Stage III Colon Cancer: The Individualized Strategy of Adjuvant Chemotherapy for Aged Under and Over 70

Background

The aim of this study was to examine the specific chemoregimens selected for adjuvant therapy in the patients with stage III colon cancer. We investigated the trends in chemotherapeutic prescribing patterns and looked for adequate therapeutic setting for these patients.

Methods

288 patients presenting with stage III colon cancer and undergoing adjuvant therapies after curative surgery for more than 3-month were enrolled between January 2006 and December 2011. Demographic characteristics and therapeutic factors were analyzed, including age, gender, histological grade, tumor sizes, tumor location, pathologic stage, performance status, serum carcinoembryonic antigen, regimens selection, interval from the operation to the start of adjuvant therapy and prolonged adjuvant therapy. Kaplan– Meier methods were utilized for drawing survival curves and Cox model was used to analyze survival, prognostic factors.

Results

The analysis showed that the patients aged under 70 received more intensive therapies than those aged over 70 (P<0.001). Later, advanced analysis in therapeutic factors was conducted between the patients aged under 70 and those over 70. In the patients aged under 70, significant differences in 4-year overall survival (OS) were noted between UFUR (oral tegafur-uracil plus leucovorin) groups and FOLFOX (5-FU plus oxaliplatin) [65.6% versus (vs) 89.8%, relative risk (RR) 3.780, 95% confidence interval (CI) 1.263–11.315, P = 0.017]. There were also differences in 4-year OS between these patients with and without oxaliplatin-contained regimens (92.1% vs 83.4%, respectively, RR 0.385, 95% CI 0.157–0.946, P = 0.037). In addition, the patients who received intravenous or combined therapy also had higher 4-year OS than those only received oral regimens (92.1% vs 76.6%, P = 0.077), though the finding did not reach statistical significance. In contrast to the survival benefits of above therapeutic settings for the patients aged under 70, there was less advantage in the old patients when they received intensive therapies or even oxaliplatin-contained regimens. Prolonged cycles of adjuvant therapy resulted in no significant benefit to survival rates regardless of ages.

Conclusions

The adequate individualized therapeutic strategy plays an important role for stage III colon cancer. Our findings suggested that benefit of oxaliplatin-contained therapy is limited to patients aged under 70 and oral fluoropyrimidines may be an effective option for old patients. In addition, prolonged adjuvant setting is suggested to be unbeneficial for managing stage III colon cancer.     

Recent results of irinotecan therapy in colorectal cancer

New results presented at ASCO Conference in 2003 added further important data to our knowledge on successful use of irinotecan in colorectal cancer (CRC). Irinotecan - just like oxaliplatin - given as neoadjuvant therapy with 5-FU - folinic acid (FUFA) can render originally unresectable liver or lung metastases of CRC resectable, giving the hope of long-term survival for a proportion of patients. Irinotecan combined with 5-FU is an essential part of the most successful palliative sequential chemotherapy of stage IV CRC. Sequential FOLFIRI before or after FOLFOX combination ensures the longest possible progression-free and overall survival for metastatic CRC patients in the palliative setting. In order to achieve the longest survival time, sequential use of both 5-FU, irinotecan and oxaliplatin is necessary. The French GERCOR Group achieved 26 months median overall survival with the sequential use of continuous infusional FUFA, oxaliplatin and irinotecan combinations in stage IV CRC. The analysis of large phase III trials using 5-FU, irinotecan and oxaliplatin revealed that the higher proportion of patients was treated with all three drugs, the longer overall survival was achieved. If applied with caution, toxicity and efficacy of irinotecan in elderly patients is not significantly different from that seen in younger population. The anti-VEGF bevacizumab increases the efficacy of first-line irinotecan therapy, while the addition of cetuximab restores irinotecan sensitivity in second line treatment of stage IV CRC. The combination of irinotecan with oral capecitabine is safe and effective in advanced CRC.     

Present status of BCG immunotherapy of malignant melanoma

Summary BCG systemic adjuvant immunotherapy may be effective for improving both the recurrence and survival rates in patients with regional metastases from malignant melanoma. Clinical trials show that many of the principles derived from the study of animal tumor systems are applicable to human cancer in that immunotherapy is most effective for a small residual number of tumor cells. BCG treatment fulfills many of the ideal criteria for adjuvant treatment following surgery when disease burden is lowest. It is relatively nontoxic; it is effective for disseminated melanoma; it has systemic activity in the adjuvant treatment of subclinical metastases. However, until clinical trials are complete, BCG adjuvant therapy must be considered investigational.Supported by USPHS grants CA05252, CA12582, and NIH 0732001 CB43852.     

Overall Survival of Stage III Colon Cancer with Only One Lymph Node Metastasis Is Independently Predicted by Preoperative Carcinoembryonic Antigen Level and Lymph Node Sampling Status

Background

This study identified predictors of favorable overall survival (OS) for stage III colon cancer patients who had only one lymph node (LN) metastasis (N1a).

Methods

Variables, including preoperative carcinoembryonic antigen (CEA) level, LN sampling status, and the choices of postoperative adjuvant chemotherapy, were recorded. Prognostic significance was determined using the log-rank test and multivariate Cox regression analysis.

Results

The median 42-month follow-up period included 363 eligible patients. Among them, 230 (63.3%) received only 5-flurouracil (5-FU) adjuvant chemotherapy; 76 (20.9%) underwent oxaliplatin-based regimens; and 57 (15.7%) chose surgery alone. The 5-year survival rate of these evaluated patients was 75%, 63%, and 77%, respectively (P = 0.823). Multivariate analysis revealed that normal preoperative CEA level (≦5 ng/mL) and adequate LN sampling (LN ≧ 12) were significant predictors for higher 5-year OS (P < 0.001; P = 0.007, respectively). However, the use of postoperative adjuvant chemotherapy in these N1a colon cancer patients did not significantly affect their 5-year OS.

Conclusions

A preoperative CEA level of less than or equal to 5 ng/mL, and curative surgery with an adequate lymphadenectomy determined a favorable OS outcome in stage III colon cancer with only one LN metastasis.     

Pharmacogenetic studies on the prediction of efficacy and toxicity of fluoropyrimidine-based adjuvant therapy in colorectal cancer

The cytotoxic effect of 5-fluorouracil (5-FU) is mediated by the inhibition of thymidylate synthase (TS), however, at the same time 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD). Efficacy of 5-FU may therefore depend on the TS and DPD activity and on pharmacogenetic factors influencing these enzymes. Our aims were (1) to determine the distribution of DPD activity, the frequency of DPD deficiency and the DPD (IVS14+1G>A) mutation in the peripheral blood mononuclear cells of colorectal cancer (CRC) patients, and study the relationship between DPD deficiency and toxicity of 5-FU; (2) to investigate the influence of TS polymorphisms and DPD activity on the survival of CRC patients receiving 5-FU-based adjuvant therapy. The frequency of DPD deficiency was determined by radiochemical methods in the peripheral blood mononuclear cells (PBMCs) of 764 CRC patients treated with 5-FU. The relationship between the TS polymorphisms, DPD activity and the disease-free and overall survival was studied in 166 CRC patients receiving 5-FU-based adjuvant therapy. TS polymorphisms were determined in the DNA samples separated from the PBMCs, by PCR-PAGE and PCR-RFLP-PAGE (restriction fragment length polymorphism) methods. Low DPD values (<10 pmol/min/106 PBMCs) were demonstrated in 160/764 patients (20.9%), and of those DPD deficiency (<5 pmol/min/106 PBMCs) was verified in 38 patients (4.9%). In the latter group severe (>Gr 3) toxicity was found in 87%. The prevalence of the DPD IVS14+1G>A mutation among the 38 DPD-deficient patients was 7.8% (3/38) and was accompanied by severe Gr 4 toxic symptoms (neutropenia, mucositis, diarrhea). TS polymorphisms showed a relationship with the survival of CRC patients. It is important to mention that by combining the 3-3 genotypes of 5'-TSER and 3'-TSUTR polymorphisms the obtained 8 genotype combinations showed significantly different Kaplan-Meier survival curves. The evaluation of these curves with Cox regression analysis resulted in two prognostically different groups: "A" good prognosis (RR<1) and "B" bad prognosis (RR>1). The disease-free- and overall survival of these two groups were significantly different. DPD activity also showed correlation with the survival; patients with DPD activity <10 pmol/min/106 PBMCs showed significantly longer disease-free and overall survival. The determination of DPD activity proved to be a more valuable parameter in the evaluation of serious 5-FU-related toxicity compared to the IVS14+1G>A mutation analysis. According to the Cox multivariate analysis the combination of germline TS polymorphisms and DPD activity is/an independent prognostic marker of survival in CRC patients treated with adjuvant 5-FU therapy.     

Checkpoint signaling, base excision repair, and PARP promote survival of colon cancer cells treated with 5-fluorodeoxyuridine but not 5-fluorouracil

The fluoropyrimidines 5-fluorouracil (5-FU) and FdUrd (5-fluorodeoxyuridine; floxuridine) are the backbone of chemotherapy regimens for colon cancer and other tumors. Despite their widespread use, it remains unclear how these agents kill tumor cells. Here, we have analyzed the checkpoint and DNA repair pathways that affect colon tumor responses to 5-FU and FdUrd. These studies demonstrate that both FdUrd and 5-FU activate the ATR and ATM checkpoint signaling pathways, indicating that they cause genotoxic damage. Notably, however, depletion of ATM or ATR does not sensitize colon cancer cells to 5-FU, whereas these checkpoint pathways promote the survival of cells treated with FdUrd, suggesting that FdUrd exerts cytotoxicity by disrupting DNA replication and/or inducing DNA damage, whereas 5-FU does not. We also found that disabling the base excision (BER) repair pathway by depleting XRCC1 or APE1 sensitized colon cancer cells to FdUrd but not 5-FU. Consistent with a role for the BER pathway, we show that small molecule poly(ADP-ribose) polymerase 1/2 (PARP) inhibitors, AZD2281 and ABT-888, remarkably sensitized both mismatch repair (MMR)-proficient and -deficient colon cancer cell lines to FdUrd but not to 5-FU. Taken together, these studies demonstrate that the roles of genotoxin-induced checkpoint signaling and DNA repair differ significantly for these agents and also suggest a novel approach to colon cancer therapy in which FdUrd is combined with a small molecule PARP inhibitor.     

Randomized controlled trial of adjuvant chemoimmunotherapy with DTIC and BCG after complete excision of primary melanoma with a poor prognosis or melanoma metastases.

A clinical study was undertaken in 57 patients with completely excised nodular or superficial spreading melanoma invasive to Clark''s level 3, 4 or 5 (stage I) and 37 patients with completely resected in transit or lymph node metastases (stage III). The patients were randomly allocated to either a treatment group or a control group. Those in the treatment group received dimethyltriazeno imidazole carboxamide (DTIC) and bacille Calmette-Guérin (BCG). Those in the control group received only careful observation--the same periodic clinical and laboratory investigation that the treatment group underwent. Among the patients in the treatment group a delay in recurrence and an increase in survival were noted only in those with stage III disease, and the improvement was not statistically significant. The survival rates of the control subjects were much higher than those suggested from previously reported studies involving historical or nonrandomized control subjects, and they provide a basis on which to estimate the number of patients required for further trials of adjuvant treatment in melanoma.     

Effect of lycopene as an adjuvant therapy with 5-florouracil in human colon cancer

Colon cancer (CC) is among the most frequent human cancers. Although, there is improvement in diagnostic techniques and existing treatment possibilities. Still, there is an unmet need for a novel treatment regimen that will improve the patient's quality of life. Here, the role of lycopene as an adjuvant therapy with 5-fluorouracil (5-FU) was explored in Caco2 colon cancer cells. Cells were exposed to a dose (3 µg/ml) of 5-FU and three doses (60, 90, 120 µg/ml) of lycopene either alone or as a mixture with 5-FU. Cytotoxicity, genotoxicity, oxidative stress, gene expression, and apoptotic parameters were investigated in this study. Findings showed that 5-FU or lycopene alone induced a dose-dependent increase in cytotoxicity which was slightly reduced in lycopene mixtures. Apoptotic assays showed that 5-FU induced a significant level of apoptosis but not necrosis. However, a lycopene mixture with 5-FU enhanced 5-FU triggered apoptosis and promoted necrosis. The mixtures were also shown to suppress mitochondrial membrane potential while gene expression analyses showed the induction of Bax expression upon exposure to mix 90 exhibited the highest Bax to Bcl-2 ratio and caspase 3 and 9 gene expression. Furthermore, the mixture treatment also inhibited cell migration in the wound healing assay compared to 5-FU alone. In conclusion, lycopene was found to sensitize Caco 2 cell lines to 5-FU treatment by inducing the expression of apoptotic genes. This, coupled with lycopene suppression of cytotoxicity and cell migration, indicates lycopene may be a promising candidate for adjuvant therapy involving 5-FU in CC.     

Efficacy of Adjuvant 5-Fluorouracil Therapy for Patients with EMAST-Positive Stage II/III Colorectal Cancer

Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) is a genetic signature found in up to 60% of colorectal cancers (CRCs) that is caused by somatic dysfunction of the DNA mismatch repair (MMR) protein hMSH3. We have previously shown in vitro that recognition of 5-fluorouracil (5-FU) within DNA and subsequent cytotoxicity was most effective when both hMutSα (hMSH2-hMSH6 heterodimer) and hMutSβ (hMSH2-hMSH3 heterodimer) MMR complexes were present, compared to hMutSα > hMutSβ alone. We tested if patients with EMAST CRCs (hMutSβ defective) had diminished response to adjuvant 5-FU chemotherapy, paralleling in vitro findings.We analyzed 230 patients with stage II/III sporadic colorectal cancers for which we had 5-FU treatment and survival data. Archival DNA was analyzed for EMAST (>2 of 5 markers mutated among UT5037, D8S321, D9S242, D20S82, D20S85 tetranucleotide loci). Kaplan-Meier survival curves were generated and multivariate analysis was used to determine contribution to risk.We identified 102 (44%) EMAST cancers. Ninety-four patients (41%) received adjuvant 5-FU chemotherapy, and median follow-up for all patients was 51 months. Patients with EMAST CRCs demonstrated improved survival with adjuvant 5FU to the same extent as patients with non-EMAST CRCs (P<0.05). We observed no difference in survival between patients with stage II/III EMAST and non-EMAST cancers (P = 0.36).There is improved survival for stage II/III CRC patients after adjuvant 5-FU-based chemotherapy regardless of EMAST status. The loss of contribution of hMSH3 for 5-FU cytotoxicity may not adversely affect patient outcome, contrasting patients whose tumors completely lack DNA MMR function (MSI-H).     

Oestrogen receptors and survival in early breast cancer.

Oestrogen receptor status was related to survival in 414 patients with primary breast cancer. Women with oestrogen receptors in their tumours survived significantly longer than those without receptors; this was true for both premenopausal and postmenopausal women and also when the patients were subdivided into those with and without axillary metastases. Patients with axillary metastases and no oestrogen receptors in their tumours had the worst prognosis, while women with axillary metastases and oestrogen receptors had a death rate similar to that of women with no axillary metastases and no receptors. Patients without oestrogen receptors and with no axillary metastases were identified as a high-risk group, and it would seem appropriate to include such patients in future trials for adjuvant therapy in early breast cancer.     

Evaluation of in vitro cytotoxicity of oxaliplatin and 5-fluorouracil in human colon cancer cell lines: combination versus sequential exposure

Adjuvant therapy has evolved to become the standard care of colon cancer, but the tumor capability of activating effective mechanisms of defence against both chemical and physical cytotoxic agents represents a serious obstacle to the successful therapy. Furthermore, the possibility to have an assay useful to measure the drug sensitivity of tumor cells could be of a great importance. As primary human colon cancer cultures from fresh tumor are technically difficult to obtain, experiments with human cancer cell lines remain essential to explore new adjuvant chemotherapy drugs, to investigate the individual responsiveness to the known agents, and particularly to clarify how these chemotherapeutic agents could be used in maximizing outcomes. In the present study we evaluate the cytotoxic effects of 5-fluorouracil (5-FU) and oxaliplatin (OHP) and of their pharmacological interaction in three human colon cancer cell lines (WiDr, HT-29 and SW620), by using an ATP luminescence assay (ATPlite; Perkin Elmer), displaying high sensitivity, linearity and reproducibility. Cell cycle, apoptosis and CD44 expression were investigated with flow cytometry. Our results show that the drug combinations inhibited the cell growth more than each drug alone in all colorectal cancer cell lines. Interestingly, the sequential exposure of OHP and 5-FU resulted in the most cytotoxic effect in all colon cancer cell lines, when compared to the simultaneous one. Our results focus on the powerful cytotoxic effect of 5-FU-OHP combination, when used in sequential exposure, suggesting interesting implications for a rational use of 5-FU, OHP combination in colon-rectal cancer therapy.     

Phase 2 study of canfosfamide in combination with pegylated liposomal doxorubicin in platinum and paclitaxel refractory or resistant epithelial ovarian cancer

We have reviewed the pivotal presentations related to gastrointestinal malignancies from 2009 annual meeting of the American Society of Clinical Oncology with the theme of "personalizing cancer care". We have discussed the scientific findings and the impact on practice guidelines and ongoing clinical trials. Adding trastuzumab to chemotherapy improved the survival of patients with advanced gastric cancer overexpressing human epidermal growth factor receptor 2. Gemcitabine plus cisplatin has become a new standard for first-line treatment of advanced biliary cancer. Octreotide LAR significantly lengthened median time to tumor progression compared with placebo in patients with metastatic neuroendocrine tumors of the midgut. Addition of oxaliplatin to fluoropyrimidines for preoperative chemoradiotherapy in patients with stage II or III rectal cancer did not improve local tumor response but increased toxicities. Bevacizumab did not provide additional benefit to chemotherapy in adjuvant chemotherapy for stage II or III colon cancer. In patients with resected stage II colon cancer, recurrence score estimated by multigene RT-PCR assay has been shown to provide additional risk stratification. In stage IV colorectal cancer, data have supported the routine use of prophylactic skin treatment in patients receiving antibody against epidermal growth factor receptor, and the use of upfront chemotherapy as initial management in patients with synchronous metastasis without obstruction or bleeding from the primary site.     

DKK1 as a robust predictor for adjuvant platinum chemotherapy benefit in resectable pStage II-III gastric cancer

BackgroundAdjuvant chemotherapy (ACT) with 5-FU alone or 5-FU plus platinum after curative surgery improves the prognosis of pStage II-III gastric cancer (GC). However, only a subset of patients benefits from adjuvant platinum. To avoid the side effects of platinum, it is significant to accurately screen the patients who would benefit maximally with this treatment. The present study aimed to assess the value of DKK1 in predicting the benefit of adjuvant platinum chemotherapy in patients with pStage II -III GC.MethodsPlatinum sensitivity-related genes were screened by bioinformatics. DKK1 expression in 380 GC specimens was detected by immunohistochemistry (IHC) staining, and the correlation with adjuvant platinum-specific benefits were analyzed.ResultsDKK1 was screened as the most significant platinum sensitivity-related gene. In patients with DKK1^high GC, the estimated absolute 5-year overall survival (OS) benefits from adjuvant platinum for pStage II-III, II, IIIA, IIIB, and IIIC were 25.5%, 17.3%, 36.4%, 29.2% and 31.1%, respectively, and the estimated absolute 5-year disease-free survival (DFS) benefits in the corresponding stages were 27.4%, 17.5%, 36.7%, 29.7% and 31.5%, respectively. These benefits were significantly higher than those in the same TNM stage without adjusting for DKK1 status. The performance of DKK1 was independent of the TNM stage and other clinicopathological variables. Similar results were obtained in the TCGA and ACRG cohorts. Furthermore, nomograms were constructed to predict the survival benefits in DKK1 subgroups.ConclusionsThe stratification strategy based on DKK1 status is more precise than the TNM staging system for the selection of pStage II-III GC patients suitable for platinum-containing ACT.     

可切除的食管胃结合部腺癌的联合治疗

近年来胃癌的发病率有所下降,相比之下胃食管结合部腺癌的发病率却快速增长。手术治疗仍然是早期食管胃结合部腺癌的标准治疗方法,同时手术联合化疗、放化疗治疗食管胃结合部腺癌也逐渐得到国际认可。尽管在手术治疗、放疗和化疗治疗技术得到完善和改进,但食管癌和食管胃结合部腺癌的预后仍然较差。目前有数个大型临床随机对照试验数据支持对食管下端和食管胃交界部腺癌使用术前联合化疗,但辅助治疗的贡献仍不能确定。最近有meta分析表明手术联合化疗、放化疗可以提高胃食管结合部腺癌患者术后存活率,但也有一些临床随机试验的数据表明手术联合化疗、放化疗并无明显好处。本文通过总结最新的临床试验及meta分析结果,阐述不同的可切除的胃食管结合部腺癌的联合治疗方法。     

Benefit with aromatase inhibitors in the adjuvant setting for postmenopausal women with breast cancer

The third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, have been shown to be effective both as alternatives to tamoxifen in first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women and following failure of first-line tamoxifen for endocrine therapy. These 3 agents are now being investigated as adjuvant therapy of early breast cancer, as alternative or complementary treatments to the standard, tamoxifen. Three treatment strategies are under investigation: replacement of tamoxifen as adjuvant therapy for 5 years (early adjuvant therapy), sequencing of tamoxifen before or after an aromatase inhibitor during the first 5 years (early sequential adjuvant therapy), or following 5 years of tamoxifen (extended adjuvant therapy). In the first adjuvant trial (Arimidex, Tamoxifen Alone or in Combination [ATAC]), anastrozole was significantly superior to tamoxifen in reducing risk of disease recurrence, and recently, the Breast International Group (BIG) trial BIG 1-98 demonstrated the significant superiority of letrozole over tamoxifen in improving disease-free survival. A large trial (International Collaborative Cancer Group [ICCG] trial 96) investigated sequencing of 2 to 3 years of exemestane after 2 to 3 years of tamoxifen and found that switching to exemestane was significantly superior in disease-free survival compared with continuing on tamoxifen. The Arimidex or Nolvadex (ARNO) and the small ITA (Italian Tamoxifen Arimidex) trials similarly sequenced anastrozole after tamoxifen and also found that sequencing reduced the hazard of recurrence compared with remaining on tamoxifen. Trial MA.17 evaluated extended adjuvant therapy with letrozole vs placebo following 5 years of tamoxifen. Disease-free survival was significantly improved with letrozole vs placebo, irrespective of whether patients had lymph node-positive or node-negative tumors. All 3 aromatase inhibitors were generally well tolerated. Results of these trials indicate that aromatase inhibitors provide important benefits relative to tamoxifen in each of these adjuvant treatment settings, but the optimal approach still needs to be defined. Other trials continue to investigate some of these adjuvant treatment strategies.     

Survival among clinical stage I–III rectal cancer patients treated with different preoperative treatments: A population-based comparison

BackgroundRadical resection is regarded as the cornerstone of rectal cancer treatment. Preoperative (chemo)radiotherapy and adjuvant chemotherapy are often administered. This population-based study compares the survival in clinical stage I–III rectal cancer patients who received either preoperative radiotherapy, preoperative chemoradiotherapy or no preoperative therapy. As secondary research questions, the association of type of radical resection and adjuvant chemotherapy on survival is also investigated.MethodsPatients diagnosed between January 2006 and December 2011 with stage I–III rectal adenocarcinoma were retrieved from the Belgian Cancer Registry database. Multivariable Cox proportional hazards regression models were applied to evaluate the association of preoperative treatment, type of radical resection and use of adjuvant chemotherapy with survival, adjusting for the baseline characteristics age, gender, WHO performance status and clinical stage.ResultsA total of 5173 rectal cancer patients were identified. Preoperative treatment was as follows: none in 1354 (26.2%), radiotherapy in 797 (15.4%) and chemoradiotherapy in 3022 (58.4%) patients. The patient group who did not receive preoperative therapy or radiotherapy followed by radical resection had a lower observed survival compared to the patient group receiving preoperative chemoradiotherapy. The patient groups who underwent abdominoperineal excision and those receiving adjuvant chemotherapy had a worse observed survival compared to the patient group treated with sphincter-sparing surgery and no adjuvant therapy respectively. These effects were age-dependent. Multivariable analysis demonstrated similar findings for the observed survival conditional on surviving the first year since surgery.ConclusionIn this population-based study among clinical stage I–III rectal cancer patients treated with radical resection, a superior observed survival was noticed in the patient group receiving preoperative chemoradiotherapy compared to the patients groups receiving no or preoperative radiotherapy only, adjusting for case mix, type of radical resection and adjuvant chemotherapy. Additionally, higher adjusted observed survival was also detected for the patient groups with sphincter-sparing surgery or no adjuvant chemotherapy.     

Combination of dasatinib and curcumin eliminates chemo-resistant colon cancer cells

Metastatic colorectal cancer remains a serious health concern with poor patient survival. Although 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) is the standard therapy for colorectal cancer, it has met with limited success. Recurrence of the tumor after chemotherapy could partly be explained by the enrichment of the chemo-resistant sub-population of cancer stem cells (CSCs) that possess the ability for self-renewal and differentiation into different lineages in the tumor. Therefore development of therapeutic strategies that target CSCs for successful treatment of this malignancy is warranted. The current investigation was undertaken to examine the effectiveness of the combination therapy of dasatinib (a Src inhibitor) and curcumin (a dietary agent with pleiotropic effect) in inhibiting the growth and other properties of carcinogenesis of chemo-resistant colon cancer cells that are enriched in CSCs sub-population. Remnants of spontaneous adenomas from APC ^{Min +/-} mice treated with dasatinib and/or curcumin were analyzed for several cancer stem cell markers (ALDH, CD44, CD133 and CD166). Human colon cancer cells HCT-116 (p53 wild type; K-ras mutant) and HT-29 (p53 mutant; K-ras wild type) were used to generate FOLFOX resistant (referred to as CR) cells. The effectiveness of the combination therapy in inhibiting growth, invasive potential and stemness was examined in colon cancer CR cells. The residual tumors from APC ^{Min +/-} mice treated with dasatinib and/or curcumin showed 80-90% decrease in the expression of the CSC markers ALDH, CD44, CD133, CD166. The colon cancer CR cells showed a higher expression of CSCs markers, cell invasion potential and ability to form colonospheres, compared to the corresponding parental cells. The combination therapy of dasatinib and curcumin demonstrated synergistic interactions in CR HCT-116 and CR HT-29 cells, as determined by Calcusyn analysis. The combinatorial therapy inhibited cellular growth, invasion and colonosphere formation and also reduced CSC population as evidenced by the decreased expression of CSC specific markers: CD133, CD44, CD166 and ALDH. Our data suggest that the combination therapy of dasatinib and curcumin may be a therapeutic strategy for re-emergence of chemo-resistant colon cancer by targeting CSC sub-population.     

The role of adjuvant chemotherapy in the treatment of non-small cell lung cancer

Postoperative treatments for lung cancer have been evaluated for more than two decades, but in the majority of the studies (especially until 1990) no significant effect on survival has been shown. In 1995, a meta-analysis of eight cisplatin-based adjuvant chemotherapy trials with NSCLC showed a 13% reduction in the risk of death (P=0.08) and 5% benefit in 5-year survival. Among four positive trials (IALT, JBR10, ANITA and CALGB study) the absolute increase in the 5-year survival rates by adjuvant chemotherapy ranged from 4% to 15%, and the hazard ratios for death ranged from 0.6 to 0.86. The author analyzes the most important studies. Conclusion: adjuvant chemotherapy after complete resection of NSCLC can be considered as a new standard of care in patients with good performance status. Patients should receive 4 cycles of platina-based chemotherapy beginning 4-8 weeks after surgery. Future perspectives: optimization of chemotherapy regimens including targeted therapy (such as EGFR inhibitors, angiogenesis inhibitors, anti-EGFR monoclonal antibodies). Further progress is anticipated through the integration of chemopreventive agents into the adjuvant treatment.     

KIN enhances stem cell-like properties to promote chemoresistance in colorectal carcinoma

Chemotherapy is widely used in colorectal cancer (CRC) treatment, especially in advanced stage patients. However, it is inevitable to develop chemoresistance. Recently, cancer cells acquired stem cell-like properties or cancer stem cells (CSC) were proved to attribute to chemoresistance. Here, we found that KIN protein was elevated in CRC cell lines and tissue specimens as compared to normal controls. Upregulation of KIN positively correlates with the metastatic status of CRC patients. Patients with high KIN expression showed poor prognosis and were with a short survival time. Overexpression of KIN enhanced, while silencing KIN impaired, chemoresistance to oxaliplatin (Ox) or 5-fluorouracil (5-FU) in CRC cell lines. Further investigation demonstrated that overexpression of KIN rendered CRC cells enriching CSC markers and CSC phenotype, and silencing KIN reduced CSC markers and CSC phenotype. Our findings suggest that the KIN level may be a suitable marker for predicting chemotherapy response in CRC, and silencing KIN plus chemotherapy may be a novel therapy for CRC treatment.     

Systemic polychemotherapy in combined treatment of colon cancer]

Seven hundreds and fifty three patients with colon cancer were operated in the Unit of Colon Surgery of the State Scientific Centre of Coloproctology within the period from 1998 to 2003. 352 (46.7%) of them were subjected to systemic chemotherapy. The patients subjected to the surgical and antitumor drug therapy were divided into 3 groups according to the main disease stage: 103 (29.3%) patients with the disease stage T4N0M0 (including those with the tumor local spread), 116 (32.9%) patients with the disease stage T(3-4)N+M0 and 133 (37.8%) patients with the disease stage T(3-4)NxM1. In the patients with the colon serous membrane diffusion and locally spread tumors (total of 103 patients) 3- and 5-year survival was stated in 81.0 +/- 2.8% and 76.5 +/- 3.7% respectively. The control group included 85 patients subjected to the surgical treatment alone. In the latter group 5-year survival was recorded in 68.0 +/- 2.9% of the patients. In the group of the patients with affection of the regional lymph nodes subjected to antitumor drug therapy 3- and 5-year survival was recorded in 64.1 +/- 3.5% and 57.5 +/- 4.2% respectively. In 52 patients not subjected to the systemic chemotherapy the analogous index was equal to 44.5 +/- 3.4%. The systemic chemotherapy was applied to 111 (78.2%) patients with metastases to the liver. In 50 of them cytoreductive operations were performed and in 61 patients palliative resection of the colon was carried out. The average period without clinical manifestations of the disease in the patients subjected to the colon palliative resection and systemic chemotherapy was equal to 8.5 +/- 3.5 months. In the patients with metastases to the liver subjected to the cytoreductive operations the average lifespan after the operations amounted to 24.5 months. The average lifespan of the patients with canceromatosis subjected to the systemic chemotherapy and cytoreductive operations amounted to 13.5 months. When the chemotherapy in such patients was effective the average lifespan was 16 months, while in case of the therapy failure it was 8.5 months.