Administration Of Dacarbazine Research Articles

Two cases of malignant melanoma with tumor regression after dacarbazine administration following immune checkpoint inhibitors

根治切除不能の悪性黒色腫にて，免疫チェックポイント阻害薬（ICI）が無効になった際の治療選択が問題となる。近年，二次治療をはさむことにより，ICIの効果を再度期待できる症例が報告されている。今回，二次治療としてダカルバジンを投与した症例を2例経験した。症例1は83歳，女性。原発巣切除後にニボルマブ術後補助療法を施行。転移が出現したため，ダカルバジンに変更したところ，転移の縮小がみられた。ニボルマブ投与再開後も，腫瘍縮小を認め，最終的に消失した。症例2は78歳，男性。口腔内悪性黒色腫に対してニボルマブ・イピリムマブ併用療法施行したが，転移出現。その後のダカルバジン投与にて一時的に縮小を認めた。しかし再増大に転じ，ニボルマブに変更後も腫瘍は増悪し死亡した。症例1においては，二次治療にてニボルマブの効果は再出現した。また両症例ともダカルバジンそのものの効果も高まっていると考えられた。

IMMU-09. NIVOLUMAB THERAPY FOR A PEDIATRIC-ONSET PRIMARY INTRACRANIAL MELANOMA

Primary intracranial malignant melanoma (PIMM) is an uncommon cancer in childhood, that accounts for approximately 1% of melanoma, and 0.07% of brain tumors even in all age group. Because extracranial malignant melanoma usually occurs as a cutaneous lesion, affected patients have a chance to receive the early diagnosis and curable resection of the isolated tumor. However, unresectable metastatic cases have a poor prognosis with a median overall survival of 8 months. We report a 12-year-old girl with PIMM who received nivolumab therapy after an administration of dacarbazine. The tumor harbored no BRAF mutation. After the intravenous administration of nivolumab, cerebrospinal fluid 5-S-cysteinyldopa levels declined and circulating CD8+HLA-DR+T cells increased, indicating the initial effect of nivolumab on PIMM. However, multiple lesions progressed for two month-immunotherapy, during which cerebrospinal fluid nivolumab concentrations attained to 1.2% of serum ones. The present case demonstrated the safety and modest effect of nivolumab for CNS melanoma. Nivolumab is a tolerable first-line therapy for diffuse PIMM, but pediatric patients need a more intensified CNS-specific immunotherapy.

Combination of DTIC and peptide-vaccination elicit a renewal of high-avidity late-differentiated T-cell clones in melanoma patients (156.6)

Abstract Combination of chemo/immunotherapy to increase the effectiveness of the antitumor immune responses associated with a clinical efficacy is an attractive antitumor strategy. We have recently reported that the administration of dacarbazine (DTIC) one day before peptide (Melan-A and gp100)-vaccination in disease-free melanoma patients increases the number of peptide-specific effector-memory CD8+ lymphocytes. Notably, patients treated with DTIC before vaccination, showing a longer survival, display a progressive enhancement of TCR repertoire diversity of Melan-A+ CD8+ clones, accompanied by the maintenance of high-avidity, whereas patients treated with vaccine alone showed a reduction of TCR repertoire diversity and a decline of their tumor lytic activity. To study the phenotype and the functional lytic activity of CD8+ T-cell clones in association with their renewal rate we have analyzed the expression of CD28 and CD27 co-stimulatory molecules, in both Melan-A- and gp100-specific T-cell clones, isolated before and at different times after the treatments. We found newly recruited clones with high-lytic activity and highly-differentiated phenotype only after the combined therapy. Studies are in progress to define the role of replicative senescence in the continuous renewal induced by the combined therapy, by studying activity and regulation of telomerase in endogenous-induced or vaccine-driven clones, in correlation with their different phenotype and anti-tumor lytic capability.

Dacarbazine Treatment before Peptide Vaccination Enlarges T-Cell Repertoire Diversity of Melan-A–Specific, Tumor-Reactive CTL in Melanoma Patients

Combination of chemotherapy and immunotherapy to increase the effectiveness of an antitumor immune response is currently regarded as an attractive antitumor strategy. In a pilot clinical trial, we have recently documented an increase of melanoma antigen A (Melan-A)-specific, tumor-reactive, long-lasting effector-memory CD8(+) T cells after the administration of dacarbazine (DTIC) 1 day before peptide vaccination in melanoma patients. Global transcriptional analysis revealed a DTIC-induced activation of genes involved in the immune response and leukocyte activation. To identify the possible mechanisms underlying this improved immune response, we have compared the endogenous and the treatment-induced anti-Melan-A response at the clonal level in patients treated with the vaccine alone or with DTIC plus vaccine. We report a progressive widening of T-cell receptor (TCR) repertoire diversity, accompanied by high avidity and tumor reactivity, only in Melan-A-specific T-cell clones of patients treated with chemoimmunotherapy, with a trend toward longer survival. Differently, patients treated with vaccine alone showed a tendency to narrowing the TCR repertoire diversity, accompanied by a decrease of tumor lytic activity in one patient. Collectively, our findings indicate that DTIC plus vaccination shapes the TCR repertoire in terms of diversity and antitumor response, suggesting that this combined therapy could be effective in preventing melanoma relapse.

Diversification of TCR repertoire in melanoma patients treated with chemotherapy before peptides-vaccination (41.19)

Abstract Combining chemotherapy and immunotherapy is an attractive antitumor strategy. Recently we have reported that the administration of dacarbazine (DTIC) one day before peptide-vaccination in disease-free melanoma patients induced an increase of peptide-specific effector-memory CD8+ lymphocytes. To investigate the functional differences between anti-Melan-A CD8+ T cell response elicited by vaccination alone (Arm 1) or by chemotherapy plus vaccination (Arm 2), we generated T cell clones from 5 patients of both Arms, before and after the treatments. A significant enhancement of tumor lytic activity of Melan-A+ clones generated by patients of Arm 2 after the treatment was observed, whereas no significant differences of tumor recognition efficiency were evident among the two arms before treatment. Ninety-six sequences were obtained and 47 clonotypes with different CDR3 regions were observed. A progressive enhancement of TCR repertoire diversity was found only in patients treated with DTIC before vaccination, whereas patients treated with vaccine alone showed a reduction of TCR repertoire diversity accompanied by a reduction of tumor lytic activity in one patient. These results suggest that a diverse Melan-A-specific T cell repertoire occurs in melanoma patients treated with DTIC plus vaccination, which may offer a new clinically advantageous anti-tumor strategy.

Efficacy of temozolomide or dacarbazine in combination with an anthracycline for rescue chemotherapy in dogs with lymphoma

To compare results of treatment with temozolomide or dacarbazine, in combination with an anthracycline, in dogs with relapsed or refractory lymphoma. Nonrandomized, controlled clinical trial. 63 dogs with relapsed or refractory lymphoma. Chemotherapy was administered in 21-day cycles. A combination of temozolomide and an anthracycline (doxorubicin or dactinomycin) was administered to 21 dogs and a combination of dacarbazine and an anthracycline was administered to 42 dogs. Efficacy and toxicoses were assessed. Results-Thirteen of the 18 (72%) dogs treated with the temozolomide-anthracycline combination and 25 of the 35 (71%) dogs treated with the dacarbazine-anthracycline combination had a complete or partial response. Median duration of response to rescue chemotherapy was 40 days (range, 0 to 217 days) for dogs in the temozolomide group and 50 days (range, 0 to 587 days) for dogs in the dacarbazine group. The incidence of high-grade hematologic toxicoses was significantly higher among dogs in the dacarbazine group than among dogs in the temozolomide group, but the incidence of gastrointestinal tract toxicoses was not significantly different between groups. There were no significant differences between groups in regard to proportion of dogs with a complete or partial response, duration of response to rescue chemotherapy, survival time following rescue chemotherapy, or overall survival time. Both combinations had promise in the treatment of dogs with relapsed or refractory lymphoma, although administration of temozolomide was more convenient than administration of dacarbazine and caused fewer hematologic toxicoses.

Oblimersen In the Treatment of Metastatic Melanoma

Oblimersen (Genasense is a Bcl-2 antisense compound that selectively targets Bcl-2 RNA for degradation by RNase H and thereby decreases Bcl-2 protein production. Bcl-2 protein plays a major role in preventing apoptosis and has been linked to chemotherapy resistance in melanoma. Preclinical studies with oblimersen in melanoma cell lines and xenograft models of melanoma have demonstrated downregulation of Bcl-2 protein, induction of apoptosis and enhanced tumor response when combined with chemotherapy. Results of a Phase I/II study have shown that reducing Bcl-2 with oblimersen coincident with the administration of dacarbazine may amplify apoptosis and improve therapeutic outcome. A subsequent Phase III trial showed that the addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes relative to dacarbazine alone based on an intent-to-treat analysis of progression-free survival and response rate (overall, complete and durable), as well as overall survival in patients with normal lactate dehydrogenase. This article reviews the biochemistry, pharmacodynamics and pharmacokinetics, safety and efficacy data related to oblimersen in melanoma.

Hemorrhagic cystitis in a patient receiving conventional doses of dacarbazine for metastatic malignant melanoma: Case report and review of the literature

Hemorrhagic cystitis is a potentially life-threatening complication in patients receiving cancer therapy. This urologic emergency is commonly associated with the chemotherapeutic use of oxazaphosphorine alkylating agents. This report describes a case of hemorrhagic cystitis associated with dacarbazine treatment. A 63-year-old man with asymptomatic metastatic malignant melanoma received 3 cycles of dacarbazine (600-850 mg/m2) monochemotherapy, each 3 weeks apart. Two weeks after the third cycle, he presented with gross hematuria and mild dysuria. Physical examination revealed no significant finding. Hematuria was confirmed by urinalysis, and urinary infection was excluded by repeated urine cultures. Ultrasonography revealed diffuse bladder wall thickening with no discrete mass or ulceration. Cystoscopy findings revealed generalized inflammation and edema of the mucosa of the bladder, confirming the diagnosis of hemorrhagic cystitis. The patient's gross hematuria continued for 2 weeks and then completely resolved with supportive care. Two weeks after complete resolution, the patient experienced 2 transient episodes of gross hematuria that lasted a few hours and subsided spontaneously. Dacarbazine is currently considered the standard first-line treatment in patients with advanced malignant melanoma. At standard prescribed doses (a single dose of 850-1000 mg/m2 or 250 mg/m2 for 5 days per cycle), dacarbazine is a reasonably well tolerated chemotherapeutic drug; nausea, vomiting, and myelosuppression are the most common adverse effects. Association of dacarbazine with hemorrhagic cystitis has not been reported previously (in a PubMed literature search from 1950-2006), and only 1 case report associates temozolomide (an analog of dacarbazine) with hemorrhagic cystitis. Based on the Naranjo adverse drug reactions probability scale, an objective assessment revealed dacarbazine to be a probable cause of hemorrhagic cystitis in this case. This case report suggests that dacarbazine at conventional doses was a probable cause of hemorrhagic cystitis. Regular urinalysis and early intervention are recommended, as a means of detecting early hematuria and subsequently reducing or discontinuing dacarbazine treatment. Adequate hydration before, during, and after dacarbazine administration may be useful in preventing this complication.

Melanoma-associated paraneoplastic retinopathy: case report and review of the literature

A 51-year-old white male suffering from metastatic malignant melanoma of the skin presented with lymph node metastases and paraneoplastic retinopathy 4 years after resection of the primary tumour. There were no cerebral metastases. Ocular symptoms consisting of night blindness and sensations of 'shimmering lights' persisted after total resection of the inguinal lymph node metastases and administration of dacarbazine and prednisone. Perimetry of both eyes was abnormal with concentric restriction. Electroretinography showed significantly reduced amplitudes in both eyes. Only 11 patients with melanoma-associated retinopathy (MAR) have been described. High titres of autoantibodies against whole retina extract were detected by enzyme-linked immunosorbent assay (ELISA) reactions. Indirect immunohistochemistry showed strong autoantibody activity against retinal bipolar cells.

A phase II study of combined administration of dacarbazine and carboplatin with home therapy of recombinant interleukin-2 and interferon-?2a in patients with advanced malignant melanoma

A phase II study of combined administration of dacarbazine and carboplatin with home therapy of recombinant interleukin-2 and interferon-?2a in patients with advanced malignant melanoma

Case Report: Development of Hodgkin's Disease in Patient Receiving Long-Term Administration of Dacarbazine and Interleukin-2 for Metastatic Melanoma

Case Report: Development of Hodgkin's Disease in Patient Receiving Long-Term Administration of Dacarbazine and Interleukin-2 for Metastatic Melanoma

Unusual Local Cutaneous Reaction to Dacarbazine

Dacarbazine is widely used in the systemic treatment of malignant melanoma and Hodgkin's disease. While side effects of nausea, vomiting, and bone marrow depression are well recognized, adverse skin reactions are less common. We report a localized skin reaction to the intravenous (IV) administration of dacarbazine that histologically resembled a fixed drug reaction. Report of a Case A 19-year-old man was hospitalized in September 1980 for recurrent Hodgkin's disease, manifested by severe peripheral lymphadenopathy. In the hospital he began treatment on a regimen of mechlorethamine hydrochloride, procarbazine hydrochloride, prednisone, doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine chemotherapy. He had previously been treated with mechlorethamine, vincristine, prednisone, and procarbazine chemotherapy, which had produced a complete remission, but paralytic ileus had developed secondary to vincristine-caused autonomic neuropathy. He had never received dacarbazine before September 1980. Four hundred milligrams of dacarbazine, diluted in 1 dL of a 5% glucose-and-water solution, was