Recent Progress in Radioimmunotherapy for Cancer

ABSTRACT: Radioimmunotherapy allows for the delivery of systemically targeted radiation to areas of disease while relatively sparing normal tissues. Despite numerous challenges, considerable progress has been made in the application of radioimmunotherapy to a wide variety of human malignancies. The greatest successes have occurred in the treatment of hematologic malignancies. Radioimmunotherapy, with or without stem-cell transplant support, has produced substantial complete remission rates in chemotherapy-resistant B-cell lymphomas. Nonmyeloablative regimens have shown so much promise that they are now being tested as initial therapy for low-grade B-cell lymphomas. Although solid tumor malignancies have been less responsive to radioimmunotherapy, encouraging results have been obtained with locoregional routes of administration, especially when the tumor burden is small. Greater tumor-to-normal tissue ratios are achievable with regional administration. Even with intraperitoneal and intrathecal administration, bone marrow suppression remains the dose-limiting toxicity. Ongoing research into new targeting molecules, improved chelation chemistry, and novel isotope utilization is likely to extend the applications of this strategy to other tumor types. The potential for radioimmunotherapy will be enhanced if this modality can be optimally adapted for integration with other agents and if the administration method can be tailored to the type and distribution of malignancy. [ONCOLOGY 11(7):979-987, 1997]

Introduction

In the 22 years since the Nobel prize-winning development of hybridomatechnology for the production of monoclonal antibodies in 1975,[1] themedical applications of antibodies have greatly expanded. Radioimmunotherapygenerally refers to the administration of a radionuclide conjugated toan antibody or antibody-derived construct for therapeutic intent. The antibody,directed to an antigen with enhanced or unique expression on tumor cells,serves as a carrier for the radioactive component. This technique deliverssystemically targeted radiation to areas of disease while relatively sparingnormal tissues.

Successful use of radiolabeled antibodies for the treatment of cancerhas been more challenging than their application as diagnostic tools.[2-6]Preclinical studies of radioimmunotherapy, including treatment of athymicmice bearing human tumors, have been helpful, although the results of thesestudies have not always directly translated into equivalent clinical progress.[7]Despite numerous obstacles, considerable progress in radioimmunotherapyhas been made over the past decade. (Due to the large volume of literatureon this novel treatment strategy, many of the references listed in thisarticle are reviews.)

The application of antibody technology to cancer therapy has been moredifficult than its use as a diagnostic tool for a variety of reasons.[4-6]The achievement of a therapeutic effect requires not only selectivity ofradionuclide localization but also delivery of adequate amounts of radionuclidefor generation of therapeutic radiation doses. Vascular dynamics and highinterstitial pressure in tumors have limited the delivery of antibody.Problems in devising the optimal procedures for linking radionuclide metalsto antibodies have also posed serious hurdles. Additional difficultieshave included the immunogenicity of murine monoclonal antibodies, cross-reactivityof antibodies with normal tissues, long circulatory half-lives of chimericor humanized antibodies, and dose-limiting bone marrow suppression.

Several radionuclides are considered suitable for radioimmunotherapy.These have been the subject of several recent reviews.[5,8,9] The choiceof radionuclide depends on its radiation emissions, as well as variouscharacteristics of the target, antibody carrier, and clinical situation,such as the bulk of disease to be treated.

One advantage of beta-emitting radionuclides as antibody conjugatesover chemotherapeutic agents or toxins is that their effective radiationrange extends beyond the antibody-bound target cell. Thus, beta-radiationcan kill surrounding tumor cells from a point of localization. This isadvantageous given the prominent variation in antigen expression and antibody/drugdelivery in various parts of tumor nodules.

Iodine-131 and ytrrium-90 have been the most extensively used beta-emittersto date. Ytrrium-90 has the longer range in tissue, with an average of2.5 mm compared to 0.3 mm for iodine-131. However, ytrrium-90 requiresa chelator and does not have gamma-emissions that allow direct imagingof radioimmunconjugate distribution.

Certain non-beta-emitting radionuclides (eg, alpha-emitters, Auger electronemitters) also have attractive features. For example, Auger electron emitters,such as iodine-125, have such a short range of energy deposition that theyrequire internalization and translocation to the nuclear DNA to effectivelykill tumor cells. Thus, normal cells that do not express the target antigenare not affected by Auger electron emission, as they are by the multi-cell-diameterrange of beta emissions. As a result, toxicity may be reduced.

The choice of antibody construct to be used as the carrier includesfull-size molecules of murine or "humanized" molecules (chimericor complementarity determining regions (CDR)-grafted), as well as traditionalfragments [FAb or F(Ab')₂] or genetic constructs. Genetic constructsvary in size, as well as in the number of antigen-combining sites, or havebeen modified to alter their biology (eg, fusion proteins). These variousantibody constructs have been reviewed by Dion,[10] Frankel,[11] and others.[12]

ClinicalResults in Hematologic Malignancies

Thus far radioimmunotherapy has had the greatest success in the treatmentof lymphomas and leukemias. The hematologic malignancies have several featuresthat make them more suitable than solid malignancies for radioimmunotherapy.First, malignant cells in the blood, spleen, lymph nodes, and bone marroware more accessible than are solid tumor cells. Also, knowledge of theantigenic expression of the various lineages and stages of hematopoieticdifferentiation have provided well-characterized monoclonal antibodies.

Although CD20 has been the target antigen for more than one clinicallysuccessful antibody, several other target antigens for hematologic malignancieshave been identified. These include CD19, CD21, CD22, CD37, CD5, CD25,CD33, and CD45, as well as anti-idiotypic antigens. Most of these antigensare expressed on more than 90% of the malignant cells targeted.

Non-Hodgkin's Lymphomas

Knox[13] and Jurcic et al[14] recently reviewed the results of clinicaltrials using radioimmunotherapy in the treatment of non-Hodgkin's lymphomasthat are resistant to standard therapy. (The review by Jurcic et al alsoincludes the leukemias.) High response rates (generally more than 50%),as well as durable complete remissions, have been reported in hematologicmalignancies using a variety of antibodies labeled with iodine-131, copper-67,or yttrium-90 administered in different treatment schemes.

Although patients with T-cell lymphomas have also responded to radioimmunotherapy,fewer patients have been treated, and most studies have shown lower responserates than have been seen in patients with B-cell lymphomas. The exceptionis the use of yttrium-90-anti-CD25. In a recent study, this treatment achieveda more than 50% response rate in patients with T-cell lymphoma.[15]

High-Dose Radioimmunotherapy With Stem-Cell Rescue--The highest responserates and longest remissions have been reported in patients with B-celllymphoma who received high-dose radioimmunotherapy that required reinfusionof bone marrow or peripheral stem cells for hematologic rescue.[16] Mostof these studies have shown complete response rates more than 50% and totalresponse rates more than 80%. Responses have been durable in a number ofpatients, some of whom have maintained a continuous complete response forover 6 years.

Radioimmunotherapy has an advantage over total-body irradiation, whichhas been traditionally used in bone marrow transplant salvage programs,in that it delivers a higher radiation dose to the tumor and a lower doseto nontarget normal tissues. Accordingly, a Seattle team[17,18] has replacedtotal-body irradiation with radioimmunotherapy in its marrow transplantsalvage protocol. In their studies, the use of high-dose radioimmunotherapyfollowed by hematologic rescue was restricted to a more select group ofpatients than in other nonmyeloablative trials since pretherapy biodistributionstudies were used to select patients in whom no normal organ would receivea dose higher than tumor. Most patients with an unfavorable distributionhad bulky disease, including splenomegaly. The Seattle group has reportedan 84% complete response rate with a median duration of complete responseof over 18 months.[17]

Nonmyeloablative Regimens--Although the most impressive rates and durationsof response have been seen with high-dose radioimmunotherapy, clinicalresponses have also been noted with nonmyeloablative doses of labeled antibody,particularly when given with large doses of unlabeled antibody.[19-22]In one of the most promising trials to date, nonmyeloablative iodine-131-labeledanti-B1 (anti-CD20) produced responses in 19 of 21 patients with low-gradenon-Hodgkin's lymphoma, two-thirds of whom had a complete response.[21]Side effects have been minimal, and close to half of the patients haveremained in complete remission for a longer time (median, 16 months) thanwith their prior chemotherapy.

Based on these encouraging results, pivotal trials of nonmyeloablativeregimens are underway in patients with low-grade non-Hodgkin's lymphoma,as are phase II trials in patients with previously untreated low-gradeB-cell lymphoma.

Hodgkin's Disease

Hodgkin's disease has also been treated with radioimmunotherapy, includinghigh-dose radioimmunotherapy followed by autologous marrow rescue. Vriesendorpet al have reviewed several trials in which iodine-131- or yttrium-90-labeledpolyclonal antiferritin was used to treat more than 130 patients with chemotherapy-resistantHodgkin's disease.[23] Since antibody responses to radioimmunconjugateshave been uncommon in Hodgkin's disease patients, many patients were ableto receive multiple administrations of radiolabeled antiferritin.

Yttrium-90-antiferritin achieved significantly better therapeutic resultsthan iodine-131-antiferritin. Patients with a longer disease history (morethan 3 years) and a tumor volume less than 30 cm³ who received atleast 0.4 mCi/kg of body weight were more likely to respond than patientswithout these characteristics. On average, patients who achieved a completeresponse survived longer than those attaining a partial response. The averagesurvival was 8 months for patients treated in the initial trials; survivalanalysis for the later trials is still in progress.

Hodgkin's disease has recurred in most of the patients. Failures occurredin previously uninvolved sites in one-third of the patients, while responsesto radioimmunotherapy have been maintained at the initial disease sites.

The initial group of 17 patients treated with high-dose yttrium-90-antiferritinhad a 65% response rate (41% complete response rate).[23] This comparesfavorably with the 17% complete response rate among patients in a lower-dosegroup who were excluded from receiving high-dose therapy due to previousbilateral iliac crest external-beam radiation or marrow involvement. Moresevere hematologic toxicity was noted in this initial trial than in morerecent studies of high-dose iodine-131; three patients in the early trialdied of prolonged aplasia.

The yttrium-90-antiferritin conjugate has also been used in conjunctionwith cyclophosphamide (Cytoxan, Neosar), carmustine (BCNU), and etoposide(VePesid) chemotherapy followed by autologous marrow rescue at the Universityof Nebraska.[24] Of the 14 patients in that series, 2 were unable to completetherapy and 5 died early, while 3 of the 4 patients who survived for morethan 2 years showed no evidence of disease.

Thus, the efficacy of radioimmunotherapy in Hodgkin's disease seemsmore limited than in B-cell lymphoma and awaits further clinical trialdevelopment.

Leukemias

Contrary to most trials of radioimmunotherapy, which attempt to sparethe bone marrow since it is the dose-limiting organ, antileukemia strategiestarget the marrow to eradicate all residual leukemic cells. This has allowedhigher doses to be delivered to the target cells than to most normal tissues.

The Memorial Sloan-Kettering Cancer Center Group[14] used an anti-CD33antibody (M195) labeled with iodine-131 to intensify induction treatmentprior to bone marrow transplantation. This radiolabeled antibody was usedin conjunction with busulfan (Myleran) and cyclophosphamide in 19 patientswith refractory acute myelogenous leukemia or accelerated blast crisisof chronic myelogenous leukemia. Of the 19 patients, 18 achieved a completeresponse. In 3 of the 15 for whom this was the first transplant, the remissionwas maintained for more than 18 to 29 months. Although little toxicitywas attributed to the iodine-131-labeled antibody, 10 patients died oftransplant-related complications while in complete remission.

The same regimen has also been used in six patients with relapsed acutepromyelocytic leukemia. Marrow deletion of a molecular marker of diseasewas seen in two of these patients. This radioimmunotherapy plus chemotherapyregimen compares favorably with other strategies for relapsed leukemia.

Matthews and colleagues added iodine-131-BC8 (anti-CD45 antibody) toa standard transplant regimen and found no increment in toxicity, as comparedwith cyclophosphamide plus total-body irradiation.[25] They have not reachedthe maximum tolerated dose of the radioimmunotherapy in patients with leukemia.With a median follow-up of 17 months, 9 of 13 patients in their seriestreated for acute myelogenous leukemia or refractory anemia with excessblasts and 2 of 7 patients treated for acute lymphocytic leukemia remaindisease-free.

Clinical Results inSolid Tumors

Phase I or II trials of radioimmunotherapy have been carried out ina variety of solid tumors, including cancers of the breast, colon, prostate,thyroid, lung, kidney, pancreas, testes, and ovary, as well as hepatomas,cholangiocarcinomas, gliomas, melanomas, and neuroblastomas.[6] Objectiveresponses have been infrequent, and bone marrow suppression has been thedose-limiting toxicity. Antitumor efficacy has been reported most commonlywith locoregional routes of administration when the tumor burden was small.

Systemic Administration of Radioimmunotherapy

High-Dose Therapy With Stem-Cell Support--High-dose radioimmunotherapyfollowed by stem-cell hematologic rescue has generally resulted in deliveryof higher radiation doses to tumors than has been achieved with lower-doseregimens. Several institutions have used this therapeutic scheme for solidtumors, including breast, prostate, and gastrointestinal cancers.[26-28]The high-affinity antibody CC49 has been used in myeloablative regimensfor gastrointestinal cancer patients at the University of Nebraska, andtrials in prostate and breast cancer have also been initiated at the Universityof Alabama at Birmingham.

Although the results of high-dose radioimmunotherapy in these solidtumors are not as impressive as results in the hematologic malignancies,antitumor effects have been noted. In prostate cancer, objective partialresponses were achieved with the combination of high-dose radioimmunotherapy,chemotherapy, and total-body irradiation followed by stem-cell rescue.[26]Studies with non-marrow-ablative radioimmunotherapy alone did not showobjective regressions, although symptomatic relief was attained in manypatients.[26]

Breast cancer patients enrolled in the University of Alabama at Birminghamphase I radioimmunotherapy trial were not sufficiently responsive to chemotherapyto be candidates for high-dose chemotherapy plus stem-cell transplant.Of the initial four breast cancer patients treated with iodine-131-CC49and total-body irradiation, two patients had objective responses and theother two had stable disease at 3-month follow-up.

As expected, higher radiation doses were delivered to tumors in gastrointestinaltumor patients who received high- dose radioimmunotherapy followed by hematologicrescue at the University of Nebraska than are usually delivered with lower-dosesystemic radioimmunotherapy, although no objective responses were noted.[28]

Nonmyeloablative Therapy--In early trials for cancer of the liver,pancreas, and biliary tree conducted at the Johns Hopkins Center, nonmyeloablativeradioimmunotherapy was used in combination with other modalities, whichmay have enhanced its effectiveness. This may account for the more favorableoutcome reported in these early studies than in many subsequent trialsin which nonmyeloablative doses of radioimmunotherapy were given aloneto patients with metastatic chemotherapy/hormone-refractory disease; theselater trials reported low response rates (and often no objective responses).[6,26,29]

Although complete responses have been rare with nonmyeloablative systemicradioimmunotherapy, many trials have shown antitumor effects, includingpalliation of symptoms, minor responses, and stabilization of disease.One of the more promising results was reported by DeNardo's team in breastcancer patients treated with iodine-131-chimeric L6.[5] They noted a 40%partial response rate and a 20% rate of minor responses.

Studies of radioimmunotherapy for colorectal cancer[29] and prostatecancer[26] have recently been reviewed. Although fewer studies have beenconducted for prostate cancer, antitumor effects were more frequently reportedthan for colorectal cancer.

Locoregional Administration of Radioimmunotherapy

There has been considerable interest in nonsystemic routes of administrationof radioimmunotherapy, including intraperitoneal, intrathecal, intra-arterial,and direct tumor injection.

Compartmental administration has produced the best results in treatingsmall disease deposits, such as those detected by cytologic studies. Theadvantages of compartmental administration include the ability to achievea higher concentration of radiolabeled antibody at disease sites and reducedradiation exposure to the bone marrow. Tumor-to-normal tissue ratios of40:1 have been common with intraperitoneal administration of radiolabeledwhole-antibody conjugate, whereas ratios of more than 200 :1 have beenachieved in some cases.[30] With direct intralesional administration ofradiolabeled antibodies, radiation doses in excess of 760 Gy have beendelivered.[31]

Intraperitoneal radioimmunotherapy has been tested clinicallyprimarily in patients with ovarian cancer, although it also has been usedto treat carcinomatosis from other cancers. Researchers at HammersmithHospital have had the most extensive experience with this therapy in ovariancancer.[32] These researchers reported disappearance of tumor cells andextended survival in patients with small-volume ovarian cancer, but noapparent responses in those with tumor nodules more than 2 cm.[33]

The Hammersmith group has attempted to improve many aspects of radioimmunotherapy.Their efforts have included testing of various antibodies and isotopes(yttrium-90 and iodine-131); infusion of ethylenediamine tetraacetic acid(EDTA) to alter the clearance of unstable metal radionuclide conjugates;and the use of the macrocyclic bifunctional chelator 2(-p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-N,N¢, N¢¢, N¢¢¢-tetraacetic acid (DOTA) toachieve more stable conjugates of yttrium-90-labeled antibodies. Theseinvestigators have also measured tissue doses using thermoluminescent dosimetersand have estimated doses using other methods. They found a discrepancybetween calculated radiation doses delivered and antitumor effects, whichled them to postulate that immune mechanisms may also contribute to tumorcell eradication.

Some trials[33,34] have documented complete pathologic responses ofovarian malignancies to radiolabeled antibody therapy at post-treatmentlaparotomies or laparoscopies. Crippa et al[34] utilized a third-look surgicalprocedure to evaluate responses of ovarian cancer patients 90 days afterintraperitoneal radioimmunotherapy with iodine-131-MOV-18. Most of thepatients in this study had disease nodules less than 5 mm or positive washingsbefore therapy. Five patients achieved a complete response, six had stabledisease, and five exhibited disease progression. Longer follow-up of thecomplete responders showed that one patient remained disease-free at 34months while the other four had a mean disease-free survival of 10.5 months.

Studies of radioimmunotherapy for ovarian cancer in the United Stateshave utilized rhenium-186 or lutetium-177 in addition to the yttrium-90and iodine-131 that have been used in the European studies.[35-37] TheUS trials of yttrium-90 have reached the same conclusion as the Europeantrials; namely, that EDTA increases urinary excretion and decreases toxicitywhen given with a yttrium-90-antibody conjugate prepared with the diethylenetriaminepenta-acetic acid (DTPA) chelator.[35]

Two recent phase I studies have had promising results, especially insmall-volume ovarian cancer. Objective responses were observed with bothrhenium-186-NR-LU-10[36] and lutetium-177-CC49.[37] While 13 of 17 patientsprogressed after 25 to 150 mCi/m² of rhenium-186-NR-LU-10, 4 patientswhose tumors were less than 5 mm had responses confirmed at subsequentlaparotomy. The most frequent toxicity was a transient elevation of liverenzymes (12/17 patients).

In a dose-escalating phase I trial of lutetium-177-CC49 (10 to 45 mCi/m²)conducted at our institution, one partial response was noted in a patientwith a 4-cm mass while other patients with disease nodules more than 1cm progressed. Of five patients treated for microscopic residual disease,one patient relapsed at 10 months and the remaining four have no evidenceof disease after follow-up of 6 to 36 months.[37]

Given the evidence of antitumor activity of intraperitoneal radioimmunotherapyin relapsed ovarian cancer, investigators have begun to test this strategyin the adjuvant setting. In a trial of adjuvant radioimmunotherapy comparedto additional chemotherapy or whole-abdominal irradiation[38] conductedby the North Thames study group,[39] actuarial survival was significantlybetter in the radioimmunotherapy group. Mortality from ovarian cancer wasless than 10% at a median follow-up of 32 months after radioimmunotherapy,as compared with the more than 80% mortality by 67 months in patients whoreceived alternate forms of therapy.[38]

Intralesional Radioimmunotherapy--Riva and associates have hadthe most experience with intralesional administration of radiolabeled antibodiesin patients with gliomas.[31] In their report of 22 patients who had anexpected survival of 2 to 10 months, 36.3% of patients responded objectivelyto radioimmunotherapy, while disease remained stable in an additional 6patients for a median of 11 months. Mean duration of partial responseswas 11 months, and the four complete responders were alive 4 to 33 monthsafter radioimmunotherapy.

These patients had undergone extensive prior therapy, including oneto two resections, standard external-beam radiation, and chemotherapy.The intralesional radioimmunotherapy procedure delivered more than 562Gy (in patients in whom doses could be calculated). After therapy, Karnofskyperformance status was 90 or greater in all patients, except one individualwith a spinal cord glioma, and quality of life was near normal.

The Duke University team and collaborators carried out a phase I trialof iodine-131-anti-tenascin antibody 81C6 in 31 adult and pediatric patientswith leptomeningeal neoplasms or resection cavities of primary brain tumorsthat had subarachnoid communication.[40] No grade 3/4 nonhematologic toxicitieswere noted. Of the 31 patients, 1 had a partial response, while diseasestabilized in 13 (42%). Twelve patients were alive at a median follow-upof more than 320 days; five showed no signs of progression for a medianof more than 409 days.

Of the 23 adults in this study, 17 had recurrent glioblastoma multiforme.Thus, these results are favorable in a group of patients who have a limitedlife expectancy. Only 4 of the 31 treated patients had not received priorradiation therapy and 8 had not received prior chemotherapy.

High doses of radiation resulting in local tumor control have also beenachieved with intralesional administration of nonantibody phosphorus-32preparations.[41]

Intra-arterial Radioimmunotherapy--Trials of intra-arterial administrationof iodine-131- and iodine-125-labeled antibodies have reported encouragingresults in gliomas. Objective responses and sustained clinical improvementhave been observed, usually with no toxicity.[42]

Brady and colleagues at Hahnemann University have extensive experiencewith intra-arterial administration. In their initial pilot study, two tothree treatments of iodine-125-labeled anti-epidermal growth factor receptorantibody 425 were given to patients with malignant astrocytomas after intenselocalization of indium-111-labeled antibody to the brain tumor was demonstrated.[43]Only 1 of 15 patients had a definite adverse event. Among the patientswith recurrent gliomas, 20% had objective responses and 40% showed diseasestabilization. In the majority of responders, the relapse-free intervalwas longer than had been seen after initial therapy.

Subsequently, these researchers used iodine-125-labeled anti-epidermalgrowth factor as adjuvant therapy in patients with primary glioblastomamultiforme, with apparent prolongation of survival.[44] Some of these patientsreceived intravenous rather than intra-arterial administration of iodine-125-labeledanti-epidermal growth factor receptor antibody 425 since the investigatorsdid not find a consistent advantage of the intra-arterial route.

Intrathecal Radioimmunotherapy--A British neuro-oncology grouphas administered a variety of antibodies, including mixtures, via the intra-thecalroute in 40 adult and pediatric patients with leukemia, medulloblastoma,or primitive neuroectodermal tumors.[45,46] All 40 patients had evidenceof leptomeningeal failure after conventional therapy, and all 7 childrenwith acute lymphocytic leukemia were in second or subsequent relapse. Likewise,13 of 14 patients with medulloblastoma had received other treatments forrelapse prior to radioimmunotherapy, and in half of these patients, multipletherapies had been used.

Four of the six leukemic patients evaluated had complete responses tointrathecal radioimmunotherapy and one patient had partial clearance ofdisease, for a response rate of 83%. Responses usually lasted no more than8 weeks.

More durable responses were achieved in the nonleukemic patients. Responsesof 3 to 15 months were reported for 5 of 11 evaluable patients with recurrentneuroblastoma. At the time of reporting, all responders were alive witha follow-up of 5 to 50 months, although 60% relapsed within 2 years.

Among 15 evaluable patients with recurrent primitive neuroectodermaltumors, 6 patients responded for 2 to 18 months. Half of the respondershad complete remissions.

Toxicities

Dose-Limiting Toxicities

The dose-limiting effect of most radioimmunotherapy regimens is bonemarrow suppression secondary to the radiation emissions. Various factorsappear to be influential in determining the tolerance to radioimmunotherapywithout stem-cell rescue. These include marrow reserve (which depends onprior chemotherapy and extent of disease involvement), total tumor burden,spleen size, and radioimmunoconjugate stability.

Data on the dose-limiting effects of radioimmunotherapy in other organshave come from high-dose/stem-cell transplant trials. These effects arenot well-defined, although cardiopulmonary and liver toxicity have beenreported.[17] Cardiopulmonary toxicity has been noted by the Seattle transplantteam after high-dose iodine-131, whereas hepatic toxicity with yttrium-90has been predicted from studies performed at the University of Nebraska,[47]as well as animal studies.[48]

Acute Toxicities

Acute symptoms are usually related to administration of the antibodyproducts and are absent in many patients. In general, symptoms with initialadministration are mild and include rash, fever, chills, myalgia, diaphoresis,pruritus, nausea, vomiting, diarrhea, nasal congestion, and hypotension.[49]These side effects are very transient and usually respond to antihistamines,acetaminophen, and nonsteroidal anti-inflammatory agents.

Rarely, more severe symptoms, such as rigors, bronchospasm, and laryngealedema, have been noted. These respond quickly to steroids, antihistamines,oxygen, and meperidine. When radiolabeled antibodies are administered intothe central nervous system, various mild, transient symptoms have beendescribed in the majority of patients. These include cerebral edema, nuchalrigidity, aseptic meningitis, increased intracranial pressure, and seizures.Steroids often ameliorate these symptoms.

A mild serum sickness-type phenomenon occurring about 2 weeks aftermurine antibody treatment has been described. It is characterized by transientjoint aching and symptoms of malaise without renal disease. This phenomenonhas been common with intraperitoneal administration (often occurring inapproximately one-third of patients) but is rare with intravenous administration.

Late Toxicities

Late bowel toxicity has not been problematic after intraperitoneal radioimmunotherapy,which is an advantage over non-tumor-specific radionuclide therapy, suchas phosphorus-32. Reduced thyroid function is a late toxic effect thathas been observed after iodine-131 radioimmunotherapy. In general, whenpatients develop abnormal thyroid function tests, thyroid hormone is prescribed.Thus, the extent to which overt hypothyroidism would develop is unknown.[17]

Efforts to ImproveRadioimmunotherapy

The reasons that radioimmunotherapy has much greater effectiveness insome cases have not been fully explained. However, the differences in theeffectiveness of this therapy, depending on the type and extent of malignancy,are not unexpected. The lymphomas are more radiosensitive than most othertumors. Also, there may be other factors that make certain tumors especiallysusceptible to low-dose-rate radioimmunotherapy. These include a poor capacityfor repairing radiation damage and the need for only a small amount ofradiation for an antitumor effect, which is characteristic of lymphomas.

Numerous areas of active research are focused on the more effectiveimplementation of radioimmunotherapy.[4-7] These can be divided into twobroad categories: those dealing with antibodies and their radiolabelingand those influencing the therapeutic ratio. Efforts to improve antibodiesand targeting include: (1) genetic engineering to decrease immunogenicpotential or produce smaller molecules that retain bifunctional reactivityor increase avidity; and (2) administration of interferon to up-regulatetarget antigen expression in adenocarcinomas.[6]

Chelator chemistry searches for the optimal stability of radioimmunoconjugateswithout immunogenicity of the chelator. A number of potentially suitableradionuclides have been assessed, but the optimal choice for each situationhas not been well defined. For instance, the shorter-range beta-emittingradionuclides are expected to have advantages over the longer range beta-emitteryttrium-90 for microscopic disease, and the reverse is true for macroscopicmasses. However, comparative clinical trials have not yet been conducted.

Strategies aimed at improving the therapeutic ratio include dose fractionationand interaction with agents that may radiosensitize the tumor or protectnormal tissues, such as certain chemotherapeutic agents, cytokines, growthfactors, and hypoxic cytotoxins, or with treatments that may alter vascularpermeability (including hyperthermia, external-beam radiation, interleukin-2,among others). Multistep strategies, such as the use of avidin-biotin systems,[30]as well as the application of gene transfer technology,[50] are promising.

Summary and Future Potential

Radioimmunotherapy has already proven to be superior or equivalent toother forms of salvage therapy for patients with lymphoma and is currentlybeing evaluated as first-line therapy for selected lymphoma patients. Thepotential success of radioimmunotherapy as a systemic form of therapy willbe enhanced if it can be optimally adapted for use with chemotherapy andother biologic response modifiers, and if the method of administrationcan be tailored to the type and distribution of malignancy. As is generallytrue with most malignancies, the best outcome will likely result when theoptimal form of radioimmunotherapy is given as adjuvant therapy in patientswith a small disease burden.

Radioimmunotherapy is still relatively early in its development. Inorder for this therapy to realize its full potential, additional researchis needed at both the preclinical and clinical levels to overcome the variousobstacles that have been encountered.

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