Allyson Ocean, MD, Weill Medical College, Cornell University
Introduction
The 2007 Gastrointestinal Cancers Symposium, held January 19-21 in Orlando, Florida, was co-sponsored by the American Society of Clinical Oncology (ASCO), the American Gastroenterological Association (AGA), the American Society for Therapeutic Radiology and Oncology (ASTRO), and the Society of Surgical Oncology (SSO). This was the fourth annual multidisciplinary symposium on gastrointestinal (GI) cancers bringing together leading experts to present and discuss new research on prevention, screening, and treatment. The presentations related to colorectal cancer concentrated on how to optimally sequence the various treatment options for patients with advanced colorectal cancer and how to manage the side effects of the treatments. Fortunately, because newer therapies have significantly extended the lives of patients with advanced colorectal cancer, quality of life has become extremely important to both patients and doctors. Research has also focused on the role and timing of surgery for patients who are diagnosed with advanced disease. The conference also served as a platform to introduce new targets in the treatment of colorectal cancer. This summary will highlight some of the abstracts presented during the colorectal cancer sessions of the conference.
Bevacizumab (Avastin®) in FOLFOX4 and XELOX Regimens
Dr. Leonard Saltz and colleagues presented results from XELOX-1/NO16966, a randomized Phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC).1 Several randomized trials have demonstrated a significant improvement in progression-free survival and overall survival with the addition of bevacizumab to standard chemotherapy compared to standard chemotherapy alone in the treatment of MCRC.2-4 Results from NO16966, the first Phase III trial to compare the addition of bevacizumab to either FOLFOX4 (oxaliplatin [Eloxatin®], 5-FU, leucovorin) or XELOX (oxaliplatin, capecitabine [Xeloda®]), also demonstrated a significant benefit from the addition of bevacizumab to either of these chemotherapy regimens. This trial included 1,401 patients with MCRC who were randomized to either FOLFOX4 or XELOX (oxaliplatin 130 mg/m2 iv, capecitabine 1,000 mg/m2 bid oral d1-14, q3w) plus bevacizumab (5mg/kg to FOLFOX or 7.5 mg/kg to XELOX) or placebo in a 2x2 factorial design.5 An independent review committee reviewed results for efficacy.
Median progression-free survival (PFS) was 9.3 months in the two treatment arms of bevacizumab plus XELOX or FOLFOX, compared with 8.0 months for the placebo arms (p=0.0023, HR 0.83, 97.5% CI, 0.72-0.95). However, only 56% of patients underwent treatment with the study drug protocol until disease progression, and 50% of patients discontinued treatment with the study drug unrelated to disease progression. For patients who remained on specific study treatment, median PFS was 10.4 months for those treated with bevacizumab plus chemotherapy, compared to only 8.1 months for those in the placebo arms (p<0.0001, HR 0.63). There were no unexpected toxicities reported.
Overall, these results indicate that the addition of bevacizumab to XELOX and FOLFOX significantly improves PFS in the treatment of MCRC (p<0.007). Furthermore, XELOX is just as effective as FOLFOX4 in terms of PFS in this patient population.
Cetuximab (Erbitux®) Dosing in MCRC
Dr. Eric Van Cutsem and colleagues presented the EVEREST study: “Cetuximab dose-escalation study in patients with metastatic colorectal cancer (MCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic and efficacy data of a randomized study.”6 Since the degree of skin responses to EGFR inhibitors is correlated with responses to therapy, the EVEREST study evaluated the potential effects of dose escalation of cetuximab among patients with epidermal growth factor receptor (EGFR)-expressing MCRC who had failed prior therapy with irinotecan (Camptosar®) and experienced minimal, if any, skin toxicity with initial doses of cetuximab. Patients in this study had more than one lesion and were initially treated with cetuximab (400 mg/m2 w1, then 250 mg/m2/w) plus irinotecan (180 mg/m2 q2). If patients had not experienced a greater than grade 1 skin reaction and tolerated cetuximab and irinotecan well, they were randomized at day 22 to either standard cetuximab doses (arm A [n=44]; 250 mg/m2/w) or dose-escalation (arm B [n=44]); cetuximab dose increased by 50 mg/m2 q2 w until greater than grade 2 toxicity was reported, tumor response or dose reaching 500 mg/m2. Patients not randomized to either arm A or B continued treatment with standard doses of cetuximab (arm C [n=77]). Skin biopsies were taken from each patient prior to therapy and during treatment.
Response rates were 30% for patients in arm B, 13% for patients in arm A, and 34% for patients in arm C. In arm B, 24 patients received 500 mg/m2/w with no safety concerns. Grade 3-4 skin reactions occurred in 9% of patients in arm B, 0% in arm A and 12% in arm C.
The researchers concluded that among patients with MCRC who do not initially demonstrate a skin response, or demonstrate a minimal skin response while being treated with cetuximab, escalating doses may improve response rates.
Table 1: Efficacy Analysis After 24 Weeks of Cetuximab Treatment |
Best Overall Response | Arm A (n =45) | Arm B (n=44) | Arm C (n=44) |
n | % | n | % | n | % |
Partial Response | 6 | 13 | 13 | 30 | 15 | 34 |
Stable Disease | 25 | 56 | 19 | 43 | 22 | 50 |
Progressive Disease | 10 | 22 | 12 | 27 | 7 | 16 |
Not Evaluable | 4 | 9 | 0 | 0 | 0 | 0 |
Response Rate (95% CI) | | 13 (5, 17) | | 30 (17, 45) | | 34 (19, 48) |
Adapted from Van Cutsem E, et al6 |
Addition of Oxaliplatin to Fluorouracil-based Chemo-radiotherapy
Dr. Carlo Aschele and colleagues presented “Pre-operative FU-based chemoradiation +/-weekly oxaliplatin in locally advanced rectal cancer: Preliminary safety findings of the STAR (Studio Terapia Adiuvante Retto)-01 randomized trial.”7
The STAR trial is an open-label, multicenter, randomized, Phase III trial evaluating the addition of oxaliplatin to standard therapy in patients with resectable locally advanced rectal cancer with tumors within 12 cm from the anal verge and involvement of the perirectal fat or regional nodes as evidenced by radiography. This trial included 410 patients who were randomized to infused fluorouracil (FU)-based therapy (225 mg/msq/day) with concomitant external-beam pelvic radiation (50.4 Gy in 28 daily fractions) (arm A), or the same regimen plus oxaliplatin (60 mg/msq weekly X 6) (arm B). Six to eight weeks following completion of pre-operative chemotherapy, a total mesorectal excision surgery was scheduled. Four cycles of adjuvant chemotherapy followed for both arms.
Completion of chemotherapy was achieved in 89% of patients in arm A and 74% of patients in arm B; the median dose of cumulative delivered radiation in both arms was 50.4 Gy. The median interval of time between completion of therapy and surgery was between 7.3 and 7.4 weeks in both arms, with 120 of 123 patients in arm A and 109 of 112 patients in arm B able to undergo surgery.
The authors concluded that these results indicate that oxaliplatin can be added to standard FU-based chemotherapy in the treatment of resectable locally advanced rectal cancer. Although there is an increase in the frequency and severity of toxicities with the addition of oxaliplatin, these toxicities did not affect the ability to perform surgery or the ability to deliver full doses of radiation therapy to these patients. Longer follow-up may determine differences in outcomes among these two groups of patients.
Panitumumab (Vectibix™) in MCRC
Panitumumab, the fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR), has demonstrated effectiveness in the treatment of patients with refractory MCRC in several clinical trials.8 Dr. Marc Peeters and colleagues presented “Efficacy and safety of panitumumab across five clinical studies in patients (pts) with metastatic colorectal cancer (MCRC).”9
In this analysis, data was evaluated from five Phase II and III clinical trials evaluating panitumumab as monotherapy in the treatment of MCRC among patients who failed prior oxaliplatin and/or irinotecan chemotherapy.10-14 The median age of patients ranged from 59 to 62 years.
Across all studies, the median duration of response and safety profile of panitumumab monotherapy remained consistent. Median duration of response was 13 to 18 weeks. Skin-related toxicity occurred in greater than 90% of patients; fatigue occurred in 24–51% of patients; hypomagnesemia (excluding the Malik study as magnesium was not collected)14 occurred in 32–46% of patients; anti-panitumumab antibodies were detected in less than 1% of patients; infusion reactions occurred in 1% of patients. These consistent results among heavily pretreated patients with MCRC demonstrated significant anti-tumor activity with panitumumab in this patient population.
Table 2: Data from 5 Phase II and III Clinical Trials |
Median Age, years | 59-62 |
Partial Response, % | 7-11 |
Stable Disease, % | 21-33 |
Progression-free Survival, Median weeks | 8-14 |
Treatment-related Adverse Events Leading to Discontinuation from Study, % | 1-7 |
Grade 3/4 Treatment-related Adverse Events, % | 12-25 |
Adapted from Peeters M, et al9 |
New Molecular Targets
Dr. Mace L. Rothenberg, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, gave a summary presentation entitled “New Molecular Targets in Colorectal Cancer.”15 Advances in metastastic colorectal cancer will require identification of other targets and pathways that contribute to colorectal cancer progression and metastasis. Inhibitors of several key molecules and pathways are currently being studied. Dr. Rothenberg’s presentation focused on three candidate proteins and pathways: Insulin-like Growth Factor-I Receptor (IGF-IR), Src, and Toll-Like Receptor 9 (TLR 9).
IGF-IR is a transmembrane tyrosine kinase and activation of the IGF-IR pathway results in increased cellular proliferation, malignant transformation, resistance to apoptosis, tissue invasion and metastasis, and angiogenesis.16 IGF-IR is overexpressed in colon cancer, but activation rather than overexpression may be the most important determinant of its pathogenic role in any given situation. There is substantial overlap in the signal transduction pathway for IGF-IR and epidermal growth factor receptor (EGFR), raising the possibility that activation of this pathway may be one way in which cells can escape EGFR inhibition. The first IGF-IR inhibitors to enter Phase I clinical testing have been monoclonal antibodies: CP-751,871, AMG 479, and IMC-A12.
Src is a non-receptor tyrosine kinase that is found on the intracellular portion of the cell membrane and was the first oncogene discovered. Src promotes angiogenesis, upregulates VEGF and interleukin (IL)-8 expression and increases vascular permeability.17 Src is overexpressed in more than 80% of human colorectal cancers. Src activity increases with cancer progression, with higher levels found in metastases than in primary tumors. Src inhibitors are currently in clinical development. Src inhibitors are unlikely to cause regression of solid tumors and more likely to influence tumor progression, invasion, and metastasis.
TLR 9 has a role in immune regulation in the gastrointestinal tract. TLR 9 may also have a role in modulating cell signaling, including signaling through the EGFR pathway. Clinical evaluation of TLR 9 agonists in cancer patients is already underway.
To successfully complete this CME activity, please read the additional 2 articles from the 2007 ASCO GI Symposium before you take the post test:
Anemia and Gastrointestinal Cancer: Updates from ASCO GI 2007
C. Dean Buckner, MD, Founding Member, Fred Hutchinson Cancer Research Center
ASCO GI 2007: Patient Communication and Expectations
Allyson Ocean, MD, Weill Medical College, Cornell University
References:
1 Saltz L, Clarke S, Diaz-Rubio E, et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: Efficacy results from XELOX-1/NO16966, a randomized Phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC). Proceedings of the American Society of Clinical Oncology Gastrointestinal Cancers Symposium. Orlando, FL. 2007. Abstract 238.
2 Hurwitz H, Fehrenbacher L, Novotnyet W, et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. N Eng J Med. 2004;350:2335-42.
3 Kabbinavar FF, Schulz J, McCleod M, et al. Addition of Bevacizumab to Bolus Fluorouracil and Leucovorin in First-Line Metastatic Colorectal Cancer: Results of a Randomized Phase II Trial. J Clin Oncol. 2005;23:3697-705.
4 Giantonio BJ, Catalano PJ, Meropol JJ, et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol. 2005;23(Suppl. 16S):1s(#2).
5 De Gramont A, Figer A, Seymour M, et al. Leucovorin and Fluorouracil With or Without Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer. J Clin Oncol. 2000;18:2938-47.
6 Van Cutsem E, Humblet Y, Gelderblom H, et al. Cetuximab dose-escalation study in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic and efficacy data of a randomized study. Proceedings of the American Society of Clinical Oncology Gastrointestinal Cancers Symposium. Orlando, FL 2007. Abstract 237.
7 Ashele C, Pinto C, Rosati G, et al. Pre-operative FU-based chemoradiation +/-weekly oxaliplatin in locally advanced rectal cancer. Preliminary safety findings of the STAR (Studio Terapia Adiuvante Retto)-01 randomized trial. Proceedings of the American Society of Clinical Oncology Gastrointestinal Cancers Symposium. Orlando, FL 2007. Abstract 233.
8 Peeters M, Van Cutsem E, Siena S, et al. A phase 3, multicenter, randomized controlled trial of panitumumab plus best supportive care (BSC) vs BSC alone in patients with metastatic colorectal cancer. Program and abstracts of the 97th Annual Meeting of the American Association for Cancer Research; April 1-5, 2006; Washington DC. Abstract CP-1.
9 Peeters M, Van Cutsem E, Hecht JR, et al. Efficacy and safety of panitumumab across five clinical studies in patients (pts) with metastatic colorectal cancer (mCRC). Proceedings of the American Society of Clinical Oncology Gastrointestinal Cancers Symposium. Orlando, FL. 2007. Abstract 336.
10 Van Cutsem E, Peeters M, Siena S, et al. Panitumumab significantly improves progressions-free survival in patients with metastatic colorectal cancer. Proceedings of the 8th World Congress on Gastrointestinal Cancer. Barcelona, Spain. 2006. Abstract O-027.
11 Van Cutsem E, Peeters M, Siena S, et al. A Phase III randomized controlled trial of panitumumab (Pmab) in patients (pts) with metastatic colorectal cancer (mCRC): Subset analyses in elderly pts and in pts with poor performance status. Proceedings of the 97th Annual Meeting of the American Association for Cancer Research. Abstract No. CP-1.
12 Berlin J, Neubauer M, Swanson P, et al. Panitumumab antitumor activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing > 10% epidermal growth factor receptor (EGFr). ASCO Annual Meeting Proceedings. J Clin Oncol. 2006;24. Abstract 3548.
13 Hecht J, Mitchell E, Baranda J, et al. Panitumumab antitumor activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing low (1-9%) or negative (<1%) levels of epidermal growth factor receptor (EGFr). ASCO Annual Meeting Proceedings. J Clin Oncol. 2006;24. Abstract 3547.
14 Malik I, Hecht JR, Patnaik A, et al. Safety and efficacy of panitumumab monotherapy in patients with metastatic colorectal cancer (mCRC). ASCO Annual Meeting Proceedings. J Clin Oncol. 2005;23. Abstract 3520.
15 Rothenberg ML. New Molecular Targets in Colorectal Cancer. Proceedings of the American Society of Clinical Oncology Gastrointestinal Cancers Symposium. Orlando, Fla. 2007.
16 Pollak, MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4:505-518.
17 Summy JM. Treatment for advanced tumors: SRC reclaims center stage. Clin Cancer Research. 2006, 12:1398-1401.
Patient Home
