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R O Dillman

Publications and source records attributed to R O Dillman.

At least 37 records · Page 2Linked to original sources
PubMed1999

What to do with IL-2?

It has been 15 years since the first positive clinical reports of Interleukin-2 (IL-2) appeared in the medical literature, ten years since moderate dose continuous infusion IL-2 was approved in Europe, and five years since high-dose bolus IL-2 was approved for general use in the United States. IL-2 is accepted as a standard treatment used alone, or in combination with chemotherapy or biotherapy in the management of metastatic melanoma and metastatic renal cell carcinoma. Various physicians utilize high-dose bolus IL-2, moderate-dose continuous infusion IL-2, and low-dose outpatient intravenous or subcutaneous IL-2. There is still no consensus regarding the best way to deliver IL-2 alone in terms of dose and schedule of administration from a risk-to-benefit standpoint. Despite yielding higher tumor response rates, regimens that combine IL-2 with chemotherapy and/or interferon have not produced better long-term survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

The feasibility of using short-term cultures of ovarian cancer cells for use as autologous tumor cell vaccines as adjuvant treatment of advanced ovarian cancer.

OBJECTIVE: We have tried to establish short-term cultures of autologous tumors from patients with stage III and IV ovarian cancer, which could be used as active specific immunotherapy, (i.e., autologous vaccine) in such patients after debulking surgery & combination chemotherapy. METHODS: Between 5/93 and 11/97 the Hoag cell biology laboratory received 53 ovarian tumor samples that had been surgically excised at the time of laparotomy, and four samples of malignant ascites. Efforts were made to establish short-term tumor cell cultures as confirmed by morphology & phenotype. RESULTS: Short-term proliferating cultures were successfully established from 21/57 samples [37%] which included 8/24 [33%] successes from samples obtained at diagnosis compared to 13/33 [37%] samples obtained at the time of a relapse [p = 0.45]. The probability of successful culture was not related to tumor size for samples with a range of 0.8-34 g (mean 5.8 g). One patient was treated in the setting of metastatic disease and one in the adjuvant setting; both received repeated injections of irradiated autologous tumor cells plus granulocyte macrophage stimulating factor (GM-CSF). In one patient a delayed tumor hypersensitivity skin test converted from negative to positive. CONCLUSIONS: Short-term cultures of autologous tumor cells for use as tumor cell vaccines can be established for about one-third of patients with ovarian cancer using this methodology and the treatment approach is feasible.

Aged↗
PubMed1999

Perceptions of Herceptin: a monoclonal antibody for the treatment of breast cancer.

In September 1998 Trastuzumab (Herceptin) became the second monoclonal antibody approved for the treatment of a malignant condition, and the first antibody approved for the treatment of a solid tumor. It is a mouse-human chimeric antibody that produces anti-tumor effects by blocking the HER2-neu receptor, and can also interact with human immune cells to effect antibody dependent cell-mediated cytotoxicity. Pivotal trials in breast cancer showed that it has activity as a single agent in a subset of patients whose tumors greatly over-express HER2, but results were even more impressive when it was used in combination with chemotherapy. It should also prove to be useful in the treatment of subsets of patients with other adenocarcinomas whose tumors over-express HER2.

Animals↗
PubMed1999

Complete remission of nonresectable pancreatic cancer after infusional colloidal phosphorus-32 brachytherapy, external beam radiation therapy, and 5-fluorouracil: a preliminary report.

This is a preliminary report of five patients diagnosed with locally advanced nonresectable pancreatic cancer who achieved improved quality of life, delay of local progression, and reduction of biomarker CA 19-9 after infusion of colloidal phosphorus 32 (32P) and administration of combined chemoradiotherapy. A phase II trial using intratumoral colloidal 32P delivery for nonresectable pancreatic cancer without metastases is in progress. Patients initially were given infusions of decadron followed by macroaggregated albumin and 30 mCi colloidal 32P to the interstitial space of the tumor by two infusions 1 week apart. Through this method, doses ranging from 750,000 to 1,800,000 cGy were delivered. After administration of colloidal 32P, external radiation to a dose of 6000 cGy minimum tumor dose, including regional lymph nodes, was given concomitantly with four intravenous infusions of 500 mg bolus 5-fluorouracil on alternating days within the first 2 weeks after initiation of external radiation. All five of these patients demonstrated cessation of local tumor growth or regression of disease on serial computed tomography scans for a minimum of 10 months from completion of therapy. Three of these patients have survived without local disease progression over 24 months from initiation of therapy, with one patient approaching 36 months. CA 19-9 values for all patients declined within weeks after completion of therapy. This new method of isotope delivery has resulted in reduction of tumor volume, normalization of the biomarker CA 19-9, and improved performance status in those patients who have localized nonresectable disease without dissemination.

Aged↗
PubMed1999

Single-agent monoclonal antibody efficacy in bulky non-Hodgkin's lymphoma: results of a phase II trial of rituximab.

PURPOSE: A phase II trial was performed to evaluate the safety and efficacy of rituximab, a chimeric anti-CD20 monoclonal antibody, in patients with bulky (> 10-cm lesion) relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-one patients received intravenous infusions of rituximab 375 mg/m(2) weekly for four doses. All patients had at least one prior therapy (median, three; range, one to 13) and had progressive disease at study entry. Patients were a median of 4 years from diagnosis. RESULTS: No patient had treatment discontinued because of an adverse event. No patient developed human antichimeric antibody. The overall response rate in 28 assessable patients was 43% with a median time to progression of 8.1 months (range, 4.5 to 18.6+ months) and median duration of response of 5.9 months (range, 2.8 to 12.1+ months). The average decrease in lesion size in patients who achieved a partial response was 76%, and patients with stable disease had a decrease in average lesion size of 26%. Median serum antibody concentration was higher in responders compared with nonresponders, and a negative correlation was shown between antibody concentration and tumor bulk at baseline. CONCLUSION: Rituximab single-agent outpatient therapy is safe and shows significant clinical activity in patients with bulky relapsed or refractory low-grade or follicular B-cell NHL.

Adult↗
PubMed1999

Combination interferon-alpha2a and 13-cis-retinoic acid enhances radiosensitization of human malignant glioma cells in vitro.

We investigated the individual and combined effects of cis-retinoic acid (CRA) and/or IFN-alpha (IFN) and/or radiation therapy (RT) against a human glioma cell line (American Type Culture Collection; U373MG) to evaluate the possible radiosensitization properties of these agents in vitro. Glioma cells were incubated for 24 h in 96-well plates (2 x 10(2) cells/well) in standard culture medium. Sets of U373 (n = 12) were exposed to CRA (3 x 10(6) microM), IFN (25 units/ml), CRA plus IFN, or standard culture medium. After an additional 24 h of incubation, the U373 cells were subjected to increasing radiation doses (up to 16 Gy). Glioma cells were harvested 92 h after irradiation, and cell survival curves were determined from [3H]thymidine incorporation data (over the last 24 h). The experiment was repeated for both the untreated control group and the combined CRA/IFN group. To verify the [3H]thymidine assays, a clonogenic assay was also performed. Single cell suspensions of U373 cells were plated out in six-well plates (n = 3). After chemical and RT treatment, colonies of 50 cells or more were counted, and cell survival curves were generated as fractions of nonirradiated controls. The amount of RT (in Gy) that would cause a 50% survival fraction (lethal dose 50 or LD50) was calculated from the survival curves by regression analysis. The following LD50s were obtained: [table: see text] The results showed that for both the [3H]thymidine incorporation assay and the clonogenic assay, the combination of IFN/CRA rendered U373 cells more susceptible to ionizing radiation than the untreated control or either single agent alone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Interferon-alpha and chemohormonal therapy for patients with advanced melanoma: final results of a phase I-II study of the Cancer Biotherapy Research Group and the Mid-Atlantic Oncology Program.

BACKGROUND: The treatment of metastatic melanoma remains unsatisfactory despite encouraging results with biotherapy and combination chemotherapy. Combining these two modalities may improve outcomes for such patients. METHODS: Patients who were eligible for this study had metastatic melanoma and were in good medical condition. The following regimen was used: dacarbazine 220 mg/m2 and cisplatin 25 mg/m2 administered intravenously (i.v.) daily x 3 days every 3 weeks, carmustine 150 mg/m2 i.v. every 6 weeks, tamoxifen 10 mg administered orally twice a day, and interferon-alpha2b 3.0 thousandths of an International Unit (mIU)/m2 administered subcutaneously on Days 1, 3, and 5 of each week a patient was on study. Patients were analyzed for toxicity, tumor response, and survival. Because of severe toxicity, partway through the trial the regimen was modified as follows: dacarbazine and cisplatin were given at the same dose every 4 weeks, and carmustine was reduced to 100 mg/m2 every 8 weeks. RESULTS: Forty-two patients with a median age of 61 years were enrolled. Twenty had liver metastases and 18 had lung metastases. Forty patients were evaluable for toxicity, 17 at the original dose and 23 at the new dose; of these, 35 were evaluable for response. Hematologic toxicity was severe at the original dose: 10 patients had a nadir < 500/microL, 10 had platelets < 25,000/microL, and 2 discontinued treatment because of toxicity. At the reduced dose, 5 had a nadir absolute neutrophil count < 500, and 10 had platelets < 25,000. Of the 35 patients evaluable for response, there were 10 partial responses (29%) and 2 minimal responses. Median duration of disease control was 4 months. Median survival was 8.9 months. One partial and one minimal responder were removed from the study because they experienced toxicity while still responding. CONCLUSIONS: The addition of interferon-alpha to this chemohormonal therapy regimen greatly increased toxicity without improving the response rate or survival for patients with metastatic melanoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Clinical experience with autologous tumor cell lines for patient-specific vaccine therapy in metastatic melanoma.

Because of their patient specificity and proliferative capacity, tumor cell lines established from autologous metastatic melanoma tumor samples may be an excellent immunogen for patient-specific vaccine therapy. Between October 1990 and July 1996, the Hoag Cancer Center cell biology laboratory received 136 fresh metastatic melanoma samples from 122 different patients. Tumor cell lines were successfully established for 92 of 136 samples (68%), for 87 of 122 patients (71%). Successful cultures were expanded to 10(8) cells (total culture time about 8 weeks), confirmed to be sterile, irradiated, and stored frozen in aliquots of 10(7) cells. Vaccines were prepared from 72 lines, and 62 vaccines were used in 57 different patients. Subcutaneous vaccination took place on weeks 1, 2 and 3, and then monthly for a total of 6 months. A delayed tumor hypersensitivity skin test (DTH) was administered at week zero and week 4. Various adjuvants were co-administered including BCG, alpha- or gamma-interferon, and GM-CSF. Patients were monitored for failure-free survival (FFS) and overall survival (OS) from the date of the first vaccination. Follow-up data is available for 52 patients, 27 who had no evident disease (NED) at the time of vaccination and 25 who had metastatic disease at the time of treatment. There were two partial responses which persisted 11.9 and 39.8+ months among the 25 patients who had detectable metastatic disease whün treatment was initiated (8%, 1 to 26%, 95%-Ci). Twenty patients had negative skin tests at week 0 and week 4; six were positive both times, and 13 converted their DTH from negative to positive, for a conversion rate of 13 of 33 (39%). Patients who received interferon-gamma and/or GM-CSF as an adjuvant had a higher rate of DTH conversion compared to patients who received other adjuvants (13 of 20 v 2 of 13, P = 0.003). For patients who were NED, nine of 19 (47%) converted their DTH test compared to four of 14 (29%) patients with metastatic disease (p = 0.33). For patients whose DTH converted from negative to positive after 3 weeks of vaccination, median FFS and OS were superior compared to patients whose DTH remained negative (19.4 v 4.0 months FFS, p = 0.0052 and 39.6 v 18.3 months OS, p = 0.0602). The autologous cell line approach to active specific immunotherapy is feasible for patients who have resectable foci of metastatic disease. Administration of such patient-specific vaccines improves survival for those patients who are NED at the time of vaccination and convert their DTH skin test, compared to those whose DTH test remains negative.

BCG Vaccine↗
PubMed1997

Cancer cells release a covalent complex containing disulfide-linked domains from urinary plasminogen activator, neural cell adhesion molecule, and haptoglobin alpha and beta chains.

We have previously reported on the secretion of a family of high Mr plasminogen activators (PAs) by a human lung cancer cell line [Harvey et al. (1991) Biochim. Biophys. Acta 1078, 360-368]. We have now extended these studies to several human cancer cell lines and a human embryonic lung cell line. In the present study with HPL-SK-1 lung cancer, A431 epidermoid cancer, ovarian carcinoma, and embryonic lung cell lines, we show that the 900- and the 660-kDa PAs are disulfide-bonded multiprotein oligomeric complexes. They are functionally and immunologically related to human urinary PA (uPA). Their size and PA activity are not destroyed by strong denaturants such as 8 M urea or 2% sodium dodecyl sulfate (SDS), suggesting that the uPA moiety is covalently associated with the rest of the molecule. It is only under strong denaturing conditions with 1.4 M beta-mercaptoethanol and 2% SDS that the uPA moiety could be released as a 21- to 23-kDa fragment along with two major polypeptide chains of 70 and 40 kDa, respectively. The presence of the uPA active center in the reduced PA660 was demonstrated by [3H]diisopropylphosphorofluoridate labeling and by Western blot using a monoclonal antibody to uPA B chain. N-terminal amino acid sequencing of the 70- and 40-kDa polypeptides, respectively, showed homology to the neural cell adhesion molecule and the beta chain of haptoglobin. A minor fragment of 18 kDa obtained under strong reduction conditions was also sequenced and shown to share homology with the alpha chain of haptoglobin. Western blot analysis of the reduced PAs with monoclonal antibody to the neural cell adhesion molecule and rabbit anti-haptoglobin confirmed the homologies obtained by the sequence data. Further, immobilized monoclonal antibodies to the neural cell adhesion molecule, uPA B chain, and rabbit anti-haptoglobin bound the multiprotein complexes with uPA activity, from A431, ovarian cancer, and embryonic lung cell lines. The bound material, after dissociation, exhibited PA activity that was inhibited by monoclonal antibody to the uPA B chain. These data suggest that in tumor and embryonal cell lines, in addition to proper folding and assembly of proteins by intramolecular disulfide bond formation in the endomembrane compartment, intermolecular disulfide bonds could also occur, producing multiprotein oligomers as in the present case. Formation of such oligomers may have a selective advantage for such cells in the focalization of proteolytic activity through the interaction of the neural cell adhesion molecule domain with the extracellular matrix and in immunosuppression of lymphocytes by the haptoglobin portion of the complex.

Binding Sites↗
PubMed1997

The Cancer Biotherapy Research Group [CBRG], formerly the National Biotherapy Study Group [NBSG]: a 10-year perspective.

The Cancer Biotherapy Research Group [CBRG], formerly known as the National Biotherapy Study Group [NBSG], celebrated its 10th anniversary in 1997. CBRG is a not-for-profit cancer clinical trials group of community oncologists whose activities for the most part have been funded by their associated community hospitals. From its inception the Group has focused on clinical investigations of biological agents in the treatment of patients with advanced cancer. This article reviews the history of the Group, its structure, accomplishments, and its current objectives and challenges.

Clinical Trials as Topic↗
PubMed1997

Long-term survival after continuous infusion interleukin-2.

PURPOSE: Between 1987-1990, 612 patients received high-dose continuous intravenous interleukin-2 (IL-2) in phase II clinical trials of the National Biotherapy Study Group (NBSG). The purpose of this analysis was to determine the long-term survival rates associated with such therapy and the correlation, if any, between objective tumor response, and survival. METHODS: Patients who are known to have survived at least 3 years or more were identified. Actual and actuarial survival rates were determined for various malignancies and by tumor response. RESULTS: At least 37 (6.0%) survived > or = 3 years from the initiation of IL-2 therapy, and it is possible the 3-year survival rate is as high as 20%. This included 14/168 (8%) of patients with renal cell carcinoma, 10/175 (6%) melanoma, 2/51 (4%) lung cancer, 0/61 colorectal, 0/36 breast, 1/17 sarcoma, 1/14 pancreas, 1/19 ovary, 3/11 lymphoma, 2 adenocystic carcinomas, 2 carcinoid, and one Hodgkin's disease. Four hundred ninety-one of 612 (80%) are known to have died, 121 were still alive at the time of the last follow-up. Median survival was 7.9 months. Among 547 evaluable patients, there were eight complete responses (CR) and 42 partial responses (PR), for an objective response rate of 9%. An additional 32 patients had mixed or minimal responses (MR) for a total response rate of 15%. The 3-year survival rates were 25% for PR, 17% for PR, 16% for MR, 8% for stable disease (SD), and 2% for patients with progressive disease (PD). Responders made up a higher proportion of patients who survived > or = 3 years than of patients who survived < or = 3 years (14/37 = 38% vs 68/500 = 14%; p < .0001, X2). A higher proportion of responders survived > or = 3 years than non-responders (14/82 = 17% vs 23/230 = 4%, p < .0001, X2). Patients with CR, PR, or MR had a > or = 3-year survival rate (14/82 = 17%) than patients who had SD (20/249 = 8%; p = .02, x2, who in turn had a > or = 3-year survival rate that was greater than patients who had PD (3/206 = 2%; p = .001, X2). For individual trials in which 10 or more patients were enrolled, the percentage of patients surviving > or = 3 years ranged between 4% and 8%. CONCLUSION: We conclude that in the setting of IL-2 therapy for metastatic cancer, the probability of surviving > or = 3 years was approximately 12 times greater for responders, and five times greater for patients with SD; as compared to patients who had PD. Furthermore, despite diagnoses of metastatic cancer, often in settings in which disease had been refractory to standard therapy there was an actual 3-year survival rate of at least 6% to 8% for patients with metastatic melanoma and renal cell carcinoma.

Humans↗
PubMed1997

Hybrid high-dose bolus/continuous infusion interleukin-2 in patients with metastatic melanoma: a phase II trial of the Cancer Biotherapy Research Group (formerly the National Biotherapy Study Group).

PURPOSE: Interleukin-2 (IL-2) is an active agent for the treatment of melanoma. In animal studies, polyethylene glycol conjugated (PEG) IL-2 was found to be effective in certain IL-2-resistant models. Bolus/infusional IL-2 administered to approximate the pharmacokinetics of PEG-IL-2 also overcame resistance in these models. Based on these observations, the Cancer Biotherapy Research Group (CBRG) [formerly the National Biotherapy Study Group (NBSG)] previously had conducted a pilot study and then a phase I trial of bolus IL-2 followed by continuous IL-2 (NBSG 90-01). METHODS: In the current study, NBSG 92-09, a phase II trial was conducted using IL-2 at a dose of 36 MIU/m2 followed by a 72-hour continuous infusion of IL-2 at 18 MIU/m2/day, so that over 3 days a total of 90 MIU/m2 of IL-2 were delivered; the same amount as previously given during 5 days of continuous i.v. IL-2 at 18 MIU/m2/day. This schedule was repeated every 2 weeks for 2 months, and then monthly for up to 6 months. RESULTS: Twenty-two patients with metastatic melanoma were enrolled in this trial. Toxicities were qualitatively similar to those seen with other IL-2 regimens, but grade 3 and 4 toxicities were observed only in patients who received at least four cycles of treatment; only one patient went off study because of toxicity. For 18 patients with measurable disease, there were two complete and two partial responses in patients ages 32, 66, 72 and 83 years, for a response rate of 22% (6% to 48%; 95% confidence interval [Ci]). The median survival for all 21 evaluable patients enrolled in the trial was 8.5 months. CONCLUSION: The hybrid schedule of drug delivery in NBSG 92-09 allowed the same dose and intensity of IL-2 to be delivered over 3 days instead of 5 days, which resulted in fewer days of hospitalization and therefore decreased cost; but with no increase in toxicity and no decrease in efficacy in patients with metastatic melanoma.

Adult↗
PubMed1997

Hybrid high-dose bolus/continuous infusion interleukin-2 in patients with metastatic renal cell carcinoma: a phase II trial of the National Biotherapy Study Group.

BACKGROUND: Interleukin-2 (IL-2) is an active agent for the treatment of renal cell carcinoma. In animal studies, polyethylene glycol conjugated (PEG) IL-2 was found to be effective in certain IL-2-resistant models. When bolus/infusion IL-2 was administered to approximate the pharmacokinetics of PEG-IL-2, resistance was also overcome in these models. Based on these observations, the National Bio-therapy Study Group (NBSG) previously had conducted a pilot study (NBSG 90-01) and then a phase I trial of a hybrid regimen of bolus IL-2 followed by continuous IL-2 (NBSG 91-04). METHODS: In the current study, NBSG 92-09, a phase II trial was conducted in patients with metastatic renal cell carcinoma using IL-2 at a dose of 36 MIU/m2 followed by a 72-hour continuous infusion of IL-2 at 18 MIU/m2 per day, so that over 3 days a total of 90 MIU/m2 of IL-2 were delivered; the same amount as previously given during 5 days of continuous intravenous (i.v.) IL-2 at 18 MIU/m2 per day. This was repeated every 2 weeks for 2 months, and then monthly for up to 4 months. RESULTS: Thirty-one patients with a median age of 62 years were enrolled in this trial. During the first 4 biweekly treatments, the percentages of planned IL-2 administered were 98% for 31 patients, 99% for 27, 98% for 23, and 99% for 20 patients. Toxicities were qualitatively the same as those seen with other IL-2 regimens. During the first 2 months, 4 patients ceased treatment because of rapidly progressive disease while 7 patients stopped because of toxicity; 5 of the 7 were > 65 years of age. At the time of formal reassessment after 2 months of treatment, 7 additional patients had progressive disease for a treatment failure rate of 55% prior to monthly maintenance therapy. There were two partial responses among 22 patients who had measurable disease for a response rate of 9% (1 to 29%, 95% CI). Median survival was 10.2 months and failure-free survival (FFS) 3.4 months for the entire group. CONCLUSION: The response rate seen with this regimen is similar to those of other schedules of IL-2 requiring more prolonged hospitalization. This hybrid bolus/continuous infusion IL-2 schedule appears to be an equally effective and less expensive schedule of IL-2 administration than previously reported inpatient regimens. However, it is not likely that this regimen is superior to outpatient combination biotherapy regimens which are currently under investigation.

Adult↗
PubMed1997

Tumor localization by tumor infiltrating lymphocytes labeled with indium-111 in patients with metastatic renal cell carcinoma, melanoma, and colorectal cancer.

BACKGROUND: Adoptive immunotherapy with autologous tumor infiltrating lymphocytes (TIL) is a promising approach for cancer bio-therapy. One issue, however, is whether such cells actually migrate to sites of tumor after intravenous infusion. There have been several reports of tumor uptake of radiolabeled TIL in patients with metastatic melanoma, but efforts to visualize tumor with radiolabeled TIL in other tumor types reportedly have been unsuccessful. METHODS: Eight patients with metastatic cancer (5 renal, 2 melanoma, 1 colon) received an intravenous infusion of 2 to 100 billion autologous TIL, including 50 million TIL which had been conjugated to 500 microCi Indium-111, co-administered with interleukin-2 (IL-2). One patient received 1 gm/m2 of cyclophosphamide one day prior to TIL; seven patients received interferon alpha 2b for 4 days prior to receiving TIL. Total body gamma camera imaging, including single photon emission computerized tomography (SPECT), was performed at 24 and 48 hours. RESULTS: All eight patients had demonstrable uptake of 111-Indium-labeled TIL into one or more known sites of tumor. There were no known sites of tumor which were not imaged. Metastatic sites imaged included bone, brain, mediastinal and perihilar lymph nodes, lung and liver parenchyma, abdominal periaortic nodes, and a pelvic mass. One patient served as a negative control in that the TIL scan was negative at a time when she had no evident disease, but a few weeks later had a positive TIL scan which lead to a diagnosis of axillary recurrence. CONCLUSION: Uptake of radiolabeled TIL, whether CD8+ or CD4+, by metastatic renal cell carcinoma and other carcinomas was similar to that previously reported in melanoma. Pretreatment with cyclophosphamide was not a prerequisite for imaging, and TIL uptake did not predict tumor response.

Adult↗
PubMed1997

Characterization of tumor-infiltrating lymphocytes derived from human tumors for use as adoptive immunotherapy of cancer.

From 1991 to 1995, we initiated cultures of 94 fresh tumor samples of various histologies in an effort to grow tumor-infiltrating lymphocytes (TIL) using flasks and subsequent expansion in semipermeable bags. The five most prevalent tumor types from which TIL were successfully initiated were melanoma (25 successful initiates in 34 tumor samples, 74% success rate), colorectal cancer (12 of 18, 67%), renal cell carcinoma (9 of 12, 75%), breast (4 of 5, 80%), and sarcoma (5 of 7, 71%). The overall success rate for all tumors was 67 of 94 (71%). There were no instances of contamination from the time of culture initiation through harvesting of the final cell product for clinical use. The mean number of days to reach successful initiation (> 5 x 10(8) cells) was 35 +/- 24 days (mean +/- SD). TIL were then expanded from these successful initiates for either a repeated low-dose therapy (TIL reinfusion numbers of 5 x 10(8)-5 x 10(9) or for a repeated high-dose therapy (> 5 x 10(9)-5 x 10(10). The mean number of days to expand a TIL culture from the time of initiation to treatment for a first low-dose TIL was 59 days (range, 27-94 days) compared with 80 days (range, 33-209 days) for high-dose TIL. For patients who received a second or third high-dose TIL treatment, the average number of days needed to expand TIL was 39 days (n = 10) if there was no intervening cryopreservation of TIL, compared with 49 days (n = 10) if the culture had to be reestablished from cryopreserved TIL. For patients who received a second or third low-dose TIL, the mean number of days needed to expand TIL was 23 days (n = 3) if there was no intervening cryopreservation compared with 42 days (n = 17) if cultures had to be reestablished after cryopreservation of TIL. Low-dose TIL displayed predominantly CD4+ phenotype in 76% of 42 cultures, whereas high-dose TIL displayed predominantly CD8+ phenotype in 84% of 44 cultures. Cells bearing the natural killer (NK) phenotype (CD3-, CD56+) and the lymphokine activated killer (LAK) phenotype (CD3+, CD56+) were present in both low- and high-dose TIL cultures, but these phenotypes were never predominant. Cytotoxicity testing consistently demonstrated the persistence of NK and LAK activity in addition to the killing of allogeneic and autologous melanoma tumor targets. This work confirms that TIL cultures from most tumor types can be successfully established and expanded for therapeutic use, and repeated expansion from continuous TIL culture or cryopreserved TIL for repeated treatments is feasible. Such cultures are predominantly T lymphocytes that are phenotypically heterogeneous, and these phenotypes do not remain constant during prolonged time in culture.

CD4-Positive T-Lymphocytes↗
PubMed1996

Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial.

BACKGROUND: For many years, high dose radiation therapy was the standard treatment for patients with locally or regionally advanced non-small-cell lung cancer (NSCLC), despite a 5-year survival rate of only 3%-10% following such therapy. From May 1984 through May 1987, the Cancer and Leukemia Group B (CALGB) conducted a randomized trial that showed that induction chemotherapy before radiation therapy improved survival during the first 3 years of follow-up. PURPOSE: This report provides data for 7 years of follow-up of patients enrolled in the CALGB trial. METHODS: The patient population consisted of individuals who had clinical or surgical stage III, histologically documented NSCLC; a CALGB performance status of 0-1; less than 5% loss of body weight in the 3 months preceding diagnosis; and radiographically visible disease. Patients were randomly assigned to receive either 1) cisplatin (100 mg/m2 body surface area intravenously on days 1 and 29) and vinblastine (5 mg/m2 body surface area intravenously weekly on days 1, 8, 15, 22, and 29) followed by radiation therapy with 6000 cGy given in 30 fractions beginning on day 50 (CT-RT group) or 2) radiation therapy with 6000 cGy alone beginning on day 1 (RT group) for a maximum duration of 6-7 weeks. Patients were evaluated for tumor regression if they had measurable or evaluable disease and were monitored for toxic effects, disease progression, and date of death. RESULTS: There were 78 eligible patients randomly assigned to the CT-RT group and 77 randomly assigned to the RT group. Both groups were similar in terms of sex, age, histologic cell type, performance status, substage of disease, and whether staging had been clinical or surgical. All patients had measurable or evaluable disease at the time of random assignment to treatment groups. Both groups received a similar quantity and quality of radiation therapy. As previously reported, the rate of tumor response, as determined radiographically, was 56% for the CT-RT group and 43% for the RT group (P = .092). After more than 7 years of follow-up, the median survival remains greater for the CT-RT group (13.7 months) than for the RT group (9.6 months) (P = .012) as ascertained by the logrank test (two-sided). The percentages of patients surviving after years 1 through 7 were 54, 26, 24, 19, 17, 13, and 13 for the CT-RT group and 40, 13, 10, 7, 6, 6, and 6 for the RT group. CONCLUSIONS: Long-term follow-up confirms that patients with stage III NSCLC who receive 5 weeks of chemotherapy with cisplatin and vinblastine before radiation therapy have a 4.1-month increase in median survival. The use of sequential chemotherapy-radiotherapy increases the projected proportion of 5-year survivors by a factor of 2.8 compared with that of radiotherapy alone. However, inasmuch as 80%-85% of such patients still die within 5 years and because treatment failure occurs both in the irradiated field and at distant sites in patients receiving either sequential chemotherapy-radiotherapy or radiotherapy alone, the need for further improvements in both the local and systemic treatment of this disease persists.

Antineoplastic Agents, Phytogenic↗
PubMed1996

High-dose chemotherapy with autologous stem cell rescue in breast cancer.

BACKGROUND: Because metastatic breast cancer is a lethal disease despite some responsiveness to systemic chemotherapy, high-dose chemotherapy with autologous stem cell rescue is being utilized with increasing frequency. This analysis was undertaken to determine the outcome for such patients treated with intensive chemotherapy between 1989-1994, at the Hoag Cancer Center in Newport Beach, CA. METHODS: During 1989, only patients with metastatic disease who had failed more than two standard breast cancer chemotherapy regimens were considered eligible for such treatment. They received high-dose BCNU/cyclophosphamide/cisplatinum chemotherapy with autologous bone marrow rescue. After January 1990, patients with metastatic disease were eligible only if they had received limited prior chemotherapy and demonstrated responsiveness to induction chemotherapy. Beginning June 1990, patients with metastatic disease were to receive mitoxantrone and thiotepa (MiTepa) followed by peripheral blood stem cell rescue, then ifosfamide, carboplatin and etoposide (ICE) chemotherapy followed by peripheral blood stem cell rescue. High-risk adjuvant patients were to receive one course of ICE followed by rescue. RESULTS: Between 1/89-12/94, 48 breast cancer patients underwent 65 intensive chemotherapy treatments followed by autologous stem cell rescue. During 1989, three of the eight patients with metastatic disease died within 60 days because of therapy-related complications. The longest failure-free survival (FFS) of these eight was 12.2 months, and the longest overall survival (OS) 20.5 months. Since 1/90, one physician has treated 24 patients with metastatic breast cancer, 17 of whom actually underwent two successive transplants with MiTepa/ICE. For the latter group, median FFS is 23.2 months; median OS is 39.7 months. There were no acute deaths, but two patients died > 60 days after initial transplant from therapy-related complications, veno-occlusive disease (5.2 months) and myelodysplastic syndrome (30.5 months), while five died of progressive disease at 22.5, 32.8, 39.4, 46.3, and 51.3 months. For the 24 metastatic patients treated 1990-1994, 1-, 2-, and 3-year FFS rates are 86%, 40%, and 17%, respectively, while OS rates are 91%, 80%, and 65%. Of 11 patients treated in the adjuvant setting, only one has relapsed (9.8 months) with follow-up from 3-61 months. CONCLUSIONS: Modifications made in the program, including selection of patients responsive to induction chemotherapy, transfusion of peripheral blood stem cells, implementation of hematopoietic colony stimulating factors, and use of tandem intensive treatments has been associated with a low rate of acute morbidity and encouraging survival rates.

Adult↗