Four-drug Chemotherapy Research Articles

ЭФФЕКТИВНОСТЬ ПРИМЕНЕНИЯ УКОРОЧЕННЫХ ЧЕТЫРЕХКОМПОНЕНТНЫХ РЕЖИМОВ ХИМИОТЕРАПИИ В КОМПЛЕКСНОМ ЛЕЧЕНИИ ТУБЕРКУЛЕЗА С МЛУ/ШЛУ МБТ У ПОДРОСТКОВ

Objective: to assess effectiveness of shortened to 12 months chemotherapy regimens containing 4 TB drugs in older children and adolescents with multidrug resistant (MDR) or extensively drug resistant (XDR) pulmonary TB. Materials and methods. We carried out a cohort retrospective study from January 2017 through December 2021. The study enrolled 37 patients aged 13–17 years with various clinical forms of pulmonary TB and established MDR/XDR. The patients were divided into two observation groups: in group 1 (main) 10 patients received continuous treatment containing 4 drugs;in group 2 (comparison) 27 patients received 5-6 drugs during the intensive phase (3 or 6 months) and 3 drugs during the continuation phase (6 or 9 months). The statistical correlation between the risk factor (four-drug chemotherapy regimen) and the outcome (TB relapse) was calculated using the Pearson’s χ2 criterion. The difference p ≤ 0.05 was considered statistically significant. Results. One year after treatment completion we observed 34 out of 37 patients. According to X-ray data, only one (4.2%) of 24 patients of the comparison group developed TB relapse. The comparison of TB relapse incidence in the two groups did not reveal a statistically significant correlation between the risk factor (four-drug chemotherapy regimen) and the outcome (TB relapse) (χ2 = 0.429; р > 0.05). Conclusion. The use of shortened four-drug chemotherapy regimens is an important achievement and changes the approach to treatment of children and adolescents with drug-resistant pulmonary TB.

Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.

Honoring Emil J. Freireich: A Visionary Medical Cancer Researcher-March 21, 1927-February 1, 2021.

![][1] Dr. Emil Freireich at MD Anderson in 2018, in conversation with Lauren Gobert, a leukemia physician assistant who had childhood acute lymphoblastic leukemia cured by combination therapy developed as a result of Dr. Freireich's research. Emil J, Freireich, a founding father of

P3.15-013 The Addition of Antiangiogenic Agents to Chemotherapy for Patients with Extensive-Stage Small Cell Lung Cancer: A Meta-Analysis

The combination chemotherapy of etoposide and a platinum salt represents the standard therapy for almost 30 years in patients with ED-SCLC (extensive-disease small-cell lung cancer). While, the survival benefit of chemotherapy is not obvious. Antiangiogenic agents have been confirmed to have survival benefits for patients with NSCLC (non-small cell lung cancer). However, there is no established role for antiangiogenic therapy in SCLC. we conducted this meta-analysis to evaluate antiangiogenic agents plus chemotherapy in patients with ED-SCLC. Pub-med, EMBASE, Cochrane Library and ClinicalTrials.gov website were systematically searched for RCTs (randomized controlled trials) that compared antiangiogenic agents plus chemotherapy with chemotherapy alone in ED-SCLC. We firstly found that antiangiogenic agents plus chemotherapy was well tolerated and could provide a statistically significant improvement in PFS (progression-free survival) for patients with ED-SCLC (HR = 0.76 [95% CI 0.65, 0.88], P = 0.0003). The results of ORR (objective response rate) (RR = 1.06 [95% CI 0.96, 1.18], P = 0.23) and OS (overall survival) (HR = 0.98 [95% CI 0.80, 1.21], P = 0.85) showed no benefit for antiangiogenic agents plus chemotherapy. Our study firstly shows that the addition of antiangiogenic agents to standard chemotherapy is well tolerated and can provide a statistically significant improvement in PFS for patients with ED-SCLC. Further, maintenance therapy with antiangiogenic agents is an effective treatment option for ED-SCLC patients who received four to six cycle of chemotherapy. Additionally, four-drug chemotherapy plus antiangiogenic agents may be better for ED-SCLC patients with PS of 1 to 2. However, whether antiangiogenic agents plus chemotherapy can influence OS for ED-SCLC needs further validation.

Sequential four-drug chemotherapy and intensity-modulated radiotherapy for larynx preservation in resectable advanced larynx and hypopharynx cancer: A pilot study

ObjectiveThe value of additional use of cetuximab with the classical cisplatin, docetaxel and 5-fluorouracil regimen in larynx preservation remains unknown. This study was designed to resolve this issue and appraise its toxicity. Materials and methodsThirteen untreated patients with stage III–IV larynx or hypopharynx squamous cell carcinoma were recruited and received two cycles of C+TPF regimen (cetuximab plus docetaxel, cisplatinand and 5-fluorouracil), followed by one more cycle of C+TPF and intensity-modulated radiotherapy (70Gy). Primary endpoint was larynx preservation (LP) rate at 3months. Secondary endpoints were larynx function preservation (LFP) and overall survival (OS) at 12, 36 and 60months. ResultsWith a two-cycle induction treatment of C+TPF protocol, four (31%) and nine (69%) patients achieved complete and partial response, respectively. The top three toxicities were dermatitis (9 cases), nausea/vomiting (6 cases), and anemia (4 cases). After the full-course treatment, 12 out of 13 patients (92.3%) obtained LP at 3months. This strategy demonstrated relatively high LFP rates of 92.3%, 69.2% and 54.5% and satisfactory OS rates of 100%, 84.6% and 54.5% at 12, 36 and 60months, respectively. ConclusionsThese preliminary results suggest induction treatment with C+TPF regimens, followed by intensity-modulated radiotherapy is well-tolerated, which warrants further evaluation.

Complex MLLrearrangement in non-infiltrated bone marrow in an infant with stage II precursor B-lymphoblastic lymphoma

Precursor B-lymphoblastic lymphoma cells are indistinguishable by morphology, and immune phenotype from lymphoblasts in acute leukemia which in infancy is associated with MLL rearrangements and a poor prognosis. The role of MLL gene deregulation in rare cases of isolated lymphoblastic lymphoma in infants is obscure. We report the case of a 10-month-old child who presented with a cutaneous nodule on the left foot. Histological diagnosis was precursor B-lymphoblastic lymphoma. The young age of the patient motivated us to investigate the presence of an MLL rearrangement. Cytogenetic analysis was performed by fluorescence in situ hybridization (FISH), and the genomic fusion partner of MLL was identified by long-distance inverse (LDI-)PCR and confirmed by direct PCR. Fluorescence in situ hybridization screening of paraffin-embedded formalin-fixed tissue indeed revealed the presence of an MLL rearrangement. The genomic fusion partner was identified as AF10 by DNA sequencing of the MLL breakpoint region. The MLL-AF10 fusion gene was further detected in cytologically normal pretreated bone marrow. Treatment was started with standard four-drug induction chemotherapy. Because of the unfavorable outcome associated with MLL rearrangements in infant leukemia, we intensified postremission treatment according to the Interfant-06 study protocol. The child is in continuous first remission 36 months after diagnosis. This is the first report of submicroscopic bone marrow involvement in MLL-rearranged isolated cutaneous B-cell precursor lymphoma in an infant. To prospectively address the role of MLL rearrangements in extramedullary B-lymphoblastic malignancies in infants, we suggest to assess both tumors and non-infiltrated bone marrow for the presence of this genetic abnormality.

Increased serum level of thymidine kinase 1 correlates with metastatic site in patients with malignant melanoma

Thymidine kinase 1 (TK1) is involved in cancer progression. Metastatic site is a prognostic factor in melanoma. We assessed whether serum levels of TK1 are associated with metastatic sites or prognosis in patients treated for stage IV melanoma. The study included 64 patients, who received dacarbazine or four-drug chemotherapy (dacarbazine, vincristine, bleomycin, and lomustine) both combined with interferon-alfa. Serum samples for TK1 were analyzed by ELISA. The patients (n = 22) with only skin and subcutaneous metastases had significantly lower mean TK1 levels (1,639 pg/ml) than the patients (n = 42) with other distant metastases (2,586 pg/ml, Mann-Whitney, p = 0.031). TK1 levels above the median (1,590 pg/ml) were significantly related to deep lymph node involvement (odds ratios 3.672; 95 % confidence intervals 1.024-12.843, p = 0.036). There were no other significant associations between TK1 levels and tumor burden nor were the levels significantly related to the response to therapy or survival. Those eight patients who had received previous adjuvant IFN-alfa therapy had lower mean TK1 levels (1,735 pg/ml) as compared to those 56 patients without previous IFN-alfa therapy (2,338 pg/ml, analysis of variance, p = 0.026). This is the first study exploring serum TK1 in melanoma. TK1 might be involved in the deep lymphatic dissemination and progression of melanoma metastasis.

The Treatment of Retinoblastoma with Four-Drug Regimen Including Cisplatin, Etoposide, Vincristine, and Cyclophosphamide

Over an 11-year period, 59 patients (83 eyes) were treated with four-drug chemotherapy (cisplatin, etoposide, cyclophosphamide, and vincristine) at Hacettepe University, Departments of Ophthalmology and Pediatric Oncology. We evaluated the clinical features, treatment modalities, and outcome of these patients with a median follow-up of 55 months (range 9–130 months). Enucleation was performed as a first-line treatment for 30 eyes due to iris neovascularization and neovascular glaucoma, tumor in the anterior chamber regardless of the tumor stage, and for the patients with the Reese–Ellsworth (RE) group Vb. Chemotherapy was given regardless of tumor stages according to the RE groups in all 59 patients (83 eyes). Fifty-three eyes were treated with chemoreduction (CRD) and focal treatment. The rates of globe preservation were 87% for bilateral tumors and 35% for unilateral tumors in the CRD group. The 5-year overall (OS) and enucleation-free survival (EnFS) was 86.9% and 40%, respectively, for the whole group. At 3rd year, ocular survival rate for the eyes with vitreal or subretinal seeding was 58% and without seeding was 66% (P = .78). Seeding or subretinal collection may not indicate poor prognosis under intensive chemotherapy. The intensive four-drug chemotherapy protocol might have satisfactory results in the retinoblastoma (RBL) patients.

Treatment of Hodgkin lymphoma: the past, present, and future

Significant advances in the biology and treatment of Hodgkin lymphoma (HL) have been accomplished over the past decades. In a landmark study, DeVita and colleagues showed that half of patients with advanced-stage HL experienced long-term disease-free survival following treatment with a four-drug chemotherapy regimen. Subsequent reports and randomized clinical trials conducted over the past 40 years have defined prognostic categories and refined the treatment options for patients with early-stage and advanced-stage HL. New treatment concepts and regimens have continued to increase the cure rate of HL, while other analyses have documented the acute and long-term morbid and potentially fatal side effects of HL therapy. Increased knowledge of HL biology has been gained, in particular, much has been learnt about the genetic and phenotypic characteristics of malignant cells and the varied oncogenic signaling pathways involved in HL. Continued translational research is needed to improve the long-term survival and to lessen the toxicities associated with therapy. Furthermore, continued clinical-trial involvement by oncologists and patients is imperative to further advance the field of HL.

Osteosarcoma: The Addition of Muramyl Tripeptide to Chemotherapy Improves Overall Survival—A Report From the Children's Oncology Group

To compare three-drug chemotherapy with cisplatin, doxorubicin, and methotrexate with four-drug chemotherapy with cisplatin, doxorubicin, methotrexate, and ifosfamide for the treatment of osteosarcoma. To determine whether the addition of muramyl tripeptide (MTP) to chemotherapy enhances event-free survival (EFS) and overall survival in newly diagnosed patients with osteosarcoma. Six hundred sixty-two patients with osteosarcoma without clinically detectable metastatic disease and whose disease was considered resectable received one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and methotrexate and underwent definitive surgical resection of primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 x 2 factorial design. The primary end points for analysis were EFS and overall survival. In the current analysis, there was no evidence of interaction, and we were able to examine each intervention separately. The chemotherapy regimens resulted in similar EFS and overall survival. There was a trend toward better EFS with the addition of MTP (P = .08). The addition of MTP to chemotherapy improved 6-year overall survival from 70% to 78% (P = .03). The hazard ratio for overall survival with the addition of MTP was 0.71 (95% CI, 0.52 to 0.96). The addition of ifosfamide to cisplatin, doxorubicin, and methotrexate did not enhance EFS or overall survival for patients with osteosarcoma. The addition of MTP to chemotherapy resulted in a statistically significant improvement in overall survival and a trend toward better EFS.

Serum VEGF-C is associated with metastatic site in patients with malignant melanoma

Vascular endothelial growth factor-C (VEGF-C) is involved in lymphatic metastatic spread. Metastatic site is a prognostic factor in melanoma. We assessed whether serum levels of VEGF-C are associated with metastatic sites or prognosis in patients treated for stage IV melanoma. The study included 64 patients, who received dacarbazine or four-drug chemotherapy (dacarbazine, vincristine, bleomycin and lomustine; BOLD) both combined with interferon-alfa. Serum samples for VEGF-C were analyzed by ELISA. The patients (n =22) with only skin and subcutaneous metastases had significantly lower mean VEGF-C levels (1 643 pg/ml) then the patients (n =42) with other distant metastases (2 584 pg/ml, Mann-Whitney, p =0.033). VEGF-C levels above the median (1 590 pg/ml) were significantly related to deep lymph node involvement (OR 3.763; 95% CI 1.038 − 13.646, p =0.034). There were no other significant associations between VEGF-C levels and tumour burden, nor were the levels significantly related to the response to therapy or survival. Those eight patients, who had received previous adjuvant IFN-alfa therapy had lower mean VEGF-C levels (1 738 pg/ml) as compared to those 56 patients without previous IFN-alfa therapy (2 335 pg/ml, ANOVA, p =0.026). This is the first study exploring serum VEGF-C in melanoma. VEGF-C might be involved in the deep lymphatic dissemination and progression of melanoma metastasis.

Follow-up results in tuberculous cervical lymphadenitis

To investigate the efficacy of medical antituberculous treatment in patients with tuberculous cervical lymphadenitis (TCL). In the period 1996-2002, 73 TCL patients were reviewed and the results of clinical and laboratory testing were documented. The efficacy of a four-drug chemotherapy regimen was investigated. Purified protein derivatives (PPD) skin test results were positive in 58 (79 per cent) patients. Chest X-rays revealed changes consistent with tuberculosis in nine (12.3 per cent) patients. The mean duration of medical treatment was 10.04 months. In follow-up evaluation, 14 (20 per cent) patients were considered suspicious for resistant TCL and total excision of all nodes was performed. Histopathology confirmed TB in only 10 of these cases. The high incidence of residual disease in our study indicates that medical treatment (at least nine months of four combined antituberculous drugs) did not seem to be effective. If lymphadenopathy persists, total surgical excision of lymph nodes should be the treatment of choice.

Adjuvant chemoradiation using 5-fluorouracil/folinic acid/cisplatin with or without paclitaxel and radiation in patients with completely resected high-risk gastric cancer: two cooperative phase II studies of the AIO/ARO/ACO

The current two studies evaluate the feasibility, toxicity and efficacy of an adjuvant combined modality treatment strategy containing a three to four-drug chemotherapy regimen plus 5-fluorouracil (FU)-based radiochemotherapy. Between December 2000 and October 2003, a total of 86 patients were included in both studies. Patients with completely resected gastric adenocarcinoma including a D1 or D2 lymph node dissection (LND) were eligible. Treatment consisted of two cycles of folinic acid 500 mg/m2, 5-FU 2000 mg/m2 continuous infusion over 24 h once weekly for 6 consecutive weeks, paclitaxel 175 mg/m2 in weeks 1 and 4 and cisplatin 50 mg/m2 in weeks 2 and 5 (FLPP; n=41) or two cycles of the same 5-FU/folinic acid schedule but with cisplatin 50 mg/m2 only in weeks 1, 3 and 5 (FLP; n=45). Radiation with 45 Gy plus concomitantly applied 5-FU 225 mg/m2/24 h was scheduled in between the two cycles. Patients characteristics were: D1/D2 LND FLP group 53%/42%; FLPP group 27%/68%; stage distribution: UICC stages III/IV(M0) FLP group 63% and FLPP group 66%. Median follow-up was 10 months (3-25) for FLP and 18 months (2-51) for FLPP patients. CTC grade 3/4 toxicities during the first cycle/chemoradiation/second cycle of FLP: granulocytopenia 3%/0/27%, anorexia 6%/10%/8%; diarrhea 8%/0/4%, nausea 3%/0/4%; FLPP: granulocytopenia 0/0/37%, anorexia 5%/11%/6%; diarrhea 5%/0/3, nausea 3%/8%/0%; early death in one patient due to Pneumocystis carinii pneumonia. Projected 2-year progression-free survival was 64% (95% CI 56% to 68%) for the FLP and 61% (95% CI 42% to 78%) for the FLPP group. Both chemoradiation regimens appear feasible with an acceptable toxicity profile indicating that cisplatin can be added to 5-FU/FA and that even a four-drug regimen can be investigated further in prospective clinical trials in completely resected gastric cancer patients. Treatment should be given in experienced centres in order to avoid unnecessary toxicity.

Establishing long-term survival and cure in young patients with Ewing's sarcoma.

This paper investigates the potential for long-term survivorship for young patients diagnosed with Ewing's sarcoma. Data are examined from two successive UKCCSG Ewing's Tumour studies (ET-1 and ET-2). Patients have been followed for up to 20 years. These studies had suggested that better 5-year survival with ET-2 over the earlier ET-1 was achieved by replacing cyclophosphamide by ifosfamide and increasing the dose of doxorubicin in a four-drug chemotherapy regimen. The updated hazard ratio, stratified for metastatic status at diagnosis, of 0.39 (95% confidence interval 0.12–0.61) confirmed the advantage of the ET-2 regimen in terms of overall survival. Cure models, based on the Weibull distribution, suggested that factors for long-term survival in addition to presence of metastases were age, primary site of tumour and study. Modelling identified the proportion cured with the ET-2 protocol as best at 70% in those who are under 10 years with a nonpelvic primary site and without metastatic disease. This contrasts to only 13% cure in those with the corresponding adverse prognostic indicators. Additionally, the risk of death remains greatest but relatively constant over the first 2 years postdiagnosis, and then declines to a lower but constant value for the next 3 years before reaching the ‘cure plateau’ at about 5 years. This investigation suggests that ‘cure’ is possible for patients with Ewing's sarcoma. This is established at approximately 5 years post diagnosis and the proportion cured depends on the presence of metastases, pelvic site and age at diagnosis.

Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study.

A prospective Children's Cancer Group study, CCG-3881, has been completed to determine if a more accurate prediction of prognosis by biologic features can identify subgroups of infants with stage IV neuroblastoma (NBL) who require differing intensities of treatment. One hundred thirty-four infants were registered from June 1989 to August 1995, with a median follow-up of 47.1 months (range, 0 to 88 months). The biologic factors examined were tumor MYCN copy number, Shimada histopathologic classification, serum ferritin, and bone marrow immunocytology (sensitivity, one tumor cell per 10(5) bone marrow cells). Patients treated on CCG-3881 (n = 116) received four-drug chemotherapy for 9 months (cisplatin, cyclophosphamide, doxorubicin, and etoposide), with surgery and local radiation to residual disease. After January 1991, all subsequent infants with tumor MYCN amplification (n = 18) were transferred after one cycle of therapy to the high-risk CCG-3891 protocol (open January 1991 to April 1996) for more intensive treatment. The 3-year event-free survival (EFS) and overall survival (mean +/- SD) for the 134 infants were 63% +/- 5% and 71% +/- 5%, respectively. Patients whose tumors were without MYCN amplification had a 93% +/- 4% 3-year EFS, whereas those with amplified MYCN had a 10% +/- 7% 3-year EFS (P <. 0001). Each of the other biologic features studied had prognostic significance in univariate analysis but not after stratifying by MYCN copy number. Infants less than 1 year of age at diagnosis with stage IV NBL have a much improved outcome compared with children >/= 1 year of age. Nonamplified MYCN tumors identify a group of infants with a 93% +/- 4% EFS, whereas amplified MYCN copy number clearly identifies patients who are unlikely to survive despite intensive chemotherapy.

MIB-1 Immunoreactivity Correlates with Blood Vessel Density and Survival in Disseminated Malignant Melanoma

The purpose of our current work was to evaluate the prognostic significance of tumor cell proliferation in advanced metastatic melanomas and to investigate a possible correlation between the proliferation index and blood vessel density in metastatic tissue. Sixty patients with disseminated malignant melanoma treated with four-drug chemotherapy combined with interferon-α were included in this study. Proliferative activity and vascularity in metastatic tissues were examined by immunohistochemistry with anti-Ki-67 (MIB-1) and anti-CD31 antibody, respectively. A significant relationship between MIB-1 index and blood vessel number was detected (rho = 0.323, p = 0.013). In survival analysis, the overall survival and disease-free survival were significantly longer (58 and 38 vs. 38 and 17 months) for patients with low MIB-1 immunoreactivity (p = 0.012 and p = 0.023, respectively). Likewise, the low MIB-1 labeling index was associated with the prolonged survival calculated from the initiation of the chemoimmunotherapy (12 vs. 7 months, p = 0.032). In multivariate Cox’s proportional hazard analysis, MIB-1 positivity was an independent prognostic factor both for overall survival and for survival after beginning of the chemoimmunotherapy (p = 0.016 and p = 0.029).

Wilms' Tumor in the Adult — Report of a Case and Review of the Literature

Wilms' tumor is rare in adults. Its histology, grading and staging are identical to those in children. Investigators agree on a combined modality approach in the treatment of adult Wilms' tumor (AWT), but differ on how aggressive it should be. Some advocate adopting the current pediatric protocols which take into account tumor stage and grade. Others recommend using advanced disease regimens for all stages and grades. We report on an 18 year-old male with stage IV favorable histology Wilms' tumor. The patient underwent radical nephrectomy and received postoperative radiotherapy with intensive four-drug chemotherapy. He had one relapse after 12 months which was successfully treated with chemotherapy and radiotherapy. He remains in remission without relapses 36 months after the initial diagnosis. The genetics of Wilms' tumor has been well studied in children but is practically unknown in adults; karyotype and molecular genetic studies in this case were normal.

The treatment of metastatic uveal melanoma.

Malignant melanoma can occur in various ocular structures and accounts for 70% of all primary eye malignancies. At the time of initial diagnosis of uveal melanoma, most patients have no demonstrable evidence of metastatic disease. However, within 5 years, metastases appear in 19-35% of patients. The median relapse-free interval for these patients is 2-4 years. Unlike cutaneous melanoma, uveal melanoma most commonly metastasises to the liver. In fact, the liver is the sole site or the initial site of metastasis in more than 50% of patients. This paper reviews major studies that evaluated different treatment options for metastatic uveal melanoma, including surgery, systemic chemotherapy, intra-arterial chemotherapy, chemoembolisation and chemoimmunotherapy. Surgery and systemic chemotherapy offer minimal benefits for these patients. However, the use of intra-arterial fotemustine demonstrated a 40% response rate for patients with liver metastases of uveal melanoma. Additionally, chemoimmunotherapy with a four-drug chemotherapy regimen and interferon alfa has provided response rates of approximately 20% and may contribute to prolonged survival. Ongoing multicentre trials are expected to determine the feasibility of this regimen. The activity of immunotherapy, particularly interferon, encourages its use in combination with other active therapies, such as intra-arterial fotemustine.

DNA flow cytometry and the outcome of chemoimmunotherapy in metastatic melanoma.

DNA ploidy and S-phase fraction (SPF) were measured by flow cytometry on tumours from 80 patients with disseminated malignant melanoma. All patients received a four-drug chemotherapy regimen (dacarbazine, vincristine, bleomycin and lomustine) plus interferon. Specimens were taken for analysis from the latest metastases biopsied before the start of the treatment. In 13 patients we also analysed sequential samples taken after the treatment at the time of progression. DNA aneuploidy was observed in 65% of the patients. Among the 40 responders there were 26 with aneuploid tumours (65%). Aneuploidy did not reach statistical significance as a prognostic sign in the unstratified study population, but when stratified by response groups, DNA aneuploidy was a significant prognostic factor for a better response (P = 0.04). SPF could be calculated in 76 tumours. Out of 40 responding patients (complete or partial response), 23 had tumours with an SPF higher than the median. Accordingly, patients with a high SPF survived longer than those with a low SPF, with median survival times of 9.8 months and 8.7 months, respectively (P = 0.18). We conclude that DNA aneuploidy and a high SPF are associated with longer survival in patients with disseminated melanoma treated with a chemoimmunotherapy regimen. Based on our findings we claim that, among patients receiving chemoimmunotherapy, high SPF and aneuploidy are not signs of unfavourable prognosis, which is in contrast to previous observations in melanoma patients receiving heterogeneous therapy.

21 Failure of GM-CSF supported dose intensification of a four-drug chemotherapy in extensive small cell lung cancer (SCLC), extended analysis of a phase III trial with determination of prognostic variables

21 Failure of GM-CSF supported dose intensification of a four-drug chemotherapy in extensive small cell lung cancer (SCLC), extended analysis of a phase III trial with determination of prognostic variables