Advanced Solid Neoplasms Research Articles

1874P Impact of infections and antibiotic therapy in a cohort of patients with advanced solid cancers who receive immune checkpoints inhibitors. An observational, retrospective study

Administration of antibiotics has been suggested to have a negative impact on cancer outcome in patients who start immune checkpoints inhibitors (iCPI) therapy due to changes in the gut microbiota. Observational, retrospective, unicentric study of a cohort of patients with advanced solid neoplasms who receive iCPi monotherapy outside clinical trial in a tertiary hospital that explores the incidence of infections and the use of antibiotics, and its possible impact on cancer response and survival. Prognostic factor and efficacy analysis were calculated using Kaplan-Meyer, Chi-square and long-rank tests. Univariant analysis included age, sex, ECOG functional status, Charlson comorbidity index, body mass index (BMI), type of neoplasm, line of therapy, administered drug, neutrophil/lymphocyte ratio (NLR), serum albumin level, serum lactic dehydrogenase level and corticoid therapy before the start of iCPI therapy. PD-L1 expression in the tumor was only available in a minority of patients, so it was not included in the analysis. 199 patients with advanced solid neoplasms (135 non-small lung cancers, 30 melanomas, 12 renal cancers, 11 head and neck cancers, 8 urothelial cancers, 1 hepatocellular carcinoma, 1 choriocarcinoma, and 1 Merkel tumor) treated with iCPI monotherapy were included from January 2013 to December 2018. After a median follow-up of 21,8 months, 65 patients (32,7%) suffered at least one infection and 98,5% of them received antibiotic therapy. Aetiologic agent was found in 23 cases: bacteria (78,2%), virus (17,4%) and fungi (4,3%). There were no differences in the rate of tumoral responses (21,7% vs19,7%), progression free survival (3, 0 vs 3,2 months) and overall survival (7,1 vs 6,9 months) between patients with and without infection. This observational, retrospective study has been unable to demonstrate a negative impact of the incidence of infections that require antibiotic therapy on response rate or survival in patients with advanced solid neoplasms who were under iCPI treatment in our hospital. Prospective studies are needed to answer this question.

340TiP - A multicenter, randomized, controlled, phase II trial exploring adjuvant combined therapy of apatinib and SHR-1210 (anti-PD-1), in patients with hepatocellular carcinoma at high risk of recurrence after radical resection

BackgroundHepatocellular carcinoma (HCC) is the most common malignancy with high rates of recurrence and metastasis after radical resection. Vascular invasion, including portal vein tumor thrombus (PVTT) and microvascular invasion (MVI), and microsatellite lesions are two significant risk factors of postoperative recurrence and metastasis for HCC. Therefore, it is necessary to discover adjuvant therapies for patients with these risk factors. Anti-angiogenesis therapy combined with immunotherapy has demonstrated clinical benefits in multiple advanced solid neoplasms, including HCC. An exploratory phase Ib study (NCT02942329) proved that combined therapy of apatinib (250mg QD) and anti-PD-1 drug, SHR-1210 (200mg Q2W) was well tolerated and had preliminary efficacy in advanced HCC. Trial designThis multicenter, randomized, controlled, phase II study will evaluate the safety and efficacy of adjuvant combined therapy of apatinib and anti-PD-1 drug, SHR-1210, compared with hepatic arterial infusion (HAI) chemotherapy, in patients with HCC at high risk of recurrence after radical resection. 200 patients, aged >18 years, Child-Pugh score 0 or 1, with histologically confirmed primary HCC, BCLC stage A or B diseases that are radical resected without other prior therapy for HCC and who are found to have microsatellite lesions, microvascular invasion or PVTT involved in second-order branch or above by preoperative imaging examination or postoperative pathological findings will be recruited and randomized (1:1) to receive apatinib (250mg QD) and SHR-1210 (200mg Q2W) for 6 months, or 2 times of standard HAI treatments (epirubicin 80-100mg or epirubicin 50mg+oxaliplatin 50mg). The primary endpoint is to compare recurrence-free survival and secondary endpoints include overall survival, safety, 1,2,3-year recurrence rate and Quality of Life score (QoL). Survival follow-up will continue for up to 3 years. The study is ongoing. Clinical trial identificationNCT 03839550. Legal entity responsible for the studyNational Cancer Center/Cancer Hospital. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Profiling of metalloprotease activities in cerebrospinal fluids of patients with neoplastic meningitis

BackgroundNeoplastic invasion into leptomeninges and subarachnoid space, resulting in neoplastic meningitis (NM) is a fatal complication of advanced solid and hematological neoplasms. Identification of malignant involvement of the cerebrospinal fluid (CSF) early in the disease course has crucial prognostic and therapeutic implications, but remains challenging. As indicators of extracellular matrix (ECM) degradation and breakdown of the blood–brain-barrier, Matrix Metalloproteases (MMPs) and A Disintegrin and Metalloproteases (ADAMs) are potential analytes for cerebral pathophysiology and metastatic dissemination of tumor cells into the CSF.MethodsWe compared protease activities in CSF samples from patients with NM and control individuals using FRET-based metalloprotease substrates with distinct enzyme selectivity profiles in a real-time, multiplex approach termed “proteolytic activity matrix assay” (PrAMA). Protease activity dynamics can be tracked by fluorescence changes over time. By simultaneously monitoring a panel of 5 FRET-substrate cleavages, a proteolytic signature can be identified and analyzed to infer the activities of multiple specific proteases. Distinct patterns of substrate cleavage comparing disease vs. control samples allow rapid, reproducible and sensitive discrimination even in small volumes of CSF.ResultsIndividual substrate cleavage rates were linked to distinct proteases, and PrAMA computational inference implied increased activities of MMP-9, ADAM8 and ADAM17 (4–5-fold on average) in CSF samples from NM patients that were inhibitable by the metalloprotease inhibitor batimastat (BB-94). The activities of these proteases correlated with blood–brain barrier impairment. Notably, CSF cell counts were not found to directly reflect the protease activities observed in CSF samples from NM patients; this may explain the frequent clinical observation of negative cytology in NM patients.ConclusionPrAMA analysis of CSF samples is a potential diagnostic method for sensitive detection of NM and may be suitable for the clinical routine.

Evaluation of the Best Power Setting of Laser Waves in Pancreatic Surgery: ECHO ND-YAG Laser Ablation on Bovine Pancreatic Tissue

Background: Pancreatic surgery is one of the most difficult and life-threatening surgical therapy especially during necrotizing pancreatitis and advanced solid neoplasms. Aim of the study: To evaluate the possibility to use ECHO Neodymium-Doped Yttrium Aluminium Garnet (ND-YAG) laser in pancreatic surgery and to establish the best power setting for the application on pancreatic tissue. Methods: An ECHO Laser ND-YAG 1064 nm, at the constant fluence of 1800 J/cm2 was used. The laser waves were inserted inside of the samples with optical fibers of 500 micron diameter for a pre-established timing (11 min, 6 min, 4 min) in order to reach the constant fluence. Samples were, then, prepared for hystological examination. Results: At 3W power setting, the pancreatic tissue was not macroscopically modified except for an increased cutting consistency. Histological examination showed no substantial microscopical differences in pancreatic cells that appeared only partially burnt (in fact, nuclei and membranes are still recognizable). The vessels in the surrounding area have the normal morphological aspects. At 5W, macroscopically the presence of a completely burnt area, corresponding to the site of direct interaction of laser and tissue, was found and the surrounding tissue did not appear substantially modified. Histological examination showed the complete absence of cells in the burnt area and an important heat damage of the surrounding cells till the 2th centimeter from the site of laser application. The vessels in the heat damage area appeared completely coagulated. At the power of 7 W, the burnt area was about twice than in the previous setting and histological examination showed the complete absence of cells in the burnt area and a larger heat damage of the nearest cells (till the 4th centimeter from the application site). The vessels in heat damage area were found completely coagulated. Conclusions: A power setting between 4 and 6 W have been found as the best one for laser application on pancreatic tissue because a complete destruction of the cells in the site of application but a limited heat damage in the surrounding healthy cells have been obtained.

Role of Hydroxamate-Based Histone Deacetylase Inhibitors (Hb-HDACIs) in the Treatment of Solid Malignancies

Hydroxamate-based histone deacetylase inhibitors (Hb-HDACIs), such as vorinostat, belinostat and panobinostat, have been previously shown to have a wide range of activity in hematologic malignancies such as cutaneous T-cell lymphoma and multiple myeloma. Recent data show that they synergize with a variety of cytotoxic and molecular targeted agents in many different solid tumors, including breast, prostate, pancreatic, lung and ovarian cancer. Hb-HDACIs have a quite good toxicity profile and are now being tested in phase I and II clinical trials in solid tumors with promising results in selected neoplasms, such as hepatocarcinoma. This review will focus on their clinical activity and safety in patients with advanced solid neoplasms.

Baseline lymphopenia as a prognostic marker for colorectal carcinoma.

e14107 Background: Baseline lymphopenia has been proved to be a marker for poor prognosis, chemotherapy-induced toxicity and increased risk of febrile neutropenia, trombocytopenia and anemia in advanced solid neoplasms. This study aims to evaluate the effect of pretreatment lymphopenia on prognosis and hematological toxicity in colorectal cancer patients who received first line systemic chemotherapy. Methods: Lymphocyte count was evaluated in 386 pretreated colorectal cancer patients who do not have a seconder malignancy, HIV infection, bone involvement and primary G-CSF prophylaxis. Overall survival, progression free survival and disease free survival were calculated from date of diagnosis to date of relapse, progression and death. Kaplan-Meier, chi-square and Student-t test were used. Results: Mean follow-up was 30 months (range 1-180 months). Mean age was 57.4±12.5 years. Of all patients, 160 (41 %) were women. Rectum ( 26.2 %) and transvers colon (4.7 %) were the most and the least common anatomic locations, respectively. Mean lymphocyte count before treatment was 1964/µl (170-7000/µl). There were no relationship between lymphopenia and age, sex, performans status, presence of initial metastasis, adjuvant or palliative chemotherapy and hematological toxicity (p>0.05). Grade 3-4 hematological toxicity was found in 40 patients and was significantly higher in patients receiving bi- or tri-chemotherapy regimen (p:0.017). Among 208 patients with relapse or progression, 40 patients had lymphopenia (19.2 %). 1, 3 and 5-year OS were significantly lower in lymphopenic patients (p:0.033). DFS was longer in non-lymphopenic patients but this data didn’t have statistical significance (p>0.05). Conclusions: This study support that lymphocyte number prior to chemotherapy may be a simple but useful prognostic and predictive marker in untreated colorectal cancer patients. Patients with lower pretreatment lymphopenia have lower OS when compared to others (p<0.05). This study has the highest colorectal cancer population in the literature.

Abstract 1818: The Aurora B inhibitor ABT-348 is not susceptible to known resistance mechanisms of other Aurora B inhibitors

Abstract The Aurora kinases (Aurora A, B, and C) play essential roles in regulating cell division in mammalian cells and their over-expression in diverse tumor types makes them appealing oncology targets. ABT-348 is a novel, ATP-competitive, multi-targeted kinase inhibitor that exhibits potent activity in multiple solid tumor-derived and leukemia cell lines. ABT-348 is active against Aurora B (IC50 7 nM) and Aurora C (IC50 1 nM), Aurora A (IC50 120 nM). The activity against Aurora B is demonstrated by inhibition of histone H3 phosphorylation and induction of polyploidy. ABT-348 is also active against Aurora-B Y156H, a mutant resistant to other Aurora-B inhibitors. In addition, ABT-348 potently inhibits most members of the VEGFR and PDGFR family of receptor tyrosine kinases, which play a critical role in stromal angiogenesis. In contrast to other Aurora kinase inhibitors, the cellular efficacy of ABT-348 is retained in cells over-expressing P-glycoprotein (Pgp) or breast cancer resistant protein (BCRP), indicating that ABT-348 is not a substrate for these commonly upregulated ATP-binding cassette drug transporters. Consistent with these in vitro studies, ABT-348 was broadly efficacious as a single agent against a wide range of tumor types in vivo, including 3 multi-drug resistant xenograft models. In summary, the potent activity and unique kinase selectivity of ABT-348 against the Aurora kinases and VEGF and PDGF receptor tyrosine kinases, engender its ability to block multiple mechanisms of tumor progression. In addition, our data provide evidence that ABT-348 may be active in tumors resistant to other well-characterized inhibitors targeting Aurora-B. ABT-348 is presently under clinical evaluation in adult patients with advanced solid and hematological neoplasms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1818. doi:1538-7445.AM2012-1818

A pilot trial of oral topotecan (TPT) in patients with refractory advanced solid neoplasms expressing HIF-1α.

e13518 Background: HIF-1α is a transcription factor that mediates tumor angiogenesis and survival. Previous studies have demonstrated that daily administration of topotecan (TPT) - a topoisomerase-1 inhibitor - inhibits HIF-1α expression, angiogenesis, and tumor growth in human xenograft models. The primary aim of this study is to investigate whether TPT inhibits HIF-1α expression in human cancers. Methods: TPT was administered orally at 1.6 mg/m2 daily × 5 for 2 weeks, of a 28-day cycle, to patients with advanced solid tumors expressing HIF-1α in at least 10% of tumor cells. Tumor biopsies were obtained before and after 2 cycles of TPT. The primary endpoint was modulation of HIF-1α expression by IHC. mRNA expression of HIF-1α target genes was assessed by real-time PCR. Radiologic correlative studies (comprising 18FDG-PET, to assess tumor metabolism, and DCE-MRI, to assess blood flow and permeability) were obtained at baseline, after 2 weeks of therapy and post cycle 2. The statistical significance of the difference in HIF-1α values was determined by a Wilcoxon signed rank test. Results: 15 patients, median age 54 (range 25-70), were treated, with n=7 undergoing paired tumor biopsies and being evaluable for the primary endpoint. Disease types: melanoma, colon (n=3), ovarian (n=2), sarcoma (n=2), lung, bladder, adrenocortical (n=2), anal, pancreatic, head and neck. Three patients received TPT 1.6 mg/m2before protocol amended to 1.2 mg/m2because of dose-limiting G3 neutropenia and G4 thrombocytopenia. The median number of cycles received was 2. Only 5 patients proceeded beyond 2 cycles (maximum 6). The median reduction in HIF-1α by IHC was -7.5% (range -50.0 to +5.0%; p=0.16). 6 of 7 patients exhibited declines in K trans on DCE-MRI (p=0.13) and 5 of 7 exhibited Kep changes (p=0.45). One patient obtained a PR and 2 patients had SD. Conclusions: This is the first study evaluating HIF-1α modulation in tumor tissue as a primary clinical trial endpoint in cancer patients. Whilst trends in both HIF-1α modulation and radiologic correlates (kTrans alteration on DC-MRI) were seen, these were not statistically significant due to low patient numbers. No significant financial relationships to disclose.

Bevacizumab (BEV) and continuous low-dose granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid tumors: final results of a prospective clinical trial

e14544 Background: BEV is potent inhibitor of VEGF-mediated tumor angiogenesis. VEGF is also crucial in antineoplastic immunortolerance by blocking the generation of dendritic cells (DC). VEGF inhibition may thus result in an improved anti-cancer immune response which may be further augmented by GM-CSF, a powerful stimulator of DC generation. In a previous study, GM-CSF was able to produce clinical responses in patients (pts) suffering from refractory carcinomas (Kurbacher et al., Oncology 2005). In this trial, we investigated BEV+GM-CSF in pts with advanced solid neoplasms. Methods: 26 pts have been enrolled: epithelial ovarian cancer, n=12; breast cancer, n= 6; primary peritoneal carcinoma, n=3; hormone-refractory prostate cancer, n=2; miscellaneous, n=3. All pts have been considered refractory to or non-treatable by chemotherapy due to their baseline bone marrow and/or organ functions. Fourteen pts had previously received BEV as part of other antineoplastic regimens. BEV was applied at a fixed dose of 6 mg/kg q2w. The starting dose of GM-CSF (sargramostim) was 125 μg/d. In cases not responding and/or not achieving moderate leukocytosis (< 20 G/L), GM-CSF was increased every 4 weeks at 25 μg increments up to a maximum of 250 μg/d. Toxicity was documented according to the NCI-CTC score, responses were recorded according to the RECIST or Rustin criteria. Results: Grade (G) 3–4 hypertension was seen in 3 pts, with 1 pt experiencing cerebral stroke 6 weeks after cessation of BEV+GM-CSF. Other G3–4 toxicities were fatigue in two pts, and fever, pain, myalgia, and central nervous symptoms in either one pt. Other side-effects like injection-site reactions, proteinuria, anemia, thrombocytopenia, and constipation did not exceed G1–2. The objective response rate was 31% (1 CR, 7 PR, 10 SD, and 8 PD); the rate of pts benefiting was 69%. Eight pts failing prior BEV benefited from BEV+GM-CSF. Until today, 13 pts have died. The median time to progression is 92 days and the median overall survival is 302 days. Conclusions: BEV+GM-CSF is an active and generally well tolerated non-cytotoxic regimen in pts with advanced solid tumors. Thus, large-scaled studies of this promising treatment are warranted. No significant financial relationships to disclose.

Dehydroepiandrosterone sulfate (DHEAS) secretion in early and advanced solid neoplasms: selective deficiency in metastatic disease.

Several endogenous hormones have been proven to stimulate cancer growth, whereas at present very few hormones are known to display oncostatic activity. The most widely investigated antitumor hormone is the pineal indole melatonin (MLT), and cancer progression has been shown to be associated with a decline in MLT secretion. Recently, another hormone, the adrenal steroid dehydroepiandrosterone-sulfate (DHEAS), has appeared to exert antitumor effects similar to those previously described for MLT. In addition, experimental studies suggest a diminished DHEAS production with neoplastic progression. This preliminary study was performed to evaluate the daily secretion of DHEAS in a group of early and advanced cancer patients. The study included 70 patients with solid tumors (gastrointestinal tract tumors: 28; breast cancer: 24; non-small cell lung cancer: 18), 28 without and 42 with distant metastases. The serum levels of DHEAS were measured by RIA in blood samples collected in the morning. The control group consisted of 100 age- and sex-matched healthy subjects. No significant difference in mean serum levels of DHEAS was observed between controls and non-metastatic patients. In contrast, metastatic patients, irrespectively of tumor histotype, showed significantly lower mean levels of DHEAS with respect to either controls or non-metastatic patients. Moreover, metastatic patients with visceral locations showed significantly lower values of DHEAS than those with bone or soft-tissue metastases. This preliminary study would suggest there to be a deficiency in the daily DHEA secretion in patients with disseminated cancer. Further studies evaluating circadian DHEAS secretion in relation in that of the pineal hormone MLT will be required to better define the biological significance of the advanced cancer-related decline in endogenous DHEAS production.

Cisplatin-paclitaxel weekly schedule in advanced solid tumors: A phase I study

The objective of our study was to determine the maximum tolerable doses (MTDs) of both paclitaxel and cisplatin when given in a weekly schedule alone or simultaneously with G-CSF in advanced solid neoplasms. Patients with advanced cancer either chemotherapy-naive or resistant to standard treatments received paclitaxel in a three-hour infusion followed by cisplatin, with or without the addition of r-HuG-CSF (5 micrograms/kg s.c. days three to five). The starting doses of CDDP and paclitaxel were 25 mg/m2/week and 45 mg/m2/week, respectively. During the first six courses the dosages of the two drugs were alternately escalated by 20% (CDDP = 5 mg/m2/week, and paclitaxel 10 mg/m2/week) at each step until the appearance of dose-limiting toxicity (DLT) in one-third or more of the patients enrolled in that cohort. Fifty-five patients with cancer (16 lung, 16 breast, 11 ovarian, 7 head and neck, 1 renal, 1 esophageal, 1 cervical, 1 soft-tissue sarcoma, and 1 of unknown primary), 25 of whom were pretreated, were entered into the study. A total of 439 weekly courses were delivered. In chemotherapy-naïve patients, the MTDs of cisplatin and paclitaxel were 30 mg/m2/week and 65 mg/m2/week, respectively, in the absence of G-CSF support, which increased to 40 mg/m2/week and 85 mg/m2/week, respectively, when G-CSF was given. There were no toxic deaths in this study. Neutropenia was the main dose-limiting toxicity (100/439 courses), but was seldom severe. Neurotoxicity was quite frequent (18 of 55 patients for the total of 88 courses) but never dose-limiting. It was more frequent and clinically relevant in cisplatin-pretreated patients. Overall 18 patients (eight ovarian, five breast, three lung, and two head and neck) achieved objective responses. The cisplatin-paclitaxel weekly administration seems a safe, practical and effective therapeutical approach in patients with advanced solid neoplasms. Large phase II trials are warranted to accurately define the efficacy of this schedule in cisplatin-paclitaxel sensitive tumors.

EFFICACY AND TOLERABILITY OF CANCER NEUROIMMUNOTHERAPY WITH SUBCUTANEOUS LOW-DOSE INTERLEUKIN-2 AND THE PINEAL HORMONE MELATONIN - A PROGRESS REPORT OF 200 PATIENTS WITH ADVANCED SOLID NEOPLASMS

The recent advances in psychoneuroimmunology have demonstrated the existence of a psychoneuroendocrine control of the antitumor immunity. Our previous preliminary studies indicated the possibility of amplifying the biological and therapeutic efficacy of IL-2 cancer immunotherapy by immunomodulating neurohormones, mainly the pineal indole melatonin (MLT), in most advanced solid tumors, including those which generally do not respond to IL-2 alone. This study reports on the results obtained by low-dose IL-2 plus MLT in 200 patients with advanced solid neoplasms, for whom no other effective standard therapy was available. Non-small cell lung cancer, pancreatic adenocarcinoma, hepatocarcinoma, colon cancer and gastric cancer were the neoplasms most frequently detected in our patients. In addition, all patients had a life expectancy less than 6 months. IL-2 was given subcutaneously at 3 million IU/day for 6 days/week for 4 weeks; MLT was given orally at 40 mg/day. In non-progressing patients, a second cycle was given after a 21-day rest period; then, patients underwent a maintenance period consisting of one week of therapy every month until progression. A complete response (CR) was achieved in 4 patients (hepatocarcinoma 2; pancreas 1; gastric cancer 1), a partial reasponse (PR) was achieved in 36 patients (lung 12; liver 6; stomach 4; pancreas 3; colon 3; breast 2; miscellaneous 6). Tumor response rate (CR+PR) was 40/200 (20%) patients. Longer than one year survival was achieved in 79 (39%) patients. Toxicity was mild in all patients, and therapy was administered as a home therapy. The present study confirms in a great number of patients the possibility to induce objective tumor regressions in most advanced solid tumor histotypes by low-dose IL-2 plus MLT. Thus, immunotherapy with IL-2 and MLT may be considered as a new well tolerated and effective therapy of almost all advanced solid tumors, including those which do not respond to IL-2 alone or to chemotherapy.

The clinical neuroimmunotherapeutic role of melatonin in oncology

In the past several years, interest in the immunophysiological role of the pineal gland and melatonin has grown to the extent that now their immunoregulatory role is widely recognized. Melatonin has immunoenhancing properties and it is able to counteract the immunodepression induced by acute stress, drug treatment (i.e., anticancer drugs), and viral infections. Here we review the therapeutic efficacy of melatonin alone or in combination with interleukin-2 (IL-2) in cancer patients who did not respond to standard anticancer chemotherapies and/or refused any aggressive treatment. In this review, we summarize a series of reports from 1986 through 1994 in which patients affected by metastatic solid tumors, metastatic non-small-cell lung cancer, advanced solid neoplasms, myelodysplastic syndrome, hepatocellular carcinoma, and advanced endocrine tumors were studied. The conclusion drawn from these studies is that melatonin protects against IL-2 and synergizes with the IL-2 anticancer action. This combined strategy represents a well tolerated intervention to control tumor growth. In most cases performance status and quality of life seem improved.

Pineal-opioid system interactions in the control of immunoinflammatory responses.

Several studies have demonstrated involvement of the pineal gland in the regulation of neuropeptide secretion and activity. In particular, the existence of links between the pineal gland and the brain opioid system has been documented. Both opioid peptides and melatonin (MLT), the most investigated pineal hormone, play an important role in neuromodulation of the immunity. Moreover, the immune effects of MLT are mediated by endogenous opioid peptides, which may be produced by both the endocrine system and the immune cells. In addition, the immune dysfunctions that characterize some human diseases, such as cancer, depend not only on the immune system per se, but also at least in part, on altered secretion of immunomodulating neurohormones, including MLT and opioid peptides. Therefore, the exogenous administration of neurohormones could potentially improve the immune status in humans. The present study evaluates the effects of MLT on changes in the number of T lymphocytes, natural killer cells, and eosinophils induced by exogenous administration of interleukin-2 (IL-2). Macrophage activity was also evaluated by determining serum levels of its specific marker, neopterin. The study was performed in 90 patients with advanced solid neoplasms, who received IL-2 at a dose of 3 million IU/day subcutaneously for 6 days a week for 4 weeks plus MLT at a daily dose of 40 mg. Both drugs were given in the evening. The results were compared to those in 40 cancer patients treated with IL-2 alone. The mean increase in T lymphocytes, natural killer cells, and eosinophils was significantly higher in patients treated with IL-2 plus MLT than in those who received IL-2 alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of the concomitant administration of the pineal hormone melatonin in cancer immunotherapy with low-dose IL-2 in patients with advanced solid tumors who had progressed on IL-2 alone.

Our preliminary studies in humans have shown that the pineal neurohormone melatonin (MLT) may enhance the antitumor activity of IL-2, by confirming the existence of a neuroendocrine control on cytokine effects. On this basis, a study was started to evaluate the influence of a concomitant administration of MLT and low-dose IL-2 in cancer patients, who had progressed during a previous immunotherapy with IL-2 alone. The study included 14 patients with advanced solid tumors (lung 6; kidney 4; stomach 2; liver 1; melanoma 1). IL-2 was given at a daily dose of 3 million IU s.c. for 6 days/week for 4 weeks. MLT was given orally at a daily dose of 40 mg every day, starting 7 days prior to IL-2. Objective tumor regression, consisting of a partial remission (PR), was achieved in 3/14 (21%) patients (lung 1; kidney 1; liver 1). Six other patients had a stable disease (SD), while the remaining 5 cases progressed. PR and SD were associated either with a significantly longer survival at 1 year, or with a significantly higher increase in lymphocyte and eosinophil mean number with respect to the patients with disease progression. This preliminary study suggests that advanced solid neoplasms resistant to IL-2 may become responsive to IL-2 therapy by a concomitant administration of the pineal hormone MLT, which could act by enhancing IL-2 antitumor immune effect and/or by increasing the susceptibility of cancer cells to the cytolysis mediated by IL-2-induced cytotoxic lymphocytes.

Neuroimmunotherapy of advanced solid neoplasms with single evening subcutaneous injection of low-dose interleukin-2 and melatonin: Preliminary results

On the basis of the demonstrated existence of immunoneuroendocrine interactions and on the previously observed synergistic action betwen the pineal hormone melatonin (MLT) and interleukin-2 (IL-2), we have designed a neuroimmunotherapeutic combination consisting of low-dose IL-2 and MLT in the treatment of advanced solid neoplasms. The study included 24 patients with advanced solid tumours (non-small cell lung cancer 9; colorectal cancer 7; gastric cancer 3; breast cancer 2; cancer of pancreas 1; hepatocarcinoma 1; unknown primary tumour 1), 21 of whom showed distant organ metastases. Not all patients responded to previous chemotherapies, or had tumours for which no standard therapy was available. Moreover, not all patients were able to tolerate IL-2 immunotherapy at the conventional doses. IL-2 was given subcutaneously at a dose of 3 × 10 6 U/day at 8.00 p.m. for 6 days/week for 4 weeks. MLT was given orally at a dose of 50 mg at 8.00 p.m. every day, starting 7 days before IL-2 injection. In non-progressed patients, a second cycle was given after a 21-day rest period. A partial response was seen in 3 24 patients (lung 2; stomach 1; duration: 11, 4, 4 months, respectively). Moreover, a minimal response (duration: 8+ months) was seen in 1 lung cancer patient. Stable disease was obtained in 14 24 patients (median duration: 6+ months), while the remaining 6 patients progressed. An improvement in performance status was seen in 7 24 patients. No important toxicity was observed. Mean eosinophil and lymphocyte levels significantly increased during the immunotherapy, and their rise was significantly higher in patients with response or stable disease than in those with progressive disease. These preliminary results show that neuroimmunotherapy with low-dose IL-2 and the pineal hormone MLT is a biologically active and well tolerated strategy, capable of determining an apparent control of tumour growth in patients with advanced solid neoplasms, for whom no standard effective therapy is available.

A phase I clinical trial of recombinant human tumor necrosis factor.

We performed a Phase I assessment of recombinant human tumor necrosis factor (rTNF-alpha) in 27 patients with advanced solid neoplasms. Therapy consisted of a 30-minute intravenous (IV) infusion on days 1 through 5, every 2 to 3 weeks. Daily doses ranged from 5 micrograms/m2 to 200 micrograms/m2. Dose-limiting sequelae were hypotension, rigors, and phlebitis. Transient fatigue and fever (median, 38 degrees C) were not clearly dose-related between 5 micrograms/m2/d and 150 micrograms/m2/d. Other reversible complications in three patients included transient leukopenia (leukocyte count, 1.3, 1.2 X 10(3)/microliters in two patients) at a dose of 5 micrograms/m2/d and 150 micrograms/m2/d, respectively; and thrombocytopenia (leukocyte count, 73 X 10(3)/microliters) at 10 micrograms/m2/d. Among 22 patients with initial and subsequent differential counts, the median number of eosinophils at the commencement of therapy was 182 cells/microliters compared with a subsequent median of 462 cells/microliters. We also detected hypertriglyceridemia in all patients. The median baseline increased from 93 mg/dl (range, 56 to 219 mg/dl) to 203 mg/dl (range, 94 to 454 mg/dl). From our experience, a clinically manageable outpatient regimen for Phase II trials consists of rTNF-alpha (150 micrograms/m2) followed by a 1-hour IV infusion of 500 ml of normal saline to abrogate hypotension daily for 5 days every 2 weeks for four cycles, then every 3 weeks thereafter to facilitate recovery from constitutional sequelae.

Recombinant leukocyte A interferon with doxorubicin. A phase I study in advanced solid neoplasms and implications for hepatocellular carcinoma.

A pilot study was performed on seven patients with advanced solid neoplasms. They received recombinant leukocyte interferon A (rIFN-alpha A) 12 X 10(6) U/m2 intramuscularly daily for 5 days plus doxorubicin, 25 mg/m2 IV on day 3 of each monthly cycle (Roferon-A, Hoffman-LaRoche, Nutley, NJ). Because of side effects, the dose was not increased above the initial level. There was a striking partial response of biopsy-confirmed hepatocellular carcinoma for 6+ months along with a decrease in alpha-fetoprotein from 39,000 to 202 ng/mL. The doxorubicin dose is approximately 33% to 42% of the typical single-agent dose, thus suggesting that the clinical toxicity from these two agents is additive.

Delayed cutaneous hypersensitivity and peripheral lymphocyte counts in patients with advanced cancer.

One hundred eighty-three patients with advanced solid neoplasms were tested for their ability to react to four common skin test antigens (tuberculin PPD, streptokinase-streptodornase, mumps, and Monilia) and their ability to develop delayed cutaneous hypersensitivity (DCH) to 2, 4 dinitrochlorobenzene (DNCB). All patients were followed for at least 6 months or until death. Histologic tumor types studied were: melanoma (65), sarcoma (28), squamous cell carcinoma (23), and adenocarcinoma (67). The rate of progression of disease within 6 months of testing was lower in patients who had a positive response to a challenging dose of 50 mug of DNCB. Reactivity to recall antigens had no prognostic value except in patients with adenocarcinomas. Among patients with adenocarcinoma, those who reacted strongly to DNCB and one or more skin test antigens had the best prognosis, while those who were nonreactive to all had the worst prognosis (progression rate: 18% vs. 78%). Peripheral lymphocyte counts were related to the results of DCH to DNCB and skin tests. The preseence or absence of lymphocytopenia (count less than 1000/mm3) had prognostic value in patients who had positive skin test(s). In such patients, the disease progression rate was much higher in patients who were anergic to DNCB and who were lymphocytopenic (90% vs. 40%). These data suggest that DCH to DNCB, recall antigens, and peripheral lymphocyte counts are useful immunologic measurements in patients with advanced cancer. Although the prognostic value of each individual test is relatively limited, the predictive worth can be increased when multiple tests are employed. Pertinent findings reported in the literature are reviewed.

TOXICITY AND CLINICAL TRIAL OF AZASERINE AND 6-THIOGUANINE IN ADVANCED SOLID MALIGNANT NEOPLASMS.

Toxicity and Clinical Trial of Azaserine and 6-Thioguanine in Advanced Solid Malignant Neoplasms