Oxaliplatin In Colorectal Cancer Research Articles

ERCC1, KRAS mutation, and oxaliplatin sensitivity in colorectal cancer: Old dogs and new tricks.

489 Background: Oxaliplatin is widely used in metastatic colorectal cancer, but currently there are not valid predictors of response to this drug. In our recent retrospective clinical study we have shown a greater efficacy of Oxaliplatin in patients with metastatic colorectal cancer with mutated (mt) K-RAS. We hypothesized that the mutational status of K-RAS could influence the expression of ERCC1, one of the main mechanisms of Oxaliplatin resistance. Methods: We used four cell lines of colorectal cancer: two K-RAS wild type (wt) (HCT-8 and HT-29) and two K-RAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxaliplatin by MTT-test and the ERCC1 levels before and after 24 h exposure to Oxaliplatin by Real-Time PCR. We silenced K-RAS in a K-RAS mt cell line to evaluate the impact on Oxaliplatin sensitivity and ERCC1 levels. We also silenced ERCC1 in order to confirm the importance of this protein as a Oxaliplatin resistance factor. Results: The K-RAS mt cell lines were more sensitive to Oxaliplatin (OR 2.68; IC 95% 1.511-4.757 p<0.001). The basal levels of ERCC1 did not show significant differences between K-RAS mt and wt cell line, however, after 24 h exposure to Oxaliplatin, only the K-RAS wt lines showed the ability to induce ERCC1, with a statistically significant difference (OR 42.9 IC 95% 17.260-106.972 p<0.0005). The silencing of K-RAS in K-RAS mt cell lines demonstrated to reduce sensitivity to Oxaliplatin associated with the acquisition of the ability to induce ERCC1. The silencing of ERCC1 in K-RAS wt cell lines enhance the sensibility to Oxaliplatin. Conclusions: The K-RAS mutated cell lines were more sensitive to Oxaliplatin. This feature seems to be secondary to the inability of these cells to induce ERCC1 after exposure to Oxaliplatin. K-RAS can thus be a predictor of response to Oxaliplatin in colorectal cancer representing a surrogate for ability to induce ERCC1.

Epigenetics and chemoresistance in colorectal cancer: An opportunity for treatment tailoring and novel therapeutic strategies

Colorectal cancer is the second leading cause of cancer-related deaths in the world. Despite many therapeutic opportunities, prognosis remains dismal for patients with metastatic disease, and a significant portion of early-stage patients develop recurrence after chemotherapy. Epigenetic gene regulation is a major mechanism of cancer initiation and progression, through the inactivation of several tumor suppressor genes. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance. In the present review, we summarize epigenetic mechanisms triggering resistance to three commonly used agents in colorectal cancer: 5-fluorouracil, irinotecan and oxaliplatin. Those epigenetic biomarkers may help stratify colorectal cancer patients and develop a tailored therapeutic approach. In addition, epigenetic modifications are reversible through specific drugs: histone-deacetylase and DNA-methyl-transferase inhibitors. Preclinical studies suggest that these drugs may reverse chemoresistance in colorectal tumors. In conclusion, an epigenetic approach to colorectal cancer chemoresistance may pave the way to personalized treatment and to innovative therapeutic strategies.

Abstract 1704: A role for glucosylceramide synthase in resistance to oxaliplatin in colorectal cancer

Abstract Colorectal cancer (CRC) is the second leading cause of cancer deaths in the U.S. Nearly 25 percent of patients who present with CRC have already developed metastatic disease. While combination therapies for metastatic CRC have improved median survival times, most patients inevitably become resistant to chemotherapy. Chemoresistance is thus the major cause of treatment failure in CRC patients, and accordingly, the development of novel therapies aimed at overcoming chemoresistance is of paramount importance. Many commonly used chemotherapeutic agents act by inducing cell death by increasing cellular levels of the bioactive sphingolipid, ceramide. In addition to serving well-known structural functions in the cell membrane, sphingolipids are increasingly recognized as important cellular signaling molecules. Studies have demonstrated that human colorectal tumors contain decreased concentrations of ceramide in comparison to normal colonic mucosa. Furthermore, multi-drug resistant cancer cells often display an altered sphingolipid content, with the presence of increased levels of the pro-survival ceramide metabolites. In this study we have examined the role of the ceramide-metabolizing enzyme, glucosylceramide synthase (GCS), in the mechanism of resistance to oxaliplatin. These studies utilize a series of oxaliplatin-resistant isogenic colorectal cancer cell lines. While much evidence has been presented establishing the role of GCS in resistance to a variety of chemotherapeutic agents, a role for GCS in oxaliplatin resistance has yet to be examined. Our studies demonstrate that oxaliplatin-resistant CRC cell lines have ∼ 2-fold more GCS protein with increased levels of the pro-survival ceramide metabolite, glucosylceramide, in comparison to the parental cell lines. We further demonstrate that inhibition of GCS by either pharmacological inhibitors or an RNAi-mediated gene knockdown results in reduced cellular glucosylceramide levels, with a concomitant increased sensitivity towards oxaliplatin. Furthermore, inhibition of GCS causes a reversion of an observed epithelial-mesenchymal transition phenotype observed in oxaliplatin-resistant CRC cell lines. Our results may offer a possible strategy with which to augment chemotherapeutic drug effectiveness in CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1704. doi:10.1158/1538-7445.AM2011-1704

Toxicity associated with capecitabine plus oxaliplatin in colorectal cancer before and after an institutional policy of capecitabine dose reduction

Background:Capecitabine plus oxaliplatin (CAPOX) is an established treatment option in colorectal cancer, but can be associated with severe toxicities.Methods:Following reporting of severe diarrhoea and dehydration with capecitabine 2000 mg m–2 per day plus oxaliplatin every 3 weeks (CAPOX 2000) in 2006, we instituted a policy change to reduce capecitabine dose to 1700 mg m–2 per day (CAPOX 1700). We undertook a retrospective analysis comparing toxicities encountered before and after this dose change.Results:Of the 400 patients treated, no significant differences were seen between the CAPOX 2000 and CAPOX 1700 in grades 3 and 4 diarrhoea (21% vs 19% P=0.80), stomatitis (0% vs 1% P=0.50) or grades 2–4 hand foot syndrome (16% vs 11% P=0.18). Grades 3 and 4 neutropenia (9.5% vs 3.5% P=0.03) and all grades hyperbilirubinaemia (60% vs 40% P<0.0001) were significantly reduced with CAPOX 1700. Rates of hospitalisation due to toxicities were not different between two groups (13% vs 11% P=0.53).Conclusions:No clinically or statistically significant differences in gastrointestinal toxicities or hospitalisation rate were seen after reducing our routine capecitabine dose from CAPOX 2000 to CAPOX 1700.

Unfunded promises as the UK health debate takes centre stage

On May 6, 2010, the UK population will vote to decide their government for the next 5 years, and health policy is likely to be a major factor in the outcome. Politicians know health is the “ace up the sleeve” if used cleverly and, with just a few days to go until the election, the card tricks have started. The Conservative leader, David Cameron, has pledged to reverse the 1% increase in national insurance (NI) contributions proposed by the Labour party, and to use the employer NI contribution saved within the National Health Service (NHS), estimated at £200 million, to fund drugs licensed since 2005 for patients with cancer, if recommended by their oncologist—even where the National Institute for Health and Clinical Excellence (NICE) has ruled against their use on the grounds of cost-effectiveness. This pledge is a laudable one—provided treatments are the most clinically effective available—and will win votes, but raises a number of questions, not least the need for NICE if it can be circumvented so easily. 10 years of NICE: still growing and still controversialThe National Institute for Health and Clinical Excellence (NICE) will have existed for 10 years on April 1, 2009. Over the past decade, the institute's methodological approach to the development of guidance and assessment of the value of health-care interventions has received international interest and acclaim. Furthermore, individual decisions, in particular those made on new cancer drugs, have generated enormous controversy. An early example was the appraisal of irinotecan and oxaliplatin for colorectal cancer in 2002. Full-Text PDF Patient access schemes for high-cost cancer medicinesInnovative new anticancer medicines are often associated with a premium price with little variation in global prices. For the UK, this can mean new cancer medicines are not adopted, because they are judged to be too expensive and not cost effective by the National Institute for Clinical Excellence (NICE). In response, pharmaceutical companies have developed patient access schemes (PAS), or risk-share schemes, that allow drugs companies to offer discounts or rebates to reduce the cost of a drug to the UK National Health Service (NHS). Full-Text PDF

Strategies for Managing Chemotherapy-Induced Sensory Neuropathy

Chemotherapy-induced sensory neuropathy occurs in most patients undergoing treatment with oxaliplatin for colorectal cancer. Although the acute form of neurotoxicity is transient, the chronic form, which is correlated with the cumulative dose of oxaliplatin administered over time, may be long lasting in a subset of patients and may have a significant impact on function and quality of life. Because treatment options for established chemotherapy-induced peripheral neuropathy are limited, recent efforts have focused on prevention. This review discusses acute and chronic neurotoxic effects of oxaliplatin, the most recent evidence for decreasing the probability of developing peripheral neuropathy, and the clinical management of existing neuropathy.

Oxaliplatin for colorectal cancer: Prevalence of delayed nausea and/or vomiting

e20610 Background: Delayed nausea and vomiting (N&amp;V) have been associated with cisplatin and carboplatin. Its prevalence with third-generation oxaliplatin was examined in patients (pts) receiving oxaliplatin-based regimens. Methods: 64 pts (53% male, 47% female) signed IRB-approved informed consent and were enrolled on day 1 of cycle 1. 53 (83%) pts had colon cancer, and received 85mg/kg of oxaliplatin, while 11 (17%) had rectal cancer, and received 65mg/kg. Age ranged from 29 to 84 years, with 65% between 50 and 69. Data was collected on the first chemotherapy cycle of 24 pts and the first and second cycles of 40 pts, for a total of 104 cycles. Baseline demographic data were collected by chart review and interview. Maximum grade of N&amp;V for each cycle was assessed by the Functional Living Index - Emesis (FLIE). Pts also maintained a daily diary of nausea, vomiting, and anti-emetic usage for 7 days after each infusion. Results: 7 pts (11%) reported a history of motion sickness. History of morning sickness was reported by 13 (43%) of the 30 female pts. All pts received anti-emetics and steroids on day 1 of each cycle. 75% of pts received 5HT3 inhibitors only, 22% received 5HT3 + an oral NK-1 receptor antagonist, and 3% received an NK-1 receptor antagonist alone. Among 40 pts for whom data were collected on both first and second cycles, the occurrence of nausea was the same during cycle 1 and cycle 2: Grade 0 - 60% and 62% respectively; Grade 1 - 20% and 21%, Grade 2 - 20% and 21%. 41% of pts used rescue antiemetics (prochlorperazine, metoclopramide, or lorazepam) in cycle 1 and 43% in cycle 2. Men experienced no nausea 69% of the time, while women had no nausea in 41% of cycles. In 57% of cycles, no nausea was reported. In 88% of cycles there was no reported vomiting. Conclusions: Oxaliplatin-based regimens (65–85 mg/kg) caused minimal nausea and negligible vomiting, with a satisfactory response to 5HT3-inhibitor antiemetics and corticosteroids. [Table: see text] [Table: see text]

Randomized phase II study of picoplatin in combination with 5-fluorouracil and leucovorin (FOLPI) as a neuropathy-sparing alternative to modified FOLFOX-6 as first-line therapy for colorectal cancer (CRC)

4026 Background: Picoplatin (Pico) was designed to overcome platinum resistance and has the potential for improved safety compared to other platinum agents. FOLFOX (5-FU, LV, oxaliplatin [oxali]) treatment for advanced CRC has dose-limiting oxali- related neurotoxicity. The incidence of grade (G) 3–4 neurotoxicity with single-agent Pico across studies was &lt;2%, suggesting that Pico may provide a neuropathy-sparing alternative to oxali. A Phase I trial identified the Pico MTD at 150 mg/m2 when infused Q4W with Q2W FU/LV. The present study evaluates Pico when administered Q4W with Q2W FU and LV (FOLPI) vs. modified (m) FOLFOX-6 (FOLFOX) as 1st line treatment for patients (pts) with advanced CRC. Methods: Each pt received LV and infusional FU per mFOLFOX-6 Q2W. Pts with no prior chemotherapy for advanced CRC received Pico Q4W (150 mg/m2) or oxali Q2W (85 mg/m2). Tumor response was assessed by RECIST using CT scans. Adverse events (AEs) were assessed with CTCAE. Neuropathy was assessed using the FACT-Neurotoxicity questionnaire and by a neurologist blinded to treatment. Results: 101 pts were randomized (50 to FOLPI, 51 to FOLFOX). Pts have received 213 (median 4, max 11) 4-week cycles of FOLPI and 414 (median 8, max 21) 2-week cycles of FOLFOX. Median dose intensity of Pico = 28 mg/m2/wk (range 19–44); mean relative dose intensity = 77%. Median dose intensity of oxali = 36 mg/m2/wk (range 28–43); mean relative dose intensity = 86%. Neurotoxicity was observed in 65% of pts on FOLFOX (10% G 3/4) and 28% of pts on FOLPI (no G 3/4). Most frequent G 3/4 AEs on FOLPI were neutropenia (60%), thrombocytopenia (40%) and anemia (14%). In the FOLFOX arm, other than neuropathy, the most frequent G 3/4 AEs were neutropenia (20%) and thrombocytopenia (12%). Disease control (CR+PR+SD) was 76% for FOLPI and 76% for FOLFOX. In the FOLPI arm there were 1 CR (2%) and 11 PR (22%). In the FOLFOX arm there were no CRs and 13 PR (26%). Conclusions: In this ongoing trial, FOLPI with Pico Q4W shows comparable disease control as measured by RECIST compared to FOLFOX. Neurotoxicity was less frequent and less severe in the FOLPI arm compared to the FOLFOX arm. Pico therefore may be a neuropathy-sparing alternative to oxaliplatin in CRC. [Table: see text]

Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer

Hyaluronic acid–coupled chitosan nanoparticles bearing oxaliplatin (L-OHP) encapsulated in Eudragit S100–coated pellets were developed for effective delivery to colon tumors. The in vitro drug release was investigated using a USP dissolution rate test paddle-type apparatus in different simulated gastrointestinal tract fluids. In therapeutic experiments the pellets of free drug, and hyaluronic acid–coupled and uncoupled chitosan nanoparticles bearing L-OHP were administered orally at the dose of 10 mg L-OHP/kg body weight to tumor-bearing Balb/c mice. In vivo data showed that hyaluronic acid–coupled chitosan nanoparticles delivered 1.99 ± 0.82 and 9.36 ± 1.10 μg of L-OHP/g of tissue in the colon and tumor, respectively after 12 hours, reflecting its targeting potential to the colon and tumor. These drug delivery systems show relatively high local drug concentration in the colonic milieu and colonic tumors with prolonged exposure time, which provides a potential to enhance antitumor efficacy with low systemic toxicity for the treatment of colon cancer. From the Clinical Editor In this study, a nanoparticle system was developed to deliver oxaliplatin to colorectal tumors. In murine models, the drug delivery system showed relatively high local drug concentration in colonic tumors with prolonged exposure time, which provides a potential for enhanced antitumor efficacy with low systematic toxicity.

Hypersensitivity Reactions to Oxaliplatin: A Retrospective Study and the Development of a Desensitization Protocol

Background: We recorded the epidemiologic and clinical features of hypersensitivity reactions (HSRs) to oxaliplatin in colorectal cancer (CRC) patients in order to provide information on the management of these patients. We also developed a desensitization protocol and evaluated its clinical application. For these reasons, we analyzed retrospectively the records of 215 CRC patients treated with oxaliplatin-containing regimens either as an adjuvant, first-line, second-line, or more. Patients and Methods: Data from 52 patients with HSRs were analyzed according to the Common Toxicity Criteria for Adverse Events (CTCAE), v3.0. Three patients were chosen for the desensitization protocol. After determining the starting point for desensitization, we applied the standard protocol for parenteral desensitization to b-lactam antibiotics. Oxaliplatin treatment was then carried out with serial 10-fold dilutions in sufficient volume to administer the total dose. A total of 52 patients (24.2%) were recorded as having an allergic reaction to oxaliplatin. Results: Hypersensitivity reactions were recorded after a mean of 6.5 (SD +/- 4.5) cycles. Only 4 patients (4 of 215; 1.8%) developed CTCAE grade 3/4 HSRs. Hypersensitivity reactions were seen more likely in patients receiving second-line or more of chemotherapy compared with chemotherapy-naive patients. No other correlations were seen (the presence of atopic disease, positive skin prick test). The 3 patients, having completed the parenteral desensitization protocol, completed their treatment uneventfully as well. Conclusion: Hypersensitivity reactions from oxaliplatin respond quickly to the discontinuation of the drug and appropriate support. Premedication and an increased infusion time could allow for readministration. The desensitization protocol we developed can provide a reliable alternative to permanent discontinuation of oxaliplatin.

10 years of NICE: still growing and still controversial

The National Institute for Health and Clinical Excellence (NICE) will have existed for 10 years on April 1, 2009. Over the past decade, the institute's methodological approach to the development of guidance and assessment of the value of health-care interventions has received international interest and acclaim. Furthermore, individual decisions, in particular those made on new cancer drugs, have generated enormous controversy. An early example was the appraisal of irinotecan and oxaliplatin for colorectal cancer in 2002. In 2003, NICE described the rationale behind its decision making. The 10th anniversary of the institute provides an opportunity to review some of the key issues affecting cancer appraisals and to explain the development of other NICE guidance programmes relevant to the provision of cancer services.

Increased levels of copper efflux transporter ATP7B are associated with poor outcome in colorectal cancer patients receiving oxaliplatin‐based chemotherapy

Recently, the copper efflux transporters ATP7B and ATP7A have been implicated in the transport of and resistance to platinum drugs in breast and ovarian cancers. Because of the extensive use of oxaliplatin in colorectal cancer (CRC), we examined the expression of both transporters in tumors from CRC patients treated with oxaliplatin/5FU and sought to determine whether their expression can predict clinical outcome in these patients. ATP7B and ATP7A levels were determined by quantitative real-time PCR in 50 primary tumors of previously untreated patients with advanced colorectal adenocarcinoma who were subsequently treated with oxaliplatin/5FU. Additionally, ATP7B protein expression was assessed by immunohistochemical staining using a tissue microarray. Patients with the lowest mRNA expression levels of ATP7B had a significantly longer time to progression (TTP) (p = 0.0009) than patients with the highest levels (12.14 months vs. 6.43 months) who also had an increased risk of progression (HR = 3.56; 95% CI, 1.6-7.9; p = 0.002). Furthermore, patients with low levels of both protein and mRNA of ATP7B derived the maximum benefit from oxaliplatin/5FU with the longest TTP as compared with patients with high levels of ATP7B protein and mRNA (14.64 months vs. 4.63 months, respectively, p = 0.01) and showed a nonsignificant trend toward a lower response rate (37.5% and 75%, respectively). In conclusion, ATP7B mRNA and protein expression in colorectal tumors is associated with clinical outcome to oxaliplatin/5FU. Prospective studies are required to evaluate the role of this marker in tailoring chemotherapy.

Does Doxycycline work in synergy with cisplatin and oxaliplatin in colorectal cancer?

BackgroundIn recent years, apart from antibacterial properties, doxycycline is reported to have cytotoxic and anti-proliferative actions in various cancers including colorectal cancer. Colorectal cancer constitutes one of the most common cancers in the western population. Apart from surgery, chemotherapy plays crucial role in the treatment of colorectal cancer. Cisplatin and oxaliplatin are most commonly used platinum compounds for the cancer chemotherapy. This study has looked for any impact of doxycycline on the cytotoxic effects of platinum compounds in colorectal cancer including its mechanisms of actions.MethodsHT 29 colorectal cancer cells were used for this study. These cells were treated with cisplatin and oxaliplatin with or without doxycycline treatment. The caspase 3 gene expression was quantitated by gel electrophoresis and qualitated by real time polymerase chain reactions. The caspase 3 activity was assessed in HT 29 cells with fluorescence kit.ResultsThe results revealed increased caspase 3 gene expressions and activities in HT 29 cells treated with cisplatin, oxaliplatin and doxycycline; however the combination of doxycycline with cisplatin and oxaliplatin did not report increased caspase 3 gene expressions and activity compared to cisplatin and oxaliplatin alone.ConclusionWe concluded that doxycycline has role in apoptosis induction in the colorectal cancer. However, it did not show any synergy with platinum compounds in the colorectal cancer cells. This study also pointed towards possible caspase-independent actions of doxycycline with cisplatin and oxaliplatin. However, further work is required to underpin the mechanisms of actions of doxycycline.

Pharmacogenomic approach for the identification of novel determinants of acquired resistance to oxaliplatin in colorectal cancer

Oxaliplatin is a third-generation platinum agent used in colorectal cancer treatment. Oxaliplatin resistance acquisition is a complex process mainly based on alteration of genes and pathways involved in its mechanism of action. Therefore, our purpose was to perform a gene expression screening in an in vitro model to identify genes that could play a role in oxaliplatin resistance acquisition processes. Four colorectal cancer cell lines and their oxaliplatin-resistant derived sublines were compared. Microarray analysis was done using Human 19K Oligo Array Slides. RNA from cells were hybridized with a commercial RNA reference sample and labeled with both fluorochromes Cy3 and Cy5. Data were analyzed by hierarchical clustering method. Subsequently, quantitative real-time PCR (qRT-PCR) was used to corroborate microarray data, considering as positively validated those genes that showed significant differences in expression levels between groups and a correlation between microarray and qRT-PCR data. By microarray analysis, 32 candidate genes were identified. After validation process by qRT-PCR, the genes AKT1, CDK5, TRIP, GARP, RGS11, and UGCGL1 were positively validated. The 3 first genes proved to be involved in regulation of nuclear factor-kappabeta antiapoptotic transcription factor previously related to drug resistance, and the other 3 genes are novel finds. We have identified 6 genes related to oxaliplatin resistance acquisition. These findings are of paramount importance to understand these processes better and open new lines of study to elucidate the relevance of this pharmacogenomic approach into the clinic.

VIB.4 Oxaliplatin in colorectal cancer in senior adults

BRD4, a member of the bromodomain and extra-terminal domain (BET) protein family, plays a role in the organization of super-enhancers and transcriptional activation of oncogenes in cancer and is recognized as a promising target for cancer therapy. microRNAs (miRNAs), endogenous small noncoding RNAs, cause mRNA degradation or inhibit protein translation of their target genes by binding to complementary sequences. miRNA mimics simultaneously targeting several tumor-promoting genes and BRD4 may be useful as therapeutic agents of tumor-suppressive miRNAs (TS-miRs) for cancer therapy. To investigate TS-miRs for the development of miRNA-based cancer therapeutics, we performed function-based screening in 10 cancer cell lines with a library containing 2,565 human miRNA mimics. Consequently, miR-1293, miR-876-3p, and miR-6571-5p were identified as TS-miRs targeting BRD4 in this screening. Notably, miR-1293 also suppressed DNA repair pathways by directly suppressing the DNA repair genes APEX1 (apurinic-apyrimidinic endonuclease 1), RPA1 (replication protein A1), and POLD4 (DNA polymerase delta 4, accessory subunit). Concurrent suppression of BRD4 and these DNA repair genes synergistically inhibited tumor cell growth in vitro. Furthermore, administration of miR-1293 suppressed in vivo tumor growth in a xenograft mouse model. These results suggest that miR-1293 is a candidate for the development of miRNA-based cancer therapeutics.

First-line gefitinib combined with simplified FOLFOX-6 in patients with epidermal growth factor receptor-positive advanced colorectal cancer

3659 Background: The orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib (IRESSA) shows promising activity in several tumor types. Preclinical studies suggest gefitinib has synergistic activity in combination with oxaliplatin in colorectal cancer (CRC) cells. This Phase II multicenter study evaluated gefitinib combined with FOLFOX-6 as first-line treatment in patients (pts) with EGFR-positive advanced CRC. Methods: Pts received gefitinib 250 mg/day combined with simplified FOLFOX-6 every 2 weeks for ≥8 weeks in order to be evaluable for response. Treatment was continued until progressive disease (PD), unacceptable toxicity, or withdrawal. Pts with clinical benefit after up to a maximum of 10 courses could continue gefitinib monotherapy. Tumor assessment (CT scan) by RECIST was made at baseline and every 4 cycles. All adverse events (AEs) were assessed by NCI-CTC. Serum EGFR was evaluated at baseline and every assessment. Results: 47/49 pts met the entry criteria: 21 male, 26 female; median age 58 years (range 39–76); ECOG performance status 0/1/2: 33/10/4; stage IV at diagnosis: 37 (78.7%); 1/2/>2 disease sites: 23/16/8. At a median follow-up of 4.3 months 39 pts were evaluable for efficacy (8 too early): 29 (74.4%) PR; 9 (23.1%) SD; 1 (2.6%) PD. In 42 pts evaluable for safety (259 cycles), grade 3/4 AEs occurred in 40.5% of pts: neutropenia/leukopenia (16.7%), diarrhea (14.3%), mucositis (7.1%), nausea (4.8%), and fatigue (4.8%). As yet it is too early to assess survival or the role of gefitinib as maintenance therapy. Serum EGFR data (n=27) did not correlate with response. Conclusions: These preliminary data show that first-line gefitinib combined with simplified FOLFOX-6 has promising activity in pts with advanced CRC. Final data will be reported at the meeting. No significant financial relationships to disclose.

Recent updates in the clinical use of platinum compounds for the treatment of lung, breast, and genitourinary tumors and myeloma

Platinum compounds have shown activity in a broad spectrum of human tumors in vitro and in vivo. The clinical utility of platinum agents in gynecologic and gastrointestinal cancers (particularly oxaliplatin in colorectal cancer) has been well documented and platinum agents continue to be evaluated in a variety of other cancers. Given preclinical evidence of synergy among some platinum compounds and new anticancer agents, clinical trials exploring platinum-based combination therapies may yield improved treatment for a variety of malignancies. Recent clinical data on new chemotherapeutic strategies for the treatment of lung, breast, and genitourinary cancers and myeloma will be presented in this review.

XPD, XPA, ERCC1 and XPG/ERCC5 single nucleotide polymorphisms (SNPs) in oxaliplatin-treated colorectal cancer (CRC)

3677 Background: Oxaliplatin damages DNA, leading to apoptosis. XPD, XPA, ERCC1 and XPG/ERCC1 are involved in DNA repair, and polymorphic variants in these genes can influence the efficacy of oxaliplatin. We analyzed SNPs in these genes and correlated the results with toxicity and response to oxaliplatin in CRC. Methods: 33 CRC patients (pts) recruited between February 2002 and September 2003 were treated with oxaliplatin-based chemotherapy. DNA was obtained from peripheral blood cells at baseline, and allelic discrimination assay with ABI Prism 7700 was used to analyze SNPs at XPD Lys751Gln, XPA 5'utr A/G, ERCC1 codon 2 Thr/Lys and XPG/ERCC5 codon 3 His/His. Results: Pts characteristics: age 62.5 (44–78); all pts, PS 0–1. Pts with XPD C/C showed greater hematological toxicity (44%) than those with A/A (9%) (p=0.08). Ptes with XPD A/C and C/C (30%) showed better objective response than those with A/A (18%) (p=ns). Pts with XPG C/C showed better objective response (70%) than those with C/T and T/T (8%) (p=0.002). Pts with XPG C/C achieved longer time to progression (8.5 mos) than those with C/T and T/T (4 mos) (p=0.002). Ptes with XPG C/C achieved better median survival (+11 mos) than those with C/T and T/T (8.4 mos) (p=0.01). Conclusions: XPD C/C may be related to greater hematological toxicity, and XPG C/C may be a predictive marker of response, time to progression and survival in oxaliplatin-treated CRC pts. Studies with a larger number of patients should be carried out to confirm these results. No significant financial relationships to disclose.

XPD, XPA, ERCC1 and XPG/ERCC5 single nucleotide polymorphisms (SNPs) in oxaliplatin-treated colorectal cancer (CRC)

3677 Background: Oxaliplatin damages DNA, leading to apoptosis. XPD, XPA, ERCC1 and XPG/ERCC1 are involved in DNA repair, and polymorphic variants in these genes can influence the efficacy of oxaliplatin. We analyzed SNPs in these genes and correlated the results with toxicity and response to oxaliplatin in CRC. Methods: 33 CRC patients (pts) recruited between February 2002 and September 2003 were treated with oxaliplatin-based chemotherapy. DNA was obtained from peripheral blood cells at baseline, and allelic discrimination assay with ABI Prism 7700 was used to analyze SNPs at XPD Lys751Gln, XPA 5'utr A/G, ERCC1 codon 2 Thr/Lys and XPG/ERCC5 codon 3 His/His. Results: Pts characteristics: age 62.5 (44–78); all pts, PS 0–1. Pts with XPD C/C showed greater hematological toxicity (44%) than those with A/A (9%) (p=0.08). Ptes with XPD A/C and C/C (30%) showed better objective response than those with A/A (18%) (p=ns). Pts with XPG C/C showed better objective response (70%) than those with C/T and T/T (8%) (p=...

Oxaliplatin: a novel platinum analog with activity in colorectal cancer.

To review selected recent data pertaining to the use of oxaliplatin in colorectal cancer and its implications for oncology nursing. Published articles, abstracts, and conference proceedings. Colorectal cancer accounts for about 15% of all new cancers. The search for more effective chemotherapy regimens is ongoing. Oxaliplatin, a member of the diaminocyclohexane family of platinum compounds, demonstrates cytotoxic efficacy and a well-tolerated safety profile. Oxaliplatin is effective in chemotherapy-naive patients with advanced colorectal cancer, as well as in those refractory to previous treatment with 5-fluorouracil (5-FU); the drug also is effective in combination with 5-FU and leucovorin for the treatment of advanced colorectal cancer. Nurses must be highly knowledgeable about oxaliplatin regimens and schedules, the associated side effects, and recommended strategies for symptom management. This article can help nurses to understand and communicate the benefits and risks associated with oxaliplatin-based therapies to colleagues and patients.