Alice Wilson's daughter finally convinced her mother to make an appointment with the family physician 2 weeks after Alice's 65th birthday. Alice organized a garden party to celebrate, and it was a great success with all 5 children, 14 grandchildren, and most of her neighbors in attendance. Alice attributed her 20-pound weight loss and fatigue to the preparations for the party. She didn't tell anyone about the pain in her stomach that had been keeping her awake off-and-on for 6 months. It was only after the party—when she could no longer explain her fatigue—that Alice reluctantly agreed to see her physician.
Instead of a garden party, Alice spent her 66th birthday in the hospital recovering from her second surgery, this time to remove 3 suspicious lymph nodes and intra-abdominal metastases seeded from the advanced adenocarcinoma removed from her colon the previous summer. Since the first surgery, one of her children or her husband Will have been driving Alice for her weekly rounds of chemotherapy with Dr. Tseng, her oncologist. Almost a year later, he knows the names of all 5 children and most of the grandchildren, including the 2-week-old granddaughter named Alice .
Alice resumed her chemotherapy 3 weeks after the second surgery. At every visit she asks Dr. Tseng the same question: "What are my numbers, Doctor?" she wants to know. Immediately following the surgery Alice 's CEA levels dropped, and for a few weeks she would joke with the nurses who started her IV. "Careful with that," she would say, smiling, as one of them slipped a needle into the vein behind her elbow. Several months later the jokes stopped as her CEA values began to creep up again, gradually at first and then faster and faster.
At a special appointment between rounds of chemotherapy, Dr. Tseng tells Alice that the surgery and chemotherapy are slowing down the cancer growth, but they haven't been able to stop it. Alice doesn't say anything. She is tired all the time, she doesn't want to eat, the pain in her stomach still keeps her awake at night, and she has lost an additional 25 pounds. She has not yet been able to take baby Alice for a walk because she is too tired to push the stroller more than a few blocks. Dr. Tseng hesitates. Should he tell Alice about Zorvax, a new angiogenesis inhibitor in Phase II clinical trials? Clinically, Alice would be an ideal patient to enroll in the trial, and the latest publications about Zorvax indicate that many patients respond favorably. "There is something else we can try," he tells her, as he explains about the experimental medication. "This drug works in a different way than your current chemotherapy," he says. "It might be able to help slow down the cancer and give you more energy." Alice pauses for a moment. "I don't know," she says at last. "I don't know how much more chemotherapy I want to do. Will I still be so tired all of the time? I just don't know. What do you think I should do?"
AW's clinical situation, unfortunately, is still commonplace in the management of stage IV colorectal cancer. There are approximately 146,900 new cases of colorectal cancer each year in the United States and approximately two-thirds of these patients present with regional or distant disease . Obviously, for both AW and the US population, this situation represents a sad public health failure, in that colorectal cancer is a preventable disease.
AW has undergone primary surgery, followed by adjuvant chemotherapy and secondary surgery, as a result of recurrent disease, which appears to be progressing intra-abdominally on the basis of a rapidly rising serum CEA. She has lost at least 20 to 25 percent of her body weight, has become weak, experiences moderately severe abdominal pain, and clearly has had a major reduction in her clinically determined performance status. Her medical oncologist has developed a close relationship with AW and her family and is being asked critically important questions related to end-of-life care.
There are several important issues to discuss concerning the current and future management of the more than 56,000 patients who will die from colorectal cancer each year. First, let us examine the role for secondary or tertiary chemotherapy of progressive, recurrent, metastatic colorectal cancer. Recently, 2 molecularly targeted agents, bevacizumab (VEGF inhibitor) and cetuximab (EGFR inhibitor) and 1 new cytotoxic agent, oxaliplatin, have been approved by the FDA to treat newly diagnosed or recurrent metastatic disease [2-4]. Responses to these agents either as first- or second-line single agents or in combination with 5-fluorouracil plus leucovorin or irinotecan are in the range of 10 to 50 percent with survival prolongation of perhaps 2 to 4 months. However, the population of patients treated in the phase III clinical trials establishing the activity of these 3 new drugs likely all had a better performance status than does AW. This is important, because response rates and survival durations are highly correlated with performance status. AW's weight loss and severe weakness generally translate to a poor performance status category (ie, performance status grade 2/3 on the Southwest Oncology Group scale) . In fact, such an excessive weight loss (ie, 45 lbs) is associated with negative nitrogen balance and significantly compromised immune function, all of which predict lack of response to either cytotoxic or molecularly targeted agents. Most early phase clinical trials of new cytotoxic or biologic drugs require a patient performance status of at least 2 (ie, moderately symptomatic, but not requiring physical assistance) and, commonly, 0-1 (ie, either a totally asymptomatic patient or one whose symptomatology does not impair function). Thus, it is unlikely that AW would qualify for a clinical trial of the new agent, Zorvax, as discussed in the case report.
Does this mean that there is no treatment or hope for AW? The answer is a resounding "no." There is treatment for this very deserving woman who wants to spend quality time with her family at this point in her disease process. Any board-certified medical oncologist should have received training in end-of-life management that included knowledge of therapeutic modalities for pain management, prevention of nausea and emesis, anorexia control, and management of severe constipation. Modern therapeutics requires intensive intervention in the end-of-life situation, and no form of cytotoxic agent or biological therapy can be successful without adequate supportive care. Finally, considerable effort is being directed toward understanding the cachexia syndrome, clearly affecting the quality of AW's life . With the identification of cachetic factors, it will be possible to develop a rational approach to therapeutics for this devastating condition.
Should Dr. Tseng put AW on a clinical trial, if she qualifies for enrollment? Obviously, the most important person to answer that question is AW. Given direct and honest answers to her questions, it is highly likely that AW would choose best supportive care for her end-of-life management. All too often, the medical oncologist replaces excellent supportive care with a cytotoxic or biologic agent that may have virtually no chance for producing tumor response or improved quality of life. The choice to pursue further drug therapy also replaces vitally important, direct and honest patient-physician communication. Unfortunately, this critically important aspect of clinical oncology is still inadequate in our post-doctoral fellowship training programs.
- Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004;54(1):8-29.
- Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342.
Cunningham D, Humblet Y,Siena S, et al. A randomized comparison of cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337-345.
- Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, 5-fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;30(8):711-713.
- Argiles J, Moore-Carrasco R, Busquets S, et al. Catabolic mediators as targets for cancer cachexia. Drug Disc Today. 2003;8(18):838-844.