SLIDES & TRANSCRIPTS
Tuesday, February 15, 2000

Present Status Therapy
Michael O'Connell, MD

DR. MAYER: Thank you very much, Stan. Let us move now to the last of these introductory talks, overview surveys which will be from Mike O'Connell, our Chair. Mike is a professor of oncology at the Mayo Clinic and is Chairman of the North Central Cancer Treatment Group.

DR. O'CONNELL: Thanks, Robert.

Before moving on with the talk or the overview of treatment of colorectal cancer, I would just like to take a moment to introduce several of the invited participants from across the Atlantic that I failed to introduce earlier this morning, Dr. Glimelius from Sweden, Dr. David Kerr from England, Dr. Van Cutsem from Belgium, Dr. Nordlinger from France, Dr. Piedbois from France, and Dr. Schmoll from Germany. We really appreciate all of you taking the time and from Pittsburgh, also -- Dr. Wolmark is from Pittsburgh B duly noted. We really appreciate having the international flavor here.

When I was talking earlier about collaborations we are thinking not only within the United States but also across the Atlantic.

What about the treatment of colorectal cancer? What I would like to do in just a few minutes is to give you my rendition of an overview of where we are at this point in time, what the state of the art is, if you will, with brief comments on staging, which you have already heard a lot about from Stan Hamilton, a few comments on surgery, radiation therapy, chemotherapy and immunotherapy.

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In my view anatomic staging, the TNM classification, the Dukes' classification is still the gold standard in the definition of prognosis and clinical decision making, and of course, it is the depth of invasion in the presence of regional lymph nodes that still has a major prognostic significance.

There are a number of approaches some of which Stan mentioned very eloquently regarding the molecular markers which I think hold great promise and perhaps 18q deletion microsatellite instability will become part of the paradigm for choosing patients for adjuvant therapy in the future. But there are other data sets, for example, the Mayo Clinic data set where 18q deletions did not correlate with survival but rather with AP deletions. So at this point I will be very interested in discussions after the first panel as to what we consider the state of the art and the future directions in the use of molecular markers for staging.

Certainly DNA flow cytometry has been studied. It is controversial. There are some studies which suggest that simple measurement of DNA content in tumor cells can help predict prognosis, but there are others which are negative. In our own practice we do utilize this in patients with Stage II disease to help define a high-risk subset.

The serum markers such as CEA, CA19-9 and other serum markers have been of limited value in staging colorectal cancer in making treatment decisions in the primary management based upon those markers, and there are a number of immunohistochemical markers such as the matrix metalloproteinase inhibitors, keratin, CEA and so on, done on tumor specimens and lymph node specimens that are currently under study. It is possible that one or more of these approaches will become part of the standard algorithm if you will for clinical management in the future, and it is certainly the direction that we think that research should go in improving the staging, improving the ability to accurately predict for a particular patient what the risk is and therefore help in clinical decision making.

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Regarding surgery, and with Dr. Wolmark here and others I speak with great trepidation, surgery is still the primary curative modality, and the principles that still apply at this point in time, number one, complete tumor resection, removal of the regional lymph nodes, negative margins, including not only proximal and distal but also the radial margins to be certain that there aren't microscopic foci of tumor left in the circumferential margin particularly of rectal cancers which may result in residual disease that can lead to tumor recurrence.

There are a number of issues that we will hear about in the panel discussion that is going to be led by Nick Petrelli. How can we identify more patients that would be appropriate for local surgical resection rather than radical procedures? This applies primarily to patients with rectal cancer where a subset of those patients can be cured with local excision. How can we identify these patients more accurately, and are there additional patients that could be treated with less radical surgery?

What about laparoscopic resection? The technique certainly has been perfected for resection of colorectal tumors and other colorectal pathology, but is laparoscopic surgery a proven adequate cancer operation at this point in time? From my point of view the answer is no, but there is a national study within the United States led by Dr. Heidi Nelson, who is here, which is addressing this particular issue.

What about mesorectal excision? Is this the standard of care? What is it? Is it new? Do we all understand it? Do we agree upon its importance, and we will hear from our surgical panel regarding their views on the current state of mesorectal resection as the standard of care for rectal cancer.

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In radiation therapy of colorectal cancer there is no question that radiation therapy can decrease local failure as a part of a multimodal approach in the management of primary rectal cancer, and there are studies now that suggest that radiation as a single modality when given in the adjuvant situation may improve survival.

There are a number of other studies, of course, of both pre- and postoperative radiation that have failed to show survival benefit. There is no question that radiation therapy can provide significant palliation of unresectable disease and the degree of pain relief and relief of other local symptoms can be substantial, and this is clearly a part of standard medical practice at the present time.

In colon cancer although there have been individual studies suggesting that certain stages of colon cancer, those with T4 lesions for example, that are adherent or invading adjacent structures with a high risk of local failure might benefit from the postoperative application of radiation therapy. However, a recent national trial performed in the community setting failed to document and improve the survival for these patients and in fact there was considerably more morbidity and toxicity. So at the present time in my view adjuvant radiation therapy has yet to be established as a part of adjuvant treatment following colon cancer resection.

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Other issues regarding radiation therapy, the technique. Certainly with megavoltage machines, multiple field techniques, other techniques to mobilize small bowel out of the field there have been major advances in perfecting the administration of external beam radiation therapy.

Is there a role for intraoperative radiation therapy and if so in what group of patients? I would submit there may be a subset of patients with high-risk rectal cancer with locally recurrent or locally advanced disease who may benefit from intraoperative radiation therapy to decrease local failure rate and possibly improve survival rates when used with external beam radiation therapy, surgical resection and chemotherapy, but that applies in my view to a very small population of patients.

What is the optimal sequence? Is there agreement on the optimal sequence of using radiation therapy when combined with surgery, and of course, the answer is no. There are proponents for pre-operative use of radiation therapy either alone or combined with chemotherapy, and there are many other proponents for postoperative use of these modalities.

How critical a question is this? How high a priority should we place on trying to answer this question in the context of a randomized trial, and both the NSABP and the other cooperative groups in this country have not been able to conduct randomized trials successfully with the appropriate number of patients to answer the scientific question in randomizing patients either pre- or postoperative treatment. There are two camps and some physicians in their particular practice prefer one approach. Others prefer a different approach. What should we use as the standard for future clinical trials?

Then there is the issue of radiation sensitizers and radiation protectors. Fluorouracil, particularly when given by continuous infusion is an effective sensitizer if you will that can increase the efficacy of radiation therapy in preventing local failure and improving outcome.

Are there new sensitizers on the horizon based upon molecular mechanisms or radioprotectors on the horizon that might allow radiation therapy to become even more effective in providing local control with decreasing the morbidity and side effects. Some are asking this heretical question in combined modality therapy for rectal cancer where chemotherapy and radiation are given together as surgical adjuvant treatment, is radiation therapy a necessary component of treatment?

From my point of view at this point in time for patients at high risk of local failure, the answer is yes. Local failure can clearly be decreased with the use of radiation as a part of the component of treatment, but as chemotherapy and other systemic therapies become more effective will colorectal cancer, rectal cancer follow the path of breast cancer, in that as systemic treatments become more effective there is more emphasis on the systemic therapies with a decreasing role for radiation therapy on a high-risk subset.

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Chemotherapy when given as an adjuvant to surgical resection can decrease systemic failures, and it can improve survival, particularly for patients with Stage III colon cancer. If one looks at the reduction in the failure rate there is a 40 percent approximately reduction in the failure rate following surgery with the use of chemotherapy, the current standard being six months of 5-FU and leukovorin given in one of several schedules. Likewise the death rate from colorectal cancer can be decreased by approximately 30 percent using available chemotherapy.

If one looks at the absolute impact, the absolute increase in 5-year survival with the use of adjuvant therapy in Stage III colon cancer that increase is approximately 10 to 15 percent.

Chemotherapy when given combined with radiation therapy can improve survival in patients with rectal cancer. The questions here are sequence, particular chemotherapy regimen, integration of new drugs into the adjuvant therapy situation and of course, chemotherapy can palliate some patients with advanced metastatic disease, 20 percent, 30 percent, 40 percent, depending upon individual studies and patient selection. And there have been studies documenting improvement in performance status, decrease in symptoms and improvement in measures of quality of life for patients receiving chemotherapy for advanced metastatic disease.

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The issues that are currently controversial in clinical practice, should adjuvant therapy, adjuvant chemotherapy be utilized for patients with Stage II colon cancer, and there are some that would advocate the use of chemotherapy for all patients with Stage II disease. There are others that would advocate it for high-risk Stage II patients and there are others that would not recommend chemotherapy for Stage II disease. Why the difference of opinion? In my view it is because any benefit is very small, and some studies show a small benefit in terms of outcome. Other studies do not. If there is a benefit it is small and when one weighs the benefit of adjuvant therapy against its potential toxicities and risks the risk/benefit ratio is relatively high, and therefore the difference of opinion with regard to utilization in clinical practice of chemotherapy for this stage of disease. Should we be spending our time and effort in further trying to dissect this question for Stage II patients?

Another interesting issue, and it is a great problem to have finally is the integration of new agents¾ for example, irinotecan (also known as CPT-11) or oxaliplatin¾ into the chemotherapy regimens for patients with metastatic disease. We now have at least three agents, different classes of drugs that have shown substantial activity, and there are studies ongoing at the present time to try to sort out which of these various combinations, fluorouracil, leukovorin, oxaliplatin, CPT-11 will be most effective in advanced disease and in the adjuvant situation.

In rectal cancer, I have already mentioned the possibility of studying the use of combination chemotherapy as a single modality to determine whether radiation will further enhance outcome as we develop more effective chemotherapy regimens. Are we ready for this type of clinical trial design in the future, and of course, the other interesting challenge and opportunity is the identification of novel therapeutic targets based upon the molecular changes that we have heard from Dr. Fearon and Dr. Hamilton, understanding the mechanism of the molecular genetic changes in the mechanisms of altered cell function open up a vast opportunity for identifying novel targets in the future, and Chuck Erlichman and his group will be discussing that further.

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At the present time, in my view, immunotherapy has not been established to be an effective modality in the treatment of colon cancer. There certainly are preliminary studies that suggest that there may be a role for immunotherapeutic management of this disease.

For example, monoclonal antibody 17-1A has been studied in a European trial in patients following surgical resection as a postoperative adjuvant where outcome was improved in patients randomly assigned to receive monoclonal antibody 17-1A, and there is a confirmatory intergroup trial ongoing now in the United States to try to verify, substantiate and quantify any potential benefit.

There is a great interest in tumor vaccines, for example, the use of autologous cells and BCG has been reported in the Lancet as having a positive effect, particularly in patients with Stage II disease, a relatively small trial that needs to be confirmed. Certainly there is a biologic basis for the study of immune directed therapies in colorectal cancer as an area ripe for further research, but at the present time in my view the state of the art is that none of these approaches is established as standard treatment in clinical practice.

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Can we identify additional tumor-specific antigens? Can we increase the expression of those antigens on the surface of the cells? We need further understanding of the human immune system which is exceedingly complex but where there have been real advances in recent years in dissecting out the various parameters of the host-immune interaction with tumors.

Will there be a role for cellular therapy in this disease? For example, dendritic cells taken from patients and exposed to antigens ex vivo and turned down, if you will, and fused back into patients can produce regressions in certain other tumors including prostate cancer. Will there be some type of manipulation, analogous manipulation with different antigens for cellular treatment, particularly in the adjuvant situation for patients with colorectal cancer, and as immune treatments become more effective in the future how can we optimally combine immunotherapy with other conventional treatment surgery, radiation therapy and chemotherapy?

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In summary I believe that there really have been substantial recent improvements in the management of colorectal cancer. Less radical surgery has been shown to be effective, curative for selected cases, has resulted in fewer colostomies for patients with rectal cancer. Surgical adjuvant therapy that is effective to some extent has been identified both for colon cancer and rectal cancer, and there are now palliative treatments with a variety of different chemotherapeutic agents that have been shown to be of value in patients with advanced disease although it is very questionable if this treatment in advanced disease has resulted in any improvement in survival.If so, it is very small and not clearly documented.

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In spite of those advances there still is much yet to be done. Too many patients still die in spite of the more effective surgical techniques and adjuvant therapy, and in patients where the optimal regional treatment is utilized, that is the optimal imaging studies, staging studies, optimal surgical technique and radiation therapy in patients managed with these techniques that we already understand if we apply what we know to the patient in that setting, then the major failure of treatment is not local control. It is metastatic disease emphasizing the importance of developing systemic adjuvants for the treatment of both rectal cancer and colon cancer in order to achieve an ultimate victory over this disease.

In spite of the local surgical procedures which are available there still are too many colostomies done. There is too much surgical morbidity associated with colorectal surgery, and it is not to denigrate the advances in surgical technique. The anorectal anastomoses, the local excisions, have definitely improved outcome and quality of life, but can we do better?

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I think that in terms of treatment of colorectal cancer that the future really does look bright based upon a better understanding of this disease at the molecular level as discussed by Eric Fearon and Stan Hamilton earlier, understanding the cellular mechanisms resulting from those molecular genetic changes and then intervening selectively and specifically on the specific pathways rather than using empirical cytotoxic treatment, which has been the best approach that we have had in the past. I believe that a better understanding of both host immunity and tumor-specific antigens will also lead to potential better treatments for this disease.

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There are a variety of novel targets that are now on our radar screen as a result of this improved understanding of the disease which should result in greater efficacy, less morbidity and toxicity. Hopefully with the predictive markers based upon that biological understanding we will be able to better individualize therapy, again, so that we are approaching each patient as an individual and with selective individualized therapy rather than using a general treatment across the board for all patients with a particular stage of disease.

Thank you very much, and we are certainly looking forward to the rest of the discussion later today.

(Applause.)

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