Chemoembolization facilitates limb salvage surgery in stage III soft tissue sarcoma.

A 26 year-old male was referred to our unit because of a stage III soft tissue sarcoma in the shoulder girdle-axillary area and reduced forearm-distal arm strength. Imaging studies revealed that the tumor encompassed the axillary artery and brachial plexus. We chemoembolized it using vincristine, adriamycin and cyclophosphamide (VAC) plus gel foam and performed limb salvage surgery (LSS) afterwards. The patient received adjuvant chemotherapy (ifosfamide/mesna, adriamycin, and dacarbazine/MAID) and finally radiation therapy (RT; 6500 cGy total dose). Thirty-six months after the operation the patient remains free of disease, without local recurrence and excellent neurological recovery and functional rehabilitation. In stage III soft tissue sarcomas, especially in proximity with major nerve/arterial bundles, a multimodality approach is mandatory; chemoembolization is very effective in shrinking the tumor and defining its margins so as to make feasible a LSS.

Surgical options in cases of tumorous destruction of the proximal humerus: twenty-one patients followed from 4-9 years.

PURPOSE: To compare the postoperative outcomes of several techniques of reconstructive surgery for malignant and aggressive benign tumors of the proximal humerus. PATIENTS AND METHODS: Twenty-one shoulder reconstructions following tumor resection were studied. Nine cases with an intracompartmental tumor were treated with endoprosthetic reconstruction. Three cases with the tumor involving the glenoid were treated with a typical Malawer VB shoulder girdle resection. In 5 patients with extracompartmental resections including the rotator cuff or the deltoid muscle a modified Tikhoff-Linberg procedure using polypropylene mesh was performed. In 4 patients with extracompartmental excision the authors proceeded to skeletal reconstruction using a modular endoprosthesis, while soft tissue reconstruction was undertaken using monofilament polypropylene mesh in order to enforce joint stability. RESULTS: All patients achieved stable shoulders. In cases where the technique was modified with mesh the functional outcome was fairly improved and the cosmetic result was excellent. CONCLUSION: For extracompartmental excisions including the deltoid or the rotator cuff the authors recommend a modified Tikhoff-Linberg procedure. Using polypropylene mesh they aim to achieve a static suspension in order to avoid the excessive traction of the neurovascular bundle, which is the most common complication of this procedure. Substitutionally such cases may be treated by reconstruction with a modular endoprosthesis. They recommend stabilization of the prosthesis with the use of mesh implant, avoiding in this way instability.

Implication of bevacizumab in fatal arterial thromboembolic incidents.

Bevacizumab, a humanized monoclonal antibody against vascular endothelial factor (VEGF), is approved for the treatment of metastatic colon cancer, but it has also shown efficacy in first line therapy of non-squamous-cell non-smallcell lung cancer, breast cancer and clear-cell renal cancer. Antiangiogenic therapy severe toxic effects such as stroke, myocardial infraction, angina, arterial thromboembolism, pulmonary embolism or haemorrhage, gastrointestinal perforation, heart failure should be taken into account during treatment with bevacizumab. We describe and discuss two cases of cancer patients who developed fatal arterial thromboembolic episodes after administration of bevacizumab. Due to the recent launch of antiangiogenic agents and the limited experience with their use in clinical practice, their adverse effects and pharmacological toxicities, sometimes fatal, are not well-established and a detailed registration of them is needed.

Preclinical studies of steroid-linked nitrosoureas in murine pancreatic adenocarcinoma PANO2.

PURPOSE: In earlier studies, this laboratory carried out research on the synthesis and anticancer evaluation of hybrid compounds, which combine two molecules in one such as homo-aza-steroidal esters (HASE) of carboxylic derivatives of N, N-bis (2-chloroethyl) aniline. In this combination, steroidal hormones are employed as carriers for transporting the alkylating agents to specific targeted tissues. Aiming to continue our research, we used alkylating agents, as nitrosoureas, instead of nitrogen mustards. In this work the N-[N- (2-chloroethyl)-N-nitroso-carbomoyl]-L-alanine (CNC-ala) has been used and was bound to 7 newly synthesized modified steroidal esters (carrier molecule) of nitrosourea and the hybrid molecules were tested for antitumor activity against PANO2 murine pancreatic adenocarcinoma. MATERIALS AND METHODS: PANO2 adenocarcinoma was used in this study. C57Bl mice were used for chemotherapy evaluation. The activity was assessed from the inhibition of tumor growth and the oncostatic parameter T/C %. RESULTS: The antitumor activity displayed by 7 hybrid steroidal esters of nitrosourea was quite interesting. It was able to discern 4 of 7 compounds that exhibited considerable antitumor activity, increasing the lifespan of the tumor-bearing mice by inhibiting the tumor growth. CONCLUSION: The comparative study of 7 newly synthesized hybrid steroidal esters of nitrosourea shows that the antitumor effects of compound 7, which has an enlarged (7 carbon atoms) A-lactamic ring and nitrosourea esterified at the position 17, which seems to be the most appropriate for the connection of a DNA cross-linking amino acid derivative is superior.

Comparative topoisomerase IIa and ki 67 protein expression in papillary thyroid carcinoma based on tissue microarrays and image analysis.

PURPOSE: Topoisomerase II alpha (Topo IIa gene location 17q21) is a nucleic enzyme involved in the DNA replication, transcription and chromosome topological formation. Topo IIa inhibition strategies include specific chemotherapeutic agents such as anthracyclines. Our aim was to investigate potential protein alterations of the enzyme comparing them to ki 67 proliferation marker expression in papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: Using tissue microarray (TMA) technology, 50 specimens consisting of histologically confirmed PTCs (n=20), multi-nodular goiters (n=20) and also normal thyroid epithelia (n=10) were cored and re-embedded in the final paraffin block. Immunohistochemical analysis was performed using monoclonal anti-Topo IIa and anti-ki 67 (MIB-1) antibodies. Digital image analysis assay was also applied for the evaluation of the protein expression results (Nuclear Labeling Index-NLI). RESULTS: Topo IIa and ki 67 proteins were overexpressed in 4/20 (20%) and 14/20 (70%) cases, respectively. Concerning multi-nodular goiters, overexpression was observed in 2/20 and 4/20 specimens, respectively. Statistical association was assessed correlating ki 67 expression to pathology type, capsular invasion and also to vascular infiltration (p=0.001, p=0.008, and p=0.012, respectively). Topo IIa protein expression was strongly correlated only to capsular invasion (p=0.004). Overall expression of the examined markers demonstrated a medium concordance (kappa=0.27), but a strong association (p=0.001). CONCLUSION: Topo IIa and also ki 67 overexpression are correlated to an aggressive phenotype in PTC. Topo IIa overexpression maybe is a reliable marker for a rational application of targeted chemotherapeutic strategies in some subgroups of patients.

Multiple cutaneous ecchymoses associated with the administration of bevacizumab.

Nowadays, the introduction of combinational therapies with biological agents against advanced or resistant to chemotherapy tumors or for the treatment of cancer patients with organ failures becomes more and more attractive. The authors describe the case of a 60-year-old female patient with a multi-refractory to conventional cytotoxic therapy laryngeal cancer that was treated with cetuximab and bevacizumab combination therapy. Bevacizumab administration was associated with appearance of multiple cutaneous ecchymoses. This is a first-time reported adverse effect. Due to the recent launch of these agents and the limited experience of their use in clinical practice, their adverse effects and pharmacological toxicities are not well established and call for their detailed registration and reporting.

Evaluation of combined h-TERT, bcl-2, and caspases 3 and 8 expression in cutaneous malignant melanoma based on tissue microarrays and computerized image analysis.

PURPOSE: Deregulation of apoptotic pathways in cutaneous malignant melanoma appears to be correlated with chemoresistance and poor prognosis. Furthermore, telomerase (especially h-TERT) expression induces proliferation and also represents a potential target for vaccination regarding some types of malignancies. MATERIALS AND METHODS: Using tissue microarrays (TMA) technology, 25 paraffin-embedded tissue samples of histologically confirmed malignant melanomas were cored at a diameter of 2 mm and re-embedded into one recipient block (final TMA density 24/25-96%). Immunohistochemistry (IHC) was performed by the use of anti-bcl-2, anti-caspase 3, anti-caspase 8 and anti- h-TERT antibodies. Protein expression levels were evaluated using a computerized image analysis system (CIA). SPSS (chi square test and inter-rater kappa) was used for statistical analysis. RESULTS: Strong protein expression was observed in 1/24 (4.1%), 1/24 (4.1%), 2/24 (8.2%), and 4/24 (16.4%) cases regarding h-TERT, caspase 3, caspase 8 and bcl-2, respectively. Moderate was observed in 7/24 (29.1%), 8/24 (32.2%), 5/24 (20.2%), and 8/24(32.2%) cases, whereas reduced or absent expression demonstrated 16/24 (65%), 15/24 (60.2%), 17/24 (68.5%), and 12/24 (50 %) cases. Statistical significance was assessed correlating age to caspase 3 (p=0.05), Breslow's thickness to telomerase (p=0.013) and to bcl-2 (p=0.053), Clark's level to telomerase (p=0.008) and to bcl-2 (p=0.022), and finally ulceration to telomerase expression (p=0.007). CONCLUSION: bcl-2 and telomerase expression are correlated to critical parameters of malignant melanoma, affecting its biological behavior. Furthermore, downregulation of proteins such as caspases 3/8, which normally induce apoptosis, is perhaps associated with resistance of the applied chemotherapeutic strategies in this type of malignancy.

Synchronous bilateral seminoma: report of a case and literature review.

Bilateral occurrence of a primary testicular tumor is unusual. The reported incidence of bilateral germ cell tumors of the testes has been between 0.5 and 7% and the majority of these cancers (90%) are metachronous. We report the case of a 27-year-old man with synchronous bilateral seminoma and discuss the value of the histopathological diagnosis in therapy and prognosis. The related literature is concisely reviewed.

Simultaneous deregulation of p16 and cyclin D1 genes in pancreatic ductal adenocarcinoma: a combined immunohistochemistry and image analysis study based on tissue microarrays.

PURPOSE: Deregulation of cell cycle control molecules, such as cyclins and their inhibitors, is a crucial event in the carcinogenetic process. Our aim was to identify potential correlations between p16 and cyclin D1 expression in pancreatic ductal adenocarcinoma (PDAC) that affect the biological behavior of this neoplasm. MATERIALS AND METHODS: Using tissue microarray (TMA) technology, 50 paraffin-embedded tissue samples of histologically confirmed primary PDACs were cored twice and re-embedded to the final recipient block. Immunohistochemistry (IHC) was performed using monoclonal anti-p16 and anti-cyclin D1 antibodies. Protein expression levels were determined by performing computerized image analysis (CIA; estimation of Nuclear Labeling Index-NLI). SPSS (chi square test and interrater Cohen's kappa) was used for statistical analysis. RESULTS: Cyclin D1 overexpression was observed in 24/50 (48%) of the examined carcinomas, whereas p16 loss or reduced expression was detected in 40/50 (80%) cases. Statistical significance was noted when correlating grade to cyclin D1 (p=0.038), stage to p16 (p=0.012) and also to cyclin D1 (p=0.011). Interestingly, combined protein alterations (p16 loss and cyclin D1 overexpression) were observed in 23/50 (46%) cases associated with advanced stage (p=0.019). Overall combined expression of the two molecules demonstrated a significantly low value (kappa=0.012; 95% confidence interval-CI: 0.010-0.014). CONCLUSION: A significant proportion of PDACs is characterized by simultaneous protein alterations regarding p16 and cyclin D1 genes. This mechanism of genetic deregulation in cell cycle potentially explains in part the aggressive phenotype of this neoplasm.

Combinational effect of topotecan and octreotide on murine leukemia cells in vivo and in vitro.

PURPOSE: The activity of topotecan (TPT) against a number of hematological malignancies is now notably increased. TPT is a drug which inhibits the DNA enzyme topoisomerase I (topo I), thereby leading to the induction of tumor cell apoptosis. On the other hand, octreotide (OCT) is a synthetic analogue of somatostatin, which can induce apoptosis and antiproliferative effects on various human tumor cell lines, human xenografts and animal tumors, as well as on lymphoproliferative neoplasms. Hereby, we studied the effects of TPT and OCT, and their combination in the treatment of the rodent P388 lymphocytic leukemia, in vitro and in vivo. MATERIALS AND METHODS: Cell cultures of P388 lymphocytic leukemia cells, as well as BDF1 male and female mice implanted with the P388 leukemia cells, were used for the in vitro and in vivo evaluation of the antineoplastic activity of OCT and TPT. RESULTS: A significant increase of antileukemic activity of the combined treatment with both TPT and OCT was demonstrated. These results suggest that OCT enhances the effectiveness of TPT in the treatment of leukemia. CONCLUSION: Our results indicate that the combination of OCT with TPT in the treatment of hematological neoplasias is effective, and represents an interesting addition to the future therapeutic options, because os its mechanism of action and its toxicity profile.

Ten years of the Journal of the Balkan Union of Oncology - a brief account.

The Balkan Union of Oncology (BUON) was founded in 1995. Eight Balkan countries are members of this Union. The official journal of the Union is the Journal of the Balkan Union of Oncology (J BUON), 11 volumes (40 issues) of which were published thus far. Meanwhile, J BUON is abstracted/indexed in some important databases. We analyzed the contribution of authors of the different countries in the content of 11 volumes of J BUON, consisting of 764 articles, 641 (83.9%) of which were written by authors from BUON countries, and 123 (16.1%) by authors from non-BUON countries. The 5 main columns (original articles, reviews, educational articles, clinical cases and special series) consisted of 558 (85.9%) articles. BUON countries varied greatly regarding the percentage of their contributions in these columns of J BUON. Greece, Serbia, Turkey, and Bulgaria contributed by 28.9%, 27.8%, 21.5% and 16.9%, respectively, while all other countries published less than 5% of these papers in J BUON.

Prevalence of autoantibodies (ANA, anti ds-DNA, ENA, IMF) and rheumatic syndromes in patients with lymphoproliferative diseases.

PURPOSE: In the development of rheumatic syndromes as well as of lymphoproliferative disorders it is probable that there are common genetic, environmental and immunoregulatory pathogenetic mechanisms. The purpose of this study was to determine the frequency of simultaneous presentation of both lymphoma or other lymphoproliferative diseases, and rheumatic syndromes. PATIENTS AND METHODS: In this study included were all patients with lymphoproliferative diseases (1920 patients) followed at our hospital during the last 5 years. 312/1920 (16.2%) patients presented with non-Hodgkin's lymphoma (NHL), 645/1920 (33.5%) had myeloma, 558/1920 (29%) had leukemia and miscellaneous other hematological malignancies (Hodgkin's lymphoma, cryoglogulinaemia etc) had 405/1920 patients (21%). Antinuclear antibodies (ANA), ribosome P and intermediate filament antibodies (IMF) were measured by immunofluorescence (IF). Anti-double-stranded DNA (ds-DNA) antibodies and extractable nuclear antigens (ENA: Sm, RNP, SSA, SSB, Scl70) were measured by ELISA and the rheumatoid factor (RF) by nephelometry. RESULTS: 388/1920 (4.6%) patients were ANA positive (antibody titres>1/160). On the other hand, clinical symptoms attributed autoimmune diseases (arthralgias, morning stiffness etc) plus autoantibodies other than ANA were present only in 8/312 (2.56%) patients with NHL, among them one with anti-cardiolipin antibodies. It is interesting that from these 8 patients, 3 had MALT lymphoma and 3 diffuse B-cell large cell lymphoma. Also, we detected anti-IMF and IgM and lgG anti-CMV antibodies in 2/312 (0.42%) patients with NHL. CONCLUSION: We conclude that the simultaneous presence of lymphoproliferative diseases and rheumatic syndromes are more frequent among lymphoma patients than in other lymphoproliferative diseases. Therefore, the screening of antibodies in NHL patients may be useful for the discovery and the treatment of an underlying autoimmune disease.

Chromogenic in situ hybridization analysis of chromosomes 7, 9, and 17 in pancreatic ductal adenocarcinoma based on tissue microarrays.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm. Many different chromosomal alterations have been identified including structural or numerical changes. In this study we performed a molecular analysis of chromosomes 7,9, and 17 based on tissue microarrays (TMA). MATERIALS AND METHODS: Using TMA technology, 50 paraffin-embedded tissue samples of histologically confirmed primary PDACs were cored twice and re-embedded to the final recipient block. Chromogenic in situ hybridization (CISH) was performed using centromeric probes of the corresponding chromosomes. SPSS(chi square test and interrater kappa) was performed for statistical analysis. RESULTS: Chromosome 17 analysis detected aneuploidy in 19 (38%) cases. Similarly, aneuploidy regarding chromosome 9 was identified in 9 (18%) cases, whereas 14 (28%) cases were aneuploid, concerning chromosome 7. Statistical significance was assessed, correlating chromosome 7 with grade and stage (p=0.016 and p=0.027, respectively) and chromosome 9 to grade (p=0.023). Similarly, analyzing normal-appearing ductal epithelia adjacent to cancer cell populations, 2 cases were found with alterations regarding chromosome 9 and 17. CONCLUSION: Molecular analysis for chromosomes 7, 9 and 17 in PDAC confirmed that there is a variety of numerical alterations, and some of them represent very early genetic events in the progression of carcinogenetic process. Performance of CISH, also, provides an easy, accurate approach for their detection, even in a small tissue sample, such as TMA cylindrical cores.

Octreotide neutralizes dexamethasone antitumor actions on P388 murine lymphocytic leukemia in vivo.

PURPOSE: A wide variety of human malignancies, including lymphoproliferative neoplasms, express somatistatin (SS) receptors (SS-R). SS induces apoptosis and exerts pronounced antiproliferative effects on various human tumors cell lines, human xenografts, and animal tumors including P388 lymphocytic leukemia. In patients with thymoma the combination of octreotide (OCT) with corticosteroids improves the overall response rate. It has been reported that SS can increase glucocorticoid activity. Hereby, we studied the in vitro and in vivo activity of the SS analogue OCT and of the glucocorticoid dexamethasone (DEX) alone or in combination against the murine P388 lymphocytic leukemia. MATERIALS AND METHODS: Cultures of P388 lymphocytic leukemia and BDF(1) male mice implanted with P388 cells where used for the in vitro an in vivo evaluation of the antileukemic activity of SS and DEX. RESULTS: OCT induced a moderate and DEX a satisfactory cytostatic effect in vitro. OCT produced borderline antileukemic effect when administered on days 1-5 while DEX was effective in all schemes and routes of administration. However, none of the combination schemes exerted any anti-leukemic activity both in vitro and in vivo. CONCLUSION: Since both SS and glucocorticoids exert direct (via receptors) and indirect antitumor actions (regulation of growth factor activity) on several cell lines, in vitro and in vivo, it becomes obvious that further in vitro studies shall provide the molecular evidence for the signal transduction pathways which are involved in the interactions of such important anticancer drugs. Based on the results of the present study, the simultaneous use of these drugs in clinical practice should be carefully considered.

A preclinical survey on the efficacy of lactandrate in the treatment of colon carcinoma.

PURPOSE: There has been a recent and dramatic increase in the pace of drug development for colorectal cancer which holds promise to further improve curative therapy. We tested lactandrate, an alkylating ester of D-lactam androsterone, for antineoplastic activity against colon adenocarcinoma in vitro and in vivo. MATERIALS AND METHODS: The cytostatic and cytotoxic activity of lactandrate were evaluated in vitro against 9 human colon adenocarcinoma cell lines. The in vitro testing was performed with the sulforhodamine B (SRB) colorimetric assay and the mean concentrations of each drug that generated 50% (GI50) or total (100%) growth inhibition (TGI), as well as the drug concentrations that produced cytotoxicity against 50% of the cultured cells (IC50) were calculated. The in vivo antitumour effect was determined against two rodent colon carcinomas, the Colon 26 and the relatively chemoresistant Colon 38 carcinoma, as well as against the human xenograft CX-1 colon carcinoma. RESULTS: Lactandrate displayed a satisfactory activity against the 9 human colon cancer cell lines, inducing significant growth inhibition and cytotoxicity. Lactandrate induced antiproliferative activity against colon cancer cell lines linearly correlated with the carcinoembryonic antigen (CEA) production. There was a non-linear polynomial correlation between CEA production and the cytotoxic effect of lactandrate. The more differentiated cell lines DLD-1 and HCC2998 appeared more resistant to the cytostatic effect of lactandrate. In vivo, the compound produced a significant antitumour activity against Colon 26 and Colon 38, as well as a moderate antitumour effect against CX-1 colon carcinoma. CONCLUSION: Preclinical research supports the high in vitro and in vivo antitumour potential of lactandrate against colon carcinoma. Therefore, lactandrate represents an important candidate drug for further clinical development.

Phase I study of postoperative radiotherapy with concomitant weekly irinotecan, 5- fluorouracil and folinic acid in locally advanced rectal cancer.

PURPOSE: 5- fluorouracil (5-FU)-based chemotherapy with concomitant pelvic radiotherapy represents the gold standard of the adjuvant treatment of high-risk rectal cancer. This study aimed to determine the maximum tolerated dose (MTD) of weekly irinotecan (CPT-11) when combined with fixed 5FU/FA doses and pelvic irradiation. PATIENTS AND METHODS: Twenty- four patients with stage II or III rectal cancer were accrued. All had undergone curative surgery before entering the study. Standard pelvic radiotherapy was delivered (50.4 Gy, 1.8 Gy/ fraction in 5.5 weeks). The 5-FU/FA doses were 350/250 (mg/m(2)) in the first 6 patients and 250/100 in the remaining patients. Weekly doses of CPT-11 started at 30 mg/m(2) with escalation steps of 10 mg/m(2). CPT-11 was escalated when 3 patients had been monitored for 8 weeks, without a dose limiting toxicity (DLT). RESULTS: Twenty-three out of 24 patients completed the chemoradiation course. Only 1 patient discontinued the treatment due to persistent grade 3 diarrhea. Of the 144 planned weekly chemotherapy cycles, only 7 were omitted as a result of persisting grade 2-3 gastrointestinal toxicity in 3 patients and grade 3 neutropenia in 1 patient. Grade 3 gastrointestinal DLTs were observed at doses at the level of 30/250/100 in 1 patient and 70/250/100 in 2 patients. Late DLTs were severe radiation dermatitis and colitis at 40/ 350/250 (1 patient) and 70/250/100 (2 patients), respectively. With a follow-up of 18 months 20 (83.3%) patients remain disease- free. CONCLUSION: The administration of weekly CPT-11/ 5FU/FA with concomitant pelvic radiotherapy is feasible and effective. This treatment schedule is associated with mild myelosuppression and mild to moderate gastrointestinal toxicity. Caution should be paid on late radiotherapy-induced toxicities. The MTD of weekly CPT-11 is 30 mg/m(2) when combined with 5FU/FA doses (mg/m(2)) of 350sol;250 and reaches 60 mgsol;m(2) with lower doses of 5FU/FA (250/100).

Antitumour effect of a- and d- lactam androgen nitrogen mustards on non-small cell lung carcinoma.

PURPOSE: We tested 3 alkylating esters of D-lactam androsterone, 3 alkylating esters of A-lactam testosterone and the alkylating nitrogen mustard components of these esters, for antineoplastic activity on non-small cell lung carcinoma (NSCLC) in vitro and in vivo. MATERIALS AND METHODS: Cytostatic and cytotoxic activity was evaluated in vitro against 10 human NSCLC cell lines. The in vitro testing was performed with the MTT metabolic-colorimetric assay and the mean concentrations of each drug that generated 50% or total (100%) growth inhibition (GI50 and TGI, respectively) as well as the drug concentrations that produced cytotoxicity against 50% of the cultured cells (IC50) were calculated. Furthermore, the in vivo antitumour effect was determined against the relatively chemo-resistant Lewis lung carcinoma (LLC) on mice. The acute toxicity of the tested compounds was appointed in C57BL mice and the antitumor effect on LLC was assessed from the percent increase in median lifespan of the treated animals over the untreated (control) (T/C%). RESULTS: The lactam steroidal esters presented lower toxicity and increased antineoplastic activity in vitro and in vivo compared to their respective alkylating components. An A-lactam testosterone ester namely: 17beta-hydroxy- 3-aza-A-homo-4alpha-androsten-4-one-p-N,N-bis (2chloroethyl) amino phenoxy acetate (ALT-CAPOA) performed significantly higher anticancer activity in vitro and in vivo. This compound generated 37.5% 90-day disease free survivors (cures) against LLC. CONCLUSION: These results indicate a high antitumor potential of lactam steroid alkylating esters depended on the alkylating moiety as well as on the modified steroidal carrier. Preclinical research supports that ALT-CAPOA generates well-tolerated toxicity as well as superior antitumor activity against NSCLC. These significant results call for further clinical development.

The RACOX phase I study: radiation (RA), capecitabine (C) and oxaliplatin (OX) as adjuvant treatment of stage II and III rectal cancer.

PURPOSE: The aim of this phase I trial was to deter- mine the maximum tolerated dose (MTD) of adjuvant che- motherapy (CT) with oxaliplatin in combination with capecitabine during concomitant pelvic radiotherapy (RT) in patients with rectal cancer. PATIENTS AND METHODS: Eligible patients had pathological stage II (T3-4N0M0) or III (any T N1-2M0) rectal adenocarcinoma, and no prior treatment other than curative resection. Fixed capecitabine dose (825 mg/m(2) bid on days 1-14 and 22-35) was given and external beam RT was delivered to the pelvis (50.4 Gy in 27 fractions in 5.5 weeks, with field reduction after 45 Gy in linear accelerator, 18Mev). Oxaliplatin was tested at 4 dose levels: 100, 110, 120 and 130 mg/m(2). The dose of oxaliplatin was escalated when all 3 entered patients at each level had been monitored for at least 8 weeks after the CT/RT course without dose limiting toxicities (DLTs). In the presence of a DLT at any dose level, a further 3 patients were enrolled. If only 1 of the 6 patients experienced a DLT, escalation could proceed. The MTD was defined as the level at which >/= 2 of 3 to 6 patients experienced DLTs. Fifteen patients (10 males and 5 females, median age 62 years) were enrolled at oxaliplatin dose levels of 100 (n=3), 110 (n=3), 120 (n=3) and 130 mg/m(2) (n=6). RESULTS: All patients completed the planned CT/RT course. Dose reduction or delay of the 2nd CT cycle was not required. No DLTs were observed at all dose levels. Overall, gastrointestinal and neurological toxicities were mild and transient. Toxicities included non-dose-limiting nausea / vomiting, diarrhea, dysesthesias in 2 level III and in 1 level IV patients. Grade II myelotoxicity, mainly neutropenia, was seen in 6 patients. With a median follow-up of 4 months (range 2-12) after the completion of CT/RT, late toxicities were restricted to grade II radiation colitis and dermatitis in 2 and 2 patients, respectively. CONCLUSION: The combination of pelvic RT, capecitabine and 3-weekly oxaliplatin is feasible and well tolerated. The MTD was not reached up to the dose of 130 mg/m(2) of oxaliplatin, which is the recommended dose.