The rationale for combining locoregional and systemic chemotherapy in advanced col-orectal cancer with metastases to the liver only is based on the following issues:
1. Locoregional chemotherapy has a well-defined activity in these patients and is possibly superior, as reported above, to systemic treatment (at least when traditional agents are administered intravenously).
2. The two therapeutic modalities have nonoverlapping side-effects (liver toxicity for intraarterial therapy, chiefly when FUDR is employed; mucositis, diarrhea, and myelotoxicity with the most frequently used intravenous agents such as biomodulated 5-FU, irinotecan and oxali-platin).
3. From a theoretical point of view, the addition of a systemic treatment should be able to reduce the occurrence of extra-hepatic relapse or progression.
4. Recently, significant progress have been registered in the availability of innovative compounds able to obtain (when given through the intravenous route) a higher objective response rate and an increased survival in comparison with the conventional agents: this should permit a more active combination with the standard locoregional treatments (FUDR or modulated 5-FU) or a promising evaluation of these new agents in the intraarterial route.
A number of phase II trials have been conducted recently with the aim of evaluating the activity of a combined locoregional x systemic treatment for patients with metastatic disease limited to the liver. However, owing to the small number of included patients and the lack of homogeneity of the therapeutic regimens, only general indications can be drawn from these experiences. A brief outline of these trials follows:
1. In Germany, Lorenz et al. (15) treated 20 patients with intraarterial FUDR (at a reduced dose of 0.2 mg/kg/d x 14 d every 4 wk) and intravenous 5-FU (700 mg/sqm/d x 3 d every 4 wk) and reported a satisfactory objective response rate, but a high percentage of extrahepatic relapse (62%), very close to the figure of 56% observed by Kemeny with locoregional treatment only
(FUDR: 0.3 mg/kg/d x 14 d every 4 wk) (16) and to the 73% reported by Niederhuber (17) with a similar regimen.
2. Again in Germany, Safi et al. (18) included 45 cases in a small controlled clinical trial in which a combination of intraarterial FUDR (0.2 mg/kg/d x 14 d every 4 wk) and the same drug given intravenously (0.09 mg/kg/d in the same period) was evaluated in comparison with FUDR administered only intraarterially at the same dose as above. In this study a response rate of 48% was obtained with the combined strategy and the percentage of extrahepatic spread of cancer during therapy seemed of interest in comparison to that observed with locoregional treatment only (33% vs 61%, even though without statistical significance due to the low power of the study). Of course, the limited number of patients and the questionable statistical design prevented any definitive conclusion about the possible superiority of the intraarterial/intra-venous chemotherapy vs the locoregional approach.
3. The Mayo Clinic group performed a trial presented by O'Connell (19) in which the reduced dose of intraarterial FUDR (0.2 mg/kg/d x 14 d) was associated, after a 1-wk rest period, with the low-dose daily-times five regimen of 5-FU (425 mg/m2/d) and LV (20 mg/m2/d) every 4 wk; the combined treatment was administered until maximal regression of hepatic metastases, whereas a maintenance therapy with intravenous 5-FU and LV was continued until disease progression. In a group of 40 evaluable patients (out of 57 enrolled in the trial) the extrahepatic relapse, once again, was quite high (45%) even though the global response rate was 62% and the overall median survival was 18 mo, with a tolerable toxicity and no cases of biliary sclerosis.
4. At the Memorial Sloan-Kettering Cancer Center (MSKCC), Kemeny (20) conducted a pilot study of hepatic arterial infusion and systemic chemotherapy in order to establish the correct doses for concurrent treatment in patients with resected disease. 5-FU was administered for 5 d as an intravenous bolus of 325 mg/m2, preceded each day by a 30-min infusion of LV at the dose of 200 mg/m2; two weeks later the first dose of FUDR (0.25 mg/kg/d) was instilled into the pump for 14 d in combination with 20 mg of dexamethasone and 50,000 IU of heparin. The treatment was recycled after a 1 wk rest for six courses. This regimen was thereafter employed in the following phase III trial (see below).
5. At the S.Carlo Borromeo Hospital (Milano, Italy) Pancera et al. (21) pioneered a monoinstitu-tional trial with intraarterial FUDR at intermediate dosage (0.25 mg/kg/d x 14 d on third and fourth week) combined with 5FU (370 mg/m2 d 1 to 4) and levo-LV (100 mg/m2 d 1 to 4) on first week; the treatment was recycled every five weeks. In a group of 27 patients, a response rate of 69.2% was obtained with a median TTP of 17 mo, a median survival of 20 mo and 35% patients alive at 2 yr; even more interestingly, a low percentage of extrahepatic relapse (23% only) was observed and toxicity was acceptable, without toxic deaths, allowing the administration of the whole treatment program on an outpatient basis. These promising data generated the successor phase III trial performed in the nineties by GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente = Italian Group for the Study of Digestive Tract Cancer), reported below.
The phase III trials in this field are very rare and this is due to several reasons: difficult collaboration among medical oncologists, surgeons, and interventional radiologists; legal and commerical obstacles to drug supply, chiefly for FUDR; an increased role for systemic chemotherapy in this disease and a reduction of interest for locoregional treatment by the vast majority of medical oncologists. On the other hand, the availability of new implant techniques should allow an easier inclusion of patients in trials evaluating the role of intraarterial chemotherapy in combination or in comparison with an optimal systemic treatment. As a matter of fact, whereas the surgical method has some potential advantages (it is well established, permits a complete intraoperative staging, and is particularly suitable for synchro nous metastases) there are also important drawbacks for this approach (it appears too aggressive for metachronous metastases and the economic costs can be too high). On the contrary, the radiological percutaneous techniques (22,23), even though more recent, are minimally invasive, require much lower costs, and allow an easier catheter substitution when necessary: The main disadvantage is the possibility of only performing an instrumental staging. On the basis of these technological improvements, the conduction of large-scale cooperative trials on this topic should be more feasible than in the last years.
The most important phase III trial evaluating the role of combined locoregional and systemic chemotherapy was published by Kemeny et al. in 1999 (24). The MSKCC team randomly assigned 156 patients resected for liver metastases from colorectal cancer to receive six courses of hepatic arterial infusion with FUDR and dexamethasone plus systemic 5-FU (usually biomodulated by LV) or six cycles of intravenous therapy alone. A stratification was performed on the basis of a previous treatment and on the number of liver metastases detected at the moment of operation. The results of this unique trial showed a significant advantage in overall survival at 2 yr for patients receiving combined chemotherapy in comparison to those treated with systemic drugs alone (86% vs 72%, p = 0.03). Also the rate of survival free from hepatic relapse was in favor of the group assigned to the associated treatment (90% vs 60%, p<0.001) and the tolerability of the two regimens was similar, except for a higher frequency of diarrhea and liver toxicity in the combined treatment arm. Therefore, the outcome at 2 yr for this selected population (patients amenable to liver resection for limited hepatic involvement) appears to be increased through the addition of a combined (locoregional + systemic) chemotherapy to the standard surgical resection. Of course, a longer observation is needed to confirm this advantage at 5 yr, when no more than 25-30% of resected only patients are expected to be alive.
Another important trial concerning the possible usefulness of a combined therapy in this setting was conducted by ECOG (Eastern Cooperative Oncology Group) and SWOG (Southwest Oncology Group) (25). Also in this experience (comparing patients treated after liver resection with intraarterial + intravenous chemotherapy vs resected only patients) an advantage for chemotherapy was detected, but it is noteworthy that a 9-yr period was needed to enroll 109 cases only.
What is the future for trials in this field? In our opinion they are still needed and we want to remind that in his editorial in the Journal of Clinical Oncology (26), commenting on a three-arm trial by Lorenz (in which a comparison among systemic therapy and two different regimens of intra-arterial treatment was performed) (27), Daniel Haller said that we are still waiting for the definitive trial on this matter: This can be true not only for the comparison between locoregional chemotherapy and "the" (or, at least, "an") optimal systemic treatment but also for the combination of the two modalities vs one or each of them.
5. THE "GISCAD" PHASE III TRIAL
In May 1993, GISCAD began a randomized trial (no. C-04) with the aim of evaluating the role of combined locoregional + systemic chemotherapy vs locoregional chemotherapy only in the treatment of advanced colorectal cancer with unresectable liver metastases and without concomitant involvement of extrahepatic organs. The purpose of this study was to confirm the interesting observation coming from the previous single-center trial and concerning the possible decrease in extrahepatic disease relapse; another issue was to evaluate whether the combined treatment was more active (in terms of response rate) and/or more effective (in terms of TTP and overall survival) in comparison with locoregional chemotherapy alone without an unacceptable increase in toxicity. Of course, a third arm with systemic therapy alone could have been warranted in such a trial (and this was the original GISCAD project) but after a long discussion inside the group we decided to delete this arm for the following reasons:
1. Most centers with expertise in intraarterial delivery of chemotherapy and with a primary involvement of surgeons did not trust in systemic treatment.
2. In the early 1990s intravenous therapy of advanced colorectal cancer was mainly based on regimens including biomodulated bolus 5-FU (such as the "Mayo Clinic" or the "Machover" combination), as 5-FU continuous infusion was used only in a very limited number of institutions and the new drugs (such as irinotecan, oxaliplatin, raltitrexed, and the oral compounds) were not available at that time: with those "standard" treatments the median overall survival did not exceed 1 yr.
3. In the selected population of patients with unresectable but "limited" (< 50% organ involvement) liver metastases, locoregional chemotherapy had been demonstrated very active (response rate about 50-70% and median survival approaching 2 yr) in several phase II trials.
4. The first results of at least 7-8 phase III studies favored the use of intraarterial administration of drugs, even though with the methodological concerns discussed before and therefore this route of delivery was considered by many of us the best therapy for this particular subset of patients.
The inclusion criteria for the trial were: unresectable liver metastases with hepatic involvement less than 50%; no evidence of disease outside the liver (a complete staging, including an accurate intraoperative assessment, was mandatory, with biopsy of every suspected lesion); no concomitant serious disease (at the hepatic, renal, cardiac, or metabolic level); a good performance status (PS), 0-2 according to ECOG score; a satisfactory bone marrow function; no major contraindication to laparotomy, when required (during a long period of this trial the percutaneous catheter insertion was not yet available); no previous chemotherapy for advanced disease (adjuvant treatment was allowed if terminated at least 1 yr before the occurrence of metastases); no previous tumour (with the exception of basocel-lular skin cancer and early cervical carcinoma); oral informed consent, and, lastly, geographic accessibility (of particular importance for this complex treatment).
A complete staging (pre- and intraoperative) was required and an accurate clinical and hematological evaluation was programmed before each drug administration. The objective response evaluation was planned after three courses of treatment and therapy was continued until disease progression or heavy toxicity or patient decision. The protocol included detailed recommendations to prevent and/or to treat the most important side-effects (with particular emphasis on hepatoxicity from FUDR) and to optimize the patient management. The treatment regimens were: *Arm A (experimental): levo-LV: 100 mg/m2/iv d 1 to 4 on first week 5-FU: 400 mg/m2 iv 15 min d 1 to 4 on first week FUDR: 0.25 mg/kg/ia x 14 d on third and fourth wk Dexamethasone: 20 mg in the pump together with FUDR Heparin (sodic): 20,000 IU in the pump together with FUDR Recycle every 5 wk * Arm B (standard):
FUDR: 0.25 mg/kg/ia x 14 d every 4 wk Dexamethasone: 20 mg in the pump together with FUDR Heparin (sodic): 20,000 IU in the pump together with FUDR
A sample of at least 120 patients was calculated assuming a 2-yr survival of 20% in the standard arm and of 38% in the experimental one (with a relative reduction of 40%), with an alpha error of 0.05 and a beta error of 0.20 (two-tailed test).
From May 1993 to November 1999 127 patients were included in the trial: this prolonged period indicates, once again, the difficulty on both sides of the Atlantic in performing these trials. However, this case list was the one planned by our group and permitted us to observe that the tolerability of both regimens was acceptable, with an increased incidence of gas-troenteric side-effects (nausea and vomiting, diarrhea, and mucositis) for arm A, in which patients received also systemic chemotherapy. The data on activity and efficacy of this trial are reported in an original paper submitted for publication to a major oncology journal and, for this reason, they cannot be quoted in this book, even though a report was made at ASCO Meeting in 2000 (28).
In 2001, GISCAD is involved in further research on the topic of locoregional (+/- systemic) treatment of colorectal liver metastases. The ongoing trial is evaluating, on a phase II basis, a combination of intravenous FOLFOX-4 regimen (I-LV: 100 mg/m2/2 h infusion. + 5-FU: 400 mg/sqm/iv bolus + 5-FU: 600 mg/m2/22 h infusion, all the drugs given on d 1 and 2, with oxaliplatin: 85 mg/m2/2 h infusion on d 1 only) with intraarterial FUDR (0.25 mg/kg/d from d 15 to 28), recycling every 5 wk. Out of six patients treated by November 30, 2000, an objective response was observed in three.
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