Metastatic Colorectal Carcinoma Patients Research Articles

Abstract 2606: Absence of transcriptomic signature of response to chemotherapy in metastatic colorectal carcinoma patients

Abstract Using whole genome tumour gene expression profiling in patients treated for metastatic colorectal cancer, we attempted to define a signature able to discriminate between responders and non-responders to first-line chemotherapy. A total of 42 patients were prospectively included between 2003 and 2006. They all suffered from histologically proven colorectal adenocarcinoma and were metastatic at the time of diagnosis. All of them gave informed consent to the study. They were treated in first line with 5-fluorouracil (according to the de Gramont regimen in most cases) associated either with irinotecan (FolFiri regimen, 180 mg/m2 every two weeks, 22 pts) or with oxaliplatin (FolFox 4 regimen, 85 mg/m2, 20 pts) according to physician's decision. Response was evaluated using WHO criteria every 2 months after initiation of chemotherapy and patients were assigned to complete response (1 pt), partial response (24 pts), stable disease (13 pts) or progressive disease (4 pts). From a tumour sample obtained at surgery (18 pts) or by biopsy (24 pts) and kept in RNA later, we extracted and purified total RNA. Gene expression profiling was performed by Cogenics using microarrays from Applied Biosystems (Human Genome Survey Microarray v2.0). We used three different methods for supervised data analysis: analysis of variance, SAM (statistical analysis of microarrays) and Limma (Bioconductor). We compared responders to non-responders in the whole set of patients and in the subsets of patients who received either irinotecan or oxaliplatin. With none of the three methods we were able to obtain a stable signature, i.e. a group of genes consistently associated with response to chemotherapy. On the contrary, we obtained very homogeneous gene expression profiles which were even difficult to clusterise using a non-supervised approach. These negative results show that the determinants of response to chemotherapy should be sought not only in the tumour molecular characteristics, but also among the processes leading to drug availability to the tumour (drug dose, drug disposition, etc.). Especially, the relatively low dose of irinotecan which is of standard use in Europe does not allow to recruit all the responders who could be identified at higher dosage, given the sharp dose-efficacy curve that has been identified long ago for this drug. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2606.

Panitumumab: a new frontier of target therapy for the treatment of metastatic colorectal cancer

Panitumumab is a fully human monoclonal IgG2 antibody targeting the EGF receptor (EGFR). This agent represents a new class of drug owing to its fully human nature, and no need for premedication and loading dose. Panitumumab selectively binds to EGFR, blocking the extracellular domain of the receptor, and has not been associated with the formation of any antibodies directed against it. The drug is indicated as monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal carcinoma with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens. The safety profile is favorable and is generally well tolerated; the most common toxicities are skin rashes and diarrhea. Therefore, panitumumab’s hypersensitivity reaction rate is lower when compared with a chimeric monoclonal antibody such as cetuximab. Panitumumab increases the clinician’s repertoire of agents to treat metastatic colorectal carcinoma. The available clinical data are the most promising for a single-agent anti-EGFR monoclonal antibody in this disease at the present time. These new data open different clinical scenarios in metastatic colorectal carcinoma patients and encourage clinicians and basic researchers to investigate new therapeutic approaches for this patient subset.

Serum Retinol, Alpha-Tocopherol and Systemic Inflammatory Response in Metastatic Colorectal Carcinoma Patients Treated with Combination Chemotherapy and Cetuximab

Cetuximab is a chimeric antibody registered for the therapy of advanced colorectal carcinoma. Cancer and anticancer therapy are associated with oxidative stress, and disorders of antioxidant balance may be involved in the toxicity associated with anticancer treatment. The aim of the present study was to investigate the changes of serum retinol, alpha-tocopherol and C-reactive protein during the first month of treatment with cetuximab and chemotherapy. Twenty-five consecutive patients with metastatic colorectal carcinoma treated with a combination of chemotherapy and cetuximab were included in the present study. Serum retinol and alpha-tocopherol were determined by high-performance liquid chromatography and serum C-reactive protein was determined using commercial kits. Significant correlation was observed between baseline concentrations of retinol and C-reactive protein (r(s)=-0.54, p<0.01). Median survival of patients who had baseline serum retinol below 1.25 µmol/L was 10 mo compared to 18 mo for patients who had serum retinol equal or above 1.25 µmol/L (p<0.05); median survival of patients who had serum C-reactive protein below 24 mg/L was significantly longer compared to patients with C-reactive protein levels equal or above 24 mg/L (18 vs. 7 mo, p<0.05), but no difference in survival was observed based on alpha-tocopherol levels. Twenty-two patients had evaluation of retinol, alpha-tocopherol and C-reactive protein at least once during the follow up. Serum concentration of alpha-tocopherol decreased significantly during the therapy, but retinol and C-reactive protein concentrations remained unchanged. In conclusion, a significant correlation was observed between serum retinol and C-reactive protein. Serum alpha-tocopherol decreased significantly during the first month of combination therapy with cetuximab. Low retinol and high C-reactive protein concentrations were predictive of poor prognosis in this patient population.

The value of XPD and XRCC1 genotype polymorphisms to predict clinical outcome in metastatic colorectal carcinoma patients with irinotecan-based regimens

Previous studies have suggested that DNA repair enzyme polymorphisms may bear prognostic value in metastatic colorectal carcinoma (MCRC). We prospectively treated 43 MCRC patients with irinotecan-based regimens (XELIRI or IFL). Allelic variants of the XRCC1 gene at codon 399 and XPD gene at codon 751 were analyzed in lymphocyte DNA by PCR-RFLP. Clinical outcome variables: overall survival (OAS), progression-free survival (PFS) and the occurrence of grade 3 or 4 hematological and gastrointestinal (GIS) toxicities were evaluated. In the univariate analysis for OAS (n = 43) only XPD and XRCC1 polymorphisms were significant (P = 0.05 and P = 0.04, respectively). After adjustment for performance status (ECOG = 0, 1 vs. 2) and disease extent (single vs. multiple metastatic site), XRCC1 genotype and performance status retained significance (HR = 2.85, P = 0.04, and HR = 3.19, P = 0.02, respectively). Gln/Gln genotype was associated with the greatest risk of death. Type of presentation (metastatic vs. local disease at first presentation) was the only significant predictor of PFS in the univariate analysis (n = 40, P = 0.003). After adjustment for performance status and disease extent, type of presentation retained its significance (HR = 4.35, P = 0.003). None of the toxicities was associated with these genotypes. XRCC1 genotype independently predicted overall survival in metastatic colorectal carcinoma patients treated with irinotecan-based chemotherapy.

Immunological evaluation of personalized peptide vaccination in combination with UFT and UZEL for metastatic colorectal carcinoma patients.

To investigate the safety and immunological responses of personalized peptide vaccination in combination with oral administration of UFT and UZEL for metastatic colorectal carcinoma (mCRC), fourteen patients were enrolled in the present study. Peptides were determined based on the presence of peptide-specific cytotoxic T lymphocyte precursors and IgG in each patient. A maximum of four peptides were subcutaneously administered weekly with UFT (300 mg/m2 day(-1)) and UZEL (75 mg/day) for 4 weeks, followed by 1 week of rest. This therapy was well-tolerated although there was a grade-3 skin reaction at the vaccination site in one patient. An increase in peptide-specific interferon-gamma production or peptide-specific IgG after the tenth vaccination was observed in nine of ten or eight of ten patients tested, respectively. IgG responses were well correlated with overall survival (P = 0.0215). The safety and immunological responsiveness of the present therapy suggest that this combination would be of clinical benefit for mCRC patients, and further trials are merited.

KRAS mutations and sensitivity to anti-EGFR monoclonal antibodies in metastatic colorectal carcinoma: an open issue

Background: Cetuximab and panitumumab, mAbs targeting EGFR, are registered for metastatic colorectal carcinoma (mCRC) patients whose tumors express EGFR as determined by immunohistochemistry. However, this method is not predictive of treatment efficacy. KRAS, the human homolog of the Kirsten rat sarcoma-2 virus oncogene, encodes a small G-protein that functions downstream of EGFR-induced signalling. Objective/Methods: To examine KRAS mutations as predictive factors of response to anti-EGFR mAbs using recently published data. Results/conclusions: Several retrospective studies show that efficacy of these mAbs is confined to patients with wild type KRAS and genotyping of tumors should be considered before treatment. The absence of KRAS mutations does not guarantee an improved likelihood of response to cetuximab and panitumumab. Investigation of other genetic and epigenetic biomarkers will be useful to further refine the responder population. Prospective studies to test the efficacy of combined therapies simultaneously targeting EGFR and the RAS/RAF/MAPK signalling pathways for mCRC are warranted.

Evaluation of Spondin-1 as a predictive marker for palliative 5-FU-based chemotherapy in metastatic colorectal cancer

4112 Background: An individualized tumor tailored chemotherapy may improve survival of patients with metastatic colorectal carcinoma (CRC). Therefore, we analyzed gene expression profiles of liver metastases and primaries of patients with CRC before application of a palliative 5-Fluorouracil based chemotherapy (AIO regimen) due to find predictive markers. These potential markers had to: (1) be highly expressed in the primary (2) and in the metastases, (3) be applicable to qRT-PCR of formalin-fixed paraffin embedded (FFPE) sections, and (4) remain their predictive power in a test set cohort. Methods: The training set consisted of 30 specimen from primary CRC and metastatic liver, which were laser micro dissected, the RNA was amplified and hybridized to Affymetrix HG U-133A microarrays. Additionally, RNA was isolated from FFPE sections of the same tumors and a qRT-PCR was performed for specific gene expression analysis. After surgery of the primary tumor all patients were treated with the AIO regimen. The test set consisted of 61 metastatic CRC patients, who were treated with the AIO regimen and where FFPE sections were available. Markers who showed promising predictive power and fulfilled criteria 1–3 (cp. background) were tested in the validation cohort. Response to chemotherapy was verified by CT scans according to WHO criteria. Results: By using statistical tests we identified some markers showing promising predictive power. However, most of them did not fulfill the further criteria. Spondin-1 expressions were very predictive for response (CR, PR) with a sensitivity of 62.5% and a specifity of 87.5% in the training set. Additionally, Spondin-1 was highly expressed as well in the tumors as in the metastases of CRC. Furthermore, the Affymetrix expression values for Spondin-1 were highly comparable with the RT-PCR data using FFPE sections from the same specimen. In the FFPE test set Spondin-1 remained its predictive value with sensitivity and specifity rates of 53.3% and 70.0%, respectively. Conclusions: Spondin-1 is an attractive candidate for further evaluation of response in CRC tumors treated with a 5-FU based chemotherapy as it is predictive and robust in terms of use in FFPE material. Further research with additional predictive markers to increase accuracy is ongoing. [Table: see text]

Preoperative Carcinoembryonic Antigen and Albumin in Predicting Survival in Patients With Colon and Rectal Carcinomas

To examine the relationship between postoperative outcomes of colorectal carcinoma patients and preoperative serum carcinoembryonic antigen (CEA) and albumin (ALB) levels and evaluate if these levels can accurately predict outcomes and/or be factor indicating adjuvant chemotherapy. CEA is a marker for colorectal carcinoma and its level usually increases before a distant metastasis is detected. Also, a low level of serum ALB is usually found in metastatic colorectal carcinoma patients. A retrospective cohort study of patients with colorectal carcinomas who were treated with curative surgery in Songklanagarind Hospital between 1998 and 2002. One hundred seventy patients were identified with a median survival of 1131 days (range 71 to 2293 d) and with an overall 5-year survival rate of 54%. Patients were stratified using CEA at 5 ng/mL and an ALB level at 3.5 g/dL into 4 groups: (1) low CEA, high ALB; (2) low CEA, low ALB; (3) high CEA, high ALB; and (4) high CEA, low ALB. The 5-year survival rates for groups 1 to 4 were 66%, 63%, 46%, and 34%, respectively. There was statistically significant difference in 5-year survival between the well-differentiated tumor with low CEA and the poorly differentiated tumor with high CEA (P=0.0115). The high CEA patients who had the well-differentiated tumor had longer survival than those with a poorly differentiated tumor (P=0.0412). A preoperative CEA level greater than or equal to 5 ng/mL and ALB level less than 3.5 g/dL predict a poor survival chance for colorectal carcinoma patients. In high CEA patients, tumor differentiated is an independent factor affecting survival.

Does serum VEGF predict prognosis in metastatic colorectal carcinoma patients treated with XELIRI?

13548 Background: Serum vascular endothelial growth factor (sVEGF) levels have been shown to possess prognostic value in different solid tumors. However, there is no solid information on the prognostic use of sVEGF in metastatic colorectal carcinoma (MCRC) patients treated with a standard regimen. Methods: 37 consecutive MCRC patients were given XELIRI chemotherapy as the 1st line treatment (irinotecan 250 mg/m2 on day one, and Capecitabine 2000 mg/m2/day, for 14 days starting on day1, repeated in every 3 weeks). Serum VEGF levels prior to the 1st cycle of chemotherapy was measured by ELISA. Kaplan-Meier survival curves and Cox regression analyses to adjust for basic clinical features were used for the survival analysis. Binary logistic regression analysis was employed to determine correlates of objective response (CR+PR). Results: Best objective response was CR+PR in 20/33(61%) cases (3 CR; 9% + 17 PR; 52%). In 4 patients, response assessment was not possible. Median sVEGF was 650(107–1865) pg/ml. Median OAS and PFS was 16.2 and 5.9 months, respectively. Increased age turned out to be the only predictor of better OAS with borderline significance (P=0.09). After adjustment for performance status (0, 1 versus 2) and disease extent (single vs. multiple metastatic sites), age was statistically significant (P=0.042, HR=0.95(0.90–0.99)). For PFS, again age (P=0.038) was the only correlate. After controlling for performance status and disease extent, age (P=0.014, HR=0.95(0.92–0.99)) and performance status (P=0.036, HR=3.27(1.08–9.88)) were significant. No factor was associated with the likelihood of objective response. Conclusion: In this study, we failed to determine any prognostic value for sVEGF in MCRC. However, older age and good performance status appear to have a borderline positive prognostic value for MCRC patients treated with XELIRI. No significant financial relationships to disclose.

The value of pharmacogenomic analysis of microsatellite instability (MSI) and XPD, XRCC1 genotype polymorphisms to predict clinical outcome in metastatic colorectal carcinoma

13011 Background: Previous work suggests that DNA repair enzyme polymorphism and microsatellite instability (MSI) may bear prognostic value in metastatic colorectal carcinoma (MCRC), but this is either retrospective or do not involve irinotecan-based regimens. Methods: We prospectively treated 43 MCRC patients with irinotecan-based regimens (XELIRI or IFL). MSI was measured by PCR at 5 different chromosomal loci: BAT-25, BAT-26, D5S346, D2S123, and D17S250. XPD (Lys751Gln) and XRCC1 (Arg399Gln) polymorphisms were also analysed by PCR-RFLP method. Clinical outcome variables; overall survival (OAS), progression free survival (PFS) and the occurrence of grade 3 or 4 hematological and gastrointestinal (GIS) toxicities were evaluated. Results: MSI subtypes MSS, MSI-L and MSI-H were seen in 23.3%, 43.3% and 33.3% of cases. In the univariate analysis for OAS (n=43) only XPD and XRCC1 polymorphisms were significant (P=0.05 and P=0.04, respectively). After adjustment for performance status (ECOG=0, 1 vs. 2) and disease extent (single vs. multiple metastatic site), XRCC1 genotype and performance status retained significance (P=0.04, HR=2.85, and P=0.02, HR=3.19, respectively). Arg/Gln versus Arg/Arg and Gln/Gln versus Arg/Gln genotypes indicated approximately 3 times increased risk of death for each comparison. Type of presentation (metastatic versus local disease at first presentation) was the only significant predictor of PFS in the univariate analysis (n=40, P=0.003). After adjustment for performance status and disease extent, type of presentation retained its significance (P=0.003, HR=4.35). MSI was not associated with survival. Although absence of “liver only” disease was associated with the occurrence of grade 3–4 GIS toxicity, it lost significance in the multivariate analysis. None of the factors tested correlated with the likelihood of grade 3–4 hematological toxicity. Conclusions: XRCC1 genotype independently predicted overall survival in metastatic colorectal carcinoma patients treated with irinotecan-based chemotherapy. However, MSI status did not emerge as a prognostic factor in our cohort. No significant financial relationships to disclose.

Biweekly oxaliplatin plus capecitabine (OXXEL) versus oxaliplatin plus folinic acid-modulated 5-fluorouracil i.v. bolus (OXAFAFU) in metastatic colorectal carcinoma (MCC): Safety interim analysis of a Southern Italy Cooperative Oncology Group (SICOG) phase III trial

3590 Background: We have previously reported that OXAFAFU regimen significantly prolonged the overall survival of MCC patients (pts) in comparison with IRIFAFU regimen (Comella, Ann Oncol 2005). Moreover, the OXXEL regimen showed promising activity in phase II study (Comella, Cancer Chemother Pharmacol 2005). Comparison of these two regimens in terms of safety and activity is the aim of the present trial. Methods: Pts with MCC were randomly treated with: oxaliplatin 85 mg/m2 iv on day (D) 1, levo-folinic acid 250 mg/m2 plus 5-fluorouracil 850 mg/m2 bolus iv on D 2 (OXAFAFU); or oxaliplatin 100 mg/m2 iv on D 1, Xeloda 1,000 mg/m2 twice daily po from D 1 (evening) to D 11 (morning). Treatment was delivered every 2 weeks up to progression, or for a maximum of 12 cycles. Results: From May 2004 to December 2005, 191 eligible pts were recruited (OXAFAFU, 96 pts; OXXEL, 95 pts). Characteristics of pts were well balanced in OXAFAFU vs OXXEL arm: primary colon, 74% vs 72%; PS 0/1–2, 57/43% vs 65/35%; previous adjuvant CT, 24% vs 20%; liver metastases, 80% vs 83%; ≥ 2 metastatic sites, 54% vs 49%. At this interim analysis, with a median number of 8 (range, 1–12) cycles delivered in both arms, 143 pts (OXAFAFU, 73; OXXEL, 70) were assessed for safety. In OXAFAFU vs OXXEL arm, occurrence of WHO grade ≥ 3 toxicity was: neutropenia, 29% vs 3%; anemia, 2% vs 7%; thrombocytopenia 3% vs 7%; diarrhea, 4% vs 13%; vomiting, 4% vs 3%; hand-foot syndrome, 1% vs 7%. Conclusions: At this interim analysis, the OXXEL regimen appeared to produce significantly less neutropenia than the OXAFAFU regimen, at a price of an acceptable non-hematologic toxicity. Accrual will continue up to reaching the final sample size of 300 pts. No significant financial relationships to disclose.

Quality of survival reporting in chemotherapy and surgery trials in patients with metastatic colorectal carcinoma

Patients with metastatic colorectal carcinoma (MCC) to the liver receive conflicting management recommendations because of the lack of prospective randomized controlled trials (RCTs) clarifying the optimal management in this disease. The objective of the current study was to evaluate the reporting of prognostic factors in MCC from chemotherapy and surgery trials and evaluate the ability to compare these results across treatments. RCTs and retrospective series of greater than 75 MCC patients published between 1980-2004 were reviewed to identify 10 critical prognostic elements of overall survival reported in both types of journals. A review 92 RCTs and 116 retrospective reports with 64,898 patients analyzed found 7 (3%) reporting all prognostic factors, with both studies demonstrating no difference in the success of reporting criteria met. The only criterion that was universally reported among both chemotherapy and surgery trials was the mortality rates of the study. All remaining prognostic factors in the evaluation of overall survival were significantly different between both chemotherapy and surgical studies. Considerable variation was observed in the disease-free interval, number of hepatic metastases, size of hepatic metastases, and performance status, and were significantly different among some of the most significant factors for patients evaluating treatment: complication reporting, surgical margin evaluation, and overall response rate. The reporting of results in MCC in chemotherapy trials and surgical reports is limited to general outcomes, with a paucity of prognostic factors, which hinders any ability to compare results across treatments. A mandatory reporting criteria of all metastatic colorectal trials is imperative to optimally manage these patients in both academic and community centers.

Immunological and anti-tumor activity of a novel a chemo-immunotherapy regimen with gemcitabine, oxaliplatin, levo-folinic acid, and 5-fluorouracil followed by GM-CSF and Interleukin-2 in patients with metastatic colorectal cancer

2538 Background: Gemcitabine + FOLFOX-4 (GOLF) regimen is a powerful multi-drug regimen which is able to determine molecular changes in colon cancer cells that make them a powerful means to induce an antigen specific CTL response in human PBMCs in vitroif taken up and processed by dendritic cells (DCs). We also showed that cancer patients’ activated DCs and CTL response may be induced with the subcutaneous (sc.) administration of GM-CSF and low dose IL-2 (IG-1 regimen). All together these results offered the rationale to design an original chemo immunotherapy protocol in colon cancer patients. Methods: We designed a phase II trial aimed to evaluate in metastatic colorectal carcinoma patients, the toxicity, the anti-tumor and the immunological activity of GOLF regimen [intravenous (iv.) GEM (1g/m2) - day 1 and 15; iv. levo-folinic acid (LF, 100 mg/m2) + iv. bolus (400 mg/m2) and 24 hour-infusional (800 mg/m2) 5-FU - day 1,2, 15,16-; and iv. 6–8 hour infusional oxaliplatin (85 mg/m2) - day 2 and 16, before LF/5-FU administration] combined with IG-1 immunotherapy [sc.GM-CSF (100 μg/day -days 3→7) and sc.IL-2 (0.5 MIU twice a day, days 8→14 and 17→30]. Twenty nine patients, 16 males and 13 females, with an average age of 69 years and an ECOG ≤ 2 were enrolled; among these, 21 had received a previous line of treatment, and 19 had liver involvement. Results: The treatment was well tolerated and induced a very high rate of objective responses (68.9%%) and disease control (96.5%), with a median time to progression of 12.5 months. An immunological study demonstrated the treatment ability to enhance a cell mediated immune response to colon carcinoma antigens and reduce the expression of regulatory T lymphocytes Conclusions: These results show that the GOLFIG regimen determines a strong immunological and anti-tumor activity in colorectal cancer patients and deserves to be investigated in future comparative phase III trials. No significant financial relationships to disclose.

High Frequency of Bone/Bone Marrow Involvement in Advanced Medullary Thyroid Cancer

High hematological toxicity has been observed with anti-carcinoembryonic antigen radioimmunotherapy (RIT) in medullary thyroid carcinoma (MTC), suggesting metastatic bone involvement (BI). This retrospective study evaluated the rate of BI in MTC patients enrolled in two phase-I/II RIT trials using anti-carcinoembryonic antigen x anti-diethylenetriamine pentaacetic acid bispecific antibodies and [(131)I]di-diethylenetriamine pentaacetic acid hapten. Thirty-five patients underwent bone scintigraphy, bone magnetic resonance imaging (MRI), and post-RIT immunoscintigraphy (IS). IS performed in MTC patients was compared with IS conducted in 12 metastatic colorectal carcinoma (CRC) patients. Quantitative analysis of bone uptake was performed in three MTC and three CRC patients. In the MTC group, bone scintigraphy detected BI in 56.6% of patients, MRI in 75.8%, and IS in 88.6%. BI was confirmed by undirected (random) bone marrow biopsy, by bone surgery, or by two positive imaging methods in 74.3% of the patients. Sensitivity per patient of bone scintigraphy, MRI, and IS were 72.7, 100, and 100%, respectively. In contrast, IS visualized BI in only 33.3% of CRC patients; bone uptake was lower in CRC than in MTC patients. Bone MRI combined with post-RIT IS disclosed a much higher BI rate in advanced MTC than previously reported in the literature.

Incidence of GM-CSF antibodies in cancer patients receiving GM-CSF for immunostimulation.

We have assessed the immunogenicity profile of GM-CSF in patients with either colorectal carcinoma (CRC) at different stages of disease or with multiple myeloma who were given recombinant human GM-CSF (Escherichia coli-derived) combination therapy. Metastatic CRC patients received a colon carcinoma-reactive antibody and high doses of GM-CSF (425--500 microg/day for 10 days), while other CRC patients and those with myeloma received low doses of GM-CSF (75--80 microg/day for 4 days) as an adjuvant along with appropriate tumor antigens. We found that 55% of the patients (11/20) given high doses of GM-CSF developed GM-CSF-reactive antibodies in comparison with an incidence of only 16% (4/25) in patients given low doses of GM-CSF. None of the patients developed neutralizing antibodies and so the biological effects of GM-CSF were not compromised. A majority of patients (80%) (36/45) also developed antibodies to E. coli proteins that were present as trace contaminants in the GM-CSF product. Treatment with recombinant GM-CSF products, therefore, may induce antibodies against this cytokine depending on the regimen and the amounts used. In this study, multiple immunizations with low doses of GM-CSF was associated with a low incidence of GM-CSF antibodies, which did not neutralize the effect of the cytokine. This therapeutic strategy was effective in inducing adjuvant-type effects and needs to be explored in further clinical trials with this cytokine.

Correlation between progression free survival and response rate in patients with metastatic colorectal carcinoma

All endpoint measures currently used to evaluate chemotherapeutic treatment benefit in clinical trials of patients with metastatic colorectal carcinoma (MCRC) have disadvantages. Overall survival (OS) is the most objective parameter but is flawed as an efficacy criterion, partly because potentially active second-line treatments are not controlled in many Phase III studies, and measured OS may be influenced (positively or negatively) to an unknown degree by second-line therapy. Measuring progression free survival (PFS) may be a means of isolating the real impact of first-line regimens. To test this hypothesis, the authors analyzed pooled data from all Phase III studies on first-line treatment in patients with MCRC reported from 1990 through 2000 for correlations between PFS, response rate (RR), and OS in MCRC patients that may suggest PFS as an improved indicator of the efficacy of first-line treatment. Spearman rho correlation coefficients (r) and regression equations were used. The authors analyzed data from 29 studies involving nearly 13,500 patients. Significant correlations were found between PFS and RR (r = 0.655; P < 0.0001; a 10% RR increment corresponded to a 1-month increase in PFS), between RR and OS (r = 0.408; P = 0.0009; an 11.4% RR increment corresponded to a 1-month increase in OS), and between PFS and OS (r = 0.481; P < 0.0001; a 1-month increase in PFS corresponded to a 0.68-month increase in OS). PFS is the most appropriate primary endpoint for MCRC studies, because it can express the antitumor activity of a first-line chemotherapy regimen regardless of measures used after disease progression. PFS deserves further evaluation as an endpoint measure.

A DOUBLE BLIND RANDOMIZED TRIAL COMPARING IMMUNIZATION WITH ANTI-IDIOTYPE GOAT ANTIBODY VACCINE SCV 106 VERSUS UNSPECIFIC GOAT ANTIBODIES IN PATIENTS WITH METASTATIC COLORECTAL CANCER

This article reports on the first double-blind randomized clinical study with an antiidiotype antibody vaccine in patients with metastatic colorectal carcinoma. The study was performed to determine immunological parameters, efficacy, and tolerability of the vaccine. Forty-two patients with metastatic colorectal cancer were randomly assigned to multiple immunizations with goat IgG antiidiotype vaccine SCV 106 (n = 21) or unspecific goat IgG as controls (n = 21). The antiidiotype vaccine mimicked the 17-1A glycoprotein antigen associated with colorectal cancer. Of the 42 patients entered, 39 were evaluable for efficacy (SCV 106, n = 18; controls, n = 21). Twenty-nine patients raised antibodies to the vaccines (immunological responders, SCV 106, n = 12; controls, n = 17). Only in the SCV 106 group was a significant increase (p = 0.002) of titers with specificity of antitumor antibody 17-1A found. According to the International Union Against Cancer (UICC) criteria no tumor response was observed. However, in the SCV 106 group the relative increase of carcinoembryonic antigen (CEA) levels between entry and observed disease progression was lower (p = 0.03) and disease progression was determined less frequently by development of new metastases (p = 0.001). On an intention-to-treat basis, the survival time difference between the two groups was not significant. Comparison of immunological responders in both groups revealed a significant survival advantage of the SCV 106-treated patients compared with controls (mean 67 versus 39 weeks; p = 0.01). Immunizations were well tolerated. Vaccination of immunologically responding metastatic colorectal carcinoma patients with SCV 106 leads to slowed disease progression and tumor dissemination and significantly prolongs survival time.

Monoclonal antibodies and cytokines for treatment of metastatic colorectal carcinoma (CRC) patients. – Is the idiotypic network response an important effector function?

Monoclonal antibodies and cytokines for treatment of metastatic colorectal carcinoma (CRC) patients. – Is the idiotypic network response an important effector function?