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ObjectivesTo investigate whether radiotherapy as metastasis-directed therapy (MDT) on oligo-progressive sites in metastatic castration-resistant prostate cancer (mCRPC) patients during treatment with androgen receptor-targeted therapy (ARTT) may lead to control resistant lesions, prolonging ARTT. We analysed progression free survival, overall survival and prognostic parameters that can identify patients that best suit to this approach.Patients and MethodsRetrospective analysis of a total of 67 lesions in 42 mCRPC patients treated with ablative or palliative RT to oligoprogressive lesions during ARTT. Twenty-eight patients (67%) underwent ARTT with Abiraterone acetate and 14 patients (33%) underwent ARTT with Enzalutamide. Median time between the start of ADT and ARTT beginning was 50.14 months (range 3.37-219 months). We treated 58 lesions (87%) with 3D conformal radiotherapy (3DCRT) and nine lesions (13%) with stereotactic body radiotherapy (SBRT). The Kaplan Meier method was used to assess the median overall survival (OS) and the progression-free survival (PFS).ResultsMedian follow-up was 28 months (range 3-82 months). Median OS was 32.5 months (95% CI 25.77-39.16), 1 and 2-year OS were 71.6% and 64.1%, respectively. Median PFS was 19,8 months (95% CI 11.34–28.31), 1 and 2-year PFS were 67.2% and 47.4%, respectively. Median OS for patients that underwent radiotherapy before 6 months from the start of ARTT was 23.4 months (95% CI 2.04-44.89) and 45.5 months (95% CI 31.19-59.8) for patients that underwent radiotherapy after 6 months (p = 0.009).ConclusionLocal ablative radiation therapy directed to progressive metastasis is a non-invasive, well tolerated treatment with efficacy on prolonging clinical benefit of systemic therapies with ARTT. Patients who underwent RT >6 months from the start of ARTT presented a statistically better OS and PFS compared with patients who underwent radiotherapy

Background and Aims The bidirectional relationship between renal disease and malignancy is well known and requires specialized approaches. For this reason, onconephrology has emerged as a new evolving field in the last few years. Method In a dedicated nephrology clinic, we followed 54 metastatic cancer patients (pts) (23 F, 31 M; mean age 68.3 ± 9.8 yrs) during target therapy (TT). They were in treatment for different types of cancer (kidney n=32, colo-rectal n 6=, breast n=5, lung n=5, neuroendocrine n=2 and other n=4). 12 pts were taking anti-VEGF (group 1), 26 pts tyrosine kinase inhib (group 2), 7 pts mTOR inhb (group 3) and 9 pts immune-checkpoint (group 4). Kidney biopsies were not performed because of increased risk or for improvement of RI when changes in TT were performed. Renal injury (RI) occurred on average after 8.9 months from the start of TT. We compared the effects of the different therapeutic interventions on changes of renal function between T0 (before TT) and T1 (during TT). We also documented changes in oncologic therapeutic prescription due to renal injury and their effects at T2 (follow up). Kidney biopsies were not performed because of increased risk or for improvement of RI when changes in TT were performed. A two way repeated measures ANOVA (group x time) was used to compare the effects of the four groups on serum creatinine (sCr), creatinine clearance and proteinuria 24 h (PU) at T0 and T1. Results Mean basal sCr of pts taking antiVEGF was 0.95 mg/dl, eGFR (MDRD) 81.9 ml/min and PU 196 mg 24h. At T1 (8.37 months on average) sCr was 1.74 mg/dl, eGFR 62 ml/min and PU 1777 mg 24h. Mean basal sCr of pts taking tyrosine kinase inhib was 1.24 mg/dl, eGFR 55 ml/min and PU 145 mg 24h. At T1 (13 months on average) sCr was 1.59 mg/dl, eGFR 46 ml/min, and PU 916 mg 24h. Mean basal sCr of pts taking mTOR inhib was 1.28 mg/dl, eGFR 57 ml/min and PU 150 mg 24 h. At T1 (6.3 months on average) sCr was 2.1 mg/dl, eGFR 31.7 ml/min and Pu 345 mg 24 h. Mean basal sCr of pts taking immune-checkpoint was 1.27 mg/dl, eGFR 59 ml/min and PU 150 mg 24h. At T1 (months on average) sCr was 3.74 mg/dl, eGFR 30 ml/min and PU 257 mg 24h. A significant increase in sCr was observed when comparing T0 and T1 among the four groups but only a statistical trend (P = 0.088) was found for the group by time interaction thus not allowing us to speculate on potential differences between the different pharmacological interventions. Lower Creatinine clearance and higher PU, were found at T1 in pts on anti-VEGF compared to those on immune-checkpoint inhibitors. We generally observed an improvement of renal function after reduction of TT dose or its temporary discontinuation (27.8%), but definitive interruption was required in 31.8% of cases. In 2 diabetics pts on tyrosine kinase inhib we observed persistent nephrotic proteinuria and progressive worsening of renal function and beginning of chronic hemodialysis neverthless discontinuation. At the end of follow-up 5 pts reached end-stage renal disease (1 pt was taking antiVEGF, 2 pts tyrosine kinase inhib, 2 immune-checkpoint) and 6 pts were dead (4 pts were taking antiVEGF and 2 pts tyrosin kinasi inhib). Conclusion Our findings suggest that careful monitoring of renal function is needed to optimize the use of TT, also considering that RI can be multifactorial. Onconephrologists work with the aim of trying to ensure the continuity of anti-tumoral therapy, knowing how far they can go to maintain a balance between kidney function (even sacrificing part of it) and patient survival. In conclusion, nephrologists should be increasingly familiar with the diagnosis, management and treatment of renal diseases and the complexity of this field may benefit from well-defined multidisciplinary management by a dedicated team

Background: Perivascular epithelioid cell tumours (PEComas) are mesenchymal neoplasms with variable biological behaviour, ranging from benign to extremely aggressive diseases able to metastasize. No prospective studies are available to define a validate approach to this type of tumours. Case presentation: We present a case report of a 53-year-old woman affected by advanced retroperitoneal PEComa who developed an abdominal disease progression after 40 months of therapy with mTOR inhibitor. The patient underwent cyto-reductive surgery followed by radiotherapy on the residual disease and started chemotherapy with olaratumab plus doxorubicin for seven cycles achieving a partial response so she continued monotherapy with olaratumab for one year with stable disease to quarterly CT evaluation. On September 2019 treatment was definitely interrupted because of marketing authorisation of olaratumab was revoked due to insufficient proof of its medical advantage in phase III trial ANNOUNCE. Currently the patient is still in follow up after 18 months from the interruption of therapy, without a disease progression. Discussion and Conclusion: In our PEComa clinical case, we highlight how a multidisciplinary approach can lead to disease control and a long clinical benefit.

107 Background: In patients (pts) with high-volume (HV) metastatic castration sensitive prostate cancer (mCSPC) the addition of six cycles of docetaxel (TXT) to androgen deprivation therapy (ADT) in the CHAARTED and STAMPEDE trials prolonged survival by 10-18 months (mo). Aim of our study was to evaluate the principal patterns of relapse after TXT and their clinical and prognostic significance. Methods: We conducted a multicentric (14 Italian Centers), prospective, observational study enrolling HV mCSPC patients treated with ADT plus early TXT. Clinical and pathological features were recorded. Time to castration resistance (TCR) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. The Chi-Square test, t-test or Wilcoxon-Mann-Whitney test were used to assess difference between the groups as appropriate. Results: We identified 166 de novo mCSPC pts, with a median age of 64 years (range 38-84). The most common metastatic sites at diagnosis were: bone (93%) and lymph nodes (81%); visceral disease (lung and liver) was present in 36% of cases. 87% of pts had good Eastern Cooperative Oncology Group Performance Status (0-1), the median baseline PSA was 359 ng/ml (range 2.64-5800) and 43% experienced cancer pain. 87% of 158 evaluable pts had a Grade Group (GG) ³4. The majority of pts (81%) completed six cycles of TXT. The median time to PSA nadir was 10.2 months (mo), PSA response > 50% was achieved in 96% of pts and the most common best response reported was partial response (58%). At the time of this analysis, 122 pts (67%) had biochemical or radiographic progressive disease (PD) to TXT and 67 of these (60%) developing new metastatic sites (NMS). No differences with respect of main clinical features was found between NMS pts and nonNMS, with the exception of GG (96% of NMS pts had GG 4-5 vs 74% of nonNMS; p = 0.002). In NMS group we found a higher rate of nodal PD (52% vs 22%, p = 0.001) and higher rate of bone PD (73% vs 47%, p = 0.005) compared to nonNMS. No differences in the rate of visceral PD. With a median follow-up of 27.9 mo, the median TCR was 14.3 mo (95%CI 12.8-16.7), without significant differences between NMS and nonNMS groups. About 90% of progressed pts received first-line treatment for mCRPC disease with similar outcomes. The median OS was 41.8 mo for the overall population, with not significant differences between NMS and nonNMS groups (22 mo and 25 mo). Overall, median OS from mCRPC diagnosis was 19.6 mo, similar in NMS and no-NMS pts (10 mo and 12 mo). Conclusions: In progressive mCSPC pts receiving early TXT, we observed more frequently the development of NMS with an elevated GG and a trophism for bone and lymph nodes. However, the NMS progression does not seem to have a prognostic role. An extended follow up and the prospective data will be provided.

Inhibiting androgen receptor (AR) signaling with androgen deprivation therapy (ADT) represents the mainstay of therapy for advanced and metastatic prostate cancer. However, about 20-60% of patients receiving first-line treatment for prostate cancer will relapse, evolving in a more aggressive and lethal form of the disease, the castration-resistant prostate cancer (CRPC), despite the use of ADT. Multiple approved systemic therapies able to prolong survival of patients with metastatic CRPC (mCRPC) exist, but almost invariably, patients treated with these drugs develop primary or acquired resistance. Multiple factors are involved in CRPC treatment resistance and elucidating the mechanisms of action of these factors is a key question and an active area of research. Due to such a complex scenario, treatment personalization is necessary to improve treatment effectiveness and reduce relapse rates in CRPC. In this review, current evidence about the major mechanisms of resistance to the available prostate cancer treatments were examined by introducing insights on new and future therapeutic approaches.

Abiraterone acetate (AA) demonstrated its efficacy in the treatment of patients with metastatic castration resistance prostate cancer (mCRPC) in predocetaxel and postdocetaxel setting. However, we learn from pivotal studies that forms of primary and acquired resistance to this drug exist. Patient selection becomes so crucial to optimize treatment results. Potential predictive biomarkers have been identified but are not yet validated. In this scenario, clinical features and disease characteristics may still be of value in selecting patients for different treatments. The objective of this retrospective study was to assess whether or not a correlation between duration of response to first androgen deprivation therapy (ADT), time to castration-resistant prostate cancer (TTCRPC), and outcome of AA therapy exists. A retrospective analysis of clinical data of mCRPC patients treated with AA at two Italian cancer centers was carried out. The Kaplan-Meier method and Cox proportional hazard model were used to analyze survival data. Correlation between median duration of response to first ADT or median TTCRPC and the outcome of patients treated with AA was analyzed. From January 2015 to November 2015, data of 59 patients with mCRPC were collected. We observed no differences in patient's median progression-free survival (PFS) and biochemical progression-free survival (bPFS), according to both median duration of response to first-line ADT (duration of first ADT

Introduction: Paraganglioma (PGL) is a rare neuroendocrine tumor. Currently, the malignancy is defined as the presence of metastatic spread at presentation or during follow-up. Several gene mutations are listed in the pathogenesis of PGL, among which succinate dehydrogenase (SDHX), particularly the SDHB isoform, is the main gene involved in malignancy. A 55-year-old male without evidence of catecholamine secretion had surgery for PGL of the urinary bladder. After 1 year, he showed a relapse of disease and demonstrated malignant PGL without evidence of catecholamine secretion with a germline heterozygous mutation of succinate dehydrogenase B (SDHB). After failure of a second surgery for relapse, he started medical treatment with sunitinib daily but discontinued due to serious side effects. Cyclophosphamide, vincristine, and dacarbazine (CVD) chemotherapeutic regimen stopped the disease progression for 7 months. Conclusion: Malignant PGL is a very rare tumor, and SDHB mutations must be always considered in molecular diagnosis because they represent a critical event in the progression of the oncological disease. Currently, there are few therapeutic protocols, and it is often difficult, as this case demonstrates, to decide on a treatment option according to a reasoned set of choices.

Background.Renal cell carcinoma accounts for about 2-3% of all malignant tumors. The prevalence of brain metastases from RCC is less than 20% of cases. Traditionally, whole brain radiotherapy as well as the latest stereotactic radiosurgery improves both survival and local tumor control. These treatments also allow stabilization of clinical symptomatology. However, validated treatment guidelines for RCC patients with brain metastases are not yet available on account of the frequent exclusion of such patients from clinical trials. Moreover, limited data about the sequential use of three therapies, changing the class of agent, have been published up to now.Case Report.We report the case of a patient with metastatic RCC who developed disease progression after sunitinib and everolimus as first-line and second-line therapy, respectively. Thus, he underwent a multimodality treatment with pazopanib, as third-line therapy, to control systemic disease and radiosurgery directed on the new brain metastasis. To date, the patient is still receiving pazopanib, with progression-free survival and overall survival of 43 and 103 months, respectively.Conclusion.In a context characterized by different emerging options, with no general consensus on the optimal treatment strategy, the use of pazopanib in pretreated patients could be a suitable choice.

In this study, a randomised phase II trial explored the effects of 6-h chronomodulated CPT-11 infusion in advanced colorectal cancer patients. Sixty-eight pre-treated patients were randomly assigned to CPT-11 administered at 180 mg/m 2 on day 1, by 1-h infusion (Arm A) or 6-h sinusoidal infusion with peak timing at 5:00 a.m. (Arm B). All patients also received chronomodulated folinic acid/5-fluorouracil (FA/5-FU). Patients in Arm B obtained a 25.7% response rate for 7.0 months duration, a progression-free survival for 8.0 months and a median survival of 28 months. The same data in Arm A were 18.2%, 4.5, 6.0 and 18 months, respectively. No differences in drugs dose-intensity or increased toxicity with prolonged chronomodulated infusion were detected. Major grade 3–4 toxicity was diarrhoea: 10 patients in Arm A and 13 in Arm B. In conclusion, this study has shown that chronomodulated infusion of CPT-11 and FA/5-FU is safe, active and can be integrated with oxaliplatin (EORTC 05011) for the treatment of advanced colorectal cancer.

485 Background: Currently there are no biomarkers to predict either toxicity or activity of targeted therapy in mRCC. The aim of this study was to correlate single nucleotide polymorphisms (SNPs) of genes encoding for efflux transporters and metabolizing enzymes with sunitinib toxicity in metastatic renal cell carcinoma (mRCC) patients (pts). Methods: We conducted an observational, retrospective analysis of 60 Caucasian pts who received sunitinib for mRCC from 2 Italian institutions. Correlation between adverse events (AE, according to CTCAE v.4.0) and 4 polymorphisms in 3 genes (ABCB1 [1236C>T, 3435C>T], CYP3A5*3 6986A>G, CYP3A4*1B-392A>G) was analyzed. SNPs were detected in blood samples using pyrosequencing technique. Association between SNPs and toxicities was evaluated using the Chi Square test. Results: 60pts (median age: 61 years; male: 63.3%) with mRCC (clear cell: 85%, other histologies: 15%) were treated with sunitinib (83.3% as first-line). The most common AE (any-grade) reported were: hypertension (85%), asthenia (83.3%), hypothyroidism (65%), anemia (61.6%), nausea/vomiting (60%), stomatitis (58.3%), diarrhoea (48.3%), neutropenia (48.3%), thrombocytopenia (46.7%), leukopenia (46.7%), hypertriglyceridemia (45%), hyperglycaemia (38.4%), hypercholesterolemia (35%), and hand-foot syndrome (35%). Treatment was discontinued and sunitinib dose was reduced due to AE in 28.3% and 61.7% of pts, respectively. The G/A-variant in CYP3A5*3 was associated with thrombocytopenia (any grade, p=0.03); homozygous C/C alleles in ABCB1 1236C>T significantly correlated with leukopenia (any grade, p=0.01), while the C/C genotype in ABCB1 3435C>T was associated with hypertension (grade≥3, p=0.05); hypertriglyceridemia showed a trend towards increased prevalence in the presence of the C allele (grade≥3, p=0.08). Conclusions: Polymorphisms in ABCB1 and CYP3A5*3 are predictive of toxicity, as hypertension, leukopenia, and thrombocytopenia in pts with mRCC treated with sunitinib. This analysis could support the selection of the more appropriate drug to the individual patient.

174 Background: Abiraterone Acetate (AA), an effective treatment for metastatic castration resistant prostate cancer (mCRPC), is highly variable in its effectiveness and it is well known that form of primary and acquired resistance to this agent, exist. This resistance may partly depend on the increased capacity of CRPC cells to synthesize testosterone and dihydrotestosterone from weak adrenal androgens (i.e. DHEA, DHEA-S) or de novo from cholesterol, in response to a chronic exposition to a low-testosterone environment. The organic anion-transporting polypeptides (OATPs) encoded by SLCO genes, mediate the cellular uptake of many compounds, including adrenal androgens. We hypothesized that germ-line variants of the androgen transporter gene SLCO2B1 (solute carrier organic anion transporter family member 2B1), altering the ability of the prostate cancer cell to stock adrenal precursors, may influence the response to AA of mCRPC patients. Methods: Three single nucleotide polymorphisms (SNPs), exonic SNP rs12422149 and intronic SNPs rs1789693 and rs1077858, were genotyped in a cohort of 21 consecutive patients with mCRPC who were treated with AA at the Sant’Andrea Hospital of Rome, Italy. The SNPs were detected in blood samples using pyrosequencing technique. The median TTBP (Time to Biochemical Progression), PFS (Progression Free Survival) and OS (Overall Survival) was estimated using the Kaplan-Meier method, with 95% CI. To test the association between SNPs and TTBP, PFS and OS the log-rank test was used. Results: The intronic polymorphism of SLCO2B1 rs1077858A > G was associated with TTBP (p = 0.03) and PFS (p = 0.04) of mCRPC patients on AA therapy. Patients carrying the SLCO2B1 rs1077858 risk genotype (GG) exhibited a TTBP that was 8 months shorter than that of patients with the major allele of SNP rs1077858 (AA or GA) (TTBP: A/A+G/A = 12 (95% CI: 12-NA) vs G/G = 4 (95% CI: NA) months). Patients carrying genotype GG of SNP rs1077858 also showed an 11 months shorter PFS on AA therapy than patients with AA or GA genotype (PFS: GG = 5.1 (95% CI:NA) vs AA+GA = 16.7 (95%CI:14.9-NA) months). Conclusions: Genetic variants of SLCO2B1 may function as pharmacogenomic determinants of resistance to AA in mCRPC.

2Debioclinic, Charenton-Le-Pont. France Summary Purpose: Oxaliplatin (L-OHP), a new platinum analogue, is an active drug in colorectal and ovarian cancer. In this phase II study we explored tolerability and activity of oxaliplatin as a single agent in metastatic breast carcinoma patients. Patients and methods: Fourteen anthracycline pretreated advanced breast cancer patients were enrolled. Oxaliplatin was given at 130 mg/m2 on day 1 and repeated every three weeks. Analysis of toxicity, response rate and survival was performed. Results: The median number of courses per patient was four (range 2-6). The median administered dose-intensity was 43.3 mg/m2/week (range 32.5-43.3) which represents 100% of projected dose-intensity. No severe toxicity was encountered. Three patients developed acute transient laryngeal symptoms. Three patients displayed a partial response (21%), (95% confidence interval (CI): 0%-43%), two stable disease (14%) and nine progressed (64%). Response lasted five, four and five months respectively. Median survival was 12 months. Conclusions: In this limited experience, oxaliplatin appeared to be well tolerated and moderately active in advanced anthracycline-pretreated breast cancer patients. Combination chemotherapy with other active drugs such as 5-fluorouraci l (5-FU), anthracyclines and taxanes should represent the next step of development of this new drug.

Prostate cancer (PC) is the second most frequently diagnosed cancer and the second leading cause of cancer deaths in man. The treatment of localized PC includes surgery or radiation therapy. In case of relapse after a definitive treatment or in patients with locally advanced or metastatic disease, the standard treatment includes the androgen-deprivation therapy (ADT). By reducing the levels of Testosterone and dihydrotestosterone (DHT) under the castration threshold, the ADT acts on the androgen receptor (AR), even if indirectly. The effects of the ADT are usually temporary and nearly all patients, initially sensitive to the androgen ablation therapy, have a disease progression after a 18-24 months medium term. This is probably due to the selection of the cancer cell clones and to their acquisition of critical somatic genome and epigenomic changes. This review aims to provide an overview about the genetic and epigenetic alterations having a crucial role in the carcinogenesis and in the disease progression toward the castration resistant prostate cancer (CRPC). We focused on the role of the androgen receptor, on its signaling cascade and on the clinical implications that the knowledge of these aspects would have on hormonal therapy, on its failure and its toxicity.

The best way to deliver infusional 5-fluorouracil (5-FU) and folinic acid (FA) has yet to be determined. The aim of this prospective phase II trial was to verify the tolerability, activity and efficacy of chronomodulated 5-FU-FA (FF(5-16)) every 3 weeks in 48 untreated patients (group A), and 28 pretreated and four non-measurable, advanced colorectal cancer (ACC) patients (group B).The sinusoidal delivery of both drugs started at 10.00 p.m. and ended at 10.00 a.m., with peak flow at 4.00 a.m. for 5 consecutive days. The initial 5-FU dose was 900 mg/m(2)/day with intra-patient dose increase at 1,000 and 1,100 mg/m(2)/day, at the second and third course, respectively; FA was injected at a fixed dose of 150 mg/m(2)/day (Garufi et al.1997).Neither death from toxicity nor hematological toxicities were encountered. Maximal toxicity consisted of Grade 3 oral mucositis in 41% of patients, in only 8% of 535 courses. It was possible to achieve objective responses in 31% of untreated patients, with a progression free survival (PFS) of 7 months, median survival of 14 months and a 2-year survival rate of 28%. Similar results for PFS and survival were obtained in pretreated patients as well. Univariate analysis and multivariate analysis showed that response was related to the occurrence of mucositis and diarrhea ( p=0.03 and p=0.0007) and to performance status (PS) ( p=0.01). Quality of life, measured with the EORTC QLQ-C30+3 questionnaire, was unaffected by treatment and was better in patients with good PS and responsiveness.In this chronomodulated FF(5-16) phase II study, the probability of obtaining a relevant tumor reduction was significantly correlated with a patient variable such as PS, and toxicity variables such as mucositis and diarrhea. This observation and the validation of predictive factors for QoL deserve further investigation in ACC patients.

The importance of evaluating patient's quality of life (QoL) in clinical practice and research is recognized clearly in oncology. In the advanced phase of disease such an evaluation represents an endpoint as important as survival. Quality of life is both a subjective and multidimensional concept evaluated mainly by validated questionnaires. In colorectal trials involving advanced stage disease the effects of different chemotherapy treatments on QoL were evaluated. Almost all the studies found no deterioration in QoL during chemotherapy. The European Organization for the Research and Treatment of Cancer (EORTC) Chronotherapy Study Group utilized three different approaches to assess QoL. The first centered on the stability of QoL during a 6mon treatment period in patients undergoing chronotherapy. The second centered on research of the biological and clinical determinants of QoL involving features of the circadian activity rhythm and patient survival and the relationship between QoL and patient performance status, response to therapy, and psychosocial variables as well as drug-induced toxicity. The third centered on the clinical effectiveness of psychological intervention on patients undergoing chronotherapy to improve psychosocial status during treatment. This papers reviews the results of EORTC Chronotherapy Group studies on QoL.

The addition of oxaliplatin (L-OHP) to a 5-fluorouracil (5-FU)/ leucovorin (FA) regimen was retrospectively evaluated in 35 consecutive advanced colorectal cancer patients after progression of disease. L-OHP, 25 mg/m2/day, was infused from 10.00-22.00 with a peak flow at 16.00 while 5-FU, 700 mg/m2/day and FA, 150 mg/m2/day of the I-form or 300 mg/m2/day of the racemic form, from 22.00 to 10.00 with a nocturnal peak at 4.00, for 5 days every 3 weeks in 24 patients and for 4 days every 2 weeks in the other 11. Diarrhea and sensitive neuropathy were the most relevant types of toxicity (17% of patients). An objective response was achieved in 8/35 patients (23%) [95% CL 9-37], stabilization in 15 patients (43%) which included five minor responses, and progression in 12. There was no relevant difference in quality of life assessed with the EORTC QLQ C30+3 questionnaire before and after treatment. Median duration of response and median progression-free survival were 6 months; median overall survival was 11 months. This retrospective study showed that it is possible to reverse resistance to chronomodulated 5-FU by adding chronomodulated L-OHP to the previous regimen; comparison with different schedules of this combination should be performed in order to identify the best tolerated and active regimen as second-line treatment of advanced colorectal cancer.

The aim of this phase I study was to establish the maximum tolerated dose (MTD) of 5-fluorouracil (5-FU), administered as a 5-day chronomodulated infusion in combination with 1-folinic acid (FA) to ambulatory metastatic colorectal cancer patients. Consecutive cohorts of 6 patients were given 5-FU and FA infusions from 10.00 p.m. to 10.00 a.m. with peak delivery at 4.00 a.m. by means of a multichannel programmable pump. The FA dose was always the same (150 mg/m2/d). For the first cohort, the 5-FU dose level was 600 mg/m2/d at the first course, escalated by 100 mg/m2 for each subsequent cohort. Intrapatient dose was also escalated by 100 mg/m2 if toxicity was less than grade 2. The courses were repeated every 3 weeks. Thirty-four patients (17 previously treated) received a total of 154 courses. Dose-limiting toxicity consisted of stomatitis and diarrhoea. No significant haematological, cutaneous or cardiac toxicity was encountered. The MTD of 5-FU was reached at the fourth level (first course at 900 mg/m2/d equal to 4500 mg/m2/course) with 5-FU increased to 1100 mg/m2/d (5500 mg/m2/course) in 4 patients. The received 5-FU dose intensity (DI) over the first 3 courses at this level was 1318 mg/m2/week. Thirty-three patients were assessed for response. An objective response was achieved in 1 out of the 13 previously-treated and in 8 out of the 20 previously-untreated patients. The chronomodulated infusion of 5-FU at a dose of 900 mg/m2/d, together with FA at 150 mg/m2/d for 5 days, was safely delivered to out-patients with metastatic colorectal cancer. The low toxic profile and activity of this regimen in previously untreated patients deserves further exploration for the treatment of 5-FU-sensitive tumours.

SummaryFrom February 1987 to December 1988, 34 patients with histologically confirmed advanced colorectal carcinoma were entered in a phase II trial with 5-fluorouracil (5-FU) and folinic acid, for evaluation of treatment effectiveness and toxicity. Our data confirmed that the association 5-FU and folates represents an effective and moderately tolerated palliative treatment, with diarrhea being the only dose-limiting toxicity.

1579 Background: Brain metastases (BM) occur in 4% of metastatic colorectal cancer (CRC) patients and are considered as a late event in the natural course of this disease with a median survival of ...

L-OHP®/5-FU/FA CM combination partially circumvented 5-FU resistance in patients (pts) with ACC ( Cancer 1992, 69, 893). L-OHP® delivered as q 3 wks CM or bolus showed a 10% (14/138) overall response rate (ORR) in ACC pts with proven progressive disease (PD) while getting 5-FU/FA treatment. The non-cross resistance and/orsynergy of L-OHP® with 5FU/FA was assessed in 25 pts with acquired resistance (20 with CT scan-proven [PD]—and 5 with median 5 months [2.5–12] disease stabilisation [ST]) while on 5-day (d) CM 5-FU (700–1000 mg/sqm/d)/FA (300 mg/sqm/d) (peak delivery at 4.00 h) (FF). LOHP ® (20 to 25 mg/sqm/d, peak at 16.00 h) was added to this schedule in 2nd (12 pts) or 3rd line (13 pts) (FFL) according to 2 different schedules: 5d q 3 wks (14 pts) or 4 d q 2 wks (11 pts). Selection criteria: Pretreated ACC, no other intercurrent chemotherapy between the 2 schedules, measurable lesion. PT Characteristics M/F = 10/15, median age = 59, colon/ŕectum = 14/11, PS 0-1 vs 2–3 = 22/3, nb of sites FFL (CM) Treatment 17l cycles, median = 7 (1–15), time to exposition = 5 mo (1–9), 5-FU DI = median 1072 mg (831–1580), L-OHP® DI = median 35.7 mg (24–43). Toxicity (per pt) grade 3–4: nausea-vomiting = 25%, diarrhea = 16%, mucositis = 8%. No gr 3–4 hematotoxicity. No renal or auditive toxicity was observed. No toxic death. Efficacy 7 PR (29.2%), 5 minor reponses (21%), 4 SD (17%) and 8 PD (33%). One pt too early. Duration of response was 8.5 mo, disease-free progression 5.8 mo and median survival 12 mo. Conclusion Addition of L-OHP® can reversed FF resistance to CM 5-FU/FA in one third of pts. This further suggests a synergistic and/or modulatory effect between 5-FU and L-OHP®.

Cell-mediated immune response was evaluated in 150 patients with histologically confirmed bronchopulmonary carcinoma using bacterial and fungal recall antigens injected intradermally (PFD, candidina, trichophyton). In the study group negative skin test reaction was found in 51 of 150 patients (34.0 %), whereas in the control population it was found in 5 of 33 cases (15.1 %) (p < 0.05). Histologic cell type and stage of disease were defined for each patient. It was possible to calculate the growth rate of the primary tumor only in 68 of 150 patients, and it was recorded as doubling time. Evaluation of the skin test reaction in each prognostic subgroup showed no statistically significant differences. The only statistically significant differences were found when each prognostic subgroup was compared with the control population according to the frequency of a negative response to the skin test, particularly in stage III M1 (p < 0.05) and stage III M0 (p < 0.02). The delayed cutaneous hypersensitivity studied with recall antigen stimulation was mainly correlated with the stage of disease, and it should not be considered as an independent prognostic factor.