isotretinoin and Bone-Neoplasms

Biologic response modifiers are becoming an important addition to surgery, chemotherapy, and radiotherapy in the management of cancer. As this field of research grows and expands, more biologic response modifiers will be incorporated into therapeutic regimens. By stimulating the immune system to eradicate minimal residual disease, these agents may improve the disease-free and long-term survival rates of patients with a variety of malignancies. The challenge is to incorporate biologic response modifiers into the treatment armamentarium in ways that will maximize their tumorigenicity.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adult; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cytokines; Drug Design; Hematopoietic Cell Growth Factors; Humans; Immunologic Factors; Immunotherapy; Infant; Interleukins; Isotretinoin; Liposomes; Neoplasms; Neuroblastoma; Osteosarcoma; Phosphatidylcholines; Phosphatidylethanolamines; Phosphatidylglycerols; Salvage Therapy; Sarcoma, Ewing

Anti-G(D2) murine antibody 3F8 plus subcutaneously (sc) administered granulocyte-macrophage colony-stimulating factor (GM-CSF) was used against primary refractory neuroblastoma in metastatic osteomedullary sites. Large study size and long follow-up allowed assessment of prognostic factors in a multivariate analysis not reported with other anti-G(D2) antibodies. In a phase II trial, 79 patients without prior progressive disease were treated for persistent osteomedullary neuroblastoma documented by histology and/or metaiodobenzyl-guanidine (MIBG) scan. In the absence of human antimouse antibody, 3F8 + scGM-CSF cycles were repeated up to 24 months. Minimal residual disease (MRD) in bone marrow was measured by quantitative reverse transcription-polymerase chain reaction pre-enrollment and post-cycle #2, before initiation of 13-cis-retinoic acid. Study endpoints were: (i) progression-free survival (PFS) compared with the predecessor trial of 3F8 plus intravenously administered (iv) GM-CSF (26 patients) and (ii) impact of MRD on PFS. Using all 105 patients from the two consecutive 3F8 + GM-CSF trials, prognostic factors were analyzed by multivariate Cox regression model. Complete response rates to 3F8 + scGM-CSF were 87% by histology and 38% by MIBG. Five-year PFS was 24 ± 6%, which was significantly superior to 11 ± 7% with 3F8 + ivGM-CSF (p = 0.002). In the multivariate analysis, significantly better PFS was associated with R/R or H/R FCGR2A polymorphism, sc route of GM-CSF and early MRD response. MYCN amplification was not prognostic. Complement consumption was similar with either route of GM-CSF. Toxicities were manageable, allowing outpatient treatment. 3F8 + scGM-CSF is highly active against chemoresistant osteomedullary neuroblastoma. MRD response may be an indicator of tumor sensitivity to anti-G(D2) immunotherapy. Correlative studies highlight the antineoplastic potency of myeloid effectors.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Gangliosides; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunoglobulin G; Infant; Isotretinoin; Male; Myeloid Cells; Neoplasm Staging; Neoplasm, Residual; Neuroblastoma; Prognosis; Survival Rate; Young Adult

The absence of iodine uptake in metastases of differentiated thyroid carcinoma makes them unresponsive to treatment with radioiodine 131I. In many of such cases symptomatic treatment remains the only available therapy. The results of studies on partial redifferentiation of metastases of thyroid cancer achieved after cis-retinoid acid therapy have drawn attention to the possibility of restoration of iodine uptake in metastases after pretreatment with cis-retinoic acid (Roaccutane). 5 patients with iodine uptake-negative metastases of differentiated thyroid carcinoma were given Roaccutane in a dose 1.5 mg/kg/24 h daily for 6 weeks before the therapy with radioiodine. In none of the patients restoration of radioiodine uptake in metastases has occurred as shown in post-therapeutic total body scintigraphy.

Topics: Adenocarcinoma, Follicular; Adult; Aged; Bone Neoplasms; Carcinoma, Papillary; Female; Humans; Iodine Radioisotopes; Isotretinoin; Lung Neoplasms; Premedication; Thyroglobulin; Thyroid Neoplasms

Retinoids, a large group of compounds structurally related to vitamin A, are able to induce redifferentiation of thyroid cancer cells. The aim of the study is to present our early results of retinoids redifferentiation therapy of thyroid cancer patients. In 15 patients with advanced thyroid cancer, whose cancer foci did not concentrate radioiodine, 13-cis retinoic acid (Roaccutan) was given for 6 weeks before radioiodine treatment. Radioiodine therapy was performed under exogenous TSH stimulation (Thyrogen). Three patients were treated twice. The planned retinoid dose was delivered to 11 patients. In the other four patients the reduction of retinoids dose was necessary due to severe side effects. In post-therapeutic scintigraphy radioiodine uptake was visible in two out of seven patients (29%) with lung metastases, in 5 out of 9 (56%) with locoregional disease and in two with bone metastases. On the whole, in 50% of patients reinduction of radioiodine uptake was visible, however, in most patients only a very discrete one. Thyroglobulin concentration before and after retinoids therapy did not differ significantly.. In a subgroup of patients 13-cis retinoic acid can induce radioiodine uptake, however, prospective studies in larger groups of patients are necessary to prove its clinical application.

Topics: Adult; Aged; Bone Neoplasms; Female; Humans; Iodine Radioisotopes; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Premedication; Thyroglobulin; Thyroid Neoplasms

Patients with high-risk neuroblastoma remain a therapeutic challenge with significant numbers of patients failing to respond sufficiently to initial therapy. These patients with poor response to induction are considered as ultra high-risk and are in need of novel treatment strategies. Isotretinoin is part of the standard of care treatment for patients with high-risk disease who undergo high-dose chemotherapy with autologous stem cell rescue although some have questioned the optimal administration schedule. Prolonged use of isotretinoin was well tolerated and may have contributed to long-term survival in a group of patients with ultra high-risk neuroblastoma.

Topics: 3-Iodobenzylguanidine; Adrenal Gland Neoplasms; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Drug Administration Schedule; Fatal Outcome; Female; Ganglioneuroblastoma; Hematopoietic Stem Cell Transplantation; Humans; Isotretinoin; Maintenance Chemotherapy; Male; Neuroblastoma; Remission Induction; Risk; Transplantation, Autologous

From January 2004 to December 2008, 50 consecutive patients with high-risk neuroblastoma were assigned to receive tandem HDCT (high-dose chemotherapy)/auto-SCT after nine cycles of induction chemotherapy. CEC (carboplatin + etoposide + cyclophosphamide) regimen and TM (thiotepa + melphalan)-TBI regimen (or TM regimen for stage 3 patients) were the first and second HDCT regimens. Local radiotherapy, differentiation therapy with 13-cis-retinoid acid and immunotherapy with interleukin-2 were given after tandem HDCT/auto-SCT. Of the 50 patients, 49 underwent a first HDCT/auto-SCT and 47 underwent a second HDCT/auto-SCT. The tumor relapsed or progressed in 14 patients, secondary malignancy developed in one patient and one patient died from chronic lung disease. Therefore, 34 patients remained event free with a median follow-up of 54.5 months (range, 14-94 months) from diagnosis. The probabilities of 5-year OS and EFS for all 50 patients were 77.0% (95% confidence interval (CI), 63.7-90.3) and 71.4% (95% CI, 58.7-84.1), respectively. However, all patients who remained event free for >3 years after tandem HDCT/auto-SCT experienced late adverse effects. Chemotherapeutic dose-escalation strategy using tandem HDCT/auto-SCT was very encouraging for survival. However, further studies incorporating newer treatment modalities are needed to reduce late adverse effects without jeopardizing the survival rate.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Combined Modality Therapy; DNA Copy Number Variations; Feasibility Studies; Humans; Induction Chemotherapy; Infant; Interleukin-2; Isotretinoin; N-Myc Proto-Oncogene Protein; Neoplasm Proteins; Neoplasm Staging; Neuroblastoma; Nuclear Proteins; Oncogene Proteins; Prognosis; Prospective Studies; Radiotherapy; Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous; Whole-Body Irradiation

Liarozole fumarate (R85,246), a novel benzimidazole derivative, reduced s.c. and bone metastasis tumor growth by the androgen-independent PC-3ML-B2 human prostatic carcinoma clone in SCID mice. The drug inhibited cell invasion of Matrigel in Boyden chamber chemotactic assays and the secretion of type IV collagenase. In vitro, liarozole failed to inhibit cell proliferation and cell attachment to various substrates (Matrigel, laminin, type IV collagen, and fibronectin). In vivo, the drug also blocked type IV collagenase production in established s.c. tumors. Liarozole has been postulated by others (R. De Coster, W. Wouters, R. Van Ginckel, D. End, et al. J. Steroid Biochem. Mol. Biol., 43: 197-201, 1992) to inhibit retinoic acid catabolism. Our data indicate that liarozole treatment can increase the tumor retinoic acid levels in vivo. Studies of retinoic acid revealed that the drug independently reduced tumor growth in vivo and inhibited cell invasion of Matrigel and the secretion of collagenase IV. Surprisingly, liarozole and retinoic acid failed to exhibit measurable synergistic activity both in vitro and in vivo. Taken together these data suggest that liarozole might inhibit retinoic acid catabolism in vivo and consequently have significant therapeutic value as an anti-prostatic tumor agent.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cell Adhesion; Cell Division; Cell Survival; Chemotactic Factors; Collagenases; Disease Models, Animal; Humans; Imidazoles; Isotretinoin; Male; Matrix Metalloproteinase 9; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Transplantation; Prostatic Neoplasms; Tumor Cells, Cultured