Neoplasia News

Volume 1 September 2006 Neoplasia News CONTENTS By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences By Zuvius Lifesciences Sponsored by Send in your Feedback, Queries Suggestions etc. to Designing the future by spreading knowledge NEOPLASIA NEWS - Medical Team Zuvius Lifesciences Pvt. Ltd.Kanara Business Centre, B/301, Nr. Everest Gardens, Link Road, Ghatkopar -East, Mumbai 400 075 Telex: +91 22 2500 6085 Website: www.zuviuslifesciences.com

Neoplasia News 2 EDITORIAL 1. Usefulness of predictive tests for cancer treatment.Dear Doctor, Rosell R, Cuello M, Cecere F, Santarpia M, Reguart N, Felip E, Taron M., Bull Cancer. 2006Aug 1; 93(8):E101-8.The battle against Cancer is a collective effort. People all over the world stand united in their crusade. To assist This review highlights the numerous molecular biology findings in the field of lung cancer with potential therapeutic impact in botheveryone, we want to reach out to the world. With our innovations, we want to make good health a celebration, the near and distant future. At least six lines of research have recently emerged as potential contributors to changes in clinicaleverywhere. Already, we are making rapid strides on a level that’s global. So, in any dialect, Spanish, Mexican, Italian practice. Abundant pre-clinical and clinical data indicate that BRCA1 mRNA expression is a differential modulator ofor Hindi... Zuvius Lifesciences will always stand for ‘Redefining health. Rediscovering life’. chemotherapy sensitivity. Low levels predict cisplatin sensitivity and antimicrotubule drug resistance, and the opposite occurs with high levels. Secondly, single nucleotide polymorphisms in the ERCC1 gene influence survival and toxicity with cisplatin-basedIn redefining health, we will redefine customer satisfaction, also. We want you to know that we are there for you. For chemotherapy. The main core of recent research has centered on EGFR mutations and gene copy numbers. For the first time, EGFRyou, we’ll try harder, we’ll go that extra mile, never stopping, even for a moment, in our dedicated quest. Customer mutations have been shown to predict dramatic responses in metastatic lung adenocarcinomas, with a threefold increase in time tosatisfaction that’s par excellence is our motto - be it in our products, our services, our manufacturing facilities or in progression and survival in patients receiving EGFR tyrosine kinase inhibitors. In contrast, K-ras mutations confer a negative effectour ethos. in these patients. Evidence has also been accumulated on the crosstalk between estrogen and EGFR receptor pathways, paving the way for clinical trials of EGFR tyrosine kinase inhibitors plus aromatase inhibitors. microRNAs control the expression of cognateFurther more we take this opportunity to launch our 1st issue of target genes, and downregulation of Dicer has been shown to be a strong predictor of relapse in surgically resected non-small-cell“Neoplasia News”. We understand that your time is precious and the data published on oncology is very vast. lung cancer patients. Finally, overexpression of the Wingless-type (Wnt) genes and methylation of Wnt antagonists like WIF andThrough this issue we will be updating you with the latest and important updates in the field of oncology. Our secreted frizzled related proteins have been documented in non-small-cell lung cancer and are believed to be an importantmedical team will always be there for you bringing together the cumulative expertise and experience, along with the mechanism of cancer stem cell maintenance.inherent visionary zeal to keep on trying harder, to keep on innovating. 2. Completely resected N1 non-small cell lung cancer: factors affecting recurrence and long-termWe look forward to your feedback and participation to make it more interactive. Feel free to send your Articles, survival.feedback, queries & suggestions to our medical team at [email protected] Fujimoto T, Cassivi SD, Yang P, Barnes SA, Nichols FC, Deschamps C, Allen MS, Pairolero PC. J Thorac Cardiovasc Surg. 2006 Sep; 132(3):499-506.Regards Epub 2006 Jul 28. Managing Director OBJECTIVE: N1 disease in non-small cell lung cancer represents a heterogeneous patient subgroup with a 5-year survival of Zuvius Lifesciences Pvt. Ltd. approximately 40%. Few reports have evaluated the correlation between N1 disease and tumor recurrence or which subgroup of patients would most benefit from adjuvant chemotherapy. METHODS: From 1997 through 2002, all patients with pathologic T1-41 N1 M0 non-small cell lung cancer who had a complete resection with systematic mediastinal lymphadenectomy were retrospectively analyzed and evaluated for factors associated with recurrence and long-term survival. RESULTS: One hundred eighty patients with N1 disease were evaluated. Sixty-six (37%) patients had either locoregional recurrence (n = 39 [22%]), distant metastasis (n = 41 [23%]), or both during follow-up. Univariate analysis demonstrated that visceral pleural invasion and age were associated with locoregional recurrence, whereas visceral pleural invasion, distinct N1 metastasis (as opposed to direct N1 invasion by the primary tumor), and multistation lymph node involvement were associated with distant metastasis (P < .05). Multivariable analysis demonstrated that visceral pleural invasion, multistation N1 involvement, and distinct N1 metastasis were the only independent predisposing factors for locoregional recurrence and distant metastasis. Overall 5-year survival was 42.5%. Survival was significantly decreased by advanced pathologic T classification (P = .015), visceral pleural invasion (P < .0001), and higher tumor grade (P = .014). CONCLUSIONS: In patients with N1-positive non-small cell lung cancer, visceral pleural invasion, multistation N1 disease, and distinct N1 metastasis are independent predictors of subsequent locoregional recurrence and distant metastasis. Advanced T classification, visceral pleural invasion, and higher tumor grade were predictors of poor survival. These patients represent a subgroup of patients with N1 disease who might benefit from additional therapy, including adjuvant chemotherapy. 3. J Clin Oncol. 2006Aug 20;24(24):3939-45. Complete response of colorectal liver metastases after chemotherapy: does it mean cure? Benoist S, BrouquetA, Penna C, Julie C, El Hajjam M, Chagnon S, Mitry E, Rougier P, Nordlinger B. Assistance Publique-Hopitaux de Paris, HopitalAmbroise Pare, Boulogne, France. [email protected] PURPOSE: Most patients with colorectal liver metastases (LMs) receive systemic chemotherapy. This study aimed to determine the significance of a complete response on imaging of LMs after chemotherapy. PATIENTS AND METHODS: Between 1998 and 2004, 586 patients were treated for colorectal LMs in one institution. Of these, 38 with the following criteria were included in the study: fewer than 10 LMs before chemotherapy; disappearance of one or several LMs on computed tomography (CT) scan and ultrasound; surgery with intraoperative ultrasound within 4 weeks of imaging; no extrahepatic disease; follow-up at least 1 year after surgery. RESULTS: Overall, 66 LMs disappeared after chemotherapy as seen on CT scan. Persistent macroscopic disease was observed at surgery at the site of 20 of 66 LMs, despite CT scan showing a complete response. The sites of 15 initial LMs that were not visible at surgery were resected. Pathologic examination of these sites of LMs, considered in complete response, showed viable cancer cells present in 12 of 15 cases. The sites of 31 initial LMs that were not visible at surgery were left in place during surgery; Neoplasia News Zuvius Lifesciences - For a better quality of life, we follow stringent quality norms.

3 Neoplasia News Neoplasia News 4after 1 year of follow-up, 23 of 31 LMs considered in complete response had recurred in situ. Overall, persistent macroscopic or A case of glassy cell carcinoma of the uterine cervix that responded to neoadjuvant chemotherapymicroscopic residual disease or early recurrence in situ were observed in 55 (83%) of 66 LMs having a complete response on imaging. with paclitaxel and carboplatin.CONCLUSION: In most patients receiving chemotherapy for colorectal LMs, a complete response on CT scan does not mean cure. Takekuma M, Hirashima Y, Takahashi N, Yamamichi G, Furukawa N, Yamada Y, Takakuwa R, Ito I.4. Radiother Oncol. 2006Aug 17; Department of Gynecology, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka, Japan. [email protected] performance of interstial fluid pressure and hypoxia as prognostic factors in cervix Glassy cell carcinoma of the uterine cervix is a rare tumor, and has a poor prognosis because of its aggressive clinical behavior andcancer. resistance to radiotherapy and chemotherapy. We report a case of bulky glassy cell carcinoma of the uterine cervix that effectively responded to paclitaxel and carboplatin in a neoadjuvant setting. The patient was a 30-year-old woman who became aware ofFylesA, Milosevic M, Pintilie M, SyedA, Levin W, Manchul L, Hill RP. vaginal bleeding and was referred to our hospital because of a cancerous tumor of the uterine cervix. Physical examination showedDepartments of Radiation Oncology, Clinical Study Coordination and Biostatistics, and Advanced Molecular Oncology, Princess Margaret Hospital/Ontario Cancer the cervical tumor to be approximately 8 cm in diameter with no involvement of the parametrium or vagina. The biopsy resultsInstitute, Canada; Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, Canada. suggested a diagnosis of glassy cell carcinoma. The final diagnosis was glassy cell carcinoma of the uterine cervix, stage 1b2. Neoadjuvant chemotherapy with paclitaxel and carboplatin was administered for downstaging. The response rate was 67.9%OBJECTIVES: Hypoxia and high interstitial fluid pressure (IFP) have been shown to independently predict for nodal and distant (partial response) under magnetic resonance imaging, and elevated serum cancer-related antigen 125 (119 U/ml) and squamousmetastases, as well as survival, in patients with cervix cancer. Using data from our prospective trial, we updated a cohort of patients cancer cell antigen (34 ng/ml) were reduced to 34 U/ml and 3.3 ng/ml, respectively. Following neoadjuvant chemotherapy, shetreated with definitive radiation alone without chemotherapy, to assess the long-term prognostic impact of these microenvironmental underwent radical hysterectomy and adjuvant chemotherapy with the same regimen. The clinical course was very good. Wefeatures. METHODS: Between April 1994 and January 1999, 107 eligible patients with cervix cancer were entered into a prospective speculate that glassy cell carcinoma is a sensitive tumor to paclitaxel and carboplatin. Further evaluation concerning diagnosis andstudy of tumor oxygenation and IFP prior to primary radiation therapy. Oxygenation data are presented as the hypoxic proportion, treatment, however, is needed to improve the prognosis of patients with glassy cell carcinoma.defined as the percentage of pO(2) readings <5mmHg (abbreviated as HP(5)). Patients with HP(5) values >50% were considered tohave hypoxic tumors. IFP is presented in mmHg, divided into high and low IFP groups by the median value. Patients ranged in age from 7. Int J Pediatr Otorhinolaryngol. 2006Aug 14;23 to 78 years with a mean of 53 years. The maximum tumor size ranged from 2 to 10cm, with a median diameter of 5cm. FIGO stagewas IB in 28 patients, IIA in 4, IIB in 42 and IIIB in 33 patients. Twenty-two patients (21%) had evidence of pelvic lymph node Prevention of oral lesions in children with acute lymphoblastic leukemia.involvement on staging CT abdomen/pelvis or MR pelvis. HP(5) ranged from 0% to 99% with a median of 48%. IFP ranged from -3 to48mmHg (median 19mmHg). Median follow-up was 6.7 years (range 0.9-10.6). RESULTS: Disease-free survival (DFS) at 5 years was Pereira Pinto L, de Souza LB, Gordon-Nunez MA, Soares RC, de Brito Costa EM, de Aquino AR, Fernandes MZ Department of Oral Pathology, School of50%. Five year DFS was 42% for patients with hypoxic tumors (HP(5)>50%), and 58% in patients with oxygenated tumors (HR 1.01 Dentistry, Health Sciences Center, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil.per %, p=0.05). DFS at 5 years was 42% for patients with interstitial hypertension (IFP >19mmHg), and 63% in patients with IFP19mmHg (HR 1.05 per mmHg, p=0.001). In a multivariate analysis only tumor size (HR 1.2, p=0.009) pelvic nodal metastases (HR 3.3, Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children and is responsible for severe stomatologicp=0.0004) and IFP (HR 1.06, p=0.0005) were predictive of DFS. Because an interaction between nodal status and oxygenation was complications. Treatment consists of four phases of chemotherapy, the main side effect of methotrexate, the drug most used duringobserved (p=0.03), further analysis indicated a borderline significant impact of HP(5) in addition to tumor size in node negative patients the intensification phase, is oral mucositis. OBJECTIVE: To evaluate the clinical aspects of the oral mucosa of children with ALL(HR 1.01, p=0.06). These results were similar when local or distant relapse was used as an endpoint. CONCLUSIONS: These results and to determine the effect of 0.12% chlorhexidine gluconate on the prevention of stomatologic complications in these patients.confirm our initial finding of the strong independent prognostic impact of IFP for relapse and survival in patients with cervix cancer. In PATIENTS AND METHODS: Thirty-three children treated for ALL ranging in age from 2 to 15 years, without distinction ofcontrast, the independent prognostic impact of HP(5) is of borderline significance and is limited to patients without imaging evidence of gender or race, were submitted to visual examination, digital palpation of the oral mucosa and cytologic examination of the buccalnodal metastases. However, these findings do not diminish the biologic significance of hypoxia, or the role of hypoxia and IFP as mucosa, and divided into two groups: group I consisted of 23 children using an oral solution of 0.12% chlorhexidine gluconatebiomarkers of treatment response and as therapeutic targets. twice a day, and group II consisted of 10 children who did not receive this solution. All children received daily oral hygiene care guided by the dentist throughout treatment. RESULTS: Mucositis was observed in six children (out of 23) of group I and eight5. Cancer Lett. 2006Aug 17; children (out of 10) of group II, and was characterized by erythema, edema and ulcers. Uniform cytologic findings were obtained for the two groups, with a clear predominance of cells of the intermediate layer in all smears, in addition to a perinuclear halo in 18%Mutational status of the epidermal growth factor receptor (EGFR) gene in thymomas and thymic of the smears. CONCLUSION: The present results suggest that systematic preventive treatment with 0.12% chlorhexidinecarcinomas. gluconate and oral hygiene care reduce the occurrence of oral complications in children with ALL undergoing antineoplastic chemotherapy.Meister M, Schirmacher P, Dienemann H, Mechtersheimer G, Schnabel PA, Kern MA, Herpel E, Xu EC, Muley T, Thomas M, Rieker RJ.Translational Research Unit, Thoraxklinik am Universitatsklinikum Heidelberg,Amalienstr. 5, 69126 Heidelberg, Germany. TherapeuticEpithelial tumours of the thymus (thymoma, thymic carcinoma) are rare tumours of the anterior mediastinum. Current treatment 8. MonaldiArch Chest Dis. 2006 Jun;65(2):75-81.options of advanced stage thymomas and thymic carcinomas include a multimodal therapy with radio- and chemotherapy as well assurgery. In recent years, new therapeutic targets such as EGFR (epidermal growth factor receptor), COX-2 and KIT have emerged as Weekly chemotherapy with cisplatin and paclitaxel in advanced NSClC: a phase II study.new potential therapeutic targets. So far, EGFR mutational status of different subtypes of epithelial tumours of the thymus has beenanalyzed only inappropriately. We have investigated 20 different subtypes of rthymomas (type A, AB, and B3) and thymic carcinomas Buccheri G, Ferrigno D, Giordano MC.for mutations in exons 18, 19, 20, and 21 of the EGFR gene and performed immunohistochemistry for EGFR. Concerningimmunohistochemistry, most of the cases (17/20) had a stong positive staining. Although sequence alterations were found in four Cuneo Lung Cancer Study Group, Struttura Complessa di Pneumologia, Ospedale A. Carle, Azienda Ospedaliera S. Croce e Carle, Cuneo, 1-12100, Italy.samples, none of these alterations led to amino acid changes in the tyrosine kinase domain of EGFR comparable to those in non-small [email protected] lung cancer. Thus EGFR-expression in thymic tumours does not rely on mutations in critical functional (activation) domains of theEGFR-gene. Experimental and therapeutic approaches have to consider this difference. BACKGROUND: This phase II study was designed to assess the activity and toxicity of administration of the cisplatin/paclitaxel combination in advanced non-small cell lung cancer (NSCLC). METHODS: Eligibility criteria included: age up to 70 years,6.Anticancer Drugs. 2006 Jul;17(6):715-8. pathological diagnosis of NSCLC, inoperable disease or post-operative tumour recurrence, performance status < or =2, no severe co-morbidity, no previous chemotherapy, and informed consent. Treatment consisted of intravenous infusion of cisplatin, 25 Today, if we bring a healthy smile to someone in Mumbai, tomorrow, we’ll bring joy to someone in Mexico. mg/m2, and paclitaxel, 80 mg/m2, every week. Chemotherapy was continued until completion of a 22-week treatment plan, disease progression, persistent toxicity, or patient refusal. RESULTS: Forty-nine patients entered the study. They received a median of 14 We want people to know that we are there for them

5 Neoplasia News Neoplasia News 6cycles (range 0-22). For both drugs, the median dose-intensity was 75% of projected. Toxicity was generally acceptable, and never life 25.5%. RESULTS: Twenty-eight patients experienced LRF. The overall 10-year cumulative incidences of isolated LRF, LRF withthreatening. Alopecia was the most common side effect, followed by anemia, leukopenia, and nausea/vomiting. Twenty patients and without distant failure (DF), and DF alone as first event were 7.1%, 10.0%, and 23.6%, respectively. Cumulative incidences forresponded (40.8% response rate), with three complete, pathologically documented responses. The estimated median time to isolated LRF as first event for patients with tumors of 5 cm or more than 5 cm were 7.0% and 7.2%, respectively (P = .9). Forprogression was 35 weeks (95% CI: 29-41); the median survival time was 56 weeks (95% CI: not calculable), with a 2-year survival rate patients who underwent no systemic treatment, chemotherapy alone, tamoxifen alone, or chemotherapy plus tamoxifen, theof 46.1%. CONCLUSIONS: When given on a weekly basis, the cisplatin/paclitaxel combination is well tolerated, active, and incidences were 12.6%, 5.6%, 4.6%, and 5.3%, respectively (P = .2). The majority of failures occurred on the chest wall (24 of 28associated to remarkably long survivals. patients). Multivariate analysis did not identify significant prognostic factors for LRF. CONCLUSION: In patients with LN- negative tumors > or = 5 cm who are treated by mastectomy with or without adjuvant systemic therapy and no PMRT, LRF as first9. Gan To Kagaku Ryoho. 2006Aug;33(8):1167-9. event remains low. PMRT should not be routinely used for these patients.[A Case of Recurrent Gastric Cancer Effectively Treated by Combined Chemotherapy of Weekly 12. Surgery. 2006 Sep;140(3):387-95.Paclitaxel (PTX) and CDDP.] Repeated hepatic intra-arterial chemotherapy based on results of anticancer drug sensitivity test inHayashi T, Yoshizawa M, Watanabe N, Murayama Y, Shimizu H. Dept. of Surgery, Murakami General Hospital. patients with synchronous hepatic metastases from colorectal cancer.The patient was a 63-year-old man who underwent distal gastrectomy for advanced gastric cancer with lymph node metastasis and Matsuoka H, Nagaya M, Tsukikawa S, Yanagi Y, IsogaiA, Kubota S. Department of General Surgery, St. Marianna University School of Medicine, Kawasaki, Japan.peritoneal dissemination.One year and eleven months after the operation,an increasing CA 19-9 concentration and metastases to theliver and peritoneum were observed. Oral TS-1 was given, but had to be discontinued because of anorexia and nausea. Chemotherapy OBJECTIVE: We determined whether hepatic intra-arterial infusion of 5-fluorouracil (5-FU) in patients with synchronous hepaticconsisting of paclitaxel (PTX) and CDDP was performed. PTX (80 mg/body) was administered weekly on day 1, 8 and 15, while CDDP metastases from colorectal cancer, in whom the primary lesion was resectable but hepatic metastatic lesions were non-resectable helped(50 mg/body) was administered weekly on day 1 as one cycle.After two cycles of PTX/CDDP administration,metastases to the liver and improve survival time when administered on the basis of the results of the anticancer drug sensitivity test. PATIENTS ANDperitoneum were not detected.The patient was treated with five courses of PTX/CDDP and survived without recurrence as of this METHODS: The study population consisted of 29 patients with synchronous hepatic metastases from colorectal cancer who underwentwriting.PTX/CDDP was associated with few adverse events in hospital visits,and thought to be an effective chemotherapy against surgical resection of the primary lesion alone. Of these 29 patients, 21 received hepatic intra-arterial infusion of 5-FU postoperativelyrecurrent gastric cancer. after the 5-FU sensitivity test. The remaining 8 patients underwent surgical resection of the primary lesion but neither sensitivity testing nor hepatic intra-arterial chemotherapy. Tissue fragments were cultured, with each concentration of 5-FU in the thermoreversible10. World J Gastroenterol. 2006Aug 28;12(32):5237-9. gelation polymer forming a three-dimensional structure at 37 degrees C. The viability of tumor cells was evaluated according to WST methods; inhibitory concentration of 50% (IC(50)) values were calculated. We considered cancer tissue to be sensitive to IC(50) valuesPharmacokinetics of paclitaxel in a hemodialysis patient with advanced gastric cancer: A case that were below twice the peak plasma concentration (120 mug/ml). RESULTS: Of the 21 patients, 10 had sensitivity to 5-FU and 11 hadreport. no sensitivity. The response rates were 90.0% and 9.1%, respectively. The median survival times were 38 months and 10 months in these groups, respectively, and 7 months in patients who received no chemotherapy. This finding indicates a significantly longer survival timeKawate S, Takeyoshi I, Morishita Y. in the sensitive group, compared with either the insensitive group or the no chemotherapy group (P = .0014 P = .0023). The cumulative survival rate was significantly higher in the sensitive group compared with the insensitive group (P = .0001) CONCLUSIONS:We report for the first time the possibility of weekly paclitaxel chemotherapy for a patient with advanced, nonresectable gastric cancer Ultimately, the group with sensitivity to 5-FU showed a significantly longer median survival time than the insensitive group.undergoing hemodialysis. A 50-year-old man with chronic renal failure due to bilateral polycystic kidneys, who had undergonehemodialysis three times a week for 5 years, presented with hematemesis in December 2004. Based on the diagnosis of gastric cancer 13.Anticancer Drugs. 2006 Jul;17(6):709-13.with lymph node metastases, surgery was performed. On the 15th postoperative day, the patient was treated with chemotherapy usingpaclitaxel. Paclitaxel was administered at a dose of 60 mg/m(2) as a 1 h iv infusion in 250 mL of saline. Hemodialysis was started 1 h Fatty liver and transaminase changes with adjuvant tamoxifen therapy.after the completion of the paclitaxel infusion and was performed for 3 h. Paclitaxel was administered weekly on d 1, 8, and 15 on a 28-dcycle. The maximum plasma concentration of paclitaxel was 1390 mug/L. The area under the curve of paclitaxel was 4398.6 mugdh/L. Liu CL, Huang JK, Cheng SP, Chang YC, Lee JJ, Liu TP. Department of General Surgery, Mackay Memorial Hospital, Taipei, Taiwan. [email protected] 2 leukopenia was encountered during the first cycle. The plasma concentrations of paclitaxel from 6 to over 24 h after theinfusion were 0.01 to 0.1 mumol/L in our patient, and these concentrations have been shown to be effective on inhibiting the growth of We investigated the time it took to develop fatty liver and changes in serum aspartate aminotransferase and alaninegastric cancer cells without producing adverse side effects in the patient. The plasma concentration of paclitaxel was not influenced by aminotransferase levels in patients with breast cancer treated with adjuvant tamoxifen. Liver sonography to detect fatty liver andhemodialysis. We conclude that the pharmacokinetics of paclitaxel is not altered in a patient with renal failure, and that weekly measurement of serum aspartate and alanine aminotransferase levels were performed regularly for patients with early breast cancer.paclitaxel is a suitable treatment regimen for hemodialysis patients with advanced gastric cancer. The results were compared in groups of patients with and without adjuvant tamoxifen as well as those on chemotherapy. Eighty- two of 156 patients treated with tamoxifen developed fatty liver, compared with eight of 62 patients not taking it. Fatty liver11. J Clin Oncol. 2006Aug 20;24(24):3927-32. appeared as early as 3 months after beginning tamoxifen and was detected within 2 years in most cases. It persisted for 48 months after discontinuing tamoxifen in 17 of the 82 patients who developed it. The incidence of fatty liver in patients receiving bothLow locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or chemotherapy and tamoxifen was the same as that in patients receiving tamoxifen alone. While 115 patients had elevations oflarger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: aspartate aminotransferase, alanine aminotransferase or both, the magnitude of the elevation was clinically significant in only 32results from five national surgical adjuvant breast and bowel project randomized clinical trials. patients. Patients on both chemotherapy and tamoxifen had a higher incidence of elevated transaminases than those on tamoxifen alone. Adjuvant tamoxifen increases the incidence of fatty liver, but has only a minimal effect on aspartate aminotransferase andTaghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. alanine aminotransferase. Fatty liver may appear as early as 3 months after beginning tamoxifen and may persist for more than 4National Surgical Adjuvant Breast and Bowel Project Operations and Biostatistical Centers, Graduate School of Public Health, University of Pittsburgh, PA, USA. years after discontinuing it. Therefore, long-term follow-up is warranted. Chemotherapy is not clearly associated with fatty liver,[email protected] but may cause a greater degree of hepatocellular damage than does tamoxifen.PURPOSE: Lymph node (LN) -negative breast cancer tumors > or = 5 cm occur infrequently, and their optimal management is not 14. J Clin Oncol. 2006Aug 1;24(22):3562-9.well defined. In this study, we assess patterns of locoregional failure (LRF) in LN-negative patients who underwent mastectomy,either with or without adjuvant chemotherapy or hormonal therapy and without postmastectomy radiation therapy (PMRT). Phase III trial comparing 4-day chrono-modulated therapy versus 2-day conventional delivery ofPATIENTS AND METHODS: Of 8,878 breast cancer patients enrolled onto National Surgical Adjuvant Breast and Bowel Project fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer:B-13, B-14, B-19, B-20, and B-23 node-negative trials, 313 had tumors that were 5 cm or larger (median, 5.5 cm; range, 5.0 to the European Organisation for Research and Treatment of Cancer Chronotherapy Group.15.5 cm) at pathology and were treated by mastectomy. Median follow-up time was 15.1 years. Therapy included adjuvantchemotherapy in 34.2% of patients; tamoxifen in 21.1%; chemotherapy plus tamoxifen in 19.2%; and no systemic therapy in Customer satisfaction that’s par excellence is our motto We are always ready, always prepared, to make a difference to lives.

7 Neoplasia News Neoplasia News 8European Organisation for Research and Treatment of Cancer Chronotherapy Group; Giacchetti S, Bjarnason G, Garufi C, Genet D, Iacobelli S, Tampellini M, Smaaland BACKGROUND: A promising regimen including 5-Fluorouracil, methotrexate and oxaliplatin is reported. PATIENTS ANDR, Focan C, Coudert B, Humblet Y, Canon JL,AdenisA, Lo Re G, Carvalho C, Schueller J,Anciaux N, Lentz MA, Baron B, Gorlia T, Levi F. METHODS: Patients with untreated measurable metastatic disease received bolus 5-Fluorouracil (600 mg/m2) on days 2 and 16, modulated by methotrexate (200 mg/m2) 24 h earlier, alternated with 4 weeks of continuous infusion of 5-Fluorouracil (200Hopital Paul Brousse and INSERM, Villejuif, France. mg/m2/daily) plus oxaliplatin (130 mg/m2) on days 29 and 56, followed by 2 weeks of rest. Serum vascular endothelial growth factor (VEGF) was analyzed at baseline and before every cycle. RESULTS: Fifty-eight patients were enrolled. Objective remissions werePURPOSE: In two previous randomized trials, the adjustment of chemotherapy delivery to circadian rhythms improved tolerability and reported in 45.6% (95% CI=34.3%, 57.3%). The median progression-free survival was 7.8 months and the median overall survival wasanticancer activity compared with constant-rate infusion during 5 days in patients with metastatic colorectal cancer. PATIENTS AND 19.4 months. No grade 4 toxicity was reported, except for one case of diarrhea. The serum VEGF evaluated in 23 patients showed aMETHODS: For this multicenter randomized trial, it was hypothesized that a chronomodulated infusion of fluorouracil, leucovorin, decreasing trend during therapy. CONCLUSION: The regimen was active, well tolerated and may be a possible option in patients notand oxaliplatin for 4 days (chronoFLO4) would improve survival by 10% compared with conventional 2-day delivery of the same drugs suitable for radical surgery.(FOLFOX2). Patients were treated every 2 weeks with intrapatient dose escalation. RESULTS: Baseline characteristics were similar inboth arms for the 564 patients (36 institutions, 10 countries). Median survival was 19.6 months (95% confidence limit [CL] = 18.2, Publication Types:21.2) with chronoFLO4 and 18.7 months with FOLFOX2 (95% CL = 17.7, 21.0; P = .55). The main dose-limiting toxicities were Clinical Trial, Phase IIdiarrhea for chronoFLO4 and neutropenia for FOLFOX2. The analysis of survival predictors showed that sex was the single mostimportant factor (P = .001). In women, the risk of an earlier death with chronoFLO4 was increased by 38% compared with FOLFOX2, 17. Onkologie. 2006 Jun;29(6):273-5.with median survival times of 16.3 and 19.1 months (P = .03), respectively. In men, the risk of death was decreased by 25% withchronoFLO4 compared with FOLFOX2, with median survival times of 21.4 and 18.3 months (P = .02), respectively. CONCLUSION: Safe use of oxaliplatin in a patient with metastatic breast cancer and combined renal and hepaticBoth regimens achieved similar median survival times more than 18 months with an acceptable toxicity. The chronomodulated failure.schedule produced a survival advantage over FOLFOX in men. The strong sex dependency of optimal scheduling of fluorouracil,leucovorin, and oxaliplatin calls for translational investigations of determinants related to the patient's molecular clock. Honecker FU, Brummendorf TH, Klein O, Bokemeyer C. Zentrum fur Innere Medizin, Medizinische Klinik und Poliklkinik, Universitatsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. [email protected] Types: · Clinical Trial, Phase III BACKGROUND: Oxaliplatin has shown activity in several malignancies. In patients with normal renal function, 40-50% of the drug is · Multicenter Study renally excreted. Increased platinum exposure in patients with impaired renal function is not associated with increased toxicity, and · Randomized Controlled Trial patients with hepatic dysfunction did not show altered clearance of oxaliplatin. No data is available regarding safety of oxaliplatin in patients with combined renal and hepatic dysfunction. CASE REPORT: A 64-year-old chemotherapy-naive woman with metastatic15. J Clin Oncol. 2006 Jul 20;24(21):3347-53. breast cancer was admitted with dyspnea, jaundice, massive peripheral edema and combined renal and hepatic failure. After correction of fluid and electrolyte imbalances, weekly oxaliplatin 50 mg/m2 was started. RESULTS: Within 5 weeks of treatment, the performanceComment in: J Clin Oncol. 2006 Jul 20;24(21):3322-4. status improved significantly. Normalization of renal function and improvement of liver function was achieved. Apart from anemia, no toxicities > grade I were observed. After 6 cycles, the patient's condition deteriorated again, with signs of progressive disease. TheRandomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or overall status of the patient declined, and chemotherapy was stopped. CONCLUSION: Weekly doses of oxaliplatin could be safelyinfused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic administered to a patient with metastatic breast cancer and combined hepatic and renal failure, achieving a good, albeit transientcolorectal cancer: a NorthAmerican Intergroup Trial. palliative effect.Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC,Alberts S. Publication Types: Case ReportsDivision of Hematology and Oncology, University of North Carolina at Chapel Hill, CB # 7305, 3009 Old Clinic Bldg, Chapel Hill, NC 27514, [email protected] 18. Br J Cancer. 2006 Jul 3;95(1):13-20. Epub 2006 Jun 13.PURPOSE: Previously, we reported results of Intergroup N9741, which compared standard bolus fluorouracil (FU), leucovorin, plus The role of haemoglobin level in predicting the response to first-line chemotherapy in advancedirinotecan (IFL) with infused FU, leucovorin, plus oxaliplatin (FOLFOX4) and irinotecan plus oxaliplatin in patients with untreated colorectal cancer patients.metastatic colorectal cancer. High rates of grade > or = 3 toxicity on IFL (resulting in some deaths) led us to reduce the starting doses ofboth irinotecan and FU by 20% (rIFL). This article compares rIFL with FOLFOX4. PATIENTS AND METHODS: The primary Tampellini M, Saini A, Alabiso I, Bitossi R, Brizzi MP, Sculli CM, Berruti A, Gorzegno G, Magnino A, Sperti E, Miraglia S, Forti L, Alabiso O, Aglietta M, Harris A,comparison was time to progression, with secondary end points of response rate (RR), overall survival, and toxicity. RESULTS: Three Dogliotti L. Department of Medical Oncology, University of Torino, San Luigi Hospital, 10043 Orbassano, Italy.hundred five patients were randomly assigned. The North Central Cancer Treatment Group Data Safety Monitoring Committeeinterrupted enrollment at a planned interim analysis when outcomes crossed predetermined stopping boundaries. The results were The purpose of the study was to evaluate the influence of baseline haemoglobin level in predicting response to 5-fluorouracil (5FU)-significantly superior for FOLFOX4 compared with rIFL for time to progression (9.7 v 5.5 months, respectively; P < .0001), RR (48% v based first-line chemotherapy in advanced colorectal cancer patients. Data from 631 patients were collected from three different32%, respectively; P = .006), and overall survival (19.0 v 16.3 months, respectively; P = .026). Toxicity profiles were not significantly institutions. Globally, overall response rate was 35.8% (226 out of 631). Factors influencing response rate were 5FU dose intensitydifferent between regimens for nausea, vomiting, diarrhea, febrile neutropenia, dehydration, or 60-day all-cause mortality. Sensory (high: 43.1%, low: 34.0%, P = 0.03); oxaliplatin (yes: 45.8%, no: 22.9%, P < 0.0001), performance status (PS 0: 46.1%, 1: 28.8%, 2:neuropathy and neutropenia were significantly more common with FOLFOX4. Approximately 75% of patients in both arms received 26.7%, P < 0.0001), and haemoglobin levels (> or = 12 g dl(-1): 40.4%, < 12 g dl(-1): 29.2%, P = 0.004). In subgroup analysis significantsecond-line therapy; 58% of rIFL patients received oxaliplatin-based second-line therapy, and 55% of FOLFOX4 patients received differences in response rate between anaemic and nonanaemic patients were recorded in those patients treated with infusionalirinotecan-based regimens as second-line therapy. CONCLUSION: FOLFOX4 led to superior RR, time to progression, and overall chemotherapies (45.7 vs 25.5%, P < 0.0001), with high 5FU dose intensity (50.3 vs 32.7%, P = 0.005), with PS = 0 (49.8 vs 37.9%, P =survival compared with rIFL. The survival benefit for FOLFOX4 observed in the earlier stage of the study was preserved with equal use 0.03), and with liver metastases (44.8 vs 33.8%, P = 0.002), whereas no difference was evident in those subjects treated with bolusof either irinotecan or oxaliplatin as second-line therapy. schedules or according to gender. Anaemia was a strong predictor for activity of first-line 5FU-based chemotherapy especially in thosePublication Types: groups that showed the best responses, for example high performance status, infusionally treated, higher 5FU dose and those with liver secondaries. Patients with higher haemoglobin levels recorded a greater response rate and a longer time to progression and survival than Multicenter Study anaemic subjects. Prospective evaluation of role of correcting anaemia on response to therapy is justified by these results. Randomized Controlled Trial 19. J Child Neurol. 2006Apr;21(4):301-8.16.Anticancer Res. 2006 May-Jun;26(3B):2425-8. Our medicines adhere to internationally recognized pharmaceutical standardsOxaliplatin combined with 5-fluorouracil and methotrexate in advanced colorectal cancer.Zampino MG, Lorizzo K, RoccaA, Locatelli M, Zorzino L, Manzoni S, Mazzetta C, Fazio N, Biffi R, De Braud F.Division of Medical Oncology, European Institute of Milan, 20141 Milan, Italy. [email protected] The day is not too far away, when people will say “Cancer? We are not worried, Zuvius Lifesciences is there’.

9 Neoplasia News Neoplasia News 10Intractable intracranial tuberculous infection responsive to thalidomide: report of four cases.Schoeman JF, Fieggen G, Seller N, Mendelson M, Hartzenberg B. Department of Paediatrics and Child Health, Tygerberg Children's Hospital, Faculty of Health Sciences,Stellenbosch University, Tygerberg, SouthAfrica. [email protected] enlargement and development of new intracranial tuberculomas and tuberculous brain abscesses on adequateantituberculosis treatment are well recognized and supposedly cytokine mediated. These lesions are often unresponsive to conventionalantituberculosis treatment, corticosteroids, and surgery. We therefore assessed the effect of adjunctive thalidomide, a tumor necrosisfactor alpha-modulating drug, in intractable intracranial tuberculosis that did not respond to standard medical and surgical therapy. Fourconsecutive children (three children with bacteriologic proof and one child with clinical evidence of intracranial tuberculosis) werestudied. Three patients each had a giant tuberculous abscess, and the fourth had chronic basal arachnoiditis with progressive loss ofvision. Three of the four patients had relentless neurologic deterioration, and all showed disease progression on neuroimaging despitefull medical and appropriate surgical treatment. Marked clinical and neuroradiologic improvement occurred after thalidomide wasadded to the antituberculosis treatment regimen of these four patients. Adjunctive thalidomide might have a role in the management ofintractable intracranial tuberculosis and needs further investigation in this regard.21. Blood. 2006 Jul 27; [Epub ahead of print]Maintenance therapy with thalidomide improves survival in multiple myeloma patients.Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L,Berthou C, Marit G, Monconduit M, Caillot D, Grobois B,Avet-Loiseau H, Moreau P, Facon T.Hopital purpan, Toulouse.Newer chemotherapeutic protocols as well as high dose chemotherapy have increased the response rate in myeloma. However, thesetreatments are not curative. Effective maintenance strategies are now required to prolong the duration of response. We conducted arandomized trial of maintenance treatment with thalidomide and pamidronate. Two months after high dose therapy, 597 patients underthe age of 65 years were randomly assigned to receive no maintenance (arm A), pamidronate (arm B), or pamidronate plus thalidomide(arm C). A complete or very good partial response was achieved by 55% of patients in arm A, 57% in arm B, and 67% in arm C (P=0.03).The 3-year post-randomization probability of event-free-survival was 36% in armA, 37% in arm B, and 52% in arm C (P<0.009). The 4-year post-diagnosis probability of survival was 77% in arm A, 74% in arm B, and 87% in arm C (P<0.04). The proportion of patientswho had skeletal events was 24% in arm A, 21% in arm B, and 18% in arm C (P=0.4). Thalidomide is an effective maintenance therapyin patients with multiple myeloma. Maintenance treatment with pamidronate does not decrease the incidence of bone events.22. Gynecol Oncol. 2006 Jul 6;Safety and efficacy of thalidomide in recurrent epithelial ovarian and peritoneal carcinoma.Chan JK, Manuel MR, Ciaravino G, Cheung MK, Husain A, Teng NN. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, StanfordUniversity School of Medicine, 300 Pasteur Drive, Room HH333, Stanford, CA, USA.OBJECTIVE.: Thalidomide is an anti-angiogenesis agent that has shown activity in some solid tumors. We performed a phase I clinicaltrial to determine the toxicity and potential efficacy of Thalidomide in recurrent epithelial ovarian carcinoma. METHODS.: Patientswith recurrent ovarian cancer were evaluated between 1998 and 2000. Data were evaluated using Kaplan-Meier and logistic regressionanalyses. RESULTS.: 17 heavily pretreated patients with recurrent epithelial ovarian cancer received oral Thalidomide starting at 100mg/day, with dose escalations of 100 mg/day every 2 weeks, up to 1200 mg/day as tolerated. The median number of courses was four(range: 1-18 courses), and median dose was 200 mg/day (range: 100-600 mg/day). Treatment duration ranged from 2 to 48 months.Common grade 1 or 2 side effects included constipation (76%), neuropathy (71%), and fatigue (65%) with few grade 3 or 4 events.Three (18%) patients had partial responses, and six (35%) had stabilization of disease after 6 months. After 1 year of treatment, six of thenine patients with an initial partial response (n = 2) or stable disease (n = 4) remained in these response categories. Median time toprogression was 10 months. Forty-seven percent of patients had a 50-70% decrease in CA125 levels. Using logistic regression andrepeated measures analyses, CA125 levels decreased by 62 units/ml per month (p = 0.07). CONCLUSION.: Our study demonstrates thesafety, tolerability, and potential efficacy of Thalidomide in recurrent and refractory epithelial ovarian cancers. Additional clinical trialsare warranted.The day is not too far away, when people will say “Cancer? We are not worried, Zuvius Lifesciences is there’. Our medicines adhere to internationally recognized pharmaceutical standards