toxic than systemic IL-2 therapy.PATIENTS AND METHODS:We review clinical experiences using inhaled IL-2 therapy for the treatment of pulmonary metastases in roughly 300 patients with a variety of primary tumors. This includes our own 10-year single-institution experience with inhaled IL-2 therapy in the treatment of 188 metastatic renal cell carcinoma patients with progressive pulmonary metastases. Patients in our clinic are treated with 18 to 36 million IU of recombinant IL-2, administered 90% by inhalation and 10% subcutaneously, until disease progression. A variety of doses and schedules of inhaled IL-2 have been investigated alone and in combination with systemic therapies.RESULTS:Inhalation of IL-2 has been reported to prevent progression of pulmonary and mediastinal metastases of metastatic renal cell carcinoma, breast and ovarian carcinoma, and melanoma. Inhaled IL-2 alone is well tolerated; a dose-dependent cough is the major adverse event. A significant dose-dependent increase in lymphocytes and eosinophils has been observed in bronchoalveolar lavage in patients and animals. Dose and schedule can influence outcome. In a phase I trial using inhaled IL-2 alone in patients with a variety of primary malignancies, once-daily inhalation of IL-2 at doses up to 15 million IU/m2 was well tolerated but did not result in prolonged stabilization of pulmonary disease. In a multidose phase I trial, using 5-times-daily inhalation of natural IL-2, pulmonary lesions in three of 14 (21%) metastatic renal cell carcinoma patients responded, and a similar multicenter trial demonstrated a 29% response rate. Among 188 metastatic renal cell carcinoma patients treated with inhaled recombinant IL-2 at the Clinic Eppendorf, progression of pulmonary metastases was prevented in 68% of patients for a median duration of 7 months, and overall survival was significantly improved compared with expected survival (Elson's risk analysis; 17.2 vs 5.3 mo). All patients, including high-risk patients, appeared to benefit. Encouraging results have also been reported in patients with metastatic melanoma and gynecologic tumors when inhaled IL-2 was used as second-line therapy to treat pulmonary metastases.CONCLUSIONS:The efficacy of inhaled IL-2, alone or in combination with systemic immunotherapy, immunochemotherapy, or chemotherapy, has been documented in a variety of malignancies. All reports confirm low toxicity, thus providing important quality-of-life benefits. Moreover, patients not eligible for systemic IL-2 therapy may be treated with inhalation therapy.
PURPOSE Dendritic cells (DC) can elicit potent immune responses to tumors through their capacity to efficiently process and present tumor-associated antigens. In a variety of animal tumor models, vaccines based on tumor lysate-pulsed DC (TP-DC) have been shown to effectively immunize against lethal tumor challenges as well as to treat established growing tumors at skin and organ sites. The antitumor effects elicited by TP-DC-based vaccines in vivo have been shown to be mediated by tumor-specific proliferative, cytotoxic, and cytokine-secreting host-derived T cells. Because of the critical involvement of T cells in the antitumor immune response, we have been investigating whether the systemic administration of recombinant interleukin (IL)-2 can enhance the therapeutic efficacy of TP-DC-based tumor vaccines. MATERIALS AND METHODS Immunization with TP-DC plus IL-2 administration was evaluated to determine if this combination could enhance protective immunity toward a weakly immunogenic sarcoma (MCA-207) and a poorly immunogenic subline (D5) of the B16 melanoma and mediate therapeutic rejection of established tumors in C57BL/6 (B6) mouse models. RESULTS We have demonstrated in our murine models that the addition of IL-2 at relatively nontoxic doses can markedly augment the antitumor activity of TP-DC-based tumor vaccine therapies against both a weakly immunogenic sarcoma and a poorly immunogenic melanoma. Animals treated with the combination exhibited significantly greater protection from tumor-cell challenge, significantly greater regression of established tumors, and significantly longer mean survival time than with either TP-DC or IL-2 therapy alone. The mechanism operative in vivo appears to involve the enhancement of immune T-cell function. CONCLUSION These preclinical studies demonstrate the potential of this novel treatment strategy and support the rationale for planned phase I/II clinical trials of TP-DC-based vaccines plus IL-2 in patients with advanced melanoma and colorectal cancer.
PURPOSE:The modest activity of chemotherapy and biologic agents in the treatment of advanced metastatic melanoma has prompted investigators to consider combinations of chemotherapy and biologic agents (i.e., biochemotherapy) as a way of improving response rates and survival. Although biochemotherapy has generated a great deal of interest over the last several years, and these regimens have produced high response rates in single-institution phase II trials, they have yet to demonstrate a significant survival benefit in randomized trials compared with either chemotherapy or biotherapy alone.METHODS:The available literature regarding the clinical experience with single- and multiagent chemotherapy, immunotherapy, and biochemotherapy was reviewed.RESULTS:Treatment of metastatic melanoma with either single-agent or combination chemotherapy regimens is clearly suboptimal; the majority of responses are partial and of short duration. In contrast, interleukin (IL)-2 produces long-term durable complete remission in a subset of patients. Over 1,000 patients have been treated with IL-2-based biochemotherapy regimens in single-institution phase II trials, and response rates have ranged from 40% to 60%. Most encouraging have been the durable responses observed in 10% to 20% of patients in most of these trials. Large databases, including two meta-analyses, have confirmed the substantial improvement in response rate associated with biochemotherapy regimens that include both IL-2 and interferon alfa (IFN-alpha) compared with chemotherapy or biotherapy alone. Biochemotherapy is currently being evaluated in randomized controlled trials to determine if this treatment strategy can provide a survival benefit compared with current standard treatments. A pilot study at Beth Israel Deaconess Medical Center has demonstrated the feasibility of administering a modification of a concurrent biochemotherapy regimen, initially described by Legha et al, consisting of cisplatin, vinblastine, and dacarbazine (CVD) plus IL-2 and IFN-alpha in the cooperative group setting.CONCLUSION:These studies provided the rationale for intergroup trial E-3695, which is currently randomizing patients to concurrent biochemotherapy with CVD plus IL-2 and IFN-alpha versus CVD alone.
PURPOSE:To review the current information available from the European Organization for Research and Treatment of Cancer (EORTC) programs on the use of interleukin (IL)-2 in stage IV melanoma patients.PATIENTS AND METHODS:A database from 631 patients treated within 27 trials with high-dose IL-2-based regimens was compiled to develop hypotheses and valid stratification factors for randomized trials. Subsequently, 126 patients were enrolled in a trial evaluating interferon alfa (IFN-alpha) and IL-2 with or without cisplatin, and 325 patients were enrolled in an ongoing EORTC trial (18951) to evaluate dacarbazine, cisplatin, and IFN-alpha, with or without IL-2.RESULTS:The database suggests long-term survival rates of 23% and a 5-year survival rate of 13% for patients receiving a combination of IFN-alpha and IL-2 with or without chemotherapy. The addition of chemotherapy improved response rate but not survival. The first randomized trial testing the role of cisplatin in a chemoimmunotherapy regimen for advanced melanoma revealed a palliative effect for cisplatin but no survival benefit. The current trial (EORTC 18951), which is testing the impact of IL-2 on survival, is still immature. In the translational research program, we have evidence that patients in continuous complete remission after IL-2-based treatment have evidence of residual disease by polymerase chain reaction assay and, at the same time, melanoma-reactive T cells are present in the peripheral blood.CONCLUSION:Mature results defining the role and, to some extent, the mechanism of IL-2 in advanced melanoma are emerging.
