Phase II Trial of Carcinoembryonic Antigen Radioimmunotherapy With 131I-Labetuzumab After Salvage Resection of Colorectal Metastases in the
http://www.100md.com
《临床肿瘤学》
the Departments of General Surgery, Nuclear Medicine, and Genetic Epidemiology, University of G?ttingen, Germany
Immunomedics, Inc, Morris Plains
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ
ABSTRACT
PURPOSE: Although complete resection (R0) of liver metastases (LM) remains the treatment of choice for colorectal cancer (CRC) patients amenable to curative therapy, only approximately one third survive for 5 years. The objective of this phase II study was to evaluate the safety and efficacy of radioimmunotherapy (RAIT) after salvage resection of LM.
PATIENTS AND METHODS: Twenty-three patients who underwent surgery for LM of CRC received a dose of 40 to 60 mCi/m2 of 131I-labetuzumab, which is a humanized monoclonal antibody against carcinoembryonic antigen. Safety (n = 23), disease-free survival (DFS; n = 19), and overall survival (OS; n = 19) were determined.
RESULTS: With a median follow-up of 64 months, the median OS time from the first liver resection for RAIT patients was 68.0 months (95% CI, 46.0 months to infinity), and the median DFS time was 18.0 months (95% CI, 11.0 to 31.0 months). The 5-year survival rate was 51.3%. RAIT benefited patients independently of bilobar involvement, size and number of LM, and resection margins. The major adverse effect was transient myelosuppression, resulting mostly in grade 3 neutropenia and/or thrombocytopenia.
CONCLUSION: Because both the median OS and 5-year survival rates seem to be improved with adjuvant RAIT after complete LM resection in CRC, compared with historical and contemporaneous controls not receiving RAIT, these results justify further evaluation of this modality in a multicenter, randomized trial.
INTRODUCTION
Colorectal cancer (CRC) is responsible for more than 15% of all malignancies in the United States and Europe,1 afflicting about 147,000 Americans and killing approximately 57,000 in 2004.2 The liver is the most common site of distant metastasis, affecting up to 60% of patients (at least 50,000 in the United States), and is the only metastatic site in 30% of CRC patients.3
In unresected patients with metastatic disease, the 5-year survival rate, irrespective of systemic therapies, is close to 0%.4,5 At present, only complete resection offers the prospect of curing liver metastases (LM)6,7 and has low rates of mortality (3% to 6%) and morbidity (15% to 25%) at specialized centers.8 After complete resection (R0) of LM, a 5-year survival rate of 25% to 37% is achievable,9 but despite postsurgical adjuvant systemic or intrahepatic chemotherapy, cancer relapse occurs in the majority of patients.3-9 Because approximately two thirds of resected CRC patients eventually relapse, with more than one half first experiencing recurrence in the liver,9-11 it is believed that microscopic tumor cells are trapped selectively in this organ.
Because of a lack of effective therapies other than surgery for patients with LM of CRC, we studied radioimmunotherapy (RAIT) with a radioiodinated antibody against carcinoembryonic antigen (CEA) as an adjuvant treatment after complete resection of LM from CRC. CEA was first described 40 years ago,12 and it has served as a serum marker and target for radiolabeled antibody imaging and other therapeutic strategies because it is expressed in more than 90% of CRC cells.13 We hypothesized that patients with no overt disease, but with a high likelihood of recurrence as a result of micrometastases, would be ideal candidates for RAIT because RAIT has been shown to be effective preclinically in a similar setting.14-16 In the current phase II trial, the objective was to assess the safety and efficacy of CEA-RAIT as an adjuvant therapy after salvage resection of CRC LM to determine whether an expanded, randomized, multicenter study is warranted.
PATIENTS AND METHODS
Antibody, Radiolabeling, and Administration
Labetuzumab (hMN-14), a CDR-grafted (humanized) anti-CEA (CEACAM5) immunoglobulin G1–subclass monoclonal antibody, was obtained from Immunomedics, Inc (Morris Plains, NJ).17 Prior clinical trials had not shown significant cross-reactivity with normal tissues, significant toxicity, or immunogenicity.16,18
Radioiodination of labetuzumab was performed using the iodogen method and resulted in a specific activity after labeling of 15 mCi/mg antibody.16,18 The amount of unbound radioiodine was less than 2% in each preparation, and the immunoreactivity was more than 85%. 131Iodine was chosen as the therapeutic radionuclide because of its high-energy gamma emission for external camera imaging of in vivo distribution, its lower beta emission energy, and its shorter range of energy deposition compared with other beta emitters, such as 90Y; thus, it is more appropriate as an adjuvant therapy for micrometastatic disease,19 as confirmed in liver phantom studies.20
131I-labetuzumab was infused over a 30-minute period in a volume of 50 mL of sterile 0.9% NaCl containing 1.0% to 2.5% human serum albumin. All patients received a single infusion at a dose level of 40 to 60 mCi/m2 based on a previous phase I, dose-finding trial.16 Two patients were re-treated at the time of recurrent disease. Whole-body scans were performed with a Picker Prim 2000 dual-head gamma camera equipped with high-energy collimators (Picker/Marconi, Cleveland, OH). Anterior and posterior whole-body scans were obtained daily from the day when each patient's whole-body activity decreased to less than 40 mCi (ie, 2 to 3 days after infusion), as described previously.16
Patient Characteristics
The entry criteria for the protocol approved by the institutional ethics committee included a patient age of at least 18 years and a diagnosis of resected primary CRC with synchronous or metachronous hepatic spread amenable to potentially curative resection. Admission to the study took place after complete resection (R0) of the LM. CEA-expressing cancer cells of resected LM had to be proven immunohistochemically.
Conventional radiologic tests (computed tomography [CT] and/or magnetic resonance imaging) had to show the absence of detectable, tumor-suspicious, extrahepatic lesions within 2 weeks before RAIT. An interval of at least 4 weeks after major surgery before LM resection, external radiation, and/or any other therapy was required; complete bone marrow recovery after primary therapy at the time of RAIT was also required. Adjuvant chemotherapy after surgical resection of the primary tumor was permitted, but no RAIT patient was administered chemotherapy after resection of the LM until there was a recurrence. Also, no prior therapy with murine or other antibodies was allowed. Women of childbearing age had to practice contraception during therapy and for 3 months after therapy.
Admission criteria were a minimal life expectancy of more than 3 months; a Karnofsky performance score of more than 70; and normal serum chemistries, peripheral CBC counts, and serum CEA (< 5 ng/mL). To exclude thyroid hyperfunction or other conditions in anticipation of administering high-dose radioiodine, the thyroid-stimulating hormone level of all patients was determined, and a scintigram of the thyroid was taken.
Twenty-three patients who underwent explorative surgery for LM of CRC were studied (Table 1). Of these 23 patients administered 131I-labetuzumab, two patients were excluded from the efficacy analysis because of extrahepatic metastases despite preoperative CT staging, and another two were excluded because postoperative chemotherapy was started (Table 2). Thus, safety was evaluated in all 23 patients, whereas disease-free survival (DFS) and overall survival (OS) were determined by the Kaplan-Meier survival estimates in 19 patients who fulfilled all inclusion criteria. In these 19 patients, LM were completely removed by either segmental resection (n = 9) or combined segmental and lobe resection of the left (n = 3) and right liver lobes (n = 7) under ultrasound control intraoperatively. The mortality rate from the operative procedure was 0%, and the postoperative morbidity rate was 15%. All patients who underwent an R0 were considered as putatively cured if imaging (intraoperative ultrasound), surgical bimanual palpation, or histopathologic examination failed to reveal macroscopic or microscopic intrahepatic or extrahepatic disease.
Table 2 lists all primary tumor stages, adjuvant and/or neoadjuvant fluorouracil (FU) -based procedures, radionuclide and antibody doses, and the corresponding hematologic toxicities. Ten patients received adjuvant FU-based chemotherapy or chemoradiotherapy after resection of the primary CRC, whereas six patients (patients 5, 9, 10, 13, 17, and 21) were treated by dose-intensified FU-based neoadjuvant chemotherapy before resection of the LM.
All patients who entered the study underwent baseline procedures within 5 days before RAIT, including CT scans of the chest, abdomen, and pelvis; abdominal ultrasound; serum CEA levels; and safety laboratories (hematology and serum chemistry). After informed consent was obtained, the patients were premedicated with potassium iodide 200 mg daily, which was initiated 24 hours before the antibody administration to decrease thyroid and gastric uptake and continued until radiation restrictions were removed.
At the time of recurrence, more than one LM occurred in 12 patients, and both lobes of the liver were affected in eight patients. Follow-up was conducted according to the guidelines of the German Cancer Society.
Imaging, Toxicity, and Follow-Up
According to the study protocol, routine blood chemistry and CBC counts with differential counts were obtained 2 weeks, and 1, 2, and 3 months after antibody administration in cooperation with the referring physicians and on an outpatient basis. Serum CEA levels were controlled monthly, whereas CT scans (chest, abdomen, and pelvis) were obtained at 1, 3, 6, and 12 months after RAIT. Thereafter, abdominal ultrasound and/or CT studies were performed every 3 to 6 months. All adverse effects of RAIT were documented according to the National Cancer Institute Common Toxicity Criteria (version 2.0; http://ctep.cancer.gov/reporting/ctc.html).
Histopathology, Staging, and Risk Assessments
LM was diagnosed histologically in 21 patients, when tumor staining for CEA was also confirmed (Table 1). Staging before RAIT was performed according to the current TNM classification of the International Union Against Cancer (UICC).22 Furthermore, the size, quantity, and location of the LM were classified according to the metastatic (m) TNM method and the determination of tumor-free margins (R classification).21,23
The risk of hepatic recurrence of CRC was assessed by a clinical scoring system described previously,23,24 which provided an evaluation of such factors as lymph node metastases of primary CRC, serosal infiltration of the primary tumor, a time interval of less than 2 years from primary surgery to LM, less than 1-cm tumor-free margin of the resected LM, more than four LM resected, more than 5-cm diameter size of the LM, and more than 60 years of age.24,25 The high-risk score (level I) included five to six of these factors; the intermediate-risk score (level II) included three to four factors; and the low-risk score (level III) included zero to two factors (Table 1).
Statistics
The Kaplan-Meier survival estimates method was used to calculate OS and DFS with 95% CIs. With regard to DFS, all patients who remained without CRC relapse were censored at the time of analysis; one patient survived cancer of the bladder without any signs of CRC relapse during the entire period of observation. Survival rates for 1, 2, and 5 years were calculated. The analysis was performed using the statistical software R version 1.9.1 (http://www.r-project.org).
RESULTS
In the 23 patients entered, the primary disease site was colon in nine patients, rectum in 12 patients, and both sites in two patients (Table 1). The classification of rectal or colon cancer was based on the TNM/UICC classification used in Germany, which considers rectal cancer to extend to 16 cm beyond the anal verge. If the US classification of up to 12 cm beyond the anal verge were used, then the primary disease site would be colon in 14 patients, rectal in seven patients, and both sites in two patients. At primary surgery, 12 of 23 patients with CRC had lymph node involvement. Fourteen patients received adjuvant chemotherapy or chemoradiotherapy (Table 1). Eight patients had synchronous hepatic metastases; the primary tumor stages were UICC stage I in two patients, UICC stage II in six patients, UICC stage III in seven patients, and UICC stage IV in eight patients (Table 1). In four patients with synchronous LM at primary surgery (patients 5, 9, 13, and 17), dose-intensified FU-based chemotherapy (+ folinic acid ± oxaliplatin) was administered to achieve resection of LM with tumor-free margins (Table 2).
Both liver lobes were involved with metastases in eight of 23 patients; and in 17 of 23 patients, the liver tumor size was 5 cm in diameter. Postoperatively, the histopathologic findings of the resected liver tumors demonstrated tumor-free margins in all patients; 13 of 23 patients had a poor prognosis (mTNM stage 3) and a high risk for hepatic recurrence. The clinical risk for developing a relapse was high (level I) in three patients and intermediate (level II) in 14 patients (Table 1). Despite this poor prognosis in 75% of the patients, they all had an acceptable performance status and normal CEA serum levels at study entry (median, 1.9 ng/mL).
All 23 patients received a single infusion of 131I-labetuzumab at a dose of 40 to 60 mCi/m2 (Table 2), and two patients (patients 9A and 12A) received second infusions 5 and 31 months later as a result of disease recurrence. At first, lower doses were administered in anticipation of optionally repeating the RAIT therapy later under the approved protocol, but instead, for logistical reasons, all but two patients received only one dose, and the majority of patients (15 of 23 patients) were administered 55 to 60 mCi/m2. During the time of observation, no infusion-related events occurred. All severe toxicities (grades 3 and 4) were hematologic. In 13 RAIT procedures administered to 12 patients (patient 12A was re-treated), grade 3 or 4 hematologic toxicities (WBC, platelets, and hemoglobin) were observed without spontaneous bleeding during the first 10 weeks after RAIT. Complete bone marrow recovery resulted in all patients, with four patients requiring granulocyte colony-stimulating factor and one undergoing platelet transfusions. These myelosuppressive side effects seemed to be independent of prior chemotherapy. No cumulative toxicity was documented in the two patients who were re-treated.
Although 23 patients were treated with 131I-labetuzumab, 19 were eligible according to the protocol for determining DFS and OS (Table 1) because four patients (patients 2, 7, 14, and 23) had to be excluded, as described earlier. The median DFS time (as of September 20, 2004) for 19 patients receiving RAIT was 18.0 months (95% CI, 11.0 to 31.0 months). Current DFS rates are 57.9% at more than 1 year and 26.3% at more than 2 years for these patients (Fig 1).
The median OS time from complete LM resection for patients receiving RAIT was 68.0 months (95% CI, 46.0 months to infinity), and the survival rates are 94.7% at more than 1 year, 78.9% at more than 2 years, and 51.3% at more than 5 years (Fig 1). With a post-RAIT follow-up time of a median of 64 months, 10 patients (52.6%) remain alive, and four patients have no evidence of disease at the last date of observation. One patient had stable disease, and five patients experienced progression (Table 2).
Cancer relapse after RAIT was primarily locoregional in four patients, hepatic in seven patients, pulmonary or peritoneal in two patients; and in three patients, there was a combination of hepatic, peritoneal, and/or pulmonary spread at the time of recurrence. Post-treatment follow-up for up to a median of 64 months demonstrated DFS in four patients (21.1%).
According to the mTNM stages and clinical risk levels of the 19 patients, 12 patients had a poor prognosis (mTNM stage 3 and risk level II), with eight patients having bilobar LM and 17 having metastases more than 2 cm (Tables 1 and 2). Interestingly, among the long-term survivors, there were four patients with mTNM stage 4 and two patients with mTNM stage 3. Independently of the involvement of both liver lobes, the size of LM, and the width of tumor-free margins at liver resection, these patients seemed to benefit from RAIT.
DISCUSSION
Because two thirds of patients with salvage R0 resection of LM have disease recurrence26 and only 10% to 20% are amenable to curative resection,27 it is clear that some form of additional therapy is essential. However, no randomized trial has been reported that confirms the survival advantage of any postoperative therapy in this population. Justification for using adjuvant chemotherapy after resection of LM has been based on data supporting the use of chemotherapy after resection of primary tumors in patients with lymph node and/or distant spread. The Eastern Cooperative Oncology Group reported that intrahepatic artery infusions with floxuridine, combined with continuous infusion of FU, may reduce the risk of recurrence compared with surgery alone, but there was no benefit in overall survival.28 The use of intrahepatic artery infusions with FU and folinic acid without systemic therapy demonstrated no benefit over surgery alone.29 At this time, no chemotherapeutic intervention for the treatment of CRC after resection of LM has been established, although recent promising results of improved survival as a result of drug combinations with or without antibody therapy provide such options.30,31 Hence, therapeutic measures with good feasibility, safety, and an enhanced efficacy are needed to improve the outcome of patients receiving salvage surgery for LM.
In this context, the anti-CEA RAIT investigated here may provide such an option. Crossfire radiation from CEA-positive cancer cells targeted by the radiolabeled antibody may deliver tumoricidal doses to surrounding intrahepatic tumor cells,19 especially to occult micrometastases smaller than 1 mm, because the average path length of 131I is 0.8 mm.19 Indeed, the potential therapeutic effects of radiolabeled antibodies on occult micrometastases or minimal disease have been described previously in preclinical models and clinical studies.14-16,19,32
In terms of safety, myelosuppression was the only significant toxicity, and a maximum single dose of 50 to 55 mCi/m2 seems to be safe for future trials. In addition, two patients (patients 9A and 12A, both treated initially with 55 mCi/m2) were re-treated with 40 and 60 mCi/m2, respectively, without signs of cumulative toxicity, suggesting that re-treatment after several months could be tolerated.
The median OS time from the first liver resection for patients receiving RAIT was 68.0 months (95% CI, 46.0 months to infinity), and on an intent-to-treat basis, including also four ineligible patients in the RAIT group, OS was maintained, although this kind of analysis is usually made in larger, phase III, randomized trials. The survival results in the treated patients seem to be much longer than the median survival of 28 to 40 months reported in the literature.9 This survival advantage for patients receiving RAIT is confirmed when they are compared with a group of 19 contemporaneous patients at our institution who did not receive RAIT (13 of 19 of these patients received adjuvant chemotherapy after completion of resection of LM; data not shown). These patients, who had similar demographics and prognostic risk scores to the RAIT patient population, had a median overall survival time of 31 months (95% CI, 24.0 to 59.0 months). The corresponding survival rates were 94.7% at more than 1 year, 78.9% at more than 2 years, and 51.3% at more than 5 years for the RAIT group, and 94.7% at more than 1 year, 64.9% at more than 2 years, and 7.4% at more than 5 years for this control population analyzed retrospectively (data not shown). At recurrence, all RAIT patients were treated by early surgical reintervention in cases of resectable disease or by different chemotherapy regimens. Patients 8, 11, 16, and 18 in the RAIT group remained disease free, and patients 9A and 12A were re-treated with RAIT at first diagnosis of CRC relapse. Of course, we appreciate that comparisons to historical or contemporaneous controls are not as rigorous as a randomized, prospective trial, but the suggested improvement encourages further study.
The median DFS time for patients receiving RAIT was 18 months (95% CI, 11 to 31 months). From the last date of observation (September 20, 2004), 21% of patients remained without any signs of CRC. The DFS rates were 57.9% at more than 1 year and 26.3% at more than 2 years for patients treated with RAIT (Fig 1).
When considering the prognostic risk scoring classifications, it was found that the patients had a better outcome than would be predicted. In an analysis of 1,596 patients, the 2-year survival rates after resection of LM were 43%, 60%, and 79% in patients with risk levels of I, II, and III, respectively.24,25 However, 15 (79%) of 19 RAIT patients with level I (n = 3) and level II (n = 12) risk scores had a more than 2-year survival rate of 78.9% (compared with the expected 43% to 60%) and a survival rate of 51% at 5 years (v the expected 28%). Similarly, when comparing the outcome of RAIT patients by mTNM stage at resection in this study, seven of 10 patients with advanced mTNM stages of 2 to 4 were long-term survivors (38 to 78 months), and four of these patients with mTNM stage 2 (n = 3) and stage 3 (n = 1) remain free of disease over a median follow-up of 64 months (Table 2). Thus, these results suggest that RAIT has a clinical benefit independent of the major risk factors, such as bilobar involvement, size and number of LM, and resection margins.
Our findings support the prospect of improving survival in patients with multiple LM from CRC by engaging a multimodal approach, combining resection with systemic RAIT. We appreciate that this was a single-institution study with a relatively small number of patients, but over a long median follow-up time of 64 months, our study clearly shows that this adjuvant therapy is feasible and has survival results that are double those reported in the literature and those of the comparable, contemporaneous, control patients analyzed retrospectively at this same institution (data not shown). The findings also provoke speculation that this modality may be useful in neoadjuvant or adjuvant settings for primary CRC therapy, either alone or in combination with other modalities, particularly chemotherapy that potentiates radiation because RAIT is targeted radiotherapy. Furthermore, recent experimental evidence demonstrated that nonradioactive labetuzumab is effective in inhibiting metastasis and enhancing the effects of chemotherapy in a metastatic CRC xenograft model,33 suggesting that even higher doses of this antibody with RAIT may increase efficacy.
In conclusion, this feasibility study of adjuvant RAIT in CRC patients after salvage resection of LM provides the first evidence of promising OS and 5-year survival rates. Therefore, these results require confirmation in a larger, multicenter, randomized trial, which is being developed.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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
This article is dedicated to the memory of Prof Wolfgang Becker, MD, who was an inspiration and participant in these studies and who fostered cooperation between surgical and nuclear radiology specialties. He served with distinction as President of the European Association of Nuclear Medicine, when he died so early and at the peak of his career.
NOTES
Presented in part at the 2005 Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology, American Gastroenterological Association, American Society for Therapeutic Radiology and Oncology, and Society of Surgical Oncology, in Hollywood, FL, January 27-29, 2005.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Immunomedics, Inc, Morris Plains
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ
ABSTRACT
PURPOSE: Although complete resection (R0) of liver metastases (LM) remains the treatment of choice for colorectal cancer (CRC) patients amenable to curative therapy, only approximately one third survive for 5 years. The objective of this phase II study was to evaluate the safety and efficacy of radioimmunotherapy (RAIT) after salvage resection of LM.
PATIENTS AND METHODS: Twenty-three patients who underwent surgery for LM of CRC received a dose of 40 to 60 mCi/m2 of 131I-labetuzumab, which is a humanized monoclonal antibody against carcinoembryonic antigen. Safety (n = 23), disease-free survival (DFS; n = 19), and overall survival (OS; n = 19) were determined.
RESULTS: With a median follow-up of 64 months, the median OS time from the first liver resection for RAIT patients was 68.0 months (95% CI, 46.0 months to infinity), and the median DFS time was 18.0 months (95% CI, 11.0 to 31.0 months). The 5-year survival rate was 51.3%. RAIT benefited patients independently of bilobar involvement, size and number of LM, and resection margins. The major adverse effect was transient myelosuppression, resulting mostly in grade 3 neutropenia and/or thrombocytopenia.
CONCLUSION: Because both the median OS and 5-year survival rates seem to be improved with adjuvant RAIT after complete LM resection in CRC, compared with historical and contemporaneous controls not receiving RAIT, these results justify further evaluation of this modality in a multicenter, randomized trial.
INTRODUCTION
Colorectal cancer (CRC) is responsible for more than 15% of all malignancies in the United States and Europe,1 afflicting about 147,000 Americans and killing approximately 57,000 in 2004.2 The liver is the most common site of distant metastasis, affecting up to 60% of patients (at least 50,000 in the United States), and is the only metastatic site in 30% of CRC patients.3
In unresected patients with metastatic disease, the 5-year survival rate, irrespective of systemic therapies, is close to 0%.4,5 At present, only complete resection offers the prospect of curing liver metastases (LM)6,7 and has low rates of mortality (3% to 6%) and morbidity (15% to 25%) at specialized centers.8 After complete resection (R0) of LM, a 5-year survival rate of 25% to 37% is achievable,9 but despite postsurgical adjuvant systemic or intrahepatic chemotherapy, cancer relapse occurs in the majority of patients.3-9 Because approximately two thirds of resected CRC patients eventually relapse, with more than one half first experiencing recurrence in the liver,9-11 it is believed that microscopic tumor cells are trapped selectively in this organ.
Because of a lack of effective therapies other than surgery for patients with LM of CRC, we studied radioimmunotherapy (RAIT) with a radioiodinated antibody against carcinoembryonic antigen (CEA) as an adjuvant treatment after complete resection of LM from CRC. CEA was first described 40 years ago,12 and it has served as a serum marker and target for radiolabeled antibody imaging and other therapeutic strategies because it is expressed in more than 90% of CRC cells.13 We hypothesized that patients with no overt disease, but with a high likelihood of recurrence as a result of micrometastases, would be ideal candidates for RAIT because RAIT has been shown to be effective preclinically in a similar setting.14-16 In the current phase II trial, the objective was to assess the safety and efficacy of CEA-RAIT as an adjuvant therapy after salvage resection of CRC LM to determine whether an expanded, randomized, multicenter study is warranted.
PATIENTS AND METHODS
Antibody, Radiolabeling, and Administration
Labetuzumab (hMN-14), a CDR-grafted (humanized) anti-CEA (CEACAM5) immunoglobulin G1–subclass monoclonal antibody, was obtained from Immunomedics, Inc (Morris Plains, NJ).17 Prior clinical trials had not shown significant cross-reactivity with normal tissues, significant toxicity, or immunogenicity.16,18
Radioiodination of labetuzumab was performed using the iodogen method and resulted in a specific activity after labeling of 15 mCi/mg antibody.16,18 The amount of unbound radioiodine was less than 2% in each preparation, and the immunoreactivity was more than 85%. 131Iodine was chosen as the therapeutic radionuclide because of its high-energy gamma emission for external camera imaging of in vivo distribution, its lower beta emission energy, and its shorter range of energy deposition compared with other beta emitters, such as 90Y; thus, it is more appropriate as an adjuvant therapy for micrometastatic disease,19 as confirmed in liver phantom studies.20
131I-labetuzumab was infused over a 30-minute period in a volume of 50 mL of sterile 0.9% NaCl containing 1.0% to 2.5% human serum albumin. All patients received a single infusion at a dose level of 40 to 60 mCi/m2 based on a previous phase I, dose-finding trial.16 Two patients were re-treated at the time of recurrent disease. Whole-body scans were performed with a Picker Prim 2000 dual-head gamma camera equipped with high-energy collimators (Picker/Marconi, Cleveland, OH). Anterior and posterior whole-body scans were obtained daily from the day when each patient's whole-body activity decreased to less than 40 mCi (ie, 2 to 3 days after infusion), as described previously.16
Patient Characteristics
The entry criteria for the protocol approved by the institutional ethics committee included a patient age of at least 18 years and a diagnosis of resected primary CRC with synchronous or metachronous hepatic spread amenable to potentially curative resection. Admission to the study took place after complete resection (R0) of the LM. CEA-expressing cancer cells of resected LM had to be proven immunohistochemically.
Conventional radiologic tests (computed tomography [CT] and/or magnetic resonance imaging) had to show the absence of detectable, tumor-suspicious, extrahepatic lesions within 2 weeks before RAIT. An interval of at least 4 weeks after major surgery before LM resection, external radiation, and/or any other therapy was required; complete bone marrow recovery after primary therapy at the time of RAIT was also required. Adjuvant chemotherapy after surgical resection of the primary tumor was permitted, but no RAIT patient was administered chemotherapy after resection of the LM until there was a recurrence. Also, no prior therapy with murine or other antibodies was allowed. Women of childbearing age had to practice contraception during therapy and for 3 months after therapy.
Admission criteria were a minimal life expectancy of more than 3 months; a Karnofsky performance score of more than 70; and normal serum chemistries, peripheral CBC counts, and serum CEA (< 5 ng/mL). To exclude thyroid hyperfunction or other conditions in anticipation of administering high-dose radioiodine, the thyroid-stimulating hormone level of all patients was determined, and a scintigram of the thyroid was taken.
Twenty-three patients who underwent explorative surgery for LM of CRC were studied (Table 1). Of these 23 patients administered 131I-labetuzumab, two patients were excluded from the efficacy analysis because of extrahepatic metastases despite preoperative CT staging, and another two were excluded because postoperative chemotherapy was started (Table 2). Thus, safety was evaluated in all 23 patients, whereas disease-free survival (DFS) and overall survival (OS) were determined by the Kaplan-Meier survival estimates in 19 patients who fulfilled all inclusion criteria. In these 19 patients, LM were completely removed by either segmental resection (n = 9) or combined segmental and lobe resection of the left (n = 3) and right liver lobes (n = 7) under ultrasound control intraoperatively. The mortality rate from the operative procedure was 0%, and the postoperative morbidity rate was 15%. All patients who underwent an R0 were considered as putatively cured if imaging (intraoperative ultrasound), surgical bimanual palpation, or histopathologic examination failed to reveal macroscopic or microscopic intrahepatic or extrahepatic disease.
Table 2 lists all primary tumor stages, adjuvant and/or neoadjuvant fluorouracil (FU) -based procedures, radionuclide and antibody doses, and the corresponding hematologic toxicities. Ten patients received adjuvant FU-based chemotherapy or chemoradiotherapy after resection of the primary CRC, whereas six patients (patients 5, 9, 10, 13, 17, and 21) were treated by dose-intensified FU-based neoadjuvant chemotherapy before resection of the LM.
All patients who entered the study underwent baseline procedures within 5 days before RAIT, including CT scans of the chest, abdomen, and pelvis; abdominal ultrasound; serum CEA levels; and safety laboratories (hematology and serum chemistry). After informed consent was obtained, the patients were premedicated with potassium iodide 200 mg daily, which was initiated 24 hours before the antibody administration to decrease thyroid and gastric uptake and continued until radiation restrictions were removed.
At the time of recurrence, more than one LM occurred in 12 patients, and both lobes of the liver were affected in eight patients. Follow-up was conducted according to the guidelines of the German Cancer Society.
Imaging, Toxicity, and Follow-Up
According to the study protocol, routine blood chemistry and CBC counts with differential counts were obtained 2 weeks, and 1, 2, and 3 months after antibody administration in cooperation with the referring physicians and on an outpatient basis. Serum CEA levels were controlled monthly, whereas CT scans (chest, abdomen, and pelvis) were obtained at 1, 3, 6, and 12 months after RAIT. Thereafter, abdominal ultrasound and/or CT studies were performed every 3 to 6 months. All adverse effects of RAIT were documented according to the National Cancer Institute Common Toxicity Criteria (version 2.0; http://ctep.cancer.gov/reporting/ctc.html).
Histopathology, Staging, and Risk Assessments
LM was diagnosed histologically in 21 patients, when tumor staining for CEA was also confirmed (Table 1). Staging before RAIT was performed according to the current TNM classification of the International Union Against Cancer (UICC).22 Furthermore, the size, quantity, and location of the LM were classified according to the metastatic (m) TNM method and the determination of tumor-free margins (R classification).21,23
The risk of hepatic recurrence of CRC was assessed by a clinical scoring system described previously,23,24 which provided an evaluation of such factors as lymph node metastases of primary CRC, serosal infiltration of the primary tumor, a time interval of less than 2 years from primary surgery to LM, less than 1-cm tumor-free margin of the resected LM, more than four LM resected, more than 5-cm diameter size of the LM, and more than 60 years of age.24,25 The high-risk score (level I) included five to six of these factors; the intermediate-risk score (level II) included three to four factors; and the low-risk score (level III) included zero to two factors (Table 1).
Statistics
The Kaplan-Meier survival estimates method was used to calculate OS and DFS with 95% CIs. With regard to DFS, all patients who remained without CRC relapse were censored at the time of analysis; one patient survived cancer of the bladder without any signs of CRC relapse during the entire period of observation. Survival rates for 1, 2, and 5 years were calculated. The analysis was performed using the statistical software R version 1.9.1 (http://www.r-project.org).
RESULTS
In the 23 patients entered, the primary disease site was colon in nine patients, rectum in 12 patients, and both sites in two patients (Table 1). The classification of rectal or colon cancer was based on the TNM/UICC classification used in Germany, which considers rectal cancer to extend to 16 cm beyond the anal verge. If the US classification of up to 12 cm beyond the anal verge were used, then the primary disease site would be colon in 14 patients, rectal in seven patients, and both sites in two patients. At primary surgery, 12 of 23 patients with CRC had lymph node involvement. Fourteen patients received adjuvant chemotherapy or chemoradiotherapy (Table 1). Eight patients had synchronous hepatic metastases; the primary tumor stages were UICC stage I in two patients, UICC stage II in six patients, UICC stage III in seven patients, and UICC stage IV in eight patients (Table 1). In four patients with synchronous LM at primary surgery (patients 5, 9, 13, and 17), dose-intensified FU-based chemotherapy (+ folinic acid ± oxaliplatin) was administered to achieve resection of LM with tumor-free margins (Table 2).
Both liver lobes were involved with metastases in eight of 23 patients; and in 17 of 23 patients, the liver tumor size was 5 cm in diameter. Postoperatively, the histopathologic findings of the resected liver tumors demonstrated tumor-free margins in all patients; 13 of 23 patients had a poor prognosis (mTNM stage 3) and a high risk for hepatic recurrence. The clinical risk for developing a relapse was high (level I) in three patients and intermediate (level II) in 14 patients (Table 1). Despite this poor prognosis in 75% of the patients, they all had an acceptable performance status and normal CEA serum levels at study entry (median, 1.9 ng/mL).
All 23 patients received a single infusion of 131I-labetuzumab at a dose of 40 to 60 mCi/m2 (Table 2), and two patients (patients 9A and 12A) received second infusions 5 and 31 months later as a result of disease recurrence. At first, lower doses were administered in anticipation of optionally repeating the RAIT therapy later under the approved protocol, but instead, for logistical reasons, all but two patients received only one dose, and the majority of patients (15 of 23 patients) were administered 55 to 60 mCi/m2. During the time of observation, no infusion-related events occurred. All severe toxicities (grades 3 and 4) were hematologic. In 13 RAIT procedures administered to 12 patients (patient 12A was re-treated), grade 3 or 4 hematologic toxicities (WBC, platelets, and hemoglobin) were observed without spontaneous bleeding during the first 10 weeks after RAIT. Complete bone marrow recovery resulted in all patients, with four patients requiring granulocyte colony-stimulating factor and one undergoing platelet transfusions. These myelosuppressive side effects seemed to be independent of prior chemotherapy. No cumulative toxicity was documented in the two patients who were re-treated.
Although 23 patients were treated with 131I-labetuzumab, 19 were eligible according to the protocol for determining DFS and OS (Table 1) because four patients (patients 2, 7, 14, and 23) had to be excluded, as described earlier. The median DFS time (as of September 20, 2004) for 19 patients receiving RAIT was 18.0 months (95% CI, 11.0 to 31.0 months). Current DFS rates are 57.9% at more than 1 year and 26.3% at more than 2 years for these patients (Fig 1).
The median OS time from complete LM resection for patients receiving RAIT was 68.0 months (95% CI, 46.0 months to infinity), and the survival rates are 94.7% at more than 1 year, 78.9% at more than 2 years, and 51.3% at more than 5 years (Fig 1). With a post-RAIT follow-up time of a median of 64 months, 10 patients (52.6%) remain alive, and four patients have no evidence of disease at the last date of observation. One patient had stable disease, and five patients experienced progression (Table 2).
Cancer relapse after RAIT was primarily locoregional in four patients, hepatic in seven patients, pulmonary or peritoneal in two patients; and in three patients, there was a combination of hepatic, peritoneal, and/or pulmonary spread at the time of recurrence. Post-treatment follow-up for up to a median of 64 months demonstrated DFS in four patients (21.1%).
According to the mTNM stages and clinical risk levels of the 19 patients, 12 patients had a poor prognosis (mTNM stage 3 and risk level II), with eight patients having bilobar LM and 17 having metastases more than 2 cm (Tables 1 and 2). Interestingly, among the long-term survivors, there were four patients with mTNM stage 4 and two patients with mTNM stage 3. Independently of the involvement of both liver lobes, the size of LM, and the width of tumor-free margins at liver resection, these patients seemed to benefit from RAIT.
DISCUSSION
Because two thirds of patients with salvage R0 resection of LM have disease recurrence26 and only 10% to 20% are amenable to curative resection,27 it is clear that some form of additional therapy is essential. However, no randomized trial has been reported that confirms the survival advantage of any postoperative therapy in this population. Justification for using adjuvant chemotherapy after resection of LM has been based on data supporting the use of chemotherapy after resection of primary tumors in patients with lymph node and/or distant spread. The Eastern Cooperative Oncology Group reported that intrahepatic artery infusions with floxuridine, combined with continuous infusion of FU, may reduce the risk of recurrence compared with surgery alone, but there was no benefit in overall survival.28 The use of intrahepatic artery infusions with FU and folinic acid without systemic therapy demonstrated no benefit over surgery alone.29 At this time, no chemotherapeutic intervention for the treatment of CRC after resection of LM has been established, although recent promising results of improved survival as a result of drug combinations with or without antibody therapy provide such options.30,31 Hence, therapeutic measures with good feasibility, safety, and an enhanced efficacy are needed to improve the outcome of patients receiving salvage surgery for LM.
In this context, the anti-CEA RAIT investigated here may provide such an option. Crossfire radiation from CEA-positive cancer cells targeted by the radiolabeled antibody may deliver tumoricidal doses to surrounding intrahepatic tumor cells,19 especially to occult micrometastases smaller than 1 mm, because the average path length of 131I is 0.8 mm.19 Indeed, the potential therapeutic effects of radiolabeled antibodies on occult micrometastases or minimal disease have been described previously in preclinical models and clinical studies.14-16,19,32
In terms of safety, myelosuppression was the only significant toxicity, and a maximum single dose of 50 to 55 mCi/m2 seems to be safe for future trials. In addition, two patients (patients 9A and 12A, both treated initially with 55 mCi/m2) were re-treated with 40 and 60 mCi/m2, respectively, without signs of cumulative toxicity, suggesting that re-treatment after several months could be tolerated.
The median OS time from the first liver resection for patients receiving RAIT was 68.0 months (95% CI, 46.0 months to infinity), and on an intent-to-treat basis, including also four ineligible patients in the RAIT group, OS was maintained, although this kind of analysis is usually made in larger, phase III, randomized trials. The survival results in the treated patients seem to be much longer than the median survival of 28 to 40 months reported in the literature.9 This survival advantage for patients receiving RAIT is confirmed when they are compared with a group of 19 contemporaneous patients at our institution who did not receive RAIT (13 of 19 of these patients received adjuvant chemotherapy after completion of resection of LM; data not shown). These patients, who had similar demographics and prognostic risk scores to the RAIT patient population, had a median overall survival time of 31 months (95% CI, 24.0 to 59.0 months). The corresponding survival rates were 94.7% at more than 1 year, 78.9% at more than 2 years, and 51.3% at more than 5 years for the RAIT group, and 94.7% at more than 1 year, 64.9% at more than 2 years, and 7.4% at more than 5 years for this control population analyzed retrospectively (data not shown). At recurrence, all RAIT patients were treated by early surgical reintervention in cases of resectable disease or by different chemotherapy regimens. Patients 8, 11, 16, and 18 in the RAIT group remained disease free, and patients 9A and 12A were re-treated with RAIT at first diagnosis of CRC relapse. Of course, we appreciate that comparisons to historical or contemporaneous controls are not as rigorous as a randomized, prospective trial, but the suggested improvement encourages further study.
The median DFS time for patients receiving RAIT was 18 months (95% CI, 11 to 31 months). From the last date of observation (September 20, 2004), 21% of patients remained without any signs of CRC. The DFS rates were 57.9% at more than 1 year and 26.3% at more than 2 years for patients treated with RAIT (Fig 1).
When considering the prognostic risk scoring classifications, it was found that the patients had a better outcome than would be predicted. In an analysis of 1,596 patients, the 2-year survival rates after resection of LM were 43%, 60%, and 79% in patients with risk levels of I, II, and III, respectively.24,25 However, 15 (79%) of 19 RAIT patients with level I (n = 3) and level II (n = 12) risk scores had a more than 2-year survival rate of 78.9% (compared with the expected 43% to 60%) and a survival rate of 51% at 5 years (v the expected 28%). Similarly, when comparing the outcome of RAIT patients by mTNM stage at resection in this study, seven of 10 patients with advanced mTNM stages of 2 to 4 were long-term survivors (38 to 78 months), and four of these patients with mTNM stage 2 (n = 3) and stage 3 (n = 1) remain free of disease over a median follow-up of 64 months (Table 2). Thus, these results suggest that RAIT has a clinical benefit independent of the major risk factors, such as bilobar involvement, size and number of LM, and resection margins.
Our findings support the prospect of improving survival in patients with multiple LM from CRC by engaging a multimodal approach, combining resection with systemic RAIT. We appreciate that this was a single-institution study with a relatively small number of patients, but over a long median follow-up time of 64 months, our study clearly shows that this adjuvant therapy is feasible and has survival results that are double those reported in the literature and those of the comparable, contemporaneous, control patients analyzed retrospectively at this same institution (data not shown). The findings also provoke speculation that this modality may be useful in neoadjuvant or adjuvant settings for primary CRC therapy, either alone or in combination with other modalities, particularly chemotherapy that potentiates radiation because RAIT is targeted radiotherapy. Furthermore, recent experimental evidence demonstrated that nonradioactive labetuzumab is effective in inhibiting metastasis and enhancing the effects of chemotherapy in a metastatic CRC xenograft model,33 suggesting that even higher doses of this antibody with RAIT may increase efficacy.
In conclusion, this feasibility study of adjuvant RAIT in CRC patients after salvage resection of LM provides the first evidence of promising OS and 5-year survival rates. Therefore, these results require confirmation in a larger, multicenter, randomized trial, which is being developed.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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
This article is dedicated to the memory of Prof Wolfgang Becker, MD, who was an inspiration and participant in these studies and who fostered cooperation between surgical and nuclear radiology specialties. He served with distinction as President of the European Association of Nuclear Medicine, when he died so early and at the peak of his career.
NOTES
Presented in part at the 2005 Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology, American Gastroenterological Association, American Society for Therapeutic Radiology and Oncology, and Society of Surgical Oncology, in Hollywood, FL, January 27-29, 2005.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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