Common cancers--immunotherapy and multidisciplinary therapy: Parts III and IV.

The refractoriness of many solid tumors to cytotoxic chemotherapy has led to the exploration of new therapeutic modalities, including immunotherapy. Immunotherapy does not have a direct cytotoxic effect on the cancer cell but is an attempt to promote rejection of the tumor by the host, chiefly through the cellular arm of the immune system. The clinical success with immunotherapy (primarily adoptive immunotherapy) among patients with unresectable malignant melanoma and cancer of the kidney has not been marked by the large numbers of patients responding but by occasional dramatic effectiveness of therapy for these cancers, which usually are refractory to chemotherapy. Long-lasting responses and even complete disappearance of all known metastases are possible for a small percentage of patients with melanoma or renal cell carcinoma who undergo immunotherapy. A reasonable approach for patients with good performance status (no symptoms or ambulatory with symptoms but not bedridden) is entrance to clinical trials, especially trials examining adoptive or active immunotherapy for melanoma or adoptive immunotherapy for renal cancer. The overall treatment of patients with cancer has changed. Primary-care physicians detect almost all cancers. The days when "taking it out" is the best we could offer a patient are over. As we learn more about the use of adjuvant or neoadjuvant chemotherapy and radiation therapy, it is likely one or both of these modalities will be incorporated into the treatment of additional solid tumors previously managed solely with surgical resection. Increasingly, additional therapy is being given for earlier-stage disease as we define how to maximize the potential for cure with minimal toxicity. Many new therapies are on the horizon, including the use of noncytotoxic treatments as an adjunct to a surgical procedure. Such therapies include the use of angiogenesis inhibitors, tumor vaccines, and immunotherapy. Now and in the future, patients will be best served when treated in an environment that can integrate medical, surgical, and radiation oncology actively.

Preliminary results of neoadjuvant paclitaxel and carboplatin in the treatment of early stage non-small cell lung cancer.

The purpose of this study is to determine the feasibility of delivering neoadjuvant paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin to patients with clinical early stage (stage I and II) non-small cell lung cancer. Although neoadjuvant chemotherapy appears to prolong survival in patients with stage IIIA non-small cell lung cancer, several studies have demonstrated an increase in perioperative mortality associated with this approach. This study is designed to address whether three cycles of paclitaxel (200 mg/m2/3 hour, day 1) and carboplatin (area under the concentration-time curve 5, day 2) can be given preoperatively to patients with clinical stage I and II non-small cell lung cancer and to assess the associated toxicities, pathologic response rate, disease-free survival, and overall survival of this group of patients. Thus far, five patients have been enrolled. Three have successfully undergone resection, with no perioperative complications noted. One patient had a pathologic complete remission and two had pathologic partial remissions. Preliminary results indicate that this approach is well tolerated and results in major tumor response.

Phase I trial of dose-escalated paclitaxel and carboplatin in combination with ifosfamide and filgrastim: preliminary results.

The ongoing phase I study reported here sought to determine the maximum tolerated doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin when given at specific times in combination with ifosfamide, mesna, and filgrastim. Patients in the trial included those with non-small cell lung cancer (three), breast cancer (two), metastatic adenocarcinomas of unknown primary site (two), prostate cancer (one), angioimmunoblastic lymphadenopathy (one), and mesothelioma (one). The median age of these 10 patients was 48 years (age range, 34 to 75 years) and none had received chemotherapy previously. Of the 12 patients who entered the study, 10 are eligible for analyses of toxicity and response. The only grade 4 toxicity observed was hematologic. One episode of neutropenic fever occurred in the 43 treatment cycles delivered so far, one patient experienced an ifosfamide-related change in mental state, and two patients developed reversible renal tubular acidosis. No other significant neurologic or renal toxicities have been observed. At dose level 1, the cycle-6 doses were delayed in one patient, and another patient required a 50% reduction of the ifosfamide dose during cycle 4 due to mental status change. At dose level 2, there were no dose reductions or delays due to side effects, although one patient withdrew due to disease progression. At dose level 3, dose delays only were required in six of 15 cycles. The response rate was 100%; four patients achieved a complete response (40%) and six a partial response (60%). This regimen appears to be tolerable and active at the dose levels completed thus far, with minimal nonhematologic toxicities.

Phase I trial of dose-escalated paclitaxel and carboplatin in combination with ifosfamide and filgrastim: preliminary results.

The purpose of this phase I study is to determine the maximally tolerated doses of paclitaxel and carboplatin (dosed by area under the concentration-time curve) when given at specified times in combination with 6 g/m2 ifosfamide (3 g/m2 at 8 AM on days 1 and 2) with mesna and 5 microg/kg/d filgrastim (from day 4 until the absolute neutrophil count is > 10,000/microL) every 21 days for six cycles. Twelve patients have been treated thus far, 10 of whom are currently eligible for toxicity and response analyses: three each at dose levels 1 and 2, and four at dose level 3. Hematologic toxicity has been the only grade 4 toxicity noted. Only one episode of neutropenic fever occurred in the 43 cycles delivered to date, and only one patient experienced an ifosfamide-related change in mental status. Two patients have developed reversible renal tubular acidosis. No other significant neurologic or renal toxicities have been noted. Patient disease distribution is three non-small cell lung cancer, two breast cancer, two adenocarcinomas of unknown primary site, one prostate cancer, one angioimmunoblastic lymphadenopathy, and one mesothelioma. The median age is 48 years (age range, 34 to 75 years), and median prior chemotherapy treatments was zero. One patient on dose level 1 required a dose delay on cycle 6 because of inadequate hematologic recoveries and one patient required a 50% reduction of the ifosfamide dose during cycle 4 due to mental status change. No patients receiving dose level 2 required dose reductions or delays. One patient at dose level 2 was removed from study due to deterioration of performance status and subsequently died. At dose level 3 dose delays have been required in six of 15 cycles, but no dose reductions have been necessary. Four patients have achieved a complete response (40%) and six a partial response (60%), for a total response rate of 100%. At the completed dose levels, this regimen appears to be tolerable and active with minimal nonhematologic toxicities.

The epidemiology of non-Hodgkin's lymphoma: why the increased incidence?

The incidence of non-Hodgkin's lymphoma continues to increase in the United States. Improvements in diagnostic techniques, changes in disease classifications, and the increase in AIDS-related lymphomas account for only a small percentage of the increase, leaving most of the increased incidence unexplained. Viruses clearly play a major role in the pathogenesis of some subtypes of non-Hodgkin's lymphoma, especially Epstein-Barr virus and HTLV-1, and improvements in molecular diagnostic techniques may identify additional viruses that have a role in the pathogenesis of lymphomas. Immunodeficiencies, whether acquired, congenital, or iatrogenic, clearly predispose to the development of non-Hodgkin's lymphoma. Numerous environmental exposures have also been linked to an increased risk of non-Hodgkin's lymphoma and may account for a portion of the continuing increased incidence of the disease.

Ifosfamide, carboplatin, and etoposide plus granulocyte-macrophage colony-stimulating factor: a phase I study with apparent activity in non-small-cell lung cancer.

PURPOSE: A phase I trial was performed to evaluate the feasibility of escalating the dose of etoposide in dose-intensive ifosfamide, carboplatin, and etoposide (ICE) with granulocyte-macrophage colony-stimulating factor (GM-CSF). PATIENTS AND METHODS: Twenty-four patients were entered between November 1990 and November 1991. Patients received ifosfamide 5 g/m2 by continuous infusion over 48 hours, carboplatin 400 mg/m2 by intravenous bolus, and GM-CSF 5 micrograms/kg/d subcutaneously from day 4 until neutrophil recovery. The etoposide dose was escalated, with six patients receiving 300 mg/m2 total dose (level 1), six receiving 600 mg/m2 (level 2), three receiving 900 mg/m2 (level 3), and five receiving 1,200 mg/m2 (level 4). Level 4B consisted of three patients who received etoposide 1,200 mg/m2 and GM-CSF 10 micrograms/kg/d. Cycles were repeated every 21 days. The maximum-tolerated dose (MTD) was prospectively defined as the dose level at which the next higher level produced greater than 7 days of grade 4 myelosuppression in two or more of six patients. RESULTS: Twenty-three patients were assessable. The median duration of neutropenia was < or = 7 days on cycle 1 at all dose levels. The initial criteria for determination of the MTD was never achieved. However, seven of eight patients treated at levels 4 and 4B required hospitalization for neutropenic fever on cycle 1 of therapy, with three of four septic events occurring at these levels. Cumulative thrombocytopenia occurred at all dose levels, with > or = 50% of patients requiring platelet transfusions on cycle 3. This became the dose-limiting toxicity above level 3. The overall response rate was 48%, with 11 of 23 objective responses, including two complete responses (CRs). Seven of 11 (64%) patients with non-small-cell lung cancer (NSCLC) responded, including one CR. Two of four (50%) heavily pretreated non-Hodgkin's lymphoma (NHL) patients responded, with one CR. CONCLUSION: The addition of GM-CSF to a dose-intensive ICE regimen permitted dose escalation of etoposide to 900 mg/m2, with cumulative thrombocytopenia as the dose-limiting toxicity. Carboplatin dosing by the area under the curve (AUC) may minimize thrombocytopenia. This appears to be an active regimen for patients with NSCLC and refractory NHL.

Dose-intensive ifosfamide/carboplatin/etoposide plus granulocyte-macrophage colony-stimulating factor for non-small cell lung cancer.

Whereas non-small cell lung cancer (NSCLC) comprises 80% of all lung cancer cases, effective prolongation of survival in NSCLC patients using currently available combination chemotherapy has been problematic. Use of dose-intensive chemotherapy along with hematopoietic growth factor support is an attractive, albeit experimental, alternative. We have conducted a phase I study to determine the maximum tolerated dose of etoposide in the ifosfamide/carboplatin/etoposide (ICE) regimen when used with granulocyte-macrophage colony-stimulating factor (GM-CSF) support. Twenty-three patients with solid tumors refractory to standard treatment who had not received previous platinum-containing chemotherapy or for whom there was no generally accepted curative therapy were treated. We present results obtained in 11 patients with previously untreated stage IV NSCLC. The use of ICE plus GM-CSF demonstrated promising activity in this group of patients; the overall response rate was 64%, and median survival was 10.0 months. The maximum tolerated dose of this regimen is 900 mg/m2 etoposide in combination with 5 g/m2 ifosfamide, 400 mg/m2 carboplatin, and 5 micrograms/kg/d GM-CSF.

Plasminogen activator in normal and tumor-bearing mice.

The plasminogen activator levels of a series of murine tumors commonly used in cancer drug screening were determined and compared to the levels found in normal mouse tissues. Tumors high in plasminogen activator included the B16 and colon 26. The Lewis lung and M5076 carcinoma showed an intermediate level of activity, while the plasminogen activator activity in the L1210 leukemia and colon 38 was barely elevated above background. The specific activity of the enzyme (per micrograms protein) in extracts of B16 and colon 26 was three or four times higher than in the most active normal organs surveyed (kidney, lung, brain and intestine). The high level of plasminogen activator activity measured in extracts of the B16 tumor was reflected in a substantial elevation of the levels of fibrin degradation products in the serum of mice carrying this tumor. This result suggests that the tumor-associated plasminogen activator activity is less subject to inhibitory controls in vivo than is the plasminogen activator of most normal tissues, since the total mass of the tumor was far less than the total mass of the fibrinolytically active tissues, and yet the bulk of the fibrin degradation products were caused by the tumor. We conclude that the high levels of plasminogen activator activity which are observed in many human tumors are found only in some of the transplantable murine tumors. Since this enzyme is active at an increased level in vivo in mice carrying the B16 tumor, plasminogen activator may be a suitable target for selective, enzyme-activated chemotherapy with this tumor test system.