Phase I Trial of Systemic Oxaliplatin Combination Chemotherapy With Hepatic Arterial Infusion in Patients With Unresectable Liver Metastases
http://www.100md.com
《临床肿瘤学》
the Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY
ABSTRACT
PURPOSE: To determine the maximum-tolerated dose (MTD) of concurrent systemic oxaliplatin (Oxal) combinations plus hepatic arterial infusion (HAI) in patients with unresectable hepatic metastases from colorectal cancer.
PATIENTS AND METHODS: Thirty-six patients (89% previously treated) with unresectable liver metastases were treated with concurrent HAI and systemic Oxal plus irinotecan (CPT-11; group A) or Oxal, fluorouracil (FU), and leucovorin (LV; group B). Systemic chemotherapy was administered every 2 weeks concurrent with 2 weeks of HAI floxuridine (FUDR) and dexamethasone (Dex) every 28 days.
RESULTS: The MTD for patients in group A was Oxal 100 mg/m2, CPT-11 150 mg/m2, and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate. The MTD for group B was Oxal 100 mg/m2, LV 400 mg/m2, and FU 1,400 mg/m2 by continuous infusion over 48 hours, with the same FUDR dose as in group A. Grade 3 or 4 toxicities in groups A and B included diarrhea (24% and 20%), neutropenia (10% and 7%), neurotoxicity (24% and 20%), and bilirubin more than 3 mg/mL (5% and 7%, respectively). The complete and partial response rate totaled 90% for group A and 87% for group B. Median survival time was 36 and 22 months for groups A and B, respectively. Seven patients in group A were ultimately able to undergo liver resection.
CONCLUSION: Combination therapy with HAI FUDR and Dex plus systemic Oxal combinations may be safely administered to patients with colorectal cancer. The high response rate (88%) and the possibility of conversion to resectability, despite disease progression on prior systemic regimens, suggest that these combinations should be evaluated in larger studies as first- or second-line therapy in patients with hepatic metastases from colorectal cancer.
INTRODUCTION
This year, 140,000 people will develop colorectal cancer in the United States, and 60% of these people will develop liver metastases during or after treatment of their disease.1 Over the last few years, significant progress has been made with new chemotherapeutic agents and new targeted therapies to increase survival.
For many years, the only treatment for colorectal cancer was a combination of fluorouracil (FU) and leucovorin (LV), which produced response rates of approximately 20% and 2-year survival rates of 20%.2 With the development of irinotecan (CPT-11) and oxaliplatin (Oxal), the response rates have increased to 30% to 45%,3,4 with median survival times of 15 to 19.5 months,3,4 but 2-year survival rates remains low at 25% to 35%. Recent data from a randomized controlled trial suggested that Oxal is effective for treating colorectal cancer. The median survival was 17.4 months when Oxal was combined with CPT-11, 19.5 months when Oxal was combined with FU/LV,5 and 15 months with CPT-11/FU/LV. In previously treated patients, however, response rates with CPT-11 or Oxal drop to less than 30%,6-9 with median survival times of only 9 to 12 months.
For patients whose metastases are confined to the liver, complete surgical resection is associated with 30% survival at 5 years.10 Therefore, the optimal approach, when feasible, is surgical resection, which is being performed more often as surgical techniques improve and more effective chemotherapeutic agents have been developed. When resection is not possible because of the number of tumors or the location of tumors, other local methods of therapy, such as radiofrequency ablation11 or cryotherapy,12 have been used. Another liver-directed therapy is the administration of hepatic arterial infusion (HAI) therapy.13 Initial trials with HAI therapy used the regional approach without added systemic therapy. These trials demonstrated increased response rates and progression-free survival, but many of these trials did not show an increase in overall survival.14 Combining new systemic chemotherapy treatments with HAI and, thereby, effectively treating extrahepatic and intrahepatic disease may further improve results.
The following phase I study explored the use of concurrent HAI floxuridine (FUDR) and dexamethasone (Dex) with two systemic Oxal combinations. The two systemic dose schedules were evaluated and escalated separately (Oxal plus CPT-11: group A, and Oxal plus FU and LV: group B). In group A, the Oxal and CPT-11 doses were escalated separately; in Group B, the Oxal dose was held constant while FU doses were escalated until the maximum-tolerated dose (MTD) was achieved. The study was conducted to assess the MTD, tolerability, and effectiveness of these combined regimens and to determine whether there were any contraindications to their joint administration.
PATIENTS AND METHODS
Eligibility Criteria, Pretreatment Evaluation, and Follow-Up
All patients had histologically confirmed colorectal adenocarcinoma with unresectable hepatic metastases. Patients were excluded from the study for any of the following reasons: extrahepatic disease, prior hepatic radiation, previous FUDR treatment, a Karnofsky performance score of less than 60, symptomatic peripheral sensory neuropathy, a WBC count of less than 3,000 cells/μL, a platelet count of less than 100,000 cells/μL, a serum total bilirubin level of 2.0 mg/dL (34.2 μmol/L), and a previous or concurrent malignancy besides colorectal carcinoma (patients free of this disease for at least 5 years were considered eligible). Prior treatment for metastatic disease was permitted if the last dose had been administered at least 1 month before the date of pump placement. All patients provided written informed consent. The protocol and informed consent were approved by the Memorial Sloan-Kettering Cancer Center Institutional Review Board.
Pretreatment evaluation included a complete history, physical examination, and laboratory studies, including CBC count, total bilirubin, alkaline phosphatase, AST, carcinoembryonic antigen (CEA), and lactate dehydrogenase (LDH), obtained within 1 week before commencement of chemotherapy. Computed tomography (CT) scans of the abdomen and pelvis and chest x-ray films were obtained within 6 weeks before surgery, and all patients underwent a preoperative hepatic CT angiogram, including visualization of the celiac and superior mesenteric arteries, to evaluate hepatic arterial blood supply. During treatment, all patients underwent evaluation of CBC and liver function tests every 2 weeks and received bimonthly CT scanning of the abdomen and pelvis and chest radiography.
Surgical guidelines for pump placement have been previously reported. Suspicious nodes and/or masses were biopsied, and a cholecystectomy was performed if not performed previously. The pump catheter was positioned at the junction of the proper and common hepatic arteries via the gastroduodenal, splenic, or celiac arteries. The distal gastroduodenal, the right gastric artery, and small branches supplying the stomach, duodenum, or pancreas were ligated, as were all accessory hepatic arteries. Intraoperative liver perfusion was tested. The catheter was secured in the artery with at least two nonabsorbable ties. Postoperatively, technetium macroaggregated human serum albumin was infused via the port of the pump to assess adequacy of perfusion.
Responses were assessed with a CT of the abdomen obtained at 2-month intervals. All responses were confirmed by our radiologists and then measured separately by a reference radiologist (L.S.). A complete response required the disappearance of all disease on CT and normalization of CEA levels. A partial response was defined as a reduction of 50% in the sum of the products of the greatest perpendicular diameters of tumor nodules measured on any follow-up CT compared with baseline. A reduction of less than 50% was considered stable disease.
Criteria for Unresectable Disease
Patients were considered unresectable if disease involved all hepatic segments or if resection would leave behind an inadequate liver remnant. Bilobar disease or number of metastases did not exclude a patient from consideration for resection, provided a complete resection was possible. Tumors that involved all three main hepatic veins or both inflow pedicles were also considered unresectable. All patient cases were reviewed at a multidisciplinary conference involving surgeons, radiologists, and medical oncologists.
Chemotherapy Administration
Patients received systemic chemotherapy and HAI concurrently. Patients were assigned to one of two treatment arms depending on space available among cohorts in each arm. In both treatment groups, chemotherapy was initiated 2 to 3 weeks after pump placement surgery. Therapy was administered on a 4-week cycle; patients received both regional (via the HAI Codman pump; Johnson & Johnson, Raynham, MA) and systemic chemotherapy on day 1 of each cycle, and on day 15, systemic chemotherapy was administered again with heparinized saline in the HAI pump (30,000 U of heparin with 30 mL of saline). A minimum of three patients were entered at each dose level and were monitored for two cycles before the next cohort of three patients could be enrolled. Patients received protocol treatment until one of the following events occurred: there was a reduction in the extent of disease that rendered the patient a candidate for resection; there was hepatic or extrahepatic progression of disease; or excessive toxicity was experienced.
Dose Schedule for Treatment Group A
Patients in group A received systemic Oxal and CPT-11 with concurrent HAI therapy. The dose of FUDR was held constant at 0.12 mg/kg x 30 mL divided by pump flow rate. FUDR was administered over 14 days with Dex 25 mg, heparin 30,000 U, and normal saline in a quantity sufficient to fill the 30-mL pump reservoir. On day 15, systemic Oxal and CPT-11 were administered again, and the pump residual fluid was removed, and heparinized saline was injected.
The doses of Oxal and CPT-11 were escalated separately (Table 1). Initially, six cohorts were planned. First, CPT-11 remained constant at 150 mg/m2, while Oxal was escalated from 85 to 100 mg/m2 and then to 130 mg/m2. Once the MTD of Oxal was found, CPT-11 was increased to 200 mg/m2, and Oxal was then escalated from 85 to 100 mg/m2 and then to 130 mg/m2. After reaching the MTD, at least six additional patients were enrolled to further evaluate this dose level. Systemic Oxal was administered over a 2-hour infusion followed by a 30-minute infusion of CPT-11 on days 1 and 15 of each cycle.
Dose Schedule for Treatment Group B
Patients in group B received systemic Oxal, FU, and LV with concurrent HAI FUDR and Dex. The doses of Oxal, LV, and FUDR were held constant at Oxal 100 mg/m2, LV 400 mg/m2, and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate. Four dose levels of a 48-hour infusion of FU were planned (Table 2). FU was escalated from 1,000 to 1,200, 1,400, and 1,600 mg/m2. On days 1 and 15 of each cycle, systemic Oxal and LV were administered separately over a 2-hour infusion via a Y tube, followed by a 48-hour infusion of FU. HAI FUDR and Dex with heparinized saline were administered over 14 days starting on day 1 of each cycle, followed by 14 days of heparinized saline starting on day 15.
Toxicity Assessment and Dose Modification
All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 2). FUDR dose modifications were dependent on liver function tests as outlined previously.22 Because patients entered the study with varying degrees of hepatic enzyme increases caused by disease, hepatic toxicity from treatment was defined as a significant increase over individual baseline values (two-fold or greater for alkaline phosphatase, three-fold or greater for AST, and bilirubin 3 mg/dL). In case of elevated transaminases and/or total bilirubin, FUDR administration was held until laboratory values improved as indicated. Epigastric pain prompted work-up with an upper GI endoscopy. If an ulcer or gastroduodenitis was documented, HAI therapy was held for 1 month to allow healing. Severe abdominal pain or diarrhea during HAI treatment prompted the immediate emptying of drug from the pump and the instillation of heparinized saline or glycerol (50%) until the results of a work-up (including a repeat flow scan to rule out extrahepatic perfusion) were available.
For the purposes of dose escalation, dose-limiting toxicity (DLT) was defined as any of the following events occurring during the first two cycles: grade 4 neutropenia or thrombocytopenia; neutropenic fever, defined as grade 3 or 4 neutropenia plus fever greater than 38.3°C; grade 3 or 4 diarrhea despite aggressive use of loperamide; total bilirubin 3.0 mg/dL not caused by disease progression (ie, biliary obstruction caused by tumor was ruled out); and serum creatinine 1.8 mg/dL that does not recover to less than 1.5 mg/dL within 2 weeks. Toxicities occurring in later cycles will also be reported.
In the event of neurosensory toxicity that lasted between 1 and 7 days but was not persistent between cycles, no dose modification was made for Oxal. However, in the event that patients experienced persistent neuropathy lasting more than 7 days and/or between cycles, Oxal dose modifications were made depending on the severity of the toxicity (Table 3).
Study Design and Statistical Analysis
The primary objective of this phase I study was to determine the MTD of biweekly intravenous Oxal and CPT-11 with HAI FUDR and Dex (group A) or intravenous Oxal, FU, and LV with HAI FUDR and Dex (group B) in patients with unresectable hepatic metastases from colorectal cancer. The two groups were enrolled under separate protocols, but accrual was simultaneous. Patients were enrolled onto the first cohort of the first protocol until the cohort was filled. Then the first cohort of the second protocol was opened for enrollment. Patient assignment proceeded in this fashion, switching between protocols as cohorts filled up. There were no other selection criteria for assigning patients to treatments.
At least three patients were entered at each dose level. If no patient experienced a DLT, the next cohort was opened for enrollment. If two of the three patients experienced a DLT, then it was concluded that the previous level was the MTD. If one of the three patients experienced a DLT, then at least three more patients were enrolled at the same dose. If none of the additional three patients experienced a DLT, then the next cohort would be opened for enrollment. If there were any DLTs in the additional patients, then it was concluded that the previous level was the MTD. This design has a high probability of escalating the dose if the current dose level is not toxic and a low probability of escalation if the current dose level is too toxic. For example, if the chance of experiencing a DLT at the current dose level is 10%, then the probability of advancing to the next dose level is 91%. This probability reduces to 49% if the chance of experiencing a DLT is 30% and to only 17% if the chance of experiencing a DLT is 50%.
RESULTS
Thirty-six patients with unresectable liver metastases from colorectal cancer were entered onto the study. Seven other patients were not registered to enter the study for the following reasons: extrahepatic disease (n = 5), variant anatomy (n = 1), or extrahepatic perfusion (n = 1). Patient characteristics are listed in Table 4. Twenty-one patients received systemic Oxal and CPT-11 plus HAI FUDR and Dex (group A). Fifteen patients received systemic Oxal, FU, and LV plus HAI FUDR and Dex (group B). Total patient characteristics include a median age of 59 years (range, 31 to 70 years), median performance status of 80% (range, 70% to 100%), and median percent liver involvement of 38% (range, 10% to 80%). Eighty-nine percent of patients (32 of 36 patients) received prior chemotherapy, and 69.4% (25 of 36 patients) were previously treated with CPT-11. Median baseline CEA was 72 ng/dL (range, 2.3 to 4,673 ng/dL), with 97% of patients having an abnormal baseline CEA. Median baseline LDH was 144 mg/dL (range, 100 to 1,322 mg/dL), with 69% of patients having an abnormal baseline LDH.
Toxicity in Treatment Group A
At the first dose level (Oxal 85 mg/m2 and CPT-11 150 mg/m2), one patient experienced a DLT and was admitted to the hospital for grade 4 neutropenic fever and grade 4 diarrhea. This patient’s toxicity resolved after 9 days when his WBC returned to normal. Subsequently, this cohort was expanded to accrue a total of six patients. No other DLTs were observed within the first two cycles of treatment, and thus, the dose of Oxal was escalated as planned. There were no toxicities exhibited in the three patients accrued to the second dose level (Oxal 100 mg/m2 and CPT-11 150 mg/m2). Dose escalation of Oxal was halted in the third dose level (Oxal 130 mg/m2 and CPT-11 150 mg/m2) when two patients experienced DLTs during the first two cycles of treatment; one patient experienced grade 3 fatigue and grade 3 neutropenia, and the other patient was admitted for grade 4 diarrhea and grade 3 vomiting, which resolved after 8 days.
After discovering the optimal Oxal dose, we escalated CPT-11 to 200 mg/m2. Because we were using CPT-11 at a higher dose, we reduced Oxal to the initial dose level of 85 mg/m2. At this dose, two of four patients experienced DLTs within the first two cycles; both patients were admitted for grade 4 neutropenic fevers (one patient also had grade 4 diarrhea, and the other patient also had syncope). In both patients, symptoms resolved after 8 days. Thus, it was determined that CPT-11 at a dose level of 200 mg/m2 was too toxic. Therefore, the MTD was CPT-11 at 150 mg/m2 and Oxal at 100 mg/m2, and six additional patients were accrued to this dose level.
The toxicities exhibited in group A patients after two cycles of treatment were as follows: eight patients experienced elevated alkaline phosphatase levels ( 2 x baseline); one patient experienced elevated bilirubin levels (> 3 mg/mL); and two patients exhibited elevated AST levels ( 3 x baseline). Grade 2 neurotoxicity was seen in 11 patients between 4 and 9 months after initiating therapy (Table 5). Five of those patients went on to experience grade 3 neurotoxicity between 4 and 11 months after treatment was started. All five patients have had improvement in neurotoxicity when Oxal was stopped, but in some patients, the improvement only occurred after 12 months.
Toxicity in Treatment Group B
In treatment group B, the dose levels of Oxal (100 mg/m2), LV (400 mg/m2), and FUDR (0.12 mg/kg x 30 mL divided by flow rate) were held constant, whereas the 48-hour infusion of FU was escalated from 1,000 to 1,200 to 1,400 mg/m2. At these dose levels, no toxicity was experienced within the first two cycles. At the dose level of 1,600 mg/m2, three patients experienced DLTs within the first two cycles of treatment, with toxicities as follows: one patient was admitted to the hospital for grade 4 neutropenic fever and grade 3 diarrhea, which resolved after 10 days; one patient was admitted for grade 3 diarrhea, nausea, and vomiting, which resolved after 5 days; and one patient experienced grade 4 diarrhea but did not require hospital admission (Table 6). Therefore, the MTD was determined to be Oxal 100 mg/m2, LV 400 mg/m2, 48-hour infusion of FU 1,400 mg/m2, and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate.
Toxicity in treatment group B after the first two cycles of treatment consisted of grade 3 thrombocytopenia in one patient. Alkaline phosphatase elevations 2 x baseline were seen in four patients, one patient had a bilirubin level of more than 3 mg/mL, and four patients exhibited elevated AST levels 3 x baseline. Ten patients experienced grade 2 neurotoxicity between 4 and 7 months, and three patients went on to experience grade 3 neurotoxicity between 6 and 9 months after the initiation of therapy.
Response and Survival
Group A. Partial responses were observed in 19 (90%) of 21 patients from group A. Seven of 21 patients were able to undergo liver resection, and two of these patients had no remaining tumor (Fig 1). Median reduction of tumor size for group A was 84%. Six patients exhibited a response to their prior therapy before eventually experiencing progression, and all patients exhibited responses to the current therapy. Of those patients who did not respond, 82% of patients responded to current pump treatment. Of the 21 patients in group A initially showing elevated baseline CEA levels, 18 (86%) showed a 50% reduction in CEA.
The median survival time from pump placement (ie, entry onto protocol) for group A patients was 35.8 months (95% CI, 23.9 months to not reached [NR]), with 11 (52%) of 21 patients still alive (Table 7). One-year survival rate was 90%, and 2-year survival rate was 65% (Fig 2). Median time from first diagnosis of liver metastases was 47 months. Median time to hepatic progression was 16.4 months (95% CI, 13.1 months to NR), and median time extrahepatic progression was 16.9 months (95% CI, 12.4 months to NR).
Group B. Partial responses were observed in 13 (87%) of 15 patients from group B. Median reduction of tumor size for group B was 78%. Five patients showed initial response to their prior therapy before eventually progressing, and four patients (80%) exhibited a response to this current therapy. Of the 10 patients with no response to their prior chemotherapy, nine (90%) exhibited a response to this therapy (Fig 3). Of 14 patients in group B initially showing elevated baseline CEA levels, 12 patients (86%) showed an overall 50% reduction in CEA.
The median survival time from the time the pump was placed was 22 months (95% CI, 15.4 months to NR), and the 1- and 2-year survival rates were 80% and 40%, respectively (Fig 2). Median survival time from first diagnosis of liver metastases was 35 months. Median time to hepatic progression was 9.4 months (95% CI, 7.6 to 19.3 months), and median time to extrahepatic progression was 10.8 months (95% CI, 7.8 to 27.1 months).
DISCUSSION
Only a decade ago, physicians were frustrated at the limited treatment options available for metastatic colorectal cancer. Currently, the frustration lies not in the limited options but, rather, in choosing the optimal treatment strategy from the treatment approaches now available. Trials on chemotherapy-na?ve patients demonstrate that combinations of CPT-11/FU/LV3 and Oxal/FU/LV4 will increase response and survival compared with FU/LV alone. Studies with bevacizumab and CPT-11/FU/LV15 demonstrate improved survival and response compared with the three drugs without bevacizumab. For patients who experience progression on first-line therapy, there are now agents that can be used for second-line therapy. CPT-11 alone,16 CPT-11 plus cetuximab,17 and Oxal/FU/LV18 will produce responses ranging from 9% to 22% in patients whose tumor has progressed on first-line chemotherapy. However, the median survival time for these patients after second-line therapy is 12 months or less. Because many patients still have liver-only disease when their disease progresses on first-line therapy, regional chemotherapy remains a viable option. Regional therapy with HAI FUDR, LV, and Dex produced a 52% response rate as second-line therapy, with a median survival time of 13.5 months.19
The advantage of HAI regional therapy is the ability to administer high doses of chemotherapy locally. For a drug such as FUDR, which has a liver extraction rate of 94%,20 systemic toxicity from HAI FUDR is extremely rare, allowing almost full doses of systemic chemotherapy to be administered concurrently. Combining HAI with systemic chemotherapy may result in improved efficacy relative to either approach alone. In a Cancer and Leukemia Group B trial (Kemeny et al, manuscript submitted for publication) comparing trial HAI FUDR/LV/Dex with systemic FU/LV, the response rate (48% v 25%, respectively) and median survival time (24 v 20 months, respectively; P = .0013) was higher in the HAI group. Although time to hepatic progression was better in the HAI arm compared with the systemic arm (9.8 v 7.3 months, respectively; P = .034), the time to extrahepatic progression was better in the systemic arm (7.7 v 14.8 months, respectively; P = .029). Therefore, combining HAI with systemic therapy should take advantage of the relative benefits of both HAI and systemic therapy. In a prior study using systemic CPT-11 plus HAI FUDR and Dex,21 the response rate was 74%, with a median survival of 16 months, in patients who had already received prior systemic therapy. With the aim of further improving outcome for patients with unresectable hepatic metastases, we designed a study combining the most promising systemic chemotherapy agents with an effective regional therapy of FUDR and Dex.
This trial was a phase I study of systemic Oxal combinations with regional therapy. Using the combination of HAI and systemic Oxal did not impact on the dose of Oxal that could be administered. The usual Oxal dose is 85 mg/m2 every other week, whereas in this trial, we were able to deliver 100 mg/m2. A national trial used Oxal 85 mg/m2 and CPT-11 200 mg/m2 every 3 weeks.5 Therefore, the combination doses used in this trial were similar to those used in systemic chemotherapy trials because the drugs in this study were administered every 2 weeks. However, the doses for the combination of Oxal plus FU/LV used in this study were lower than the doses usually used in systemic chemotherapy–alone trials. The standard Oxal dose was maintained at 100 mg/m2 every 2 weeks, but the MTD of FU (1,400 mg/m2) was much lower than what is usually administered in systemic chemotherapy trials, where a 48-hour infusion of FU at 2,000 mg/m2 can be administered.7 Because FU and FUDR are both fluoropyridines, the dose of the two agents together may have increased the toxicities most commonly observed with FU. Therefore, we could not escalate the FU dose close to the level used with systemic therapy alone.
Although this was a phase I study to examine toxicity, the response rate was high compared with other second-line therapies. The protocol and complete response rates were 90% and 87% with the HAI plus Oxal/CPT-11 and HAI plus Oxal/FU/LV combinations, respectively. More than 50% of patients showed a greater than 75% reduction in their tumor, and seven patients were able to undergo liver resection, two of whom had complete pathologic response. In a reported study, neoadjuvant HAI therapy alone in chemotherapy-na?ve patients allowed enough downstaging in six of 23 patients so that resection was possible.22 Although there is increasing interest in the use of neoadjuvant systemic therapy23 for patients with unresectable disease, such treatment rarely renders patients resectable after tumor progression on first-line therapy.
In conclusion, combination therapy with HAI FUDR and Dex plus systemic Oxal/CPT-11 or Oxal/FU/LV is safe and well tolerated. The high response rates observed with HAI and systemic Oxal-based combinations provide a rationale for further investigation of these regimens in the neoadjuvant setting even in patients who have experienced progression on first-line chemotherapy.
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, or 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.
Acknowledgment
We thank Maria-Leticia E. Bravo for manuscript preparation.
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
PURPOSE: To determine the maximum-tolerated dose (MTD) of concurrent systemic oxaliplatin (Oxal) combinations plus hepatic arterial infusion (HAI) in patients with unresectable hepatic metastases from colorectal cancer.
PATIENTS AND METHODS: Thirty-six patients (89% previously treated) with unresectable liver metastases were treated with concurrent HAI and systemic Oxal plus irinotecan (CPT-11; group A) or Oxal, fluorouracil (FU), and leucovorin (LV; group B). Systemic chemotherapy was administered every 2 weeks concurrent with 2 weeks of HAI floxuridine (FUDR) and dexamethasone (Dex) every 28 days.
RESULTS: The MTD for patients in group A was Oxal 100 mg/m2, CPT-11 150 mg/m2, and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate. The MTD for group B was Oxal 100 mg/m2, LV 400 mg/m2, and FU 1,400 mg/m2 by continuous infusion over 48 hours, with the same FUDR dose as in group A. Grade 3 or 4 toxicities in groups A and B included diarrhea (24% and 20%), neutropenia (10% and 7%), neurotoxicity (24% and 20%), and bilirubin more than 3 mg/mL (5% and 7%, respectively). The complete and partial response rate totaled 90% for group A and 87% for group B. Median survival time was 36 and 22 months for groups A and B, respectively. Seven patients in group A were ultimately able to undergo liver resection.
CONCLUSION: Combination therapy with HAI FUDR and Dex plus systemic Oxal combinations may be safely administered to patients with colorectal cancer. The high response rate (88%) and the possibility of conversion to resectability, despite disease progression on prior systemic regimens, suggest that these combinations should be evaluated in larger studies as first- or second-line therapy in patients with hepatic metastases from colorectal cancer.
INTRODUCTION
This year, 140,000 people will develop colorectal cancer in the United States, and 60% of these people will develop liver metastases during or after treatment of their disease.1 Over the last few years, significant progress has been made with new chemotherapeutic agents and new targeted therapies to increase survival.
For many years, the only treatment for colorectal cancer was a combination of fluorouracil (FU) and leucovorin (LV), which produced response rates of approximately 20% and 2-year survival rates of 20%.2 With the development of irinotecan (CPT-11) and oxaliplatin (Oxal), the response rates have increased to 30% to 45%,3,4 with median survival times of 15 to 19.5 months,3,4 but 2-year survival rates remains low at 25% to 35%. Recent data from a randomized controlled trial suggested that Oxal is effective for treating colorectal cancer. The median survival was 17.4 months when Oxal was combined with CPT-11, 19.5 months when Oxal was combined with FU/LV,5 and 15 months with CPT-11/FU/LV. In previously treated patients, however, response rates with CPT-11 or Oxal drop to less than 30%,6-9 with median survival times of only 9 to 12 months.
For patients whose metastases are confined to the liver, complete surgical resection is associated with 30% survival at 5 years.10 Therefore, the optimal approach, when feasible, is surgical resection, which is being performed more often as surgical techniques improve and more effective chemotherapeutic agents have been developed. When resection is not possible because of the number of tumors or the location of tumors, other local methods of therapy, such as radiofrequency ablation11 or cryotherapy,12 have been used. Another liver-directed therapy is the administration of hepatic arterial infusion (HAI) therapy.13 Initial trials with HAI therapy used the regional approach without added systemic therapy. These trials demonstrated increased response rates and progression-free survival, but many of these trials did not show an increase in overall survival.14 Combining new systemic chemotherapy treatments with HAI and, thereby, effectively treating extrahepatic and intrahepatic disease may further improve results.
The following phase I study explored the use of concurrent HAI floxuridine (FUDR) and dexamethasone (Dex) with two systemic Oxal combinations. The two systemic dose schedules were evaluated and escalated separately (Oxal plus CPT-11: group A, and Oxal plus FU and LV: group B). In group A, the Oxal and CPT-11 doses were escalated separately; in Group B, the Oxal dose was held constant while FU doses were escalated until the maximum-tolerated dose (MTD) was achieved. The study was conducted to assess the MTD, tolerability, and effectiveness of these combined regimens and to determine whether there were any contraindications to their joint administration.
PATIENTS AND METHODS
Eligibility Criteria, Pretreatment Evaluation, and Follow-Up
All patients had histologically confirmed colorectal adenocarcinoma with unresectable hepatic metastases. Patients were excluded from the study for any of the following reasons: extrahepatic disease, prior hepatic radiation, previous FUDR treatment, a Karnofsky performance score of less than 60, symptomatic peripheral sensory neuropathy, a WBC count of less than 3,000 cells/μL, a platelet count of less than 100,000 cells/μL, a serum total bilirubin level of 2.0 mg/dL (34.2 μmol/L), and a previous or concurrent malignancy besides colorectal carcinoma (patients free of this disease for at least 5 years were considered eligible). Prior treatment for metastatic disease was permitted if the last dose had been administered at least 1 month before the date of pump placement. All patients provided written informed consent. The protocol and informed consent were approved by the Memorial Sloan-Kettering Cancer Center Institutional Review Board.
Pretreatment evaluation included a complete history, physical examination, and laboratory studies, including CBC count, total bilirubin, alkaline phosphatase, AST, carcinoembryonic antigen (CEA), and lactate dehydrogenase (LDH), obtained within 1 week before commencement of chemotherapy. Computed tomography (CT) scans of the abdomen and pelvis and chest x-ray films were obtained within 6 weeks before surgery, and all patients underwent a preoperative hepatic CT angiogram, including visualization of the celiac and superior mesenteric arteries, to evaluate hepatic arterial blood supply. During treatment, all patients underwent evaluation of CBC and liver function tests every 2 weeks and received bimonthly CT scanning of the abdomen and pelvis and chest radiography.
Surgical guidelines for pump placement have been previously reported. Suspicious nodes and/or masses were biopsied, and a cholecystectomy was performed if not performed previously. The pump catheter was positioned at the junction of the proper and common hepatic arteries via the gastroduodenal, splenic, or celiac arteries. The distal gastroduodenal, the right gastric artery, and small branches supplying the stomach, duodenum, or pancreas were ligated, as were all accessory hepatic arteries. Intraoperative liver perfusion was tested. The catheter was secured in the artery with at least two nonabsorbable ties. Postoperatively, technetium macroaggregated human serum albumin was infused via the port of the pump to assess adequacy of perfusion.
Responses were assessed with a CT of the abdomen obtained at 2-month intervals. All responses were confirmed by our radiologists and then measured separately by a reference radiologist (L.S.). A complete response required the disappearance of all disease on CT and normalization of CEA levels. A partial response was defined as a reduction of 50% in the sum of the products of the greatest perpendicular diameters of tumor nodules measured on any follow-up CT compared with baseline. A reduction of less than 50% was considered stable disease.
Criteria for Unresectable Disease
Patients were considered unresectable if disease involved all hepatic segments or if resection would leave behind an inadequate liver remnant. Bilobar disease or number of metastases did not exclude a patient from consideration for resection, provided a complete resection was possible. Tumors that involved all three main hepatic veins or both inflow pedicles were also considered unresectable. All patient cases were reviewed at a multidisciplinary conference involving surgeons, radiologists, and medical oncologists.
Chemotherapy Administration
Patients received systemic chemotherapy and HAI concurrently. Patients were assigned to one of two treatment arms depending on space available among cohorts in each arm. In both treatment groups, chemotherapy was initiated 2 to 3 weeks after pump placement surgery. Therapy was administered on a 4-week cycle; patients received both regional (via the HAI Codman pump; Johnson & Johnson, Raynham, MA) and systemic chemotherapy on day 1 of each cycle, and on day 15, systemic chemotherapy was administered again with heparinized saline in the HAI pump (30,000 U of heparin with 30 mL of saline). A minimum of three patients were entered at each dose level and were monitored for two cycles before the next cohort of three patients could be enrolled. Patients received protocol treatment until one of the following events occurred: there was a reduction in the extent of disease that rendered the patient a candidate for resection; there was hepatic or extrahepatic progression of disease; or excessive toxicity was experienced.
Dose Schedule for Treatment Group A
Patients in group A received systemic Oxal and CPT-11 with concurrent HAI therapy. The dose of FUDR was held constant at 0.12 mg/kg x 30 mL divided by pump flow rate. FUDR was administered over 14 days with Dex 25 mg, heparin 30,000 U, and normal saline in a quantity sufficient to fill the 30-mL pump reservoir. On day 15, systemic Oxal and CPT-11 were administered again, and the pump residual fluid was removed, and heparinized saline was injected.
The doses of Oxal and CPT-11 were escalated separately (Table 1). Initially, six cohorts were planned. First, CPT-11 remained constant at 150 mg/m2, while Oxal was escalated from 85 to 100 mg/m2 and then to 130 mg/m2. Once the MTD of Oxal was found, CPT-11 was increased to 200 mg/m2, and Oxal was then escalated from 85 to 100 mg/m2 and then to 130 mg/m2. After reaching the MTD, at least six additional patients were enrolled to further evaluate this dose level. Systemic Oxal was administered over a 2-hour infusion followed by a 30-minute infusion of CPT-11 on days 1 and 15 of each cycle.
Dose Schedule for Treatment Group B
Patients in group B received systemic Oxal, FU, and LV with concurrent HAI FUDR and Dex. The doses of Oxal, LV, and FUDR were held constant at Oxal 100 mg/m2, LV 400 mg/m2, and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate. Four dose levels of a 48-hour infusion of FU were planned (Table 2). FU was escalated from 1,000 to 1,200, 1,400, and 1,600 mg/m2. On days 1 and 15 of each cycle, systemic Oxal and LV were administered separately over a 2-hour infusion via a Y tube, followed by a 48-hour infusion of FU. HAI FUDR and Dex with heparinized saline were administered over 14 days starting on day 1 of each cycle, followed by 14 days of heparinized saline starting on day 15.
Toxicity Assessment and Dose Modification
All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 2). FUDR dose modifications were dependent on liver function tests as outlined previously.22 Because patients entered the study with varying degrees of hepatic enzyme increases caused by disease, hepatic toxicity from treatment was defined as a significant increase over individual baseline values (two-fold or greater for alkaline phosphatase, three-fold or greater for AST, and bilirubin 3 mg/dL). In case of elevated transaminases and/or total bilirubin, FUDR administration was held until laboratory values improved as indicated. Epigastric pain prompted work-up with an upper GI endoscopy. If an ulcer or gastroduodenitis was documented, HAI therapy was held for 1 month to allow healing. Severe abdominal pain or diarrhea during HAI treatment prompted the immediate emptying of drug from the pump and the instillation of heparinized saline or glycerol (50%) until the results of a work-up (including a repeat flow scan to rule out extrahepatic perfusion) were available.
For the purposes of dose escalation, dose-limiting toxicity (DLT) was defined as any of the following events occurring during the first two cycles: grade 4 neutropenia or thrombocytopenia; neutropenic fever, defined as grade 3 or 4 neutropenia plus fever greater than 38.3°C; grade 3 or 4 diarrhea despite aggressive use of loperamide; total bilirubin 3.0 mg/dL not caused by disease progression (ie, biliary obstruction caused by tumor was ruled out); and serum creatinine 1.8 mg/dL that does not recover to less than 1.5 mg/dL within 2 weeks. Toxicities occurring in later cycles will also be reported.
In the event of neurosensory toxicity that lasted between 1 and 7 days but was not persistent between cycles, no dose modification was made for Oxal. However, in the event that patients experienced persistent neuropathy lasting more than 7 days and/or between cycles, Oxal dose modifications were made depending on the severity of the toxicity (Table 3).
Study Design and Statistical Analysis
The primary objective of this phase I study was to determine the MTD of biweekly intravenous Oxal and CPT-11 with HAI FUDR and Dex (group A) or intravenous Oxal, FU, and LV with HAI FUDR and Dex (group B) in patients with unresectable hepatic metastases from colorectal cancer. The two groups were enrolled under separate protocols, but accrual was simultaneous. Patients were enrolled onto the first cohort of the first protocol until the cohort was filled. Then the first cohort of the second protocol was opened for enrollment. Patient assignment proceeded in this fashion, switching between protocols as cohorts filled up. There were no other selection criteria for assigning patients to treatments.
At least three patients were entered at each dose level. If no patient experienced a DLT, the next cohort was opened for enrollment. If two of the three patients experienced a DLT, then it was concluded that the previous level was the MTD. If one of the three patients experienced a DLT, then at least three more patients were enrolled at the same dose. If none of the additional three patients experienced a DLT, then the next cohort would be opened for enrollment. If there were any DLTs in the additional patients, then it was concluded that the previous level was the MTD. This design has a high probability of escalating the dose if the current dose level is not toxic and a low probability of escalation if the current dose level is too toxic. For example, if the chance of experiencing a DLT at the current dose level is 10%, then the probability of advancing to the next dose level is 91%. This probability reduces to 49% if the chance of experiencing a DLT is 30% and to only 17% if the chance of experiencing a DLT is 50%.
RESULTS
Thirty-six patients with unresectable liver metastases from colorectal cancer were entered onto the study. Seven other patients were not registered to enter the study for the following reasons: extrahepatic disease (n = 5), variant anatomy (n = 1), or extrahepatic perfusion (n = 1). Patient characteristics are listed in Table 4. Twenty-one patients received systemic Oxal and CPT-11 plus HAI FUDR and Dex (group A). Fifteen patients received systemic Oxal, FU, and LV plus HAI FUDR and Dex (group B). Total patient characteristics include a median age of 59 years (range, 31 to 70 years), median performance status of 80% (range, 70% to 100%), and median percent liver involvement of 38% (range, 10% to 80%). Eighty-nine percent of patients (32 of 36 patients) received prior chemotherapy, and 69.4% (25 of 36 patients) were previously treated with CPT-11. Median baseline CEA was 72 ng/dL (range, 2.3 to 4,673 ng/dL), with 97% of patients having an abnormal baseline CEA. Median baseline LDH was 144 mg/dL (range, 100 to 1,322 mg/dL), with 69% of patients having an abnormal baseline LDH.
Toxicity in Treatment Group A
At the first dose level (Oxal 85 mg/m2 and CPT-11 150 mg/m2), one patient experienced a DLT and was admitted to the hospital for grade 4 neutropenic fever and grade 4 diarrhea. This patient’s toxicity resolved after 9 days when his WBC returned to normal. Subsequently, this cohort was expanded to accrue a total of six patients. No other DLTs were observed within the first two cycles of treatment, and thus, the dose of Oxal was escalated as planned. There were no toxicities exhibited in the three patients accrued to the second dose level (Oxal 100 mg/m2 and CPT-11 150 mg/m2). Dose escalation of Oxal was halted in the third dose level (Oxal 130 mg/m2 and CPT-11 150 mg/m2) when two patients experienced DLTs during the first two cycles of treatment; one patient experienced grade 3 fatigue and grade 3 neutropenia, and the other patient was admitted for grade 4 diarrhea and grade 3 vomiting, which resolved after 8 days.
After discovering the optimal Oxal dose, we escalated CPT-11 to 200 mg/m2. Because we were using CPT-11 at a higher dose, we reduced Oxal to the initial dose level of 85 mg/m2. At this dose, two of four patients experienced DLTs within the first two cycles; both patients were admitted for grade 4 neutropenic fevers (one patient also had grade 4 diarrhea, and the other patient also had syncope). In both patients, symptoms resolved after 8 days. Thus, it was determined that CPT-11 at a dose level of 200 mg/m2 was too toxic. Therefore, the MTD was CPT-11 at 150 mg/m2 and Oxal at 100 mg/m2, and six additional patients were accrued to this dose level.
The toxicities exhibited in group A patients after two cycles of treatment were as follows: eight patients experienced elevated alkaline phosphatase levels ( 2 x baseline); one patient experienced elevated bilirubin levels (> 3 mg/mL); and two patients exhibited elevated AST levels ( 3 x baseline). Grade 2 neurotoxicity was seen in 11 patients between 4 and 9 months after initiating therapy (Table 5). Five of those patients went on to experience grade 3 neurotoxicity between 4 and 11 months after treatment was started. All five patients have had improvement in neurotoxicity when Oxal was stopped, but in some patients, the improvement only occurred after 12 months.
Toxicity in Treatment Group B
In treatment group B, the dose levels of Oxal (100 mg/m2), LV (400 mg/m2), and FUDR (0.12 mg/kg x 30 mL divided by flow rate) were held constant, whereas the 48-hour infusion of FU was escalated from 1,000 to 1,200 to 1,400 mg/m2. At these dose levels, no toxicity was experienced within the first two cycles. At the dose level of 1,600 mg/m2, three patients experienced DLTs within the first two cycles of treatment, with toxicities as follows: one patient was admitted to the hospital for grade 4 neutropenic fever and grade 3 diarrhea, which resolved after 10 days; one patient was admitted for grade 3 diarrhea, nausea, and vomiting, which resolved after 5 days; and one patient experienced grade 4 diarrhea but did not require hospital admission (Table 6). Therefore, the MTD was determined to be Oxal 100 mg/m2, LV 400 mg/m2, 48-hour infusion of FU 1,400 mg/m2, and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate.
Toxicity in treatment group B after the first two cycles of treatment consisted of grade 3 thrombocytopenia in one patient. Alkaline phosphatase elevations 2 x baseline were seen in four patients, one patient had a bilirubin level of more than 3 mg/mL, and four patients exhibited elevated AST levels 3 x baseline. Ten patients experienced grade 2 neurotoxicity between 4 and 7 months, and three patients went on to experience grade 3 neurotoxicity between 6 and 9 months after the initiation of therapy.
Response and Survival
Group A. Partial responses were observed in 19 (90%) of 21 patients from group A. Seven of 21 patients were able to undergo liver resection, and two of these patients had no remaining tumor (Fig 1). Median reduction of tumor size for group A was 84%. Six patients exhibited a response to their prior therapy before eventually experiencing progression, and all patients exhibited responses to the current therapy. Of those patients who did not respond, 82% of patients responded to current pump treatment. Of the 21 patients in group A initially showing elevated baseline CEA levels, 18 (86%) showed a 50% reduction in CEA.
The median survival time from pump placement (ie, entry onto protocol) for group A patients was 35.8 months (95% CI, 23.9 months to not reached [NR]), with 11 (52%) of 21 patients still alive (Table 7). One-year survival rate was 90%, and 2-year survival rate was 65% (Fig 2). Median time from first diagnosis of liver metastases was 47 months. Median time to hepatic progression was 16.4 months (95% CI, 13.1 months to NR), and median time extrahepatic progression was 16.9 months (95% CI, 12.4 months to NR).
Group B. Partial responses were observed in 13 (87%) of 15 patients from group B. Median reduction of tumor size for group B was 78%. Five patients showed initial response to their prior therapy before eventually progressing, and four patients (80%) exhibited a response to this current therapy. Of the 10 patients with no response to their prior chemotherapy, nine (90%) exhibited a response to this therapy (Fig 3). Of 14 patients in group B initially showing elevated baseline CEA levels, 12 patients (86%) showed an overall 50% reduction in CEA.
The median survival time from the time the pump was placed was 22 months (95% CI, 15.4 months to NR), and the 1- and 2-year survival rates were 80% and 40%, respectively (Fig 2). Median survival time from first diagnosis of liver metastases was 35 months. Median time to hepatic progression was 9.4 months (95% CI, 7.6 to 19.3 months), and median time to extrahepatic progression was 10.8 months (95% CI, 7.8 to 27.1 months).
DISCUSSION
Only a decade ago, physicians were frustrated at the limited treatment options available for metastatic colorectal cancer. Currently, the frustration lies not in the limited options but, rather, in choosing the optimal treatment strategy from the treatment approaches now available. Trials on chemotherapy-na?ve patients demonstrate that combinations of CPT-11/FU/LV3 and Oxal/FU/LV4 will increase response and survival compared with FU/LV alone. Studies with bevacizumab and CPT-11/FU/LV15 demonstrate improved survival and response compared with the three drugs without bevacizumab. For patients who experience progression on first-line therapy, there are now agents that can be used for second-line therapy. CPT-11 alone,16 CPT-11 plus cetuximab,17 and Oxal/FU/LV18 will produce responses ranging from 9% to 22% in patients whose tumor has progressed on first-line chemotherapy. However, the median survival time for these patients after second-line therapy is 12 months or less. Because many patients still have liver-only disease when their disease progresses on first-line therapy, regional chemotherapy remains a viable option. Regional therapy with HAI FUDR, LV, and Dex produced a 52% response rate as second-line therapy, with a median survival time of 13.5 months.19
The advantage of HAI regional therapy is the ability to administer high doses of chemotherapy locally. For a drug such as FUDR, which has a liver extraction rate of 94%,20 systemic toxicity from HAI FUDR is extremely rare, allowing almost full doses of systemic chemotherapy to be administered concurrently. Combining HAI with systemic chemotherapy may result in improved efficacy relative to either approach alone. In a Cancer and Leukemia Group B trial (Kemeny et al, manuscript submitted for publication) comparing trial HAI FUDR/LV/Dex with systemic FU/LV, the response rate (48% v 25%, respectively) and median survival time (24 v 20 months, respectively; P = .0013) was higher in the HAI group. Although time to hepatic progression was better in the HAI arm compared with the systemic arm (9.8 v 7.3 months, respectively; P = .034), the time to extrahepatic progression was better in the systemic arm (7.7 v 14.8 months, respectively; P = .029). Therefore, combining HAI with systemic therapy should take advantage of the relative benefits of both HAI and systemic therapy. In a prior study using systemic CPT-11 plus HAI FUDR and Dex,21 the response rate was 74%, with a median survival of 16 months, in patients who had already received prior systemic therapy. With the aim of further improving outcome for patients with unresectable hepatic metastases, we designed a study combining the most promising systemic chemotherapy agents with an effective regional therapy of FUDR and Dex.
This trial was a phase I study of systemic Oxal combinations with regional therapy. Using the combination of HAI and systemic Oxal did not impact on the dose of Oxal that could be administered. The usual Oxal dose is 85 mg/m2 every other week, whereas in this trial, we were able to deliver 100 mg/m2. A national trial used Oxal 85 mg/m2 and CPT-11 200 mg/m2 every 3 weeks.5 Therefore, the combination doses used in this trial were similar to those used in systemic chemotherapy trials because the drugs in this study were administered every 2 weeks. However, the doses for the combination of Oxal plus FU/LV used in this study were lower than the doses usually used in systemic chemotherapy–alone trials. The standard Oxal dose was maintained at 100 mg/m2 every 2 weeks, but the MTD of FU (1,400 mg/m2) was much lower than what is usually administered in systemic chemotherapy trials, where a 48-hour infusion of FU at 2,000 mg/m2 can be administered.7 Because FU and FUDR are both fluoropyridines, the dose of the two agents together may have increased the toxicities most commonly observed with FU. Therefore, we could not escalate the FU dose close to the level used with systemic therapy alone.
Although this was a phase I study to examine toxicity, the response rate was high compared with other second-line therapies. The protocol and complete response rates were 90% and 87% with the HAI plus Oxal/CPT-11 and HAI plus Oxal/FU/LV combinations, respectively. More than 50% of patients showed a greater than 75% reduction in their tumor, and seven patients were able to undergo liver resection, two of whom had complete pathologic response. In a reported study, neoadjuvant HAI therapy alone in chemotherapy-na?ve patients allowed enough downstaging in six of 23 patients so that resection was possible.22 Although there is increasing interest in the use of neoadjuvant systemic therapy23 for patients with unresectable disease, such treatment rarely renders patients resectable after tumor progression on first-line therapy.
In conclusion, combination therapy with HAI FUDR and Dex plus systemic Oxal/CPT-11 or Oxal/FU/LV is safe and well tolerated. The high response rates observed with HAI and systemic Oxal-based combinations provide a rationale for further investigation of these regimens in the neoadjuvant setting even in patients who have experienced progression on first-line chemotherapy.
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, or 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.
Acknowledgment
We thank Maria-Leticia E. Bravo for manuscript preparation.
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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