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[Current status of the neo-adjuvant and adjuvant therapy for the resectable non-small cell lung cancer].

Generally, the surgical resection has been considered to be the standard therapy for the clinical Stage I-IIIA non-small cell lung cancer (NSCLC). However, the 5 year-survival rate has been reached approximately less than 20%. To improve the prognosis, especially for the Stage IIIA NSCLC, many clinical trials have been performed to assess the availability of the chemotherapy or radiation therapy in the preoperative or postoperative period. Although some clinical trials concerning about the neo-adjuvant therapy have reported the improvement of the postoperative survival rate, the availability of both neo-adjuvant and adjuvant therapy is still controversial. Further assessment for the well designed phase III clinical trials will be necessary to establish the availability of such modalities for the treatment of respectable NSCLC.

Antineoplastic Combined Chemotherapy Protocols↗

High-grade gliomas: results in patients treated with adjuvant radiotherapy alone and with adjuvant radio-chemotherapy.

BACKGROUND: Despite advances in the surgical, radiotherapeutic and chemotherapeutic fields, the outcome for patients with high-grade gliomas remains poor. Our experience of patients treated with and without chemotherapy is reported. MATERIALS AND METHODS: From April 1999 to July 2003, 30 patients with high-grade gliomas were treated: 13 received adjuvant radiotherapy (RT) alone whereas 17 received temozolomide 75 mg/m2/d during the irradiation time and 200 mg/m2 daily per 5 consecutive days, every 28 days for three to six cycles, starting 4 weeks after the end of radiotherapy. RESULTS: The median follow-up was 12.5 months. The median overall survival (OS) was 15 months. In patients treated with RT plus chemotherapy, no statistical difference was observed between those who had undergone partial surgical resection and those with total resection (p=0.5128). In patients with glioblastoma multiforme (GBM) treated with combined radiochemotherapy, the median OS was 18 months, while it was 7 months (p=0.0204) in those treated without chemotherapy. Multivariate analysis (Cox model) evidenced statistical differences for performance status (p =0.002) and for the type of adjuvant therapy (p=0.006). CONCLUSION: Radio-chemotherapy plus adjuvant temozolomide seemed to offer the best results in patients not submitted to debulking surgery. The performance status remained the most important prognostic factor. Tolerance to the combined regimen was very good.

Adult↗

Delayed-type hypersensitivity in rabbits. Comparison of the adjuvants dimethyl dioctadecyl ammonium bromide and Freund's complete adjuvant.

Injection of rabbits with antigen mixed with the cationic surface-active lipid dimethyl dioctadecyl ammonium bromide (DDA) induced delayed-type hypersensitivity (DH), which could be measured as skin reactions and was confirmed by histology of the skin test sites. 1 week after injection of a conjugate of bovine serum albumine (BSA) with dinitrophenol (DNP30-BSAj) mixed with DDA, DH was detectable in most but not in all rabbits. Similar results were obtained using FCA as adjuvant. The animals treated with the latter adjuvant, however, produced a long-lasting DH (1-3 weeks) complicated by circulating anti-DNP antibodies (Arthus-type reactions). Skin testing with heterologous hapten-carrier complexes revealed that individual rabbits immunized with DNP30-BSA in DDA expressed DH with different reaction patterns, either to hapten, carrier or both. In conclusion, DDA is a useful adjuvant for the induction of a state of pure DH in rabbits. However, not all rabbits do respond, or respond similarly.

Adjuvants, Immunologic↗

Balance of Th1/Th2 cytokines associated with the preventive effect of incomplete Freund's adjuvant on the development of adjuvant arthritis in LEW rats.

Complete Freund's adjuvant (CFA) could induce adjuvant arthritis (AA) in LEW rats and incomplete Freund's adjuvant (IFA) could induce oil induced arthritis (OIA) in DA but not in LEW rats. Lymph node cells (LNCs) from these AA and OIA rats showed increased mRNA expression of IFN-gamma, IL-2 and TNF-alpha but not IL-4. LNCs from IFA immunized LEW rats showed increased expression of IL-4, reduced expression of IFN-gamma and TNF-alpha and no IL-2, in contrast to IFA immunized DA rats. The pretreatment of IFA before CFA challenge could completely prevent AA in LEW rats and their LNCs showed increased expression of IL-4 and IFN-gamma but not IL-2 and TNF-alpha. In F1 (LEW x DA) rats, IFA could not induce OIA but the pretreatment of IFA before CFA challenge could induce very mild AA with 80% incidence, LNCs showing an elevated expression of all the above cytokines. These findings suggest that increased Th1 cytokine expression is associated with disease development and that increased IL-4 expression or the balance of Th2 over Th1 cytokine expression plays an important regulatory role in disease development.

Animals↗

Influence of hydrophobicity on the adjuvant effect of particulate polymeric adjuvants.

The hydrophobicity of particulate polymeric acrylic adjuvants was altered by insertion of hydroxyl groups, exchange of a methyl group against a cyano group or elongation of the ester side chain length. These adjuvants were tested by determination of the antibody response after immunization using bovine serum albumin or by measuring the protection against infection using influenza as the antigen. In addition, the hydrophobicity was determined by measurement of the water contact angles. The adjuvant effect increased with increasing hydrophobicity.

Adjuvants, Immunologic↗

Postoperative adjuvant randomised trial comparing chemoendocrine therapy, chemotherapy and immunotherapy for patients with stage II breast cancer: 5-year results from the Nishinihon Cooperative Study Group of Adjuvant Chemoendocrine Therapy for Breast Cancer (ACETBC) of Japan.

Between 1985 and 1988, the effect of using ftorafur (FT) or PSK (an immunotherapy agent) in combination with the conventional postoperative adjuvant therapy using mitomycin (MMC) plus tamoxifen (TAM) was assessed in stage II, oestrogen receptor-positive (ER+) breast cancer patients. Furthermore, in ER- breast cancer stage II patients, the effects of postoperative adjuvant therapy using MMC plus FT were compared with the effects of postoperative adjuvant therapy using MMC plus PSK. Patients had primary stage II breast cancer and had undergone total mastectomy plus axillary dissection or more radical surgery. On the day of surgery, MMC (13 mg/m2) was administered intravenously. Then, ER+ patients received one of three regimens of drug therapy, starting 2 weeks after surgery: regimen A (daily oral treatment with 30 mg of TAM), regimen B (daily oral treatment with 30 mg of TAM and 600 mg of FT) or regimen C (daily oral treatment with 30 mg of TAM and 3 g of PSK) [corrected]. ER- patients received either regimen D (daily oral treatment with 600 mg of FT) or regimen E (daily oral treatment with 3 g of PSK), starting 2 weeks after surgery. Of the 540 ER+ patients registered, 525 were evaluated. The 5-year overall survival rate for ER+ patients was higher for patients who received regimen B (94.2%) than for those who received regimen A (86.9%) or regimen C (89.9%) (P = 0.063). The 5-year relapse-free survival rate was higher for regimen B (88.9%) than for regimen A (78.6%) and regimen C (77.2%) (P = 0.010). Stratified analysis revealed better results with the FT-combined therapy in patients positive for lymph node metastasis and premenopausal patients. These results indicate the effectiveness of using FT in combination with TAM. Of the 376 ER- patients registered, 364 were evaluated. The 5-year overall and relapse-free survival rate for ER- patients did not differ significantly between patients who received regimen D and those who received regimen E.

Adult↗

The efficacy of CpG oligodinucleotides, in combination with conventional adjuvants, as immunological adjuvants to swine streptococcic septicemia vaccine in piglets in vivo.

Oligodinucleotides containing CpG motifs (CpG ODN) are strong adjuvants for immune responses, particularly in mice, the immunostimulatory effects of CpG in combination with aluminum hydroxide (alum) or Emulsigen (Em) were investigated in cattle, rabbits or mice, but not piglets. In this report, using the swine streptococcus as model bacteria, the efficacy of CpG ODN as an adjuvant for piglets was assessed alone and in combination with alum (CpG/alum) or Em (CpG/Em). The CpG/alum or CpG/Em combination elicited greater immune responses to swine streptococcic septicemia killed vaccine (SSSK vaccine) compared with CpG alone, or alum or Em. A GpC/alum or GpC/Em combination did not have the same effects as CpG/alum or CpG/Em suggesting that the adjuvanticity was related to the CpG motifs. In addition, we also found that the 10% Em in combination with CpG ODN had similar immunological effects as 30% Em combination. Our results demonstrate that the addition of CpG ODN to alum or to Em significantly improves the efficiency of the adjuvants in piglets.

Adjuvants, Immunologic↗

Comparison of the safety, tolerability, and immunogenicity of a MF59-adjuvanted influenza vaccine and a non-adjuvanted influenza vaccine in non-elderly adults.

The adjuvanted influenza vaccine FLUAD is composed of subunit influenza antigens combined with the MF59-adjuvant emulsion. The vaccine was developed primarily for use in elderly populations, but non-elderly individuals might also benefit. To evaluate this hypothesis, 301 healthy adults were assigned randomly to receive two intramuscular injections of either FLUAD (150 subjects) or a non-adjuvanted vaccine, Fluzone (151 subjects), in two trials conducted at a 1-year interval. Injections consisted of 15 micrograms per 0.5 ml dose. Vaccine composition was A/Texas/36/91 (H1N1), A/Johannesburg/33/94 (H3N2), and B/Harbin/7/94 for the first injection and A/Texas/36/91 (H1N1), A/Nanchang/933/95 (H3N2), and B/Harbin/7/94 for the second injection. Immunogenicity was evaluated at 28 and 180 days post-immunization. FLUAD was generally well tolerated in healthy adults when compared with Fluzone. FLUAD was associated with increased pain at the injection site after immunization. A statistically significant increase in the incidence of injection-site warmth, chills, myalgia, and analgesic/antipyretic use occurred in the FLUAD group after the first injection but not after the second injection. In both groups, most of these local and systemic reactions were classified as mild. FLUAD was more immunogenic than Fluzone following both injections. After the first injection, statistically significant differences were found in the percentage of subjects with four-fold rises in hemagglutinin inhibition (HI) titers at 28 days post-immunization for the B antigen. After the second injection, the FLUAD group had significantly higher HI titers, a significantly higher percentage with a four-fold increase in titer, and a significantly greater percentage of subjects with titers >/=160 for the H3N2 antigen at 28 days. Only minor immunogenicity differences between the two groups were seen at 180 days. Compared with Fluzone, FLUAD was associated with increased immunogenicity and mild post-immunization reactions in healthy adults. The magnitude of increased immunogenicity in healthy adults was less than that seen in elderly populations.

Adjuvants, Immunologic↗

A bovine ephemeral fever vaccine incorporating adjuvant Quil A: a comparative study using adjuvants Quil A, aluminium hydroxide gel and dextran sulphate.

Various vaccines containing the 919 strain of ephemeral fever virus were evaluated in experimental calves and in commercial cattle. The vaccine virus was mixed with one of the adjuvants, Quil A (a saponin derivative), aluminium hydroxide gel, dextran sulphate or combinations of these. The response of experimental calves was evaluated by measuring the production of neutralising antibodies and by resistance to challenge with virulent virus; the response of commercial cattle was judged only by the production of neutralising antibody. Twelve calves given two doses of vaccine containing Quil A produced neutralising antibodies to bovine ephemeral fever virus and all were resistant to challenge with virulent virus given 28 to 76 days after the second vaccination. The vaccine given in three of these calves also contained aluminium hydroxide gel. Six of eight unvaccinated control calves succumbed to experimental challenge. In commercial cattle (17 to 26 animals per group) the serological response after two doses of vaccine containing Quil A or Quil A and dextran sulphate was significantly better than that after vaccines containing only dextran sulphate or after vaccines containing combinations of aluminium hydroxide gel and Quil A. The adjuvant Quil A alone was tested in cattle and shown to produce a transient soft swelling at the injection site as well as a rise in rectal temperature of greater than 1 degree C one day after inoculation. At least 99.99 per cent of viral infectivity was destroyed when the vaccine was mixed with Quil A, suggesting that live virus may not be essential in the immunogenicity of the vaccine. This vaccine overcame two of the problems associated with previous attenuated vaccines tested in Australia; the necessity for adjuvant and virus to be mixed immediately before use and the large volume of the vaccine.

Adjuvants, Immunologic↗

Long-term cardiac follow-up in relapse-free patients after six courses of fluorouracil, epirubicin, and cyclophosphamide, with either 50 or 100 mg of epirubicin, as adjuvant therapy for node-positive breast cancer: French adjuvant study group.

PURPOSE To evaluate long-term cardiac function in patients without disease who had received six cycles of fluorouracil 500 mg/m(2), epirubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC 50) or the same regimen with epirubicin 100 mg/m(2) (FEC 100) as adjuvant chemotherapy for node-positive breast cancer in the French Adjuvant Study Group-05 trial. PATIENTS AND METHODS One hundred fifty patients (FEC 50, n = 65; FEC 100, n = 85) who were without disease and who gave their informed consent were enrolled for long-term cardiac assessment. The assessment included cardiac events occurring after the end of chemotherapy, vital signs, concomitant disease, ECG, isotopic left ventricular ejection fraction (LVEF), and echographic parameters. Abnormal files were blindly reviewed by cardiologists and oncologists. Results The median follow-up time was 102 months. After FEC 100, LVEF was less than 50% in five patients (radioisotopic method), and two patients experienced congestive heart failure (CHF) that was possibly related to treatment. Asymptomatic left ventricular dysfunction (LVD) was experienced in 18 patients after FEC 100 and in one patient after FEC 50. In these patients, treatment causality was probable in eight patients. Two additional years after this assessment, all 18 patients were still asymptomatic. CONCLUSION After more than 8 years of follow-up, the cardiac toxicity observed after adjuvant treatment with FEC 100 comprised two cases of well-controlled CHF and 18 cases of asymptomatic LVD. In the majority of women with primary breast cancer, the benefits of treatment with FEC 100 in terms of disease-free and overall survival outweigh the risks, and cardiac risk factors should be carefully evaluated in patient selection.

Adult↗

Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial.

PURPOSE: The French Adjuvant Study Group 05 (FASG-05) showed that fluorouracil 500 mg/m2, cyclophosphamide 500 mg/m2, and epirubicin 100 mg/m2 (FEC 100) was superior to the same regimen with epirubicin 50 mg/m2 (FEC 50) in terms of disease-free survival (DFS) and overall survival (OS) in adjuvant treatment of early breast cancer. We report 10-year data on efficacy, and long-term side effects for FASG-05. PATIENTS AND METHODS: We randomly assigned 565 patients to treatment with FEC 50 or FEC 100 after surgery. Postmenopausal patients also received tamoxifen for 3 years, and almost all patients (96%) also received radiotherapy. RESULTS: Median follow-up was 110 months. The 10-year DFS was 45.3% (95% CI, 41.9% to 48.7%) with FEC 50 and 50.7% (95% CI, 47.3% to 54.1%) with FEC 100 (Wilcoxon P = .036; log-rank P = .08). The 10-year OS was 50.0% (95% CI, 46.7% to 53.3%) with FEC 50 and 54.8% (95% CI, 51.3% to 58.3%) with FEC 100 (Wilcoxon P = .038; log-rank P = .05). Delayed cardiac toxicity (before relapse) occurred in four patients (1.5%) in the FEC 50 arm and three patients (1.1%) in the FEC 100 arm. Cardiac toxicity after relapse occurred in six (4.3%) and five (4.1%) patients treated with FEC 50 and FEC 100, respectively. CONCLUSION: Treatment with adjuvant FEC 100 demonstrated superior DFS and OS versus FEC 50 at 10 years of follow-up. This survival advantage was not offset by long-term complications such as cardiac toxicity and second malignancy. Given the risk-benefit ratio, FEC 100 is a more optimal regimen for long-term survival in patients with poor prognosis.

Adult↗

[Serological response of the dog after primary antirabies vaccination using adjuvant or non-adjuvant vaccines].

The serological responses following a primary vaccination carried out one year before in two groups of dogs which received an inactivated cell culture vaccine containing or not an adjuvant (alumine-hydroxide) are compared. Neutralizing antibody titers assayed in mice, obtained with only one injection of the adjuvanted vaccine are at the same or a greater level than those induced by two injections of the non-adjuvanted vaccine administered two to four weeks apart (statutory schedule of rabies primary vaccination applied in France).

Adjuvants, Immunologic↗

Randomized trial of adjuvant tamoxifen combined with postoperative radiation therapy or adjuvant chemotherapy in postmenopausal breast cancer.

From 1976 to 1984, 427 postmenopausal women with high-risk breast cancer (pN + or pT greater than 30 mm) were randomized between postoperative radiation therapy (RT), radiation therapy plus tamoxifen (RT-TAM), adjuvant chemotherapy (CT), or chemotherapy plus tamoxifen (CT-TAM). Surgery was a modified radical mastectomy in all cases. The radiation therapy was given with high-voltage techniques and included the chest wall and regional nodes. The dose was 4600 cGy/4 1/2 weeks. Tamoxifen was given at a dose of 40 mg daily for 2 years. The adjuvant chemotherapy consisted of 12 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (or chlorambucil, methotrexate, and 5-fluorouracil [LMF] for patients entered before 1978). At a median follow-up time of 6 1/2 years the recurrence-free survival was significantly better for patients allocated to radiation therapy compared to chemotherapy and for patients allocated to tamoxifen compared to no adjuvant endocrine treatment (P less than 0.01). At 10 years the recurrence-free survival for patients in the RT-TAM, RT, CT-TAM, and CT groups was 63%, 57%, 47%, and 31%, respectively. A significant reduction of treatment failures with tamoxifen was only observed among patients with estrogen receptor-positive tumors. The overall survival difference in favor of patients allocated to radiation therapy or tamoxifen was not significant: the respective survival percentage at 10 years in the RT-TAM, RT, CT-TAM, and CT group was 65%, 62%, 52%, and 50%. The results indicate that postoperative radiation therapy continues to play an important role in the primary management of postmenopausal women with high-risk breast cancer and that the addition of tamoxifen may further improve the results among ER-positive patients.

Aged↗

Adjuvant polyarthritis. VIII. Differences in immunopathogenesis between type II collagen arthritis and adjuvant arthritis.

The severity of type II collagen-induced arthritis was found to correlate with the serum titers of anti-type II collagen antibody, but not with cell-mediated immunity to type II collagen. In contrast, no significant levels of either the humoral or the cell-mediated immunity to type II collagen were found in rats with Freund's complete adjuvant-induced arthritis. Pre-treatment of young rats with an oily preparation of type II collagen prevented the development of arthritis in these animals in response to a subsequent injection of oily preparation of type II collagen, but had no effect on the development of arthritis in response to a subsequent injection of Freund's complete adjuvant. It is concluded that while an immune response directed toward the injected type II collagen is responsible for the development of type II collagen arthritis, it does not play an important role in the induction of Freund's adjuvant-induced arthritis.

Animals↗

[Cooperative study of postoperative long-term adjuvant therapy of breast cancer. First study of a series--comparative study between postoperative tegafur administration and no adjuvant chemotherapy].

A prospective randomized study was performed in 22 institutions from July 1978, to evaluate the efficiency of long-term adjuvant chemotherapy with tegafur alone for primary breast cancer. Five hundred and eighty-seven eligible patients, classified into T1a, T2a, T3a, N0, N1a, N1b, and M0 were divided into two groups: Group A, radical mastectomy receiving no adjuvant chemotherapy; and Group B, radical mastectomy followed by 4 courses of adjuvant chemotherapy, each one consisting of daily administration of tegafur 600 mg p.o. for 8 weeks and 4 weeks rest. At the 66th month of median follow up time, there were no differences between the two groups on 5 year cumulative survival and disease free survival rate. In subgroup patients who have histologically 1-3 axillary involvements, there seemed to be a more meaningful prolongation of the disease-free interval in group B than in group A (logrank test; p = 0.11 generalized Wilcoxon test; p = 0.13).

Adenocarcinoma, Scirrhous↗

Systemic adjuvant therapy in treatment of primary operable breast cancer: National Surgical Adjuvant Breast and Bowel Project experience.

This report provides an overview of information presented by us at a recent National Institutes of Health Consensus Development Conference on Adjuvant Chemotherapy. The data, derived from 7 randomized clinical trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) since 1958, permit us to conclude that the use of systemic adjuvant therapy is of benefit in both premenopausal and postmenopausal patients with primary breast cancer. Data from the first NSABP trial begun in 1958 with short-course perioperative thiotepa demonstrated a long-term survival benefit in premenopausal but not postmenopausal patients. Ten-year findings from a second trial evaluating response to melphalan (P) implemented in 1972 indicated that, when related to age and nodes, there was a benefit from this drug in both the 1-3 and greater than or equal to 4 positive node premenopausal groups but those with fewer nodes were most improved. In this group characterized by premenopausal women with 1-3 positive nodes, mortality was reduced 64% with a cumulative odds ratio of 3.25 (P = .009) at 10 years after surgery. When related to nuclear grade, there was a striking benefit in survival from P in patients less than or equal to 49 and greater than or equal to 50 years with undifferentiated tumors. The addition of 5-fluorouracil (F) to melphalan (PF) resulted in an increase in disease-free survival and survival over that observed with P in patients less than or equal to 49 and greater than or equal to 50 years of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗

Adjuvant polyarthritis. VI. Effect of oxonate-induced hyperuricemia on the development of acute inflammation, immune response and adjuvant arthritis.

In humans, there is a negative correlation between gout and rheumatoid arthritis. Similarly, rats rendered hyperuricemic by an oxonate diet appeared resistant to develop adjuvant arthritis. These animals exhibited a normal inflammatory response to a subplantar injection of carrageenin and normal humoral and cell-mediated immune responses to a sensitizing dose of EL4 cells. However, unlike that of normal animals, the cell-mediated immune system of the oxonate-treated rats was found to be unable to respond to adjuvant stimulation, which may be the basis for their resistance to develop adjuvant disease.

Animals↗

Acute toxicity during adjuvant chemotherapy for breast cancer: the National Surgical Adjuvant Breast and Bowel Project (NSABP) experience from 1717 patients receiving single and multiple agents.

Since 1972, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has carried out a series of clinical trials evaluating the worth of adjuvant chemotherapy in the management of patients with primary breast cancer. This report provides information concerning (a) protocol compliance relative to drug administration and (b) acute toxicity encountered by patients in three separate trials who were given one-, two- or three-drug chemotherapy within 1 month of operation. The findings are derived from 1548 women who received 20,765 courses of chemotherapy, the most extensively documented experience yet reported. They indicate that despite the large number of physicians and the heterogeneity of the institutions participating, large cooperative efforts can be accomplished with credibility. Only 13 (0.8%) of the women failed to complete all courses of therapy for reasons directly related to nonprotocol compliance by physicians. Only 4.3% failed to complete therapy for miscellaneous reasons other than toxicity, treatment failure, occurrence of a second primary, or death unrelated to tumor. While almost all patients experienced toxic reactions during the therapy, only 3%--4% of recipients of melphalan (L-PAM; P) and 4%--5% of recipients of L-PAM + 5-FU(F)(PF) failed to complete 2 years of therapy because of toxicity. Of those patients receiving PF + methotrexate (MTX; M) (PMF), 15% did not finish their treatment for that reason. While there was little difference in hematologic and nonhematologic toxicity between those patients receiving P or PF, and such toxicity was generally acceptable to both patients and physicians, the addition of MTX (PMF) resulted in greater toxicity (vomiting, stomatitis, and alopecia) which was less readily accepted. Tolerance of any of these regimens was unrelated to patient age, despite the belief that older women are less tolerant of chemotherapy. The earlier toxicity occurred, the greater was the number of subsequent courses associated with toxicity, and the lower was the total amount of drug received. The extent of the toxicity produced by the NSABP regimens and the end results obtained with them, must be compared with the end results and toxicity obtained by other regimens before making a choice of the adjuvant therapy to be used.

Aged↗