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Articles/Books/Teleconferences

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Article

10/19/07 – Sequential and Combination Chemotherapy for Advanced Colorectal Cancer

After forty years of 5-FU for the treatment of advanced or metastatic colorectal cancer (mCRC), clinicians have been excited to offer 6 new therapies. These therapies can be given in various combinations, and are delineated in the National Comprehensive Cancer Network (NCCN) 2007 treatment guidelines for CRC.1 However, clinicians may be confused which therapy is best for an individual at a certain point in time, given the various options in first, second or third line settings. Researchers have attempted to answer this important question to increase overall survival (OS) time of the patient with mCRC.

An important paper by Tournigand2 examined the question of whether FOLFIRI followed by FOLFOX or the reverse (FOLFOX followed by FOLFIRI) is superior in the treatment of patients with mCRC. The results essentially showed that both regimens were equal in OS of more than 20 months, giving clinicians the option of choosing either therapy as a starting regimen. These options are choices outlined in the NCCN 2007 guidelines. However, capecitabine is also a potential choice and the optimal timing for each regimen in the overall treatment plan for mCRC patients has not yet been established.

This problem was further studied in two trials recently published in The Lancet. In the CApecitabine, IRinotecan and Oxaliplatin (CAIRO) trial, sequential versus combination chemotherapy of the same drugs was given to patients with advanced CRC.3 820 patients were randomized in a phase III trial.

  • First-line treatment capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin (sequential)
  • First-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (combination)

The primary end point for the study was OS. Median OS for the patients receiving sequential therapy was 16.3 months versus 17.4 months for combination treatment, with similar frequency of grade 3-4 toxicity. Grade 3 hand-foot syndrome was seen more frequently in sequential therapy than combination. The researchers concluded that the use of combination treatment does not significantly improve the OS as compared to sequential therapy.3

The second trial Fluorouracil, Oxaliplatin, and CPT11 (irinotecan-Use and Sequencing) (FOCUS) examined different strategies of both sequential and combination chemotherapy with mCRC patients who had poor prognoses in a large trial of 2,135 patients.4 The patients were randomized to receive three different strategies:

  • Strategy A (control group) received single-agent 5-FU as continuous infusion with levofolinate until failure, then placed on single-agent irinotecan
  • Strategy B received continuous infusion 5-FU until failure, then combination chemotherapy with either
    • B-ir (irinotecan 350 mg/m2 or FOLFIRI) or
    • B-ox (FOLFOX)
  • Strategy C received combination therapy with either
    • FOLFIRI
    • FOLFOX as first-line therapy

Although all the regimens were considered well tolerated and safe

  • Neutropenia and neuropathy were the main toxicities of the oxaliplatin patients
  • Diarrhea and alopecia more common with single-agent irinotecan and equivalent for the FOLFIRI and FOLFOX regimens.

The OS for all 4 groups in strategies B and C was longer than strategy A (the control group); with irinotecan in the first-line combination treatment significantly better. When irinotecan was compared to oxaliplatin, either in first-line combination, second-line combination, or any other time, there was no significant difference noted.

  • The OS for strategy A patients was 13.9 months, versus strategy B at 15 months (FOLFIRI) and 15.2 months (FOLFOX)
  • Patients who received combination therapy upfront had an OS of 16.7 months (FOLFIRI) versus 15.4 months with FOLFOX

The researchers concluded that the maximum tolerated treatment used in the first-line setting is no worse than the staged approach of initial single-agent treatment and can be an option for patients when starting therapy. There are clinicians who challenge this assumption, particularly since OS in some studies show patients receiving initial combination therapy approaching 20 or more months.

Grothey and colleagues5,6 have shown that patient survival correlates with the number of drugs received, and the availability of 5-FU, irinotecan and oxaliplatin improves survival whether doublet or single-agent therapy is used first line. Goldberg et al7 also points out the need to offer available therapies with an awareness of the toxicity profile of the agents to minimize side effects and improve quality of life. The question of determining the most favorable course and sequence of therapy for patients with mCRC or advanced CRC has not yet been answered, but these trials continue to add valuable information to the search for optimal therapy.

References

  1. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: colon cancer, v2.2007. Available at: http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed August 29, 2007.
  2. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol. 2004;22:229-237
  3. Koopman M, Antonini NF, Douma J, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomized controlled trial. Lancet. 2007;370:135-142.
  4. Seymour M, Maughan TS, Ledermann JA, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomized controlled trial. Lancet. 2007;370:143-152.
  5. Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol. 2005;23:9441-9442.
  6. Grothey A, Sargent D, Goldberg RM, et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol. 2004;22:1209-1214.
  7. Goldberg RM, Rothenberg ML, Van Cutsem E, et al. The continuum of care: a paradigm for the management of metastatic colorectal cancer. Oncologist. 2007;12:38-50.

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9-28-07- Series of 3 articles on EGFR Toxicities in CRC

The July-August 2007 supplement to Cancer Nursing is focused on epidermal growth factor receptors (EGFRs) in colorectal carcinoma. Included in the issue is an overview article by Sandra Kurtin RN, MS, AOCN, ANP-C detailing the current state of knowledge in the use of EGFRs in CRC. Ocular and dermatologic toxicities are addressed by Dr Surendra Basti and Dr Mario Lacouture, respectively. A link to the abstracts and full text articles (by subscription) can be found here

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Articles

8-15-07- Endpoints in Adjuvant Treatment Trials: A Systematic Review of the Literature in Colon Cancer and Proposed Definitions for Future Trials

This recent article by Punt and colleagues confirms the importance of disease-free survival (DFS) as the primary end point for adjuvant treatment trials in cancer therapy.1 The authors point out that historically, overall survival (OS) has been the primary end point for such trials.1 However, data from the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) study showed a statistically significant improvement in DFS in patients receiving FOLFOX (leucovorin, fluorouracil [5-FU], and oxaliplatin) compared with the then-standard adjuvant therapy for CRC (5-FU and leucovorin). These results led to the approval of oxaliplatin in the treatment of CRC even though the OS showed no statistical difference.1 The MOSAIC trial data, showing an end point of 3-year DFS, therefore challenged the OS endpoint and generated some controversy among clincicans.2 Other trials have shown similar results, with benefits in DFS and no obvious improvement in OS.1

  • OS is considered to be the period from trial randomization to death from any cause
  • DFS is usually defined as the time from trial randomization to disease relapse or death, which typically is observed over 5 years or longer3

Because most colon cancer relapses occur in the first 3 years after surgery, some believe that 3-year DFS is a valid end point for efficacy and a way of allowing clinical study results to be reported more rapidly, to be absorbed into clinical practice, and to benefit patients more quickly.3 A meta-analysis of 15 previous trials studying adjuvant therapy in more than 12,000 patients confirmed that the 3-year survival rate does serve as an accurate predictor of 5-year OS.4 A slightly larger analysis of 18 trials, published in the Journal of Clinical Oncology, confirms the value of the DFS end point after 3 years of median follow-up.5 Therefore, the Food and Drug Administration (FDA) Oncologic Drug Advisory (ODA) Committee accepted the 3-year DFS as the new end point for the approval of adjuvant therapies in colon cancer.6

The article by Punt and colleagues discusses a much larger meta-analysis of 52 phase 3 studies of adjuvant therapy in colon cancer, published between 1997 and 2006.1 Eight other end points were used to define survival in these trials; the end points and time measurement intervals varied significantly.1 These surrogate end points included relapse-free survival, disease-free intervals and time to recurrence, as well as differing definitions for the same end points. The discrepancies in definitions make it difficult to compare results among studies and point to the need for more uniformity—in definitions and use of end points—for studies in adjuvant cancer care.1

On the basis of this large meta-analysis, a panel reached consensus as to end point definitions in CRC studies as well as the appropriate contribution of various events (locoregional recurrence, distant metastases, etc.) to those definitions.1 With 6 end points fully defined, the panel concluded that DFS is the most appropriate primary end point for future trials of adjuvant therapy for colon or any other type of cancer1 because DFS

  • Includes all clinically relevant events
  • Is less likely to be biased
  • Is observed earlier than OS
  • Should be statistically sensitive to real treatment benefits1

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References

  1. Punt CJA, Buyse M, Kohne CH, et al. Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials. J Natl Cancer Inst. 2007;99:998-1003. The full text free article is available at: http://jnci.oxfordjournals.org/cgi/reprint/99/13/998
  2. Grem J. Adjuvant therapy for colon cancer: a historical perspective. J Natl Cancer Inst. 2004;96:1116-1117
  3. Andre T, de Gramont A. An overview of adjuvant systemic chemotherapy for colon cancer. Clin Colorectal Cancer. 2004;4(suppl 1):S22-S28.
  4. Sargent DJ, Wieand S, Benedetti J, et al. Disease-free survival (DFS) vs. overall survival (OS) as a primary endpoint for adjuvant colon cancer studies: individual patient data from 12,915 patients on 15 randomized trials. Proc Am Soc Clin Oncol. 2004;23:246. Abstract 3502.
  5. Sargent DJ, Wieand HS, Haller DG, et al. Disease-free survival versus overall survival as a primary end point for adjuvant cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2005;23:8664-8670.
  6. Goetz MP, Grothey A. Developments in combination chemotherapy for colorectal cancer. Expert Rev Anticancer Ther. 2004;4:627-637.

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Articles

4-18-07- Oral Glutamine: Preventing Oxaliplatin-Induced Neuropathy in CRC Patients

Neurotoxicity, a significant side effect of oxaliplatin therapy, is a reason for dose reduction or even therapy cessation. Results of a pilot study published in the March issue of The Oncologist suggests that oral glutamine was effective in reducing the incidence and severity of peripheral neuropathy for patients with metastatic CRC.

Wei-Shu Wang and colleagues from the Taipei Veterans General Hospital in the Republic of China reported on 86 patients randomized in a non–placebo-controlled study. The glutamine group (n = 42) received 15 grams orally twice a day for 7 consecutive days every 2 weeks, starting on the day of oxaliplatin infusion.

Findings

  • No significant differences were seen in the percentage of grade 3-4 nonneurologic toxicities
  • Differences were seen in the incidence of neurotoxicity: between the glutamine group and control group:
    • After 2 cycles, grade 1-2 neuropathy was 16.7% (glutamine) versus 38.6% (control)
    • After 4 cycles, grade 3-4 neuropathy was 4.8% versus 18.2%
    • After 6 cycles grade 3-4 neuropathy was 11.9% versus 31.8%
  • Glutamine was also successful in reducing the incidence of transient (cold-induced) peripheral nerve hyperexcitability that can occur with administration of oxaliplatin (33.3% vs 56.8%)
  • Glutamine-treated patients had
    • Less interference with activities of daily living (16.7% vs 40.9%)
    • Less need for oxaliplatin dose reduction (7.1% vs 27.3%)
    • No between-group differences in response to chemotherapy (52.4% vs 47.8%) or in the median survival time (17.3 months vs 18.6 months)

Mechanisms of Action

Although the true mechanism of action for oxaliplatin-induced neuropathy is not yet established, it may be an alteration of the properties of voltage-gated sodium channels or a slowing of the clearance of platinum compounds from the peripheral nervous system, causing drug accumulation.

Other treatments for reducing oxaliplatin-related neurotoxicity:

  • Calcium and magnesium infusions (may reduce incidence and intensity)
  • Xaliproden, a neurotrophic agent not yet FDA approved, has been studied in this setting, showing efficacy in the reduction of grade 3-4 peripheral sensory neurotoxicity

Glutamine is a:

  • Gluconeogenic nonessential amino acid that serves as the primary carrier of nitrogen
  • Main energy source for cells that proliferate quickly
  • Protector against doxorubicin-induced cardiac toxicity
  • Preventative to peripheral neuropathy related to administration of vincristine, cisplatin, or paclitaxel
  • Neuroprotector, possibly by upregulation, of circulating nerve growth factor, which has a role in chemotherapy-related neurotoxicity

Conclusion

The authors suggest that larger, placebo-controlled studies are needed to confirm the benefit of glutamine in this setting. Oral glutamine adds approximately $150 per month in treatment costs. Glutamine may also have additional benefits in reduction of other side effects, and continued study is needed.

Wang WS, Lin JK, Lin TC, et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in CRC patients. Oncologist. 2007;12:312-319.

The full-text article is available free of charge at http://theoncologist.alphamedpress.org/cgi/reprint/12/3/312

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Articles

2-28-07- New Resource: Evidence-Based Interventions for Fatigue and Chemotherapy-Induced Nausea and Vomiting (CINV)

Mitchell et al., reports on evidence-based interventions for fatigue during and after cancer and cancer treatment in the February, 2007 issue of Clinical Journal of Oncology Nursing,. Cancer-related fatigue continues to be under-reported and under treated, yet it significantly impacts patients' physical functioning and quality of life.

Mitchell SA, Beck SL, Hood LE, et al. Putting evidence into practice: evidence-based interventions for fatigue during and following cancer and its treatment. Clin J Oncol Nurs. 2007;11:99-113.

In the same issue Tipton and colleagues review and summarize empirical evidence of past and current interventions related to CINV, described as one of the most distressing side effects of chemotherapy. Despite advances in antiemetic therapy CINV continues to challenge the physical and psychological well-being of patients with cancer. Tipton JM, McDaniel RW, Barbour L, et al. Putting evidence into practice: evidence-based interventions to prevent, manage, and treat chemotherapy-induced nausea and vomiting. Clin J Oncol Nurs. 2007;11:69-78.

To access the full-text articles:
Click here for the ONS Web site: http://www.ons.org/
Click here http://www.ons.org/publications/
Click http://www.ons.org/publications/journals/CJON/index.shtml
Click here under Latest Issue of CJON.

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Book

Gastrointestinal Cancers

The Oncology Nursing Society has released a new text Gastrointestinal Cancers with Joyce P. Griffin-Sobel, as the editor. Chapters in this new volume include: an overview of GI cancers; anatomy and physiology of the GI tract, biology; prevention and screening; esophageal and gastric cancers; colorectal and anal cancers; nursing care of patients with GI cancers, symptom management and evidence-based practice. Information is available at http://esource.ons.org/ProductDetails.aspx?sku=INPU0566

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Article

The Oncologist: The continuum of care: A paradigm for the management of metastatic colorectal cancer

The January 2007 issue of The Oncologist contains a CME article by Goldberg et al, entitled “The continuum of care: A paradigm for the management of metastatic colorectal cancer.” The authors propose a shift in treatment strategy from the traditional - changing treatment regimen only at disease progression - to planned shifts in chemotherapy prior to progression, utilization of maintenance therapy and drug holidays, and surgical resection of metastases in selected patients. This affords mCRC patients the benefit of exposure to all active agents and modalities while minimizing unnecessary treatment and toxicity. The goals of this new paradigm in treatment are improved quality of life and improved survival. (Goldberg et al. The continuum of care: A paradigm for the management of metastatic colorectal cancer. Oncologist 2007;12:38-50. Link to full-text article available at: http://theoncologist.alphamedpress.org/cgi/reprint/12/1/38.

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Article

Hospice and Palliative Care

The Journal of Hospice and Palliative Care, official journal of the American Academy of Hospice and Palliative Medicine, has made the entire December 2006 issue available full text without charge. The table of contents and links to full text articles can be found at http://www.liebertonline.com/toc/jpm/9/6

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Article

A supplement to the November 2006 Seminars in Oncology Nursing features articles on CRC. The link to the supplement is http://www.seminarsoncologynursing.com/issues/contents. Full-text articles are available to subscribers only. Note: Two members of the Expert Panel for this Web site, manageCRC.com, contributed to the supplement.

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Article

Colorectal cancer is the feature of the October issue of The Oncologist

Topics range from adjuvant treatment, metastatic therapy, angiogenesis-directed treatments, nonsurgical approaches, genomics and their role in new technologies, challenges using EGFR and treating older patients with Stage III disease.

Articles are available without registration and free of charge here.

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Teleconference

Redefining the Paradigm of Cancer Care

This audio (25 minutes) or print option highlights issues on colon cancer from
the 2006 ASCO meeting. The format is a “Meet the Expert” interview. Issues discussed
are treatment of stage 2 colon cancer, chemotherapy in metastatic disease, side effects
and targeted therapies. Each issue is recorded separately.

Click here for the teleconference.

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Article

Diagnostic Approach and Management of Lynch Syndrome
(Hereditary Nonpolyposis Colorectal Carcinoma): A Guide for Clinicians.
Hendriks Y, deJong A, Morreau H, et al. CA Cancer J Clin 2006;56:213-225.

Click here for the article.

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Article

Oral Calcium Ameliorating Oxaliplatin-Induced Peripheral Neuropathy

Muhammad Wasif Saif, MD
University of Alabama at Birmingham, Birmingham, Alabama
Currently, Associate Professor of Medicine,
Section of Medical Oncology,
Yale New Haven School of Medicine,
New Haven, CT

Click here to view article.

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2006 ASCO Annual Meeting Abstracts Colorectal Cancer (including liver metastases)

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