[MOL] Conference Ingo. Rectal and Metastatic Colorectal Cancer..... [00294]

Despite intensive research on the treatment of colorectal cancer and the availability of many modalities, outcomes can be much improved. ECCO 10 opened on Monday, September 13, with a session devoted to presentations addressing improved surgical technique, the effects of radiation on tumor and normal tissues, and the integration of biology and novel computational approaches to the definition of prognostic subgroups. In addition, the role of chemotherapy in the management of colorectal cancers in both advanced disease and in the adjuvant setting is expanding.

Surgical Approaches To Rectal Cancer
The Impact of Education
Dr. LE Rutqvist described the changing approaches to the surgical management of rectal cancer in the Greater Stockholm region.^[1] With the observation in the early 1990s that total mesorectal excision (TME) may reduce local recurrence to under 5%, the Stockholm Rectal Cancer Study Group embarked on a large-scale education and monitoring effort. All the colorectal surgeons in the city participated in one of three workshops held in 1994, 1995, and 1997. Clinical, demographic, and outcome data on all rectal cancer patients from a 2-year period (1995-1996) were collected prospectively in a regional data center. Results were compared with outcomes from two earlier studies: Stockholm I (849 patients [pts], 1980-1987) and Stockholm II (557 pts, 1987-1993). TME was performed in 83% of those having a curative resection in the most recent period. The rate of abdominoperineal resection declined to 26% from 60% and 55% in the previous trials. Local recurrence was only 6% (21/381), compared with 16% and 14% previously, while the incidence of metastatic disease was unchanged. Thus, in a population-based study, a concentrated teaching effort can have a marked effect on therapeutic outcome. The study confirmed the low local recurrence rates associated with TME, associated with the greater use of sphincter-sparing procedures over these time periods.
Consequences of TME
A poster presentation by Oosterhuis and colleagues analyzed the functional consequences of TME on long-term follow-up in 88 patients.^[2] Impaired erectile or ejaculatory function was reported by 33% of patients, while impaired bowel control was observed in 41%. Larger studies with longer follow-up are needed to investigate these outcomes further, and to determine the factors involved in their causation.
Spacing Irradiation and Surgery
Gerard and colleagues in Lyon addressed the optimal interval between preoperative XRT and surgery in a randomized study involving 201 patients.^[3] The objective response rate was 53% when surgery was performed within 2 weeks of the end of XRT, versus 72% when delayed until after 6 weeks. A histologically negative specimen was observed in 5% with the short interval, compared with 15% with the longer time between treatments. Local recurrence rates (9%) were the same in the two arms. It appears that for patients with tumors within 5 cm of the anal verge, the longer interval may permit a higher probability of sphincter-sparing surgery (38% vs 22%).

Another surgical presentation from Hohenburger and colleagues from Berlin showed that chemotherapy (mainly systemic, but some intrahepatic) did not adversely affect the morbidity of patients undergoing subsequent hepatectomy.^[4]

Irradiation

Radiation toxicity is often ascribed to damaged blood vessels, and consequently the importance of the tumor vasculature as a determinant of response has received a great deal of attention. Noninvasive methods for blood flow analysis have the potential to elucidate the basis for sensitivity/resistance to therapy and to serve as surrogate markers for antiangiogenic or antivascular interventions.

A step in this direction was taken with the preliminary presentation of an MRI analysis of rectal tumor blood flow (using a gadolinium marker) before and during treatment with radiation and continuous infusion 5-fluorouracil (5-FU). DeVries and colleagues from Innsbruck studied 11 patients with clinical stage T3 tumors.^[5] Heterogeneous patterns of blood supply emerged, and both hot spots and cold spots were observed. A measure of global tumor perfusion increased in the initial 2-4 weeks of treatment. This study provides important initial data that will permit the correlation of vascularity patterns, their response to therapy, and treatment outcome.

The late effects of therapy were also reviewed from the radiation perspective. Jacob-Heutmann analyzed 53 patients who received radiation and chemotherapy for rectal cancer; most (41) also underwent surgery.^[6] Severe late enteritis (median, 493 days) was observed in 12/53 (23%) patients, 15% of whom required surgical re-exploration. The investigators concluded that further improvement in irradiation techniques and supportive care is needed to prevent these severe late effects.

Chemotherapy
Rectal Cancer
The role of chemotherapy in the adjuvant treatment of rectal cancer is more controversial than in colon cancer, especially in Europe, and two studies addressed this role. Cionini, reporting for the Italian GI Cooperative Group, provided preliminary information on a study in which all locally advanced (T3, T4) rectal cancer patients received preoperative chemoradiation, followed postoperatively by randomization to no further chemotherapy versus 6 cycles of 5-fluorouracil/leucovorin.^[7] Excellent compliance with the initial therapy was demonstrated by 541 evaluable patients.

Age emerged as a determinant of toxicity risk: while the whole group had a 22% incidence of grade 2 or greater toxicity, this rose to 50% in the population older than 70 years. The effectiveness of preoperative treatment was confirmed: 98% of patients had operations with curative intent. Fifty-seven percent of patients were downstaged, and in 52% tumor was either absent or confined within the bowel wall. The results of the postoperative randomization remain blinded at this time.

Dr. Athanassiou reported a Hellenic Cooperative Oncology Group trial of postoperative chemoradiation alone versus chemoradiation followed by additional chemotherapy for rectal cancer.^[8] Among 230 randomized patients, no disease-free or overall survival advantage could be demonstrated with additional chemotherapy.
Combination Therapy for Metastatic Disease
Data eagerly awaited were the final results of the randomized study of irinotecan (CPT-11) plus 5-FU (two schedules, weekly or biweekly) versus 5-FU alone, presented by Rougier (Hôpital à Pare, Bourgogne).^[9] The results are summarized in Table I.
Table I. Results of Combination Irinotecan/5-FU vs 5-FU Alone for Metastatic Colorectal Cancer

Regimen N Grade 3 or 4 diarrhea Grade 3 or 4 neutropenia Response Rate Overall Survival (months) 1-yr Survival

CPT/5-FU 199 22% 42% 41% 16.8 69%

5-FU 188 10% 11% 23% 14.0 59%

The combination regimen significantly prolonged survival and increased response rates while presenting manageable side effects. No quality of life differences were observed between the two arms. The demonstration of a survival benefit in this trial is likely to increase the enthusiasm for the use of both CPT-11 and 5-FU in the initial treatment of patients with advanced colorectal cancer.

Pozzo from Rome presented another multicenter study of CPT-11 versus 5-FU for the treatment of metastatic colorectal cancer, in which a crossover was allowed at progression.^[10] Among 159 patients randomized, responses to initial therapy were: CPT-11, 16.2%; 5-FU, 9.6%. Time to progression was longer with CPT-11 (6.4 mo) than with 5-FU (3.9 mo, P=0.03), but overall survival was the same. This study provides further evidence that in the initial therapy of metastatic colon cancer, CPT-11 is at least as effective as 5-FU.

Becouarn and colleagues (Bordeaux) examined whether patients who had failed one prior 5-FU-containing regimen would respond similarly to a simple combination of CPT-11 and oxaliplatin as to alternating 5-FU/CPT-11 and 5-FU/oxaliplatin.^[11] Both regimens were well-tolerated in the 62 patients randomized in this study. While response rates were a little higher with the two-drug combination, time to progression and survival were similar in the two groups. On the basis of this and the previous study, small as they are, it will be of interest to explore the optimal sequence of combinations of the three active drugs for advanced colon cancer.

Finally, Twelves expanded the analysis of a randomized trial of the oral fluoropyrimidine capecitabine versus 5-FU.^[12] The response rates, time to progression (TTP), and survival are not significantly different between the two arms, as determined by independent review. The regimens are therefore equivalent. However, an economic analysis shows that the IV approach consumes substantially more resources that the oral. Hospitalizations and medication costs for supportive care were all greater on the IV regimen. While unscheduled physician consultations were slightly higher on the Xeloda arm, the physician resources were still higher for the IV 5-FU. These results lend additional support toward the oral use of fluoropyrimidines in colorectal cancer, and emphasize the need to incorporate these agents in regimens designed to test combinations with CPT-11 and oxaliplatin.

Genetics of Colorectal Cancer

An analysis of genetic subtypes of 134 colorectal cancers was presented by Csuka and colleagues from Budapest.^[13] Mutations -- APC (MLH-1) and MSH-2 -- were detected using polymerase chain reaction (PCR) techniques, and correlations were sought with expression of various genes measured by reverse transcriptase PCR. Mutant APC tumors (20%) had a high rate of p53 mutation (45%) as well as elevated cyclin D and E2F1 expression. These tumors also had low expression of p16, associated with hypermethylation of its promoter. In contrast, tumors bearing mutant MLH-1 had lower cyclin D and p53 expression and frequent mutation of TGFBR-II and E2F-4. Prospective use of these markers has the potential to guide therapeutic decision making.

A different marker was used by Vogel and associates from Kiel, Germany.^[14] Cytokeratin-20 (CK-20) is an intermediate filament protein restricted in its expression to epithelial cells and tumors derived from them. Expression of this marker in the marrow of the peripheral blood was detectable in 2/52 patients without known malignancy. Among 122 patients treated with an R0 resection, the incidence of CK-20 was directly correlated with increasing stage (5/11 Stage IV). The survival of patients with detectable CK-20 was inferior to those in whom it was undetectable (P= 0.008). A multivariate analysis of known prognostic factors in these patients yielded CK-20 detectability as an independent determinant of survival. Thus, this marker may identify tumors with high metastatic potential that may require additional therapy.

Summary -- Implications for Clinical Practice

Increased physician education about effective approaches to the treatment of rectal cancer -- specifically, TME -- can lead to greatly improved outcomes.

Increasing the time between preoperative irradiation and surgery may improve outcomes in rectal cancer.

Combination therapy or use of an oral fluorouracil prodrug for metastatic colorectal cancer appears to be more effective than single-agent treatment with 5-FU.

References

Lehander A, Holm T, Rutqvist LE, Moran BJ, Heald RJ, Cedermark B. The impact of surgical training workshops on the outcome in rectal cancer in the population of Stockholm. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 200.
Oosterhuis JWA, van Berlo CLH, Reinders JFM. Functional results after total mesorectal excision (TME) in rectal cancer. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 208.
Gerard JP, Francois Y, Nemoz C, Adeleine P. Influence of the interval between pre operative radiotherapy (preop RXT) and surgery on downsizing and sphincter preservation for rectal cancer. The LYON R90 01 randomized trial. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 202.
Hohenberger P, Kilpert B, Schlag PM. Liver resection after preop. chemotherapy for colorectal metastases: Morbidity and treatment results. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 210.
DeVries A, Griebel J, Kremser Chr, et al. In vivo monitoring of tumor microcirculation changes during radiotherapy in patients with rectal carcinomas: Preliminary results and possible implications for therapy. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 203.
Jacob-Heutmann D, Thilmann C, Adamietz IA, Böttcher HD. Late side effects of combined treatment modalities in rectal cancer. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 209.
Cionini L, Cartei F, Valentini V, et al. Preop chemoradiation (CTRT) postop chemo (CT) in locally advanced rectal cancer. Preliminary results. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 201.
Athanassiou E, Dafni U, Liaros A, et al. Postoperative radiation (RT) and concomitant bolus fluorouracil (FU) with or without additional chemotherapy (CT) as adjuvant treatment in patients with high risk rectal cancer. A randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 212.
Rougier P, Cunningham D, Roth AD, et al. Irinotecan (Iri) in combination with high-dose infusional (HDI) 5FU/FA either weekly or bi-weekly: Evidence of survival advantage and quality of life (QoL) improvement in metastatic colorectal cancer. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 206.
Pozzo C, Pyrhönen S, Bodrogi I, et al. A randomized phase II trial assessing irinotecan (IRI) and 5FU/folinic acid (LV), "Mayo regimen", in first line palliative chemotherapy patients (pts) with metastatic colorectal cancer (MCRC). Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 213.
Becouarn Y, Mousseau M, Gamelin E, Coudert B, Marceau-suissa J, Bekradda M. CPT-11 and L-OHP combination versus alternated combination of LV5FU2 CPT-11/ LV5FU2 L-OHP in 5-FU resistant advanced colorectal cancer (CRC): Preliminary results. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 219.
Twelves C, Van Custem E, Hieke K, et al. Medical resource use in a phase III trial (SO 14796) of Xeloda^TM (capecitabine) in previously untreated advanced/metastatic colorectal cancer. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 207.
Csuka O, Doleschall Z, Kámory E, et al. Characterization of genetic subtypes of colorectal cancers. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 224.
Vogel I, Soeth E, Röder C, Kremer B, Kalthoff H, Henne-Bruns D. Disseminated tumor cells detected by CK 20 RT-PCR in the blood and the bone marrow of patients with colorectal carcinoma represent an independent prognostic factor. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 204.