Phase I/II Trial of Anticarcinoembryonic Antigen Radioimmunotherapy,Gemcitabine,and Hepatic Arterial Infusion of Fluorodeoxyuridine Postresection of Liver Metastasis for Colorectal Carcinoma

Abstract

Objectives:

Report the feasibility, toxicities, and long-term results of a Phase I/II trial of ⁹⁰Y-labeled anticarcinoembryonic antigen (anti-CEA) (cT84.66) radioimmunotherapy (RIT), gemcitabine, and hepatic arterial infusion (HAI) of fluorodeoxyuridine (FUdR) after maximal hepatic resection of metastatic colorectal cancer to the liver.

Methods:

Patients with metastatic colorectal cancer to the liver postresection or ablation to minimum disease were eligible. Each cohort received HAI of FUdR for 14 days on a dose escalation schedule. The maximum HAI FUdR dose level planned was 0.2 mg/kg/day, which is the standard dose for HAI FUdR alone. On day 9, ⁹⁰Y-cT84.66 anti-CEA at 16.6 mCi/m² as an i.v. bolus infusion and on days 9–11 i.v. gemcitabine at 105 mg/m² were given. Patients could receive up to three cycles every 6 weeks of protocol therapy. Four additional cycles of HAI FUdR were allowed after RIT.

Results:

Sixteen patients were treated on this study. A maximum tolerated dose of 0.20 mg/kg/day of HAI FUdR combined with RIT at 16.6 mCi/m² and gemcitabine at 105 mg/m² was achieved with only 1 patient experiencing grade 3 reversible toxicity (mucositis). After surgery, 10 patients had no evidence of visible disease and remained without evidence of disease after completion of protocol therapy. The remaining 6 patients demonstrated radiological visible disease after surgery and after protocol therapy 2 patients had a CR, 1 patient had PR, 2 had stable disease, and 1 had progression. With a median follow-up of 41.8 months (18.7–114.6), median progression free survival was 9.6 months. Two patients demonstrated long-term disease control out to 45+ and 113+ months.

Conclusion:

This study demonstrates the safety, feasibility, and potential utility of HAI FUdR, RIT, and systemic gemcitabine. The trimodality approach does not have higher hematologic toxicities than seen in prior RIT-alone studies. Future efforts evaluating RIT in colorectal cancer should integrate RIT with systemic and regional therapies in the minimal tumor burden setting.

Introduction

Nearly half of patients diagnosed with colorectal cancer will develop hepatic metastasis during the course of their disease. Surgery alone can provide a cure in ∼20% of patients with limited hepatic metastases.¹ However, subsequent recurrences in the liver as well as in extrahepatic sites are the rule. Therefore, further adjuvant therapies are needed.

The rapidly growing field of molecular medicine offers exciting new strategies for targeted delivery of cancer therapy. Monoclonal antibodies (MAb) against tumor antigens were some of the first of these agents to be evaluated. Conjugated to radionuclides, MAb-guided radiation therapy or radioimmunotherapy (RIT) demonstrated significant promise in animal models. This promise has been realized in the clinic for the more radiosensitive hematological malignancies.^{2

–10} For the more radioresistant solid tumors, results have been less successful, but remain encouraging. Radiosensitization with concomitant delivery of chemotherapeutic agents can increase the tumoricidal efficacy of RIT.^11

–14 Laboratory and clinical studies have demonstrated strong radiosensitization properties when gemcitabine is combined with radiotherapy.^15

–20

Carcinoembryonic antigen (CEA) is a well-studied tumor surface antigen that has proven to be a useful target for RIT. CEA is expressed in many common tumor types such as colon, breast, nonsmall cell lung, gastric, pancreatic, biliary, cervix, uterine, and ovarian cancers.^21

–24 Radiolabeled anti-CEA antibodies have been successfully used in the clinic to treat and image CEA-producing malignancies.^25,26 Radiolabeled anti-CEA antibodies have been the most extensively studied in colorectal cancer, since 90%–95% of tumors produce CEA. Chimeric T84.66 (cT84.66) was radiolabeled with ¹¹¹In and evaluated in imaging/biodistribution trials in patients with CEA-producing malignancies. A Phase I therapy trial was initiated that defined maximum tolerated dose (MTD) of intravenously administered ⁹⁰Y-cT84.66 at 16.6 mCi/m².²⁷ Successor Phase I trials demonstrated the feasibility of combining chemotherapy first with 5-fluorouracil (5-FU) and then gemcitabine.^18,19,27,28 Prospective trials using resection and hepatic arterial infusion (HAI) fluorodeoxyuridine (FUdR) demonstrated the value of adjuvant therapy following complete resection of hepatic metastases in preventing disease recurrence.^29,30 Further randomized studies of HAI FUdR have demonstrated evidence of benefit.^30

–33

Based on these studies, the authors designed this Phase I trial to integrate the experience of HAI FUdR with combined RIT/chemotherapy. Patients with colorectal cancer after hepatic resection or ablation of liver metastases to ≤3.0 cm received FUdR by HAI in combination with systemic gemcitabine and ⁹⁰Y-cT84.66. The primary objective was to determine the MTD and associated toxicities of HAI FUdR when added to a regimen from a previous phase I trial of gemcitabine at 105 mg/m² and ⁹⁰Y-cT84.66 RIT 16.6 mCim². This protocol therapy was designed to incorporate important elements felt to be critical for successful application of RIT. This trial evaluates RIT in combination with established radiation-enhancing chemotherapy delivered systemically and regionally. This trial also evaluates this approach in smaller volume or subclinical disease. Studies predict that RIT will have its greatest impact on subclinical disease.^34
–36

Materials and Methods

Antibody production and conjugation

Human/murine cT84.66 is an anti-CEA intact IgG1, with high affinity (KA = 1.16 × 1011 M⁻¹). Details of its production, characterization, purification, conjugation, and radiolabeling have been reported previously.¹⁸ The final vialed lot of purified conjugated antibody met standards set by the Food and Drug Administration. Investigational New Drug applications for ¹¹¹In-DTPA-cT84.66 and ⁹⁰Y-DTPA-cT84.66 are currently on file with the Food and Drug Administration (IND 5327).

Clinical trial design

The primary objective of this trial was to determine the MTD and associated toxicities of HAI FUdR in combination with intravenous gemcitabine and ⁹⁰Y-DTPA-cT84.66. A therapy cycle consisted of systemic gemcitabine, systemic ⁹⁰Y-DTPA-cT84.66, and the HAI administration of FUdR. Patients were enrolled in cohorts of 3 with dose levels of FUdR defined on this phase I trial at 0.10, 0.15, and 0.20 mg/kg/day for 14 days. Each treatment cycle was 6 weeks for a maximum of three cycles. After maximum hepatic resection and/or ablation and placement of an HAI pump, patients began protocol therapy approximately a month later. Protocol treatment began on day 1 with HAI/FUdR for 14 days. Gemcitabine was administered on days 9 and 11 at a dose of 105 mg/m²/day by bolus intravenous infusion over 30 minutes. On day 9, ⁹⁰Y-DTPA-cT84.66 (16.6 mCi/m²) was administered as a single i.v. bolus infusion. This RIT dose was determined from a previous phase I study of ⁹⁰Y-DTPA-cT84.66 as a single agent.¹⁹ The gemcitabine dose was determined from a previous phase I trial combining gemcitabine with 16.6 mCi/m² of ⁹⁰Y-DTPA-cT84.66. HAI FUdR dose escalation continued to a maximum dose level as defined by the trial of 0.2 mg/kg/day for 14 days or until a dose-limiting toxicity (DLT) was noted, defined as any treatment-related grade 3 nonhematologic toxicity not reversible to grade 2 or less within 24 hours, or any grade 4 toxicity. Up to three cycles of therapy were allowed with DLTs determined based on first cycle tolerance. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 2.0, which was the most current version at the time of trial initiation. MTD was defined as the highest level at which ≤1 of 6 patients experienced a DLT.

Before antibody administration, complete blood count and platelet count, complete metabolic panel, creatinine clearance, electrocardiogram, pulmonary function tests, urinalysis, serum HIV testing, serum pregnancy testing if indicated, serum CEA levels, and human anti-chimeric antibody (HACA) response were taken within 2 weeks of infusion. Imaging consisted of chest X-ray, and computed tomography (CT) or magnetic resonance imaging scans of relevant anatomic locations corresponding to areas of metastatic or suspected metastatic disease were obtained within 6 weeks of antibody infusion.

For the initial cycle of therapy, each patient first received an imaging dose of 5 mCi/5 mg ¹¹¹In-DTPA-cT84.66, which was used to track antibody activity and evaluate biodistribution. The therapeutic dose of ⁹⁰Y-DTPA-cT84.66 was subsequently given within 2 weeks and included 5 mCi of ¹¹¹In-DTPA-cT84.66 and ⁹⁰Y-DTPA-cT84.66. Initially, a test dose of 100 μg of radiolabeled antibody was administered i.v. over 5 minutes. After 15 minutes, if there were no side effects, the remainder of the antibody was administered over 30 minutes. Subsequent cycles of therapy were not preceded by a separate imaging infusion. Serial blood samples were taken for pharmacokinetics at 30 minutes, 1, 4 hours, and at each scan time after antibody infusion. Urine collections (24 hours) were done daily for five consecutive days after antibody administration for pharmacokinetic analysis. Planar and whole-body imaging studies were done at 6, 24, 48 hours, and 4–7 days after antibody administration using a Toshiba dual head 7200 camera with single-photon emission CT capability. In all cases, 20% energy windows were set over each of the two γ-ray energies of ¹¹¹In. Single-photon emission CT scans were done of relevant areas at 48 hours and 4–7 days after antibody administration.

To assess response, imaging studies, including CT scans, were repeated at 5–6 weeks post therapy. Responses were defined as: complete response—disappearance of all measurable and evaluable disease, and no new lesions; partial response—≥50% decrease from baseline in the sum of the products of perpendicular diameters of all measurable lesions, with no progression of evaluable disease or development of new lesions; stable disease—does not qualify for complete response, partial response, or progression; progressive disease—25% increase in the sum of products of measurable lesions over the smallest sum observed, or reappearance of any lesion that had disappeared, or appearance of any new lesion/site. Response endpoints included progression-free survival (PFS), overall survival (OS), and sites of recurrence. Every effort to biopsy recurrence of malignant disease was made whenever possible. Suspicious imaging findings alone did not constitute treatment failure. Elevated CEA alone was not considered treatment failure.

Before infusion and at ∼2 weeks and 1, 3, and 6 months after infusion, serum HACA response was assayed as previously described.³⁷ Serum samples incubated with ¹¹¹In-labeled DTPA-cT84.66 were also examined by size exclusion HPLC using Superose 6 columns to detect possible immune responses not found by RIA.

After treatment with ⁹⁰Y-MxDTPA-cT84.66/gemcitabine/HAI FUdR, patients proceeded to further systemic therapy. Systemic therapy, at the discretion of the treating physician, was allowed to be combined with additional cycles of HAI FUdR or after completion of the HAI FUdR. Additional HAI of FUdR was permitted for a maximum of four cycles (including cycles delivered during enrollment on this protocol with RIT/gemcitabine).

Results

Sixteen patients with metastatic colorectal cancer were enrolled on this study from December 2005 to July 2010. There were 6 females and 10 males. At the time of surgery, patients had between 1 and 22 (median 2) hepatic lesions, which were resected. At the time of enrollment, 6 patients had measurable disease following operative debulking and hepatic pump placement. Of these 6 patients, 1 had elevated CEA only, 1 had 2 subcentimeter liver lesions that were not ablated surgically, 1 had a single subcentimeter liver metastasis visible on postoperative imaging, 1 had a 1.5 cm enlarged celiac lymph node, 1 had a 1.2 cm cervical lymph node, and 1 had a 1.3 cm sclerotic right lesion in the right superior iliac bone. Ten were without clinical evidence of disease. Patient demographic details are displayed in Table 1.

Table 1.

Patient Summary Demographic Data

Patient demographics and pretreatment information	All patients (n = 16)
Age, median (range)	56.9 (35.5–77.7)
Gender, n (%)
F	6 (37.5)
M	10 (62.5)
Diagnosis site, n (%)
Colon, NOS	9 (56.3)
Ascending colon	2 (12.5)
Sigmoid colon	2 (12.5)
Transverse colon	1 (6.3)
Rectum, NOS	2 (12.5)
Stage at diagnosis, n (%)
2	2 (12.5)
3	3 (18.8)
4	11 (68.8)
Karnofsky performance status at enrollment, n (%)
60	1 (6.3)
80	4 (25.0)
90	9 (56.3)
100	1 (6.3)
No. of liver lesions at surgery, n (%)
0	1 (6.3)
1	5 (31.3)
2–3	4 (25.0)
4–5	4 (25.0)
≥6	2 (12.5)
Prestudy (before surgery) CEA (ng/mL), n (%)
<2.5	5 (31.3)
2.5–3.9	4 (25.0)
4.0–5.9	2 (12.5)
Unknown	1 (6.3)
Postoperative disease status, n (%)
NED	10 (62.5)
Only serological dz	1 (6.3)
With dz	5 (31.3)
Prior drug therapy, n (%)	15 (93.8)
No. of prior regimens, median (range)	1 (0–5)
0	1 (6.3)
1	8 (50.0)
2	4 (25.0)
3	2 (12.5)
5	1 (6.3)
≥6	4 (25.0)
Unknown	1 (6.3)
Prior regimen setting, n (%)
Adjuvant	2 (12.5)
Adjuvant + Mets/Recur	2 (12.5)
Mets/Recur	11 (68.8)
Prior surgery	16 (100.0)
Prior radiation	3 (18.8)
Prior immunotherapy	13 (81.2)
Bevacizumab	11 (68.8)
Bevacizumab + ABX-EGF	1 (6.3)
Bevacizumab + ABX-EGF + cetuximab	1 (6.3)

CEA, carcinoembryonic antigen; dz, disease; Mets/Recur, Metastases/Recurrence; NED, no evidence of disease; NOS, not otherwise specified.

The primary objective of this Phase I/II trial was to define the DLTs and MTD of HAI FUdR given with ⁹⁰Y-MxDTPA-cT84.66/gemcitabine. Total administered activity ranged from 22.8 to 34.7 mCi of ⁹⁰Y. One patient experienced a DLT at the highest FUdR dose level with grade 3 mucositis and did not receive further trial therapy. A second patient who had gastrointestinal toxicity after HAI was infused into the stomach vasculature. One patient subsequently developed acute myelogenous leukemia (AML), which was possibly related to treatment. Details of all other grade 3 and higher toxicity are listed in Table 2.

Table 2.

Grade 3—5 Toxicities

Adverse event	Grade 3, n (%)	Grade 4, n (%)	Grade 5, n (%)
Alkaline phosphatase increase	1 (6)
ALT, SGPT increase	7 (44)
AST, SGOT increase	4 (25)
Dehydration	1 (6
Diarrhea	2 (13)
Fatigue (asthenia, lethargy, malaise)	2 (13)
Leukocytes (total WBC)	6 (38)
Lymphopenia	9 (56)	1 (6)
Mucositis/stomatitis (clinical exam)	1 (6)
Mucositis/stomatitis (functional/symptomatic)	1 (6)
Neutrophils/granulocytes (ANC/AGC)	3 (19)
Pain	2 (13)
Platelets	1 (6)
Secondary malignancy, possibly related to cancer treatment (T-AML)			1 (6)

AGC, absolute granulocyte count; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; AML, acute myelogenous leukemia; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; WBC, white blood cells.

Thirteen patients demonstrated HACA response after the first cycle and received no additional RIT. One patient received a second cycle of ⁹⁰Y-DTPA-cT84.66 after which an HACA response was detected. Before progression, 2 patients received further adjuvant chemotherapy (1 had further cycles of FUdR, the other had capecitabine and oxaliplatin) off protocol.

Median follow-up was 41.8 months (18.7–114.6). After surgery, 10 patients had no evidence of visible disease and remained without evidence of disease after completion of protocol therapy. The remaining 6 patients demonstrated radiological visible disease after surgery and after protocol therapy 2 patients had a CR, 1 patient had PR, 2 had stable disease, and 1 had progression. Median PFS was 9.6 (95% confidence interval [CI]: 5.1–12.9) months with median OS of 41.2 months (95% CI: 23.2–73.2). Details of patient response are presented in Table 3 and Figure 1.

FIG. 1.

Kaplan–Meier survival curve for OS (line) and PFS (dashed line). OS, overall survival; PFS, progression-free survival.

Table 3.

Patient Outcomes

Treatment and outcomes	All patients (n = 16)
Study arm, n (%)
1 (0.1 mg/kg/day)	3 (18.8)
2 (0.15 mg/kg/day)	3 (18.8)
3 (0.2 mg/kg/day)	10 (62.5)
No. of courses FUdR received, n (%)
1	2 (12.5)
2	1 (6.3)
3	5 (31.3)
4	8 (50.0)
No. of RIT cycles, n (%)
1	15 (93.7)
2	1 (6.3)
Cycle 1 HACA, n (%)
POS	13 (81.3)
Neg	3 (18.8)
Best response, n (%)
NED	10 (62.5)
Complete response	2 (12.5)
Partial response	1 (6.3)
Progression	1 (6.3)
Stable disease	2 (12.5)
Duration of response (not clinical), median (range)	9.6 (1.0–50.0)
Reason off RIT, n (%)
DLT	1 (6.3)
GI toxicities (due to perfusion to the stomach)	1 (6.3)
HACA	13 (81.3)
PD (and HACA)	1 (6.3)
Off treatment reason, n (%)
Treatment completed per protocol	8 (50.0)
Progression	2 (12.5)
Toxicity	5 (31.3)
Other	1 (6.3)
OS
No. of events/No. of fails	12/16
Median OS (months) (95% CI)	41.2 (23.2–73.2)
PFS from treatment start date
No. of events/No. of fails	14/16
Median PFS (months) (95% CI)	9.6 (5.1–12.9)

CI, confidence interval; DLT, dose-limiting toxicity; HACA, human anti-chimeric antibody; OS, overall survival; PD, progressive disease; PFS, progression-free survival; RIT, radioimmunotherapy.

Two patients exhibited prolonged PFS. The first was a 50-year-old female presenting with stage IIIB colon adenocarcinoma involving the transverse colon. She received adjuvant chemotherapy and was subsequently found to have a solitary liver metastasis. After resection, she was rendered no evidence of disease (NED) and was enrolled on trial. She received the lowest dose level of FUdR (0.1 mg/kg/day) for four cycles. She had one cycle of RIT before developing HACA response. No additional therapies were given and she remains disease free at 113 months. The second patient was a 62-year-old male who presented with stage IV cancer of the sigmoid colon. He presented with imaging evidence of a liver metastasis, however, no lesions were found at surgery. He subsequently received bevacizumab and multiagent chemotherapy. However, the liver lesion subsequently enlarged on abdominal imaging associated with an elevated CEA. He was enrolled on protocol at the highest FUdR dose level (0.2 mg/kg/day). He received three cycles of FUdR and one cycle of RIT before developing HACA response. After protocol, he had a complete response. He remained without evidence of recurrence of colorectal adenocarcinoma; however, he died 45 months later of AML.

Discussion

Ionizing radiation remains an essential component of cancer therapy. For over a hundred years, using various techniques, radiotherapy has resulted in dramatic responses and cures for many tumor histologies. Generally, radiation therapy is most effective with small volume disease and when directed at microscopic residual disease in the adjuvant setting. The development of MAb and RIT ushered in the promise of targeted systemic radiotherapy. However, response rates for solid tumors and macroscopic disease were infrequent. As the challenges to delivery of antibody-conjugated therapies became better understood, it became clear that doses achievable through RIT would be better applied toward subclinical or microscopic disease in the adjuvant setting. Multiple studies have estimated the dose of radiotherapy delivered per cycle of RIT to be on the order of 200–3700 cGy/cycle.^{27,37

–48} These doses can result in clinically important effects particularly for microscopic disease and, depending on the tumor's α/β ratio, have been demonstrated to cause equivalent cell killing as single-fraction external beam radiotherapy.^49,50 In an important review of the role of radiotherapy for subclinical disease, Withers et al. described an inverse linear relationship between radiation doses and tumor recurrence.⁵¹ Central to this analysis was the observation that there was no threshold effect and even lower doses had measurable effects on tumor control. Compared with macroscopic disease, which requires doses >5000 cGy, doses in the range of 2000–3000 cGy can result in benefit to patients with microscopic tumor burdens. Lower doses of radiation have proven efficacious in randomized trials of rectal, esophageal, and anal cancers^52

–55 when combined with radiosensitizing chemotherapy agents. Therefore, a combined RIT chemotherapy approach in a minimal tumor burden setting has the potential to have clinically important effects.

In this study, the authors demonstrated the feasibility of combining ⁹⁰Y-cT84.66 RIT, systemic gemcitabine, and HAI FUdR in colorectal cancer patients with surgically debulked, minimal residual disease. FUdR and gemcitabine are known radiosensitizing chemotherapy agents. HAI FUdR has also been used in this patient population. Only 1 patient's therapy was halted due to a DLT. The doses of FUdR and ⁹⁰Y-cT84.66 anti-CEA RIT achievable at the MTD were similar to those seen with each agent alone and were likely secondary to nonoverlapping toxicities.²⁸ With a median follow-up of 41.8 months (18.7–114.6), median PFS was 9.6 months. Two patients demonstrated long-term disease control out to 45+ and 113+ months.

In this study, 6 patients had measurable disease after surgery. Of these, 2 had a CR, 1 had a PR, 2 had SD, and only 1 had progression. While lower absorbed doses (2000–3000 cGy) can result in benefit to patients with microscopic tumor burdens, much higher doses have been reported in resected tumors for which doses have been calculated.⁵⁶ It is possible that these responses are, therefore, related to high absorbed doses from the RIT.

Similar combined modality approaches incorporating RIT have been studied in patients with metastatic colorectal cancer. Initial efforts were with RIT alone in patients with bulky disease. In a phase I trial in patients with bulky metastatic disease, ⁹⁰Y-cT4.66 RIT alone showed no objective response; however, 3 out of 21 patients had stable disease up to 28 weeks.²⁷ In an effort to improve response rates in this same population of patients with chemorefractory bulky disease, the authors evaluated RIT in combination with radiation-enhancing chemotherapy agents. In a phase I study ⁹⁰Y-cT4.66 RIT was combined with infusional 5-FU with 11 of 21 patients with progressive disease entering the study demonstrating radiological stable disease of 3–8 months duration.²⁸ A phase I trial combining RIT with escalating doses of gemcitabine in a heavily pretreated patient population, showed clinical response in 5/36 patients and only 13 patients had disease progression.²⁰ This trial escalated gemcitabine to a MTD of 150 mg/m² with 3 patients with grade 3 or higher toxicity at gemcitabine doses of 165 mg/m². Ongoing experience combining RIT and low-dose gemcitabine for pancreatic cancer has shown promising results with tolerable toxicity.⁵⁷ The recently closed PANCRIT-1 trial was a randomized, international, multi-institutional, phase III trial investigating this approach for pancreatic cancer.⁵⁸

RIT alone after hepatic resection has been shown to be a safe and promising approach both in the initial and retreatment settings.^59
–61 Liersch et al. reported the results of a trial using ¹³¹I-labetuzamab (anti-CEA humanized MAb) after salvage resection of colorectal liver metastases. They showed this approach was safe, and they compared outcomes to a nonrandomized contemporaneous control group and reported improved median OS (58.0 vs. 31.0 months, p = 0.032) in patients treated with RIT.^59,60 Sahlmann et al. reported results from the same group that showed the safety of repeated use of ¹³¹I-labetuzamab in this patient population with median OS as high as 75.6 months in patients treated in the adjuvant setting.⁶¹

Despite an increasing number and effectiveness of systemic therapy options for colorectal cancer, few patients are cured with chemotherapy or biologic therapy alone.^62,63 Chemotherapy alone, therefore, is considered a palliative option in metastatic colorectal cancer. Six recent trials have examined the role of adjuvant systemic therapies after liver resection for colorectal cancer metastasis.^64

–68 No study showed improvement in OS, and only the European Organization for Research and Treatment of Cancer (EORTC) showed an improvement in disease-free survival with perioperative leukovorin, 5-FU, and oxaliplatin (FOLFOX) versus observation. While proven effective in the palliative setting, the utility of adjuvant chemotherapy after hepatic resection remains an open question. Two recent randomized studies have evaluated the role for HAI FUdR after hepatic resection demonstrating both high rates of intrahepatic control and DFS.^30,69 In addition, the combination of pump-based therapy and systemic chemotherapy with oxaliplatin and capecitabine demonstrated extended survival in the adjuvant setting.⁷⁰ Their study combines these approaches—systemic and regional chemotherapy—along with RIT.

The contemporary management of colon cancer metastatic to the liver includes arterial radioembolization with ⁹⁰Y microspheres with and without systemic chemotherapy.^71
–73 While not RIT, these techniques have shown the safety, efficacy, and widespread adoption of internal radiotherapy in combination with systemic agents. These therapies, combined with the current study's outcomes, represent a hypothesis-generating approach to combine multimodality therapy toward the management of liver metastasis.

Conclusion

In summary, these phase I results demonstrate the feasibility of combining systemic and liver-directed chemotherapy with anti-CEA RIT. This approach had minimal and acceptable toxicity with favorable disease control rates. Compared with their previous trials of RIT and infusional 5FU, this combined approach has prolonged PFS intervals. Results from this study support the hypothesis that RIT may have a clinically important role in multimodality approach in patients with small volume, subclinical disease. Further studies evaluating this strategy are warranted.

Footnotes

Acknowledgments

The authors thank Tammy Kloythanomsup, RN (Protocol Nurse), Jennifer Simpson, BA (Clinical Research Associate), Oscar Martin, Pharm D, and Sharon Denison, Pharm D (Investigational Drug Services); Anne-Line Anderson, MS and Erasmus Poku (Radiolabeling Specialists); Nicole Bowles (Research Associate); and Martin Brechbiel, PhD (National Cancer Institute) for supplying the 1B4M-DTPA. Financial Support: NIH CA PO1 43904.

Disclosure Statement

No competing financial interests exist.

References

Fortner

, Fong

. Twenty-five-year follow-up for liver resection: The personal series of Dr. Joseph G. Fortner. Ann Surg, 2009; 250:908.

Press

, Eary

, Appelbaum

, et al. Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support. N Engl J Med, 1993; 329:1219.

Kaminski

, Zasadny

, Francis

, et al. Radioimmunotherapy of B-cell lymphoma with [131I]anti-B1 (anti-CD20) antibody. N Engl J Med, 1993; 329:459.

DeNardo

, Lewis

, DeNardo

, et al. Effect of Lym-1 radioimmunoconjugate on refractory chronic lymphocytic leukemia. Cancer, 1994; 73:1425.

Knox

, Goris

, Trisler

, et al. Yttrium-90- labeled anti-CD20 monoclonal antibody therapy of recurrent B-cell lymphoma. Clin Cancer Res, 1996; 2:457.

Matthews

, Appelbaum

, Eary

, et al. Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation. Blood, 1995; 85:1122.

Appelbaum

, Matthews

, Eary

, et al. The use of radiolabeled anti-CD33 antibody to augment marrow irradiation prior to marrow transplantation for acute myelogenous leukemia. Transplantation, 1992; 54:829.

Jurcic

, Caron

, Nikula

, et al. Radiolabeled anti-CD33 monoclonal antibody M195 for myeloid leukemias. Cancer Res, 1995; 55(23 Suppl):5908s.

Juweid

, Sharkey

, Markowitz

, et al. Treatment of non-Hodgkin's lymphoma with radiolabeled murine, chimeric, or humanized LL2, an anti-CD22 monoclonal antibody. Cancer Res, 1995; 55(23 Suppl):5899s.

10.

Vriesendorp

, Herpst

, Germack

, et al. Phase I-II studies of yttrium-labeled antiferritin treatment for end-stage Hodgkin's disease, including Radiation Therapy Oncology Group 87-01. J Clin Oncol, 1991; 9:918.

11.

Tannock

. Combined Modality treatment with radiotherapy and chemotherapy. Radiother Oncol, 1989; 16:83.

12.

Roth

, Putnam

, Lichter

, et al. Cancer of the esophagus. In: DeVita

, Hellman

, Rosenberg

(eds.), Cancer: Principles and Practice of Oncology, 4th ed. Philadelphia, PA: J.B. Lippincott, Co., 1993; 776–817.

13.

McGinn

, Kinsella

. Non-hypoxic cell sensitizers. In: Loeffler

, Mauch

(eds.), Radiation Oncology: Technology and Biology. Philadelphia, PA: W.B. Saunders Co., 1994; 90–112.

14.

Philips

. Drug-radiation interactions. In: Loeffler

, Mauch

(eds.), Radiation Oncology: Technology and Biology. Philadelphia, PA: W.B. Saunders Co., 1994; 113–151.

15.

Cabilly

, Riggs

, Pande

, et al. Generation of antibody activity from immunoglobulin polypeptide chains produced in Escherichia coli. Proc Natl Acad Sci U S A, 1984; 81:3273.

16.

Kuhn

, Corbisiero

, Buras

, et al. Intraoperative gamma detection probe with presurgical antibody imaging in colon cancer. Arch Surg, 1991; 126:1398.

17.

, Shively

, Raubitschek

, et al. Minibody: A novel engineered anti-carcinoembryonic antigen antibody fragment (singlechain Fv-CH3) which exhibits rapid, high-level targeting of xenografts. Cancer Res, 1996; 56:3055.

18.

Gold

, Schutsky

, Modrak

, et al. Low-dose radioimmunotherapy (90)Y-PAM4) combined with gemcitabine for the treatment of experimental pancreatic cancer. Clin Cancer Res, 2003; 9(10 Pt 2):3929S.

19.

Graves

, Dearstyne

, Lin

, et al. Combination therapy with Pretarget CC49 radioimmunotherapy and gemcitabine prolongs tumor doubling time in a murine xenograft model of colon cancer more effectively than either monotherapy. Clin Cancer Res, 2003; 9(10 Pt 1):3712.

20.

Shibata

, Raubitschek

, Leong

, et al. A phase I study of a combination of yttrium-90-labeled anti-carcinoembryonic antigen (CEA) antibody and gemcitabine in patients with CEA-producing advanced malignancies. Clin Cancer Res, 2009; 15:2935.

21.

Hansen

, Snyder

, Miller

, et al. Carcinoembryonic antigen (CEA) assay. A laboratory adjunct in the diagnosis and management of cancer. Hum Pathol, 1974; 5:139.

22.

Neville

, Laurence

. Report of the workshop on the carcinoembryonic antigen (cea): The present position and proposals for future investigation. Int J Cancer, 1974; 14:1.

23.

Steward

, Nixon

, Zamcheck

, et al. Carcinoembryonic antigen in breast cancer patients: Serum levels and disease progress. Cancer, 1974; 33:1246.

24.

Seppala

, Pihko

, Ruoslahti

. Carcinoembryonic antigen and alpha fetoprotein in malignant tumors of the female genital tract. Cancer, 1975; 35:1377.

25.

Stillwagon

, Order

, Klein

, et al. Multi-modality treatment of primary nonresectable intrahepatic cholangiocarcinoma with 131I anti-CEA—A Radiation Therapy Oncology Group Study. Int J Radiat Oncol Biol Phys, 1987; 13:687.

26.

Beatty

, Duda

, Williams

, et al. Preoperative imaging of colorectal carcinoma with 111In-labeled anticarcinoembryonic antigen monoclonal antibody. Cancer Res, 1986; 46(12 Pt 1):6494.

27.

Wong

JYC

, Chu

, Yamauchi

, et al. A phase I radioimmunotherapy trial evaluating 90yttrium-labeled anti-carcinoembryonic antigen (CEA) chimeric T84.66 in patients with metastatic CEA-producing malignancies. Clin Cancer Res, 2000; 6:3855.

28.

Wong

, Shibata

, Williams

, et al. A Phase I trial of 90Y-anti-carcinoembryonic antigen chimeric T84.66 radioimmunotherapy with 5-fluorouracil in patients with metastatic colorectal cancer. Clin Cancer Res, 2003; 9(16 Pt 1):5842.

29.

Wagman

, Kemeny

, Leong

, et al. A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol, 1990; 8:1885.

30.

Kemeny

, Adak

, Gray

, et al. Combined modality treatment for resectable metastatic colorectal carcinoma to the liver: Surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy—An intergroup study. J Clin Oncol, 2002; 20:1499.

31.

Kemeny

, Huang

, Cohen

, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med, 1999; 341:2039.

32.

Lorenz

, Muller

, Schramm

, et al. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg, 1998; 228:756.

33.

Kemeny

, Jarnagin

, Gonen

, et al. Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer. J Clin Oncol, 2003; 21:3303.

34.

Williams

, Duda

, Proffitt

, et al. Tumor uptake as a function of tumor mass: A mathematic model. J Nucl Med, 1988; 29:103.

35.

Jain

. Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res, 1990; 50(3 Suppl):814s.

36.

Goldenberg

. Carcinoembryonic antigen as a target cancer antigen for radiolabeled antibodies: Prospects for cancer imaging and therapy. Tumour Biol, 1995; 16:62.

37.

Wong

, Thomas

, Yamauchi

, et al. Clinical evaluation of indium-111-labeled chimeric anti-CEA monoclonal antibody. J Nucl Med, 1997; 38:1951.

38.

Meredith

, Bueschen

, Khazaeli

, et al. Treatment of metastatic prostate carcinoma with radiolabeled antibody CC49. J Nucl Med, 1994; 35:1017.

39.

Juweid

, Sharkey

, Behr

, et al. Radioimmunotherapy of patients with small-volume tumors using iodine-131-labeled anti-CEA monoclonal antibody NP-4 F(ab′)2. J Nucl Med, 1996; 37:1504.

40.

Denardo

, O'Grady

, Richman

, et al. Radioimmunotherapy for advanced breast cancer using I-131-ChL6 antibody. Anticancer Res, 1997; 17(3B):1745.

41.

van Zanten-Przybysz

, Molthoff

, Roos

, et al. Radioimmunotherapy with intravenously administered 131I-labeled chimeric monoclonal antibody MOv18 in patients with ovarian cancer. J Nucl Med, 2000; 41:1168.

42.

Breitz

, Weiden

, Vanderheyden

, et al. Clinical experience with rhenium-186-labeled monoclonal antibodies for radioimmunotherapy: Results of phase I trials. J Nucl Med, 1992; 33:1099.

43.

Borjesson

, Postema

, de Bree

, et al. Radioimmunodetection and radioimmunotherapy of head and neck cancer. Oral Oncol, 2004; 40:761.

44.

DeNardo

, Kramer

, O'Donnell

, et al. Radioimmunotherapy for breast cancer using indium-111/yttrium-90 BrE-3: Results of a phase I clinical trial. J Nucl Med, 1997; 38:1180.

45.

Wiseman

, White

, Stabin

, et al. Phase I/II 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin's lymphoma. Eur J Nucl Med, 2000; 27:766.

46.

Vose

, Colcher

, Gobar

, et al. Phase I/II trial of multiple dose 131Iodine-MAb LL2 (CD22) in patients with recurrent non-Hodgkin's lymphoma. Leuk Lymphoma, 2000; 38:91.

47.

Kaminski

, Zasadny

, Francis

, et al. Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol, 1996; 14:1974.

48.

Lamborn

, DeNardo

, et al. Treatment-related parameters predicting efficacy of Lym-1 radioimmunotherapy in patients with B-lymphocytic malignancies. Clin Cancer Res, 1997; 3:1253.

49.

Wong

JYC

, Williams

, Demidecki

, et al. Radiobiologic studies comparing yttrium-90 irradiation and external beam irradiation in vitro. Int J Radiat Oncol Biol Phys, 1991; 20:715.

50.

Buras

, Wong

JYC

, Kuhn

, et al. Comparison of ⁹⁰Y-labeled anti-CEA monoclonal antibody therapy with external beam radiotherapy in colon cancer. Int J Radiat Oncol Biol Phys, 1993; 25:473.

51.

Withers

, Peters

, Taylor

. Dose-response for subclinical disease—In response to Dr. Ben-Josef. Int J Radiat Oncol Biol Phys, 1995; 32:1267.

52.

Dahl

, Horn

, Morild

, et al. Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Results of a randomized multicenter trial in western Norway. Cancer, 1990; 66:2286.

53.

Gerard

, Buyse

, Nordlinger

, et al. Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg, 1988; 208:606.

54.

Franklin

, Steiger

, Vaishampayan

, et al. Combined modality therapy for esophageal squamous cell carcinoma. Cancer, 1983; 51:1062.

55.

Nigro

, Seydel

, Considine

, et al. Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer, 1983; 51:1826.

56.

Bardies

, Bardet

, Faivre-Chauvet

, et al. Bispecific antibody and iodine-131-labeled bivalent hapten dosimetry in patients with medullary thyroid or small-cell lung cancer. J Nucl Med, 1996; 37:1853.

57.

Ocean

, Pennington

, Guarino

, et al. Fractionated radioimmunotherapy with (90) Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial. Cancer, 2012; 118:5497.

58.

Phase 3 Trial of 90Y-Clivatuzumab Tetraxetan & Gemcitabine vs Placebo & Gemcitabine in Metastatic Pancreatic Cancer 2014 (August 4, 2015). Online document at https://clinicaltrials.gov/ct2/show/NCT01956812

59.

Liersch

, Meller

, Kulle

, et al. Phase II trial of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after salvage resection of colorectal metastases in the liver: 5-year safety and efficacy results. J Clin Oncol, 2005; 23:6763.

60.

Liersch

, Meller

, Bittrich

, et al. Update of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after salvage resection of colorectal liver metastases: Comparison of outcome to a contemporaneous control group. Ann Surg Oncol, 2007; 14:2577.

61.

Sahlmann

, Homayounfar

, Niessner

, et al. Repeated Adjuvant Anti-CEA Radioimmunotherapy after resection of colorectal liver metastases: safety, feasibility, and long-term efficacy results of a prospective phase 2 study. Cancer, 2016; 20.

62.

Saltz

, Cox

, Blanke

, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med, 2000; 343:905.

63.

Saltz

, Clarke

, Diaz-Rubio

, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: A randomized phase III study. J Clin Oncol, 2008; 26:2013.

64.

Portier

, Elias

, Bouche

, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol, 2006; 24:4976.

65.

Parks

, Gonen

, Kemeny

, et al. Adjuvant chemotherapy improves survival after resection of hepatic colorectal metastases: Analysis of data from two continents. J Am Coll Surg, 2007; 204:753.

66.

Nordlinger

, Sorbye

, Glimelius

, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): Long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol, 2013; 14:1208.

67.

Primrose

, Falk

, Finch-Jones

, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: The new EPOC randomised controlled trial. Lancet Oncol, 2014; 15:601.

68.

Ychou

, Hohenberger

, Thezenas

, et al. A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol, 2009; 20:1964.

69.

Bozzetti

, Gennari

, Regalia

, et al. Morbidity and mortality after surgical resection of liver tumors. Analysis of 229 cases. Hepatogastroenterology, 1992; 39:237.

70.

Alberts

, Roh

, Mahoney

, et al. Alternating systemic and hepatic artery infusion therapy for resected liver metastases from colorectal cancer: A North Central Cancer Treatment Group (NCCTG)/National Surgical Adjuvant Breast and Bowel Project (NSABP) phase II intergroup trial, N9945/CI-66. J Clin Oncol, 2010; 28:853.

71.

Cosimelli

, Golfieri

, Cagol

, et al. Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases. Br J Cancer, 2010; 103:324.

72.

Gray

, Van Hazel

, Hope

, et al. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol, 2001; 12:1711.

73.

Mulcahy

, Lewandowski

, Ibrahim

, et al. Radioembolization of colorectal hepatic metastases using yttrium-90 microspheres. Cancer, 2009; 115:1849.