Hepatic Arterial Oxaliplatin Infusion Plus Intravenous Chemotherapy in Colorectal Cancer With Inoperable Hepatic Metastases: A Trial of the
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《临床肿瘤学》
the Gastrointestinal Unit and Department of Public Health, Institut Gustave Roussy, Villejuif
Centre Val d’Aurelle, Montpellier
Centre Paul Papin, Angers
Centre Hospitalier de Colmar, Colmar
Centre Paoli Calmettes, Marseille
Centre Fran?ois Baclesse, Caen, France
ABSTRACT
PURPOSE: Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. Oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m2, FU 400 mg/m2 IV bolus, FU 600 mg/m2 22-hour continuous infusion on days 1 and 2 every 2 weeks).
PATIENTS AND METHODS: Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery, patients were treated with oxaliplatin 100 mg/m2 HAI combined with FU + leucovorin IV according to the LV5FU2 protocol. Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months.
RESULTS: Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively.
CONCLUSION: The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer.
INTRODUCTION
The long-term survival of patients presenting with colorectal cancer and hepatic metastases is essentially conditioned by the complete resectability of the hepatic metastases.1 Worldwide, of the 945,000 patients diagnosed with colorectal cancer each year,2 approximately 30% present with exclusively hepatic, synchronous, or metachronous metastases, and only 10% to 20% of these patients are operable or suitable for radiofrequency ablation or cryotherapy, which induced complete remission. For inoperable patients, the short-term prognosis is poor because only palliative treatment can be proposed.3
The standard treatment for metastatic colorectal cancer, even in disease restricted to the liver, remains systemic chemotherapy. Fluorouracil (FU) was the main treatment for more than 40 years, with modest results when administered as single-agent therapy.4 Continuous infusion has been shown to be slightly more effective than bolus administration with regard to median survival (12.1 v 11.3 months, respectively).5 However, the main progress has been made by modulating FU with leucovorin.4
The administration of chemotherapy by hepatic artery infusion (HAI) is logical because the hepatic site is frequently the only metastatic site. Moreover, hepatic metastases are perfused by the hepatic artery network, whereas healthy tissue is perfused by the portal vein.6 Finally, certain drugs undergo a marked liver first-pass effect.7 Floxuridine (FUDR) is the most widely used drug administered using HAI, with reported response rates of greater than 50%. Because of the frequency of cross over from the systemic route to HAI, randomized studies have not been able to demonstrate an improvement in survival.
In two studies in which cross over was not authorized, superior survival was demonstrated in the HAI arm versus the control group.8,9 However, the control groups in those two studies were undertreated compared with current standards. In one of the studies, the control patients did not receive any anticancer treatment,9 and in the other study, the control patients were treated with intravenous (IV) FU only upon request.8
A meta-analysis of seven studies on more than 500 patients confirmed the superiority of HAI with FUDR or FU compared with IV single-agent chemotherapy with fluoropyrimidines in terms of objective response (OR; 41% v 14%, respectively; P < .01), with no impact on survival (median survival time, 16 v 12.2 months, respectively; P = not significant).10 A recent British study failed to demonstrate a difference in survival between LV5FU2 chemotherapy (the so-called "de Gramont regimen"; leucovorin 2-hour infusion of 200 mg/m2 followed by IV bolus FU 400 mg/m2 followed by a 22-hour infusion of FU 600 mg/m2 on days 1 and 2 every 2 weeks) administered by the IV route and the same treatment administered by the intra-arterial route (14.7 v 13.4 months, respectively; P = not significant), but HAI may have been adversely influenced in that study by the occurrence of numerous technical problems preventing optimum treatment administration.11
Oxaliplatin (diaminocyclohexane platine) is effective in colorectal cancer and in particular in combination with FU + leucovorin. Oxaliplatin is endowed with a synergistic activity with FU in vitro.12 Systemic administration of the FU + leucovorin-oxaliplatin combination is effective in the treatment of advanced colorectal cancer, both in first-line (response rate, 29% to 66%; median survival, 15 to 19 months) and second-line settings (response rate, 13% to 57%; median survival, 9 to 17 months).13 Oxaliplatin has been administered to rabbits by HAI. The tissue concentrations were significantly higher in the tumor versus healthy hepatic tissue in a ratio of 4.3,14 suggesting that the drug could be administered by the intra-arterial route with a potential benefit in terms of efficacy and toxicity. This prospective phase II study was designed to evaluate the efficacy and safety of the combination of oxaliplatin administered by HAI and systemic LV5FU2 chemotherapy in patients presenting with isolated hepatic metastases of colorectal cancer.
PATIENTS AND METHODS
Patient Eligibility
For inclusion, the patients were required to be younger than 75 years of age, have a WHO performance status 2, and present with histologically documented and inoperable hepatic metastases of colorectal cancer, liver invasion assessed by computed tomography (CT) scan as less than 50% of the liver, satisfactory hematologic results (WBC 4 x 109/L, neutrophils 1.5 x 109/L, and platelets 100 x 109/L), satisfactory biochemical results (serum creatinine < 130 μmol/L and bilirubin < 35 μmol/L), and measurable disease (hepatic lesion diameter 20 mm). The patients were also required to sign an informed consent form. The patients were not to present with detectable extrahepatic disease (including during laparotomy for hepatic artery catheterization), peripheral neuropathy, heart failure, respiratory insufficiency, severe coronary artery disease, or failure of other organs that would contraindicate treatment. The patients were not to have received prior IV chemotherapy, including oxaliplatin, but could have received, at most, one previous line of IV chemotherapy for metastatic disease. An initial FU-based chemotherapy for metastatic disease was thus authorized, but the patients were to present with stable or progressive disease. The patients were not to have a history of another malignant disease that was not considered cured. Pregnant women, women of child-bearing age, women not using effective contraception, and patients who could not be regularly observed because of their psychological condition were not included. Finally, inclusion was only definitively validated after having checked that the hepatic CT scan was recorded less than 15 days previously and that control of the catheter evidenced good patency, enabling HAI implementation.
Treatment Modalities
The catheter for HAI of the chemotherapy was to be surgically implanted and connected, by the surgeon, to the subcutaneous access located in a right prethoracic position. The pumps used were to be electrical syringes or external ambulatory pumps. Disposable infusers were proscribed because they do not enable sufficient counter pressure.
The dose regimen is shown in Figure 1. The regimen mainly consisted of HAI administration of oxaliplatin 100 mg/m2 infused over 2 hours on day 1, combined with IV FU and leucovorin according to the classic LV5FU2 de Gramont regimen.
Treatment was to be continued until emergence of disease progression, toxicity preventing pursuit of treatment, technical nonfeasibility, or the patient’s request to discontinue treatment. In the event of a complete response, treatment was to be pursued for at least 3 months after obtaining the response, if toxicity permitted. After withdrawal of the patient from the study, the treatment was left to the investigator’s discretion. Surgical resection of metastases was authorized in the event of a good response to treatment after at least eight courses.
The dose was to be reduced in the event of severe toxicity at the nadir or at day 15. FU was to be reduced by 25% in the event of a neutrophil count of less than 0.5 x 109/L or less than 1 x 109/L plus fever or infection and/or a platelet count of less than 75 x 109/L at the nadir. Oxaliplatin dose was to be reduced to 85 mg/m2, in addition to the reduction in FU dose, in the event of a platelet count of less than 75 x 109/L. A further 25% reduction in FU dose and reduction of oxaliplatin to 60 mg/m2 was to be implemented in the event of new toxicity as defined earlier. On day 15, in the event of a neutrophil count of less than 1.5 x 109/L or a platelet count of less than 100 x 109/L, the course was to be postponed to day 18 or day 21. In the event of further toxicity after two dose decreases or nonrecovery of satisfactory hematologic parameters at day 29, treatment was to be withdrawn. With regard to nonhematologic toxicity, a 25% reduction in FU dose was required in the event of mucositis and grade 3 to 4 diarrhea. In the event of vomiting of grade 3 or greater, despite adequate prophylaxis, the oxaliplatin dose was to be reduced to 85 mg/m2 and then to 50 mg/m2 in the event that those symptoms persisted. Oxaliplatin was to be withdrawn in the event of paresthesias associated with permanent dysesthesia. In the event of more mild or intermittent symptoms, the dose was to be reduced to 85 mg/m2.
Patient Follow-Up
In the 7 days preceding the first course of therapy, a physical examination, including body weight and WHO performance status evaluation, laboratory tests (CBC, platelets, electrolytes, urea, creatinine, AST, ALT, alkaline phosphatase, gamma-glutamyltransferase, prothrombin time, activated partial thromboplastin time, carcinoembryonic antigen, and CA 19-9), an ECG, and a chest x-ray, was to be conducted. In the 14 days preceding the first course, a liver CT scan and investigation for extrahepatic metastases were conducted.
During treatment, the laboratory tests consisted of CBC weekly and electrolytes, urea, creatinine, AST, ALT, alkaline phosphatase, and gamma-glutamyltransferase every 2 weeks. A physical examination was conducted every 2 weeks, a liver CT scan was performed every 2 months, and control of catheter patency by radiology or angioscintigraphy was assessed every 12 weeks.
Treatment Evaluation
Tumor response was assessed every 2 months by abdominal CT scan. Patients were assigned to a response category on the basis of WHO standard definitions.15 Complete response required the total disappearance of all clinical and radiologically detectable disease for at least 4 weeks. Partial response was defined as a greater than 50% reduction in the product of the two-dimensional measurements for a minimum of 1 month, with no new lesions appearing. Progressive disease was defined as a greater than 25% increase in tumor size or the appearance of any new lesion.
Statistical Considerations
The statistical design and analysis of the study were performed by one of the authors (A.L.) in the department of Public Health at Institut Gustave Roussy (Villejuif, France). The primary end point of this phase II trial was the OR rate (complete plus partial response). Patients were accrued using a two-stage phase II design.16 An OR rate exceeding 40% was required to conclude that the chemotherapy protocol was effective, and an OR rate of less than 25% was required to conclude that it was inactive. Twenty patients were to be enrolled during the first stage of the study. If fewer than six ORs were observed, no additional patients would be accrued; if six or more ORs were observed, 16 additional patients were to be accrued. On the basis of 36 patients, the chemotherapy protocol would be considered ineffective if fewer than 14 ORs were observed and effective if 14 ORs or more were observed. Treatment results were expressed as percentages with 95% CIs or as medians and ranges. Survival was calculated using the Kaplan-Meier method17 with Rothman’s CIs.18
RESULTS
Patients Characteristics
Five oncology centers and one university hospital enrolled 28 patients onto the trial from May 1999 to December 2001. The enrollment in the second stage of the trial was initiated because more than six ORs were observed at the end of the first stage. Inclusions were stopped after the accrual of 28 patients because more than 14 ORs were observed.
The patient characteristics are listed in Table 1. The catheter was inserted a median of 31 days (range, 6 to 509 days) before initiation of intra-arterial chemotherapy in the right gastroduodenal artery (73% of patients) or right hepatic artery (27% of patients). An arterial ligature was associated in seven patients. Two extrahepatic infusions were detected during the postoperative controls.
Treatment Characteristics
In the context of the protocol, two patients did not receive any course of intra-arterial chemotherapy; one patient presented with complete and definitive obstruction of the artery and catheter, and the second patient withdrew consent before treatment initiation. Both patients received IV chemotherapy outside of the protocol. The median number of courses administered to the 28 patients was eight courses (range, zero to 20 courses). Two hundred courses were administered, and 27 were delayed for more than 7 days as a result of toxicity. The oxaliplatin dose was reduced for administration of 21 courses. The reasons for the dose reduction were abdominal pain (two courses), hematologic toxicity (two courses), hematologic toxicity and mucositis (nine courses), neurotoxicity (five courses), hand-foot syndrome (two courses), and occlusion of the catheter during infusion (one course). The FU dose was reduced for 17 courses for the following reasons: anginal pain (one course), hematologic toxicity (12 courses), hand-foot syndrome (three courses), and unknown reason (one course). Treatment was discontinued for the following reasons: definitive obstruction of the catheter (10 patients), toxicity (six patients), death or disease progression (seven patients), patient request (two patients), surgical decision (two patients), and complete response (one patient).
Tumor Response
The best tumor response observed after four or eight courses of therapy was 18 patients with OR (two complete responses and 16 partial responses) and three patients with stable diseases. Until the eighth course, no patient presented with disease progression. The intent-to-treat OR rate observed in the 28 patients included was 64% (95% CI, 44% to 81%). After response to therapy, five patients could proceed to surgical resection of their metastases with curative intent. Eight patients presented extrahepatic progression of the disease.
Patient Survival
With a median follow-up of 23 months, nine deaths occurred (four from cancer secondary to hepatic progression, two from cancer secondary to extrahepatic progression, one from cancer secondary to both hepatic and extrahepatic progression, and two from toxicity). At 12 months, the overall and disease-free survival rates were 82% (95% CI, 64% to 92%) and 67% (95% CI, 48% to 82%), respectively. At 24 months, the overall and disease-free survival rates were 63% (95% CI, 40% to 81%) and 55% (95% CI, 35% to 74%), respectively. The median overall and progression-free survival times were 27 and 27 months, respectively (Fig 2).
Tolerance
Safety was evaluated in the 26 patients treated. The main toxicities observed are listed in Table 2. Grade 3 to 4 toxicity was rare. The most frequent toxicity was grade 3 neutropenia (eight patients) and grade 4 neutropenia (two patients). Two patients presented with grade 4 diarrhea, and one presented with grade 4 mucositis. No grade 4 neurotoxicity was observed, and only one patient presented with grade 3 symptoms. One patient presented with febrile neutropenia, which, initially, was inadequately treated at home. This female patient, who only received care 3 days after the start of the febrile neutropenia, rapidly developed fatal septic shock. Another death occurred in a woman with massive hepatic metastases (50%) who, 3 days after the first course of treatment, presented with rapidly progressive jaundice followed by coma and a state of shock, without associated neutropenia. With regard to the toxicity directly related to the intra-arterial chemotherapy, there was no gastrointestinal ulceration or hemorrhage. Temporary catheter obstruction was observed in five patients. The other toxicities reported were hepatic artery stenosis (three patients), infection at the injection site (one patient), diffusion around the catheter (two patients), and pain during oxaliplatin administration, which was sometimes severe and led to concomitant morphine treatment (six patients).
DISCUSSION
Concomitant administration of oxaliplatin and FU + leucovorin yielded promising results in the study, with greater than 60% ORs and median survival and progression-free survivals greater than those observed in all the recent combined IV chemotherapy trials.19-22 Despite these encouraging results, the position of intra-arterial chemotherapy remains difficult to determine, even though it seems illogical that patients presenting with inoperable isolated hepatic metastases of colorectal cancer are administered systemic chemotherapy without taking into account the specificity of the single organ lesion.
The response rate of 64% observed in this study is reported for the intent-to-treat population. The response rate does not seem much greater than the rate observed with more conventional HAI chemotherapy with FUDR.23,24 However, the results in terms of progression-free survival were markedly superior to the results obtained with FUDR (median progression-free survival of 27 months v 7.5 months for Porta et al24 and 9 months for O’Connell et al23). The median overall survival time obtained in this study was 27 months, which is, once again, markedly superior to the median overall survival time observed with intra-arterial FUDR combined with FU + leucovorin IV (9 to 18 months, depending on the study).23,24 Safi et al25 combined HAI and IV FUDR, and the median overall survival for the 21 patients who received the combination treatment was only 16 months.
The concept of combining local chemotherapy with systemic chemotherapy remains debatable. The strongest argument in favor of the combination of intra-arterial and IV administration is the high frequency of extrahepatic lesions when only the liver is treated (up to 83% of patients).26 One of the first studies of combined intra-arterial and IV chemotherapy evaluated FUDR administered by both routes versus intra-arterial FUDR alone.25 The only observed difference was the lower remote relapse rate with the combination (61% relapses for local administration v 33% for the combination).
The major contribution of irinotecan and oxaliplatin to the IV treatment of patients presenting with metastatic colorectal cancer has led several teams to evaluate the contribution of the two drugs when the patients are treated by HAI chemotherapy. The main strategy used in recent trials has been to combine the new drugs with standard intra-arterial treatment with FUDR. In the first study (a phase I to II study), which included 46 patients with unresectable liver metastases, the maximum-tolerated dose of irinotecan combined with HAI FUDR was determined. The response rate obtained in the 46 patients was 74% partial responses and, thus, slightly higher than the rate observed in the present study; however, that study had a more cumbersome and toxic treatment regimen than the present study.27 In the same population of patients with unresectable liver metastases, it has been recently demonstrated that it is possible to combine HAI of FUDR and IV administration of oxaliplatin plus irinotecan or FU + leucovorin + oxaliplatin,28 but these results are preliminary. In the second study, 185 patients with unresectable FU-resistant hepatic metastases underwent surgical cytoreduction followed by adjuvant chemotherapy with systemic irinotecan and HAI FUDR.29 The treatment was feasible, and the progression-free survival and overall survival times were longer with postoperative chemotherapy compared with the survival times observed with no further treatment. In the third study, FUDR administered by HAI was combined with irinotecan IV to prevent relapses after complete resection of hepatic metastases. The 27 patients receiving the maximum-tolerated dose of irinotecan (phase I to II study) and FUDR were alive at 2 years, and the overall survival rate of the population was 89% with a median follow-up of 26 months.30 This showed that it is possible, even after hepatic resection, to combine a new IV drug with intra-arterial FUDR. On the basis of the present results, the authors consider that it was more appropriate to attempt to administer at least some of the new drugs by HAI, while reducing the HAI time to decrease the risk of chronic hepatobiliary toxicity. Oxaliplatin seems to be the best candidate in that setting. The use of tetrahydropyranyl-doxorubicin combined with LV5FU2 + irinotecan did not yield encouraging results because of hematologic toxicity and a median progression-free survival of only 9.1 months, which is markedly less than the progression-free survival observed in this study and at the cost of much greater therapy-associated trouble.31
Oxaliplatin has been seldom administered via HAI. A phase I study combined HAI oxaliplatin with an FU + leucovorin protocol administered systemically. Twenty-one patients presenting with isolated hepatic metastases of colorectal cancer were treated in the study.32 Therapy, which was administered every 3 weeks, consisted of FU 600 mg/m2 and leucovorin 200 mg/m2 IV combined with 25 mg/m2 oxaliplatin HAI with dose increments of 25 mg/m2. The limiting toxicities observed at an oxaliplatin dose of 150 mg/m2 were leukopenia, occlusion of the hepatic artery, and acute pancreatitis. The recommended dose was 125 mg/m2 every 3 weeks, which is similar to the recommended dose for IV oxaliplatin monotherapy.33 The efficacy results for that phase I study were similar to those reported here (59% OR; 24% complete responses and 35% partial responses). The median time to progression had not been reached at the cutoff date, with a median follow-up of 6.7 months. The authors selected the dose of 100 mg/m2 every 2 weeks to increase the dose-intensity relative to the conventional FOLFOX4 regimen (LV5FU2 plus oxaliplatin 85 mg/m2 administered as a 2-hour infusion every 2 weeks; ie, the equivalent of 130 mg/m2 every 3 weeks) given that that dose was not limiting in terms of toxicity. The dose is, in fact, equivalent to the dose used IV in the FOLFOX6 regimen (oxaliplatin 100 mg/m2 administered as a 2-hour infusion on day 1 combined with a 2-hour infusion of leucovorin 400 mg/m2 followed by FU 400 mg/m2 IV bolus followed by FU 2,400 mg/m2 continuous 48-hour infusion every 2 weeks),22 enabling prevention of excessive systemic availability of oxaliplatin to reduce the risk of neurotoxicity. However, the aim was also to achieve sufficient systemic oxaliplatin availability for optimally effective control of extrahepatic disease.
The toxicity profile observed in this study was comparable to that in the phase I study and little different from the toxicity observed with IV oxaliplatin and infused FU plus leucovorin, except, perhaps, for a longer time to the emergence of neuropathy necessitating treatment withdrawal. The decrease in neurotoxicity observed in the phase I study and in this phase II study is considered to be a result of the low systemic availability of oxaliplatin administered by the intra-arterial route. The occurrence of abdominal pain during or immediately after HAI seems characteristic of the intra-arterial administration of the drug. The same pains were observed in the phase I study by Kern et al32 but with a lower frequency than in our phase II study (23% v 70%, respectively). The pathophysiology of the pain has yet to be elucidated. In our study, the oxaliplatin dose had to be reduced in only 10% of the courses, with all toxicities taken together, although the follow-up was long.
Compared with FUDR administration by HAI, no hepatic or biliary toxicity was observed in our study, whereas the rates of these toxicities with FUDR ranged from 9.3%24 to 57%25 in the studies published to date, even when dexamethasone was systematically administered concomitantly and the treatment periods were shortened. The fact that oxaliplatin has no inherent hepatic toxicity and is administered in the form of a short infusion (2 hours) undoubtedly explains the different toxicity profile. The hematologic toxicity in our study was more marked compared with that in the FUDR studies, and it induced a febrile neutropenia with septic shock.
With a median of eight courses administered (range, zero to 20 courses), the main cause for treatment discontinuation was definitive catheter obstruction, which remains the major problem with HAI chemotherapy. This difficulty probably explains the totally negative results of a recent randomized study comparing, in 290 patients, LV5FU2 IV versus the same protocol administered by the HAI route.11 The high frequency of catheter complications (in more than half the patients receiving HAI) may explain the absence of benefit in the group treated via HAI.
The initial results for oxaliplatin administered by HAI in combination with systemic FU + leucovorin shows that the protocol is feasible and promising. The median progression-free and overall survivals were long compared with these survival times in other studies. These results require confirmation on a larger scale, optimally during a phase III study versus systemic chemotherapy alone or in combination with FUDR administered by HAI. On the basis of these data, HAI administration of oxaliplatin seems a potentially promising candidate for the treatment of hepatic metastases after complete resection.
Authors’ Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, of for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Supported by a grant from Sanofi-Aventis, Paris, France.
Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Centre Val d’Aurelle, Montpellier
Centre Paul Papin, Angers
Centre Hospitalier de Colmar, Colmar
Centre Paoli Calmettes, Marseille
Centre Fran?ois Baclesse, Caen, France
ABSTRACT
PURPOSE: Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. Oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m2, FU 400 mg/m2 IV bolus, FU 600 mg/m2 22-hour continuous infusion on days 1 and 2 every 2 weeks).
PATIENTS AND METHODS: Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery, patients were treated with oxaliplatin 100 mg/m2 HAI combined with FU + leucovorin IV according to the LV5FU2 protocol. Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months.
RESULTS: Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively.
CONCLUSION: The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer.
INTRODUCTION
The long-term survival of patients presenting with colorectal cancer and hepatic metastases is essentially conditioned by the complete resectability of the hepatic metastases.1 Worldwide, of the 945,000 patients diagnosed with colorectal cancer each year,2 approximately 30% present with exclusively hepatic, synchronous, or metachronous metastases, and only 10% to 20% of these patients are operable or suitable for radiofrequency ablation or cryotherapy, which induced complete remission. For inoperable patients, the short-term prognosis is poor because only palliative treatment can be proposed.3
The standard treatment for metastatic colorectal cancer, even in disease restricted to the liver, remains systemic chemotherapy. Fluorouracil (FU) was the main treatment for more than 40 years, with modest results when administered as single-agent therapy.4 Continuous infusion has been shown to be slightly more effective than bolus administration with regard to median survival (12.1 v 11.3 months, respectively).5 However, the main progress has been made by modulating FU with leucovorin.4
The administration of chemotherapy by hepatic artery infusion (HAI) is logical because the hepatic site is frequently the only metastatic site. Moreover, hepatic metastases are perfused by the hepatic artery network, whereas healthy tissue is perfused by the portal vein.6 Finally, certain drugs undergo a marked liver first-pass effect.7 Floxuridine (FUDR) is the most widely used drug administered using HAI, with reported response rates of greater than 50%. Because of the frequency of cross over from the systemic route to HAI, randomized studies have not been able to demonstrate an improvement in survival.
In two studies in which cross over was not authorized, superior survival was demonstrated in the HAI arm versus the control group.8,9 However, the control groups in those two studies were undertreated compared with current standards. In one of the studies, the control patients did not receive any anticancer treatment,9 and in the other study, the control patients were treated with intravenous (IV) FU only upon request.8
A meta-analysis of seven studies on more than 500 patients confirmed the superiority of HAI with FUDR or FU compared with IV single-agent chemotherapy with fluoropyrimidines in terms of objective response (OR; 41% v 14%, respectively; P < .01), with no impact on survival (median survival time, 16 v 12.2 months, respectively; P = not significant).10 A recent British study failed to demonstrate a difference in survival between LV5FU2 chemotherapy (the so-called "de Gramont regimen"; leucovorin 2-hour infusion of 200 mg/m2 followed by IV bolus FU 400 mg/m2 followed by a 22-hour infusion of FU 600 mg/m2 on days 1 and 2 every 2 weeks) administered by the IV route and the same treatment administered by the intra-arterial route (14.7 v 13.4 months, respectively; P = not significant), but HAI may have been adversely influenced in that study by the occurrence of numerous technical problems preventing optimum treatment administration.11
Oxaliplatin (diaminocyclohexane platine) is effective in colorectal cancer and in particular in combination with FU + leucovorin. Oxaliplatin is endowed with a synergistic activity with FU in vitro.12 Systemic administration of the FU + leucovorin-oxaliplatin combination is effective in the treatment of advanced colorectal cancer, both in first-line (response rate, 29% to 66%; median survival, 15 to 19 months) and second-line settings (response rate, 13% to 57%; median survival, 9 to 17 months).13 Oxaliplatin has been administered to rabbits by HAI. The tissue concentrations were significantly higher in the tumor versus healthy hepatic tissue in a ratio of 4.3,14 suggesting that the drug could be administered by the intra-arterial route with a potential benefit in terms of efficacy and toxicity. This prospective phase II study was designed to evaluate the efficacy and safety of the combination of oxaliplatin administered by HAI and systemic LV5FU2 chemotherapy in patients presenting with isolated hepatic metastases of colorectal cancer.
PATIENTS AND METHODS
Patient Eligibility
For inclusion, the patients were required to be younger than 75 years of age, have a WHO performance status 2, and present with histologically documented and inoperable hepatic metastases of colorectal cancer, liver invasion assessed by computed tomography (CT) scan as less than 50% of the liver, satisfactory hematologic results (WBC 4 x 109/L, neutrophils 1.5 x 109/L, and platelets 100 x 109/L), satisfactory biochemical results (serum creatinine < 130 μmol/L and bilirubin < 35 μmol/L), and measurable disease (hepatic lesion diameter 20 mm). The patients were also required to sign an informed consent form. The patients were not to present with detectable extrahepatic disease (including during laparotomy for hepatic artery catheterization), peripheral neuropathy, heart failure, respiratory insufficiency, severe coronary artery disease, or failure of other organs that would contraindicate treatment. The patients were not to have received prior IV chemotherapy, including oxaliplatin, but could have received, at most, one previous line of IV chemotherapy for metastatic disease. An initial FU-based chemotherapy for metastatic disease was thus authorized, but the patients were to present with stable or progressive disease. The patients were not to have a history of another malignant disease that was not considered cured. Pregnant women, women of child-bearing age, women not using effective contraception, and patients who could not be regularly observed because of their psychological condition were not included. Finally, inclusion was only definitively validated after having checked that the hepatic CT scan was recorded less than 15 days previously and that control of the catheter evidenced good patency, enabling HAI implementation.
Treatment Modalities
The catheter for HAI of the chemotherapy was to be surgically implanted and connected, by the surgeon, to the subcutaneous access located in a right prethoracic position. The pumps used were to be electrical syringes or external ambulatory pumps. Disposable infusers were proscribed because they do not enable sufficient counter pressure.
The dose regimen is shown in Figure 1. The regimen mainly consisted of HAI administration of oxaliplatin 100 mg/m2 infused over 2 hours on day 1, combined with IV FU and leucovorin according to the classic LV5FU2 de Gramont regimen.
Treatment was to be continued until emergence of disease progression, toxicity preventing pursuit of treatment, technical nonfeasibility, or the patient’s request to discontinue treatment. In the event of a complete response, treatment was to be pursued for at least 3 months after obtaining the response, if toxicity permitted. After withdrawal of the patient from the study, the treatment was left to the investigator’s discretion. Surgical resection of metastases was authorized in the event of a good response to treatment after at least eight courses.
The dose was to be reduced in the event of severe toxicity at the nadir or at day 15. FU was to be reduced by 25% in the event of a neutrophil count of less than 0.5 x 109/L or less than 1 x 109/L plus fever or infection and/or a platelet count of less than 75 x 109/L at the nadir. Oxaliplatin dose was to be reduced to 85 mg/m2, in addition to the reduction in FU dose, in the event of a platelet count of less than 75 x 109/L. A further 25% reduction in FU dose and reduction of oxaliplatin to 60 mg/m2 was to be implemented in the event of new toxicity as defined earlier. On day 15, in the event of a neutrophil count of less than 1.5 x 109/L or a platelet count of less than 100 x 109/L, the course was to be postponed to day 18 or day 21. In the event of further toxicity after two dose decreases or nonrecovery of satisfactory hematologic parameters at day 29, treatment was to be withdrawn. With regard to nonhematologic toxicity, a 25% reduction in FU dose was required in the event of mucositis and grade 3 to 4 diarrhea. In the event of vomiting of grade 3 or greater, despite adequate prophylaxis, the oxaliplatin dose was to be reduced to 85 mg/m2 and then to 50 mg/m2 in the event that those symptoms persisted. Oxaliplatin was to be withdrawn in the event of paresthesias associated with permanent dysesthesia. In the event of more mild or intermittent symptoms, the dose was to be reduced to 85 mg/m2.
Patient Follow-Up
In the 7 days preceding the first course of therapy, a physical examination, including body weight and WHO performance status evaluation, laboratory tests (CBC, platelets, electrolytes, urea, creatinine, AST, ALT, alkaline phosphatase, gamma-glutamyltransferase, prothrombin time, activated partial thromboplastin time, carcinoembryonic antigen, and CA 19-9), an ECG, and a chest x-ray, was to be conducted. In the 14 days preceding the first course, a liver CT scan and investigation for extrahepatic metastases were conducted.
During treatment, the laboratory tests consisted of CBC weekly and electrolytes, urea, creatinine, AST, ALT, alkaline phosphatase, and gamma-glutamyltransferase every 2 weeks. A physical examination was conducted every 2 weeks, a liver CT scan was performed every 2 months, and control of catheter patency by radiology or angioscintigraphy was assessed every 12 weeks.
Treatment Evaluation
Tumor response was assessed every 2 months by abdominal CT scan. Patients were assigned to a response category on the basis of WHO standard definitions.15 Complete response required the total disappearance of all clinical and radiologically detectable disease for at least 4 weeks. Partial response was defined as a greater than 50% reduction in the product of the two-dimensional measurements for a minimum of 1 month, with no new lesions appearing. Progressive disease was defined as a greater than 25% increase in tumor size or the appearance of any new lesion.
Statistical Considerations
The statistical design and analysis of the study were performed by one of the authors (A.L.) in the department of Public Health at Institut Gustave Roussy (Villejuif, France). The primary end point of this phase II trial was the OR rate (complete plus partial response). Patients were accrued using a two-stage phase II design.16 An OR rate exceeding 40% was required to conclude that the chemotherapy protocol was effective, and an OR rate of less than 25% was required to conclude that it was inactive. Twenty patients were to be enrolled during the first stage of the study. If fewer than six ORs were observed, no additional patients would be accrued; if six or more ORs were observed, 16 additional patients were to be accrued. On the basis of 36 patients, the chemotherapy protocol would be considered ineffective if fewer than 14 ORs were observed and effective if 14 ORs or more were observed. Treatment results were expressed as percentages with 95% CIs or as medians and ranges. Survival was calculated using the Kaplan-Meier method17 with Rothman’s CIs.18
RESULTS
Patients Characteristics
Five oncology centers and one university hospital enrolled 28 patients onto the trial from May 1999 to December 2001. The enrollment in the second stage of the trial was initiated because more than six ORs were observed at the end of the first stage. Inclusions were stopped after the accrual of 28 patients because more than 14 ORs were observed.
The patient characteristics are listed in Table 1. The catheter was inserted a median of 31 days (range, 6 to 509 days) before initiation of intra-arterial chemotherapy in the right gastroduodenal artery (73% of patients) or right hepatic artery (27% of patients). An arterial ligature was associated in seven patients. Two extrahepatic infusions were detected during the postoperative controls.
Treatment Characteristics
In the context of the protocol, two patients did not receive any course of intra-arterial chemotherapy; one patient presented with complete and definitive obstruction of the artery and catheter, and the second patient withdrew consent before treatment initiation. Both patients received IV chemotherapy outside of the protocol. The median number of courses administered to the 28 patients was eight courses (range, zero to 20 courses). Two hundred courses were administered, and 27 were delayed for more than 7 days as a result of toxicity. The oxaliplatin dose was reduced for administration of 21 courses. The reasons for the dose reduction were abdominal pain (two courses), hematologic toxicity (two courses), hematologic toxicity and mucositis (nine courses), neurotoxicity (five courses), hand-foot syndrome (two courses), and occlusion of the catheter during infusion (one course). The FU dose was reduced for 17 courses for the following reasons: anginal pain (one course), hematologic toxicity (12 courses), hand-foot syndrome (three courses), and unknown reason (one course). Treatment was discontinued for the following reasons: definitive obstruction of the catheter (10 patients), toxicity (six patients), death or disease progression (seven patients), patient request (two patients), surgical decision (two patients), and complete response (one patient).
Tumor Response
The best tumor response observed after four or eight courses of therapy was 18 patients with OR (two complete responses and 16 partial responses) and three patients with stable diseases. Until the eighth course, no patient presented with disease progression. The intent-to-treat OR rate observed in the 28 patients included was 64% (95% CI, 44% to 81%). After response to therapy, five patients could proceed to surgical resection of their metastases with curative intent. Eight patients presented extrahepatic progression of the disease.
Patient Survival
With a median follow-up of 23 months, nine deaths occurred (four from cancer secondary to hepatic progression, two from cancer secondary to extrahepatic progression, one from cancer secondary to both hepatic and extrahepatic progression, and two from toxicity). At 12 months, the overall and disease-free survival rates were 82% (95% CI, 64% to 92%) and 67% (95% CI, 48% to 82%), respectively. At 24 months, the overall and disease-free survival rates were 63% (95% CI, 40% to 81%) and 55% (95% CI, 35% to 74%), respectively. The median overall and progression-free survival times were 27 and 27 months, respectively (Fig 2).
Tolerance
Safety was evaluated in the 26 patients treated. The main toxicities observed are listed in Table 2. Grade 3 to 4 toxicity was rare. The most frequent toxicity was grade 3 neutropenia (eight patients) and grade 4 neutropenia (two patients). Two patients presented with grade 4 diarrhea, and one presented with grade 4 mucositis. No grade 4 neurotoxicity was observed, and only one patient presented with grade 3 symptoms. One patient presented with febrile neutropenia, which, initially, was inadequately treated at home. This female patient, who only received care 3 days after the start of the febrile neutropenia, rapidly developed fatal septic shock. Another death occurred in a woman with massive hepatic metastases (50%) who, 3 days after the first course of treatment, presented with rapidly progressive jaundice followed by coma and a state of shock, without associated neutropenia. With regard to the toxicity directly related to the intra-arterial chemotherapy, there was no gastrointestinal ulceration or hemorrhage. Temporary catheter obstruction was observed in five patients. The other toxicities reported were hepatic artery stenosis (three patients), infection at the injection site (one patient), diffusion around the catheter (two patients), and pain during oxaliplatin administration, which was sometimes severe and led to concomitant morphine treatment (six patients).
DISCUSSION
Concomitant administration of oxaliplatin and FU + leucovorin yielded promising results in the study, with greater than 60% ORs and median survival and progression-free survivals greater than those observed in all the recent combined IV chemotherapy trials.19-22 Despite these encouraging results, the position of intra-arterial chemotherapy remains difficult to determine, even though it seems illogical that patients presenting with inoperable isolated hepatic metastases of colorectal cancer are administered systemic chemotherapy without taking into account the specificity of the single organ lesion.
The response rate of 64% observed in this study is reported for the intent-to-treat population. The response rate does not seem much greater than the rate observed with more conventional HAI chemotherapy with FUDR.23,24 However, the results in terms of progression-free survival were markedly superior to the results obtained with FUDR (median progression-free survival of 27 months v 7.5 months for Porta et al24 and 9 months for O’Connell et al23). The median overall survival time obtained in this study was 27 months, which is, once again, markedly superior to the median overall survival time observed with intra-arterial FUDR combined with FU + leucovorin IV (9 to 18 months, depending on the study).23,24 Safi et al25 combined HAI and IV FUDR, and the median overall survival for the 21 patients who received the combination treatment was only 16 months.
The concept of combining local chemotherapy with systemic chemotherapy remains debatable. The strongest argument in favor of the combination of intra-arterial and IV administration is the high frequency of extrahepatic lesions when only the liver is treated (up to 83% of patients).26 One of the first studies of combined intra-arterial and IV chemotherapy evaluated FUDR administered by both routes versus intra-arterial FUDR alone.25 The only observed difference was the lower remote relapse rate with the combination (61% relapses for local administration v 33% for the combination).
The major contribution of irinotecan and oxaliplatin to the IV treatment of patients presenting with metastatic colorectal cancer has led several teams to evaluate the contribution of the two drugs when the patients are treated by HAI chemotherapy. The main strategy used in recent trials has been to combine the new drugs with standard intra-arterial treatment with FUDR. In the first study (a phase I to II study), which included 46 patients with unresectable liver metastases, the maximum-tolerated dose of irinotecan combined with HAI FUDR was determined. The response rate obtained in the 46 patients was 74% partial responses and, thus, slightly higher than the rate observed in the present study; however, that study had a more cumbersome and toxic treatment regimen than the present study.27 In the same population of patients with unresectable liver metastases, it has been recently demonstrated that it is possible to combine HAI of FUDR and IV administration of oxaliplatin plus irinotecan or FU + leucovorin + oxaliplatin,28 but these results are preliminary. In the second study, 185 patients with unresectable FU-resistant hepatic metastases underwent surgical cytoreduction followed by adjuvant chemotherapy with systemic irinotecan and HAI FUDR.29 The treatment was feasible, and the progression-free survival and overall survival times were longer with postoperative chemotherapy compared with the survival times observed with no further treatment. In the third study, FUDR administered by HAI was combined with irinotecan IV to prevent relapses after complete resection of hepatic metastases. The 27 patients receiving the maximum-tolerated dose of irinotecan (phase I to II study) and FUDR were alive at 2 years, and the overall survival rate of the population was 89% with a median follow-up of 26 months.30 This showed that it is possible, even after hepatic resection, to combine a new IV drug with intra-arterial FUDR. On the basis of the present results, the authors consider that it was more appropriate to attempt to administer at least some of the new drugs by HAI, while reducing the HAI time to decrease the risk of chronic hepatobiliary toxicity. Oxaliplatin seems to be the best candidate in that setting. The use of tetrahydropyranyl-doxorubicin combined with LV5FU2 + irinotecan did not yield encouraging results because of hematologic toxicity and a median progression-free survival of only 9.1 months, which is markedly less than the progression-free survival observed in this study and at the cost of much greater therapy-associated trouble.31
Oxaliplatin has been seldom administered via HAI. A phase I study combined HAI oxaliplatin with an FU + leucovorin protocol administered systemically. Twenty-one patients presenting with isolated hepatic metastases of colorectal cancer were treated in the study.32 Therapy, which was administered every 3 weeks, consisted of FU 600 mg/m2 and leucovorin 200 mg/m2 IV combined with 25 mg/m2 oxaliplatin HAI with dose increments of 25 mg/m2. The limiting toxicities observed at an oxaliplatin dose of 150 mg/m2 were leukopenia, occlusion of the hepatic artery, and acute pancreatitis. The recommended dose was 125 mg/m2 every 3 weeks, which is similar to the recommended dose for IV oxaliplatin monotherapy.33 The efficacy results for that phase I study were similar to those reported here (59% OR; 24% complete responses and 35% partial responses). The median time to progression had not been reached at the cutoff date, with a median follow-up of 6.7 months. The authors selected the dose of 100 mg/m2 every 2 weeks to increase the dose-intensity relative to the conventional FOLFOX4 regimen (LV5FU2 plus oxaliplatin 85 mg/m2 administered as a 2-hour infusion every 2 weeks; ie, the equivalent of 130 mg/m2 every 3 weeks) given that that dose was not limiting in terms of toxicity. The dose is, in fact, equivalent to the dose used IV in the FOLFOX6 regimen (oxaliplatin 100 mg/m2 administered as a 2-hour infusion on day 1 combined with a 2-hour infusion of leucovorin 400 mg/m2 followed by FU 400 mg/m2 IV bolus followed by FU 2,400 mg/m2 continuous 48-hour infusion every 2 weeks),22 enabling prevention of excessive systemic availability of oxaliplatin to reduce the risk of neurotoxicity. However, the aim was also to achieve sufficient systemic oxaliplatin availability for optimally effective control of extrahepatic disease.
The toxicity profile observed in this study was comparable to that in the phase I study and little different from the toxicity observed with IV oxaliplatin and infused FU plus leucovorin, except, perhaps, for a longer time to the emergence of neuropathy necessitating treatment withdrawal. The decrease in neurotoxicity observed in the phase I study and in this phase II study is considered to be a result of the low systemic availability of oxaliplatin administered by the intra-arterial route. The occurrence of abdominal pain during or immediately after HAI seems characteristic of the intra-arterial administration of the drug. The same pains were observed in the phase I study by Kern et al32 but with a lower frequency than in our phase II study (23% v 70%, respectively). The pathophysiology of the pain has yet to be elucidated. In our study, the oxaliplatin dose had to be reduced in only 10% of the courses, with all toxicities taken together, although the follow-up was long.
Compared with FUDR administration by HAI, no hepatic or biliary toxicity was observed in our study, whereas the rates of these toxicities with FUDR ranged from 9.3%24 to 57%25 in the studies published to date, even when dexamethasone was systematically administered concomitantly and the treatment periods were shortened. The fact that oxaliplatin has no inherent hepatic toxicity and is administered in the form of a short infusion (2 hours) undoubtedly explains the different toxicity profile. The hematologic toxicity in our study was more marked compared with that in the FUDR studies, and it induced a febrile neutropenia with septic shock.
With a median of eight courses administered (range, zero to 20 courses), the main cause for treatment discontinuation was definitive catheter obstruction, which remains the major problem with HAI chemotherapy. This difficulty probably explains the totally negative results of a recent randomized study comparing, in 290 patients, LV5FU2 IV versus the same protocol administered by the HAI route.11 The high frequency of catheter complications (in more than half the patients receiving HAI) may explain the absence of benefit in the group treated via HAI.
The initial results for oxaliplatin administered by HAI in combination with systemic FU + leucovorin shows that the protocol is feasible and promising. The median progression-free and overall survivals were long compared with these survival times in other studies. These results require confirmation on a larger scale, optimally during a phase III study versus systemic chemotherapy alone or in combination with FUDR administered by HAI. On the basis of these data, HAI administration of oxaliplatin seems a potentially promising candidate for the treatment of hepatic metastases after complete resection.
Authors’ Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, of for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Supported by a grant from Sanofi-Aventis, Paris, France.
Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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