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Popescu RA, Norman A, Ross PJ, et al.
J Clin Oncol. 1999;17:2412-2418.
The surgical treatment of colorectal cancer in elderly patients (aged 70 years or older) has improved, but data on adjuvant and palliative chemotherapy tolerability and benefits in this growing population remain scarce. Elderly patients are underrepresented in clinical trials, and results for older patients are seldom reported separately.
Using a prospective database, we analyzed demographics, chemotherapy toxicity, response rates, failure-free survival (FFS), and overall survival (OS) of colorectal cancer patients receiving chemotherapy at the Royal Marsden Hospital. We also sought to identify elderly patients, defined as aged 70 years or older, among this group.
Of the total 1387 patients reviewed, 844 patients received first-line chemotherapy with various fluorouracil (5-FU)-containing regimens or raltitrexed for advanced disease, and 543 patients were administered adjuvant, protracted venous infusion 5-FU or bolus 5-FU/folinic acid (FA) chemotherapy. Of the total study population, 310 patients were 70 years or older. There was no difference in overall or severe (Common Toxicity Criteria III to IV) toxicity between the 2 age groups, with the exception of more frequent severe mucositis in older patients receiving adjuvant bolus 5-FU/FA. For patients receiving palliative chemotherapy, no difference in response rates (24% vs 29%, P = .19) and median FFS (164 vs 168 days) were detected when the older patients were compared with younger patients.
Median OS was 292 days for the older group and 350 days for the younger patients (P = .04), and 1-year survival was 44% and 48%, respectively. The length of inpatient hospital stay was identical.
Older patients with good performance status tolerated adjuvant and palliative chemotherapy for colorectal cancer as well as the younger patients and gained similar benefits from palliative chemotherapy.
Study Suggests Little Difference in Response to Adjuvant Colorectal Cancer Therapy Among Those Younger and Older Than 70 Years; but Is Therapeutic Method the Key?
Editorial Comment by Emily K. Bergsland, MD
Keywords:
Colorectal cancer
Chemotherapy; adjuvant, palliative
Colorectal cancer is the second most common cause of cancer death in the United States and Western Europe, and its incidence sharply increases with age. As the size of the geriatric population grows, an increasing number of elderly patients (aged 70 years and older) are presenting with this disease, yet the optimal management of colorectal cancer in this population remains controversial. Published studies on chemotherapy for colorectal cancer in the elderly have largely focused on the palliative setting and have generated conflicting results. Furthermore, there is not much data on the toxicity and benefits of adjuvant and palliative chemotherapy in this growing population, largely because elderly patients are underrepresented in clinical trials and the results for older patients are seldom reported separately. Thus, physicians are reluctant to treat elderly patients with cytotoxic therapy because of the perceived higher toxicity in this group. Patients older than 70 years are half as likely to receive adjuvant treatment after surgery for colorectal cancer as patients who are younger than 60 years; those 80 years and older are one sixth as likely.
Popescu et al analyzed the toxicity and response to chemotherapy in patients with colorectal cancer treated at the Royal Marsden Hospital in London over an 8-year period. Five hundred forty-three patients received adjuvant therapy (124 were older than 70 years, 43 were at least 75 years, and 3 were older than 80 years). Nearly half of the patients received 5-FU by protracted venous infusion. No significant differences in overall or severe toxicity were seen between younger patients and those older than 70 years, except for stomatitis, which was worse in the elderly receiving bolus 5-FU. The survival data in this population has not yet matured.
Eight hundred forty-four patients received palliative chemotherapy with a variety of 5-FU-containing regimens for advanced disease (186 were older than 70 years, 74 were at least 75 years old, and 14 were older than 80 years). There was no difference in the length of hospital stay or overall toxicity between patients older than 70 years and those who were younger than 70 years. In addition, the response rate and median failure-free survival were similar in both groups. The median overall survival was only slightly lower in elderly patients.
The results of this study suggest that elderly patients with good performance status tolerate adjuvant and palliative chemotherapy for colorectal cancer just as well as young patients. Furthermore, while the data regarding adjuvant therapy have not yet matured, elderly patients experienced similar benefits from palliative chemotherapy compared with younger patients. While encouraging, it is important to point out that nearly half of the patients receiving adjuvant therapy and two thirds of the patients treated with palliative therapy received 5-FU by protracted venous infusion. Since this method is not commonly used in the United States, caution should be taken in extrapolating these data for use in clinical practice. The toxicity of 5-FU is known to be schedule-dependent. The administration of 5-FU by protracted venous infusion, although traditionally perceived as less convenient, may be associated with similar efficacy and lower toxicity than bolus 5-FU, except for palmar-plantar erythrodysesthesia. The question is whether similar results would have been obtained had all patients received 5-FU by bolus infusion. Another feature of this study with important implications is that elderly patients with a poor performance status were generally not treated.
As with other published studies, the absolute number of older patients included in the study was relatively small and essentially limited to patients between the ages of 70 and 80 years. However, these results suggest that elderly patients should not be automatically excluded from treatment with either adjuvant or palliative chemotherapy simply because of age. The decision to treat is complicated and should integrate assessments of organ function, comorbid illness, functional status, and the goals of therapy. The routine reporting of results stratified by age coupled with an expanded effort to enroll elderly patients in clinical trials are needed to facilitate our understanding of the relative risks and benefits of chemotherapy in this growing population.
Jessup JM, McGinnis LS, Steele GD Jr, et al. The National Cancer Data Base: report on colon cancer. Cancer. 1996;78:918-926.
Popescu RA, Norman A, Ross PJ, et al. Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older. J Clin Oncol. 1999;17:2412-2418.
Douillard JY, Cunningham D, Roth AD, et al.
Lancet. 2000;355:1041-1047.
Irinotecan is active against colorectal cancer in patients whose disease is refractory to fluorouracil. We investigated the efficacy of combination therapy with these 2 agents as first-line treatment for metastatic colorectal cancer.
A total of 387 patients who had not previously received chemotherapy (other than adjuvant) for advanced colorectal cancer were randomly assigned open-label irinotecan plus fluorouracil and calcium folinate (irinotecan group, n = 199) or fluorouracil and calcium folinate alone (no-irinotecan group, n = 188). Infusion was administered either once weekly or every 2 weeks, and the schedules were chosen by each participating center. We assessed response rates and time to progression, as well as response duration, survival, and quality of life. Analyses were done on the intention-to-treat population and on patients meeting evaluation criteria.
The response rate was significantly higher for patients in the irinotecan group compared with those in the no-irinotecan group (49% vs 31%, P < .001 for patients meeting evaluation crieteria, 35% vs 22%, P < .005 by intention to treat). Time to progression was significantly longer in the irinotecan group compared with the no-irinotecan group (median 6.7 months vs 4.4 months, P < .001), and overall survival was higher (median 17.4 months vs 14.1 months, P = .031). Some grade 3 and 4 toxic effects were significantly more frequent in the irinotecan group than in the no-irinotecan group, but those effects were predictible, reversible, noncumulative, and manageable.
Irinotecan combined with fluorouracil and calcium folinate was well-tolerated and increased response rate, time to progression, and survival. The combination also appeared to slow mechanisms related to deterioration in quality of life. This combination should be considered as a first-line treatment for metastatic colorectal cancer.
Salonga D, Danenberg KD, Johnson M, et al.
Clin Cancer Res. 2000;6:1322-1327.
Previously, in Leichman et al (J Clin Oncol.1997;15:3223-3229) and Metzger et al (Clin Cancer Res.1998;4:2371-2376), we demonstrated that high gene expressions (messenger RNA levels) of thymidylate synthase (TS) and thymidine phosphorylase (TP) in pretreatment tumor biopsies could identify tumors nonresponsive to 5-fluorouracil (5-FU)-based therapy.
In this study, we investigated the association between intratumoral gene expression of the pyrimidine catabolism enzyme dihydropyrimidine dehydrogenase (DPD) and the response of colorectal tumors to the same 5-FU-based protocol. DPD expressions were measured by quantitative reverse transcription-PCR in 33 pretreatment biopsies of colorectal tumors from patients who went on to receive treatment with 5-FU and leucovorin (LV).
The range of DPD gene expression in tumors that were nonresponsive to 5-FU was much broader than that of the responding tumors. None of the tumors with basal-level DPD expressions above a DPD:beta-actin ratio of 2.5 3 10 (14 of 33) were responders to 5-FU/LV therapy, whereas those tumors with DPD gene expressions below DPD:beta-actin ratio of 2.5 3 10 had a response rate of 50%. There was no correlation among DPD, TS, and TP expression values in this set of colorectal tumors, which indicated that these gene expressions are independent variables.
All of the tumors that responded to 5-FU therapy (11 of 33) had expression values of all 3 of the genes, TS, TP, and DPD, below their perspective nonresponse cutoff values. Whereas, at least 1 of these gene expressions was high in each of the nonresponding tumors. The patients with low expression of all 3 of the genes had significantly longer survival than did patients with a high value of any 1 of the gene expressions.
The results of this study show that intratumoral gene expression level of DPD is associated with tumor response to 5-FU and that the use of more than 1 independent determinant of response permits the identification of a high percentage of responding patients.
Informed Chemotherapeutic Protocols in Colorectal Cancer May Be Within Reach
Editorial Comment by Alan P. Venook, MD
Keywords:
5-fluorouracil (5-FU)
Colorectal cancer, advanced
After decades of frustrated tinkering with 5-fluorouracil (5-FU) and its pathways in an attempt to improve treatment of colorectal cancer, oncologists have suddenly encountered a new but less problematic challenge: When to use 5-FU and when to use irinotecan in the management of that disease. These 2 studies provide data that may help to clarify the place for these 2 agents in the management of advanced colorectal cancer.
The study by Douillard et al randomly assigned previously untreated patients with advanced colorectal cancer to either 5-FU and leucovorin or the 2 drugs in combination with irinotecan. There were 2 different 5-FU protocols used at the discretion of the different participating centers.
In less than 1 year, 387 patients were entered in the trial, which was conducted in Europe. The groups appeared well-matched, although more patients in the "no-irinotecan" group had synchronous metastases. The overall response rate was much greater in patients treated with the 3-drug combination (34.8% vs 21.9%), and the overall survival also favored patients treated with irinotecan (17.4 months vs 14.1 months). Each of these differences reached statistical significance. Diarrhea, both severe and mild, was more common in the patients who received irinotecan, but despite that side effect, a companion quality-of-life study appeared to favor that group.
These results were pivotal in establishing the combination of irinotecan, 5-FU, and leucovorin as the approved first-line therapy for advanced colorectal cancer patients. This study does not, however, address the question of whether the 3-drug combination is superior to the sequential use of the same agents. Although irinotecan has been demonstrated to improve survival in patients with progressive cancer on 5-FU-based therapies, only 31% of patients in the no-irinotecan group crossed over to receive irinotecan at the time of tumor progression. Many of the 58% of the patients who were deemed candidates for subsequent treatment did not receive irinotecan.
For that reason, it remains uncertain if the employment of all 3 agents up front leads to a survival advantage, compared with reserving irinotecan as second-line treatment, although it would appear to be appropriate to use the more active combination in selected patients. The combination of irinotecan, 5-FU, and leucovorin is also being compared in clinical trials with 5-FU/leucovorin alone in the adjuvant setting for patients with node-positive colon cancer, a situation where greater activity may translate into a meaningful survival advantage.
The study by Salonga et al is not of the same scale as the Douillard study, but if the results are confirmed, its impact could be even greater. In a collaborative effort among numerous laboratories, pretreatment colorectal tumor biopsies of 33 patients were analyzed and then compared with the clinical results of treatment with 5-FU-based chemotherapy.
The analysis involved the measurement of intra-tumoral levels of 3 enzymes: thymidylate synthase (TS), the enzyme critical for 5-FU activity; thymidine phosphorylase (TP), a catabolic enzyme active in the
5-FU pathway; and dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme for the catabolism of 5-FU. Levels of TS and TP had been previously shown to be predictive of responsiveness to 5-FU, with higher levels predicting drug resistance.
The melding of data on all 3 enzymes yielded an intriguing picture. The levels of TS, TP, and DPD were independent of one another, suggesting no biological correlation or interdependence of the enzymes. In any patient, having any of the 3 enzyme levels in excess of a threshold level led to tumor nonresponsiveness. In contrast, all 11 patients in whom all 3 enzyme levels fell below the cut-off for activity had tumor responses. Such patients had a markedly improved survival.
These results need validation. The laboratory method of enzyme analysis, assignment of threshold level, criteria for tumor response, and specific chemotherapies employed may have introduced bias. Also, the ability to obtain this information in real-time is as yet untested. However, if true, identifying patients who will not benefit from 5-FU-based chemotherapy may be possible and the use of chemotherapeutics may be rationalized.
These studies confirm the fact that we are making progress in treating colorectal cancer. The availability of new agents -- and the ability to make informed rather than empiric treatment choices -- suggest that we will make a greater impact on colorectal cancer in the future.
Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355:1041-1047.
Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352:1413-1418.
Salonga D, Danenberg KD, Johnson M, et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Can Res.2000;6:1322-1327.
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