CANCER BIOTHERAPY & RADIOPHARMACEUTICALSVolume 17, Number 1, 2002© Mary Ann Liebert, Inc.

Clinical Trial Design and Scoring of RadionuclideTherapy Endpoints: Normal Organ Toxicity andTumor Response

Ruby Meredith, M.D., Ph.D.University of Alabama at Birmingham

Like other cancer therapy agents under development, radionuclide therapies are usually evaluated in aprogressive series of clinical trials after basic science, human cell culture and animal model studies. Tox-icities during these trials are graded using common scoring systems that are in widespread use such asthe Common Toxicity Criteria from the National Cancer Institute. Information on normal tissue toxicityfrom radionuclides is more limited than that from external beam radiation and is more variable. Vari-ability is likely due to many biologic factors as well as less precise dose quantitation than those used inexternal beam radiation practice. As expected based on known radiobiologic effects, tolerance to ra-dionuclide therapy appears to exceed that from high dose rate external beam radiation in most organs.Although the correlation between reported dose estimates and toxicity has progressively and substantiallyimproved over the past two decades, further progress is needed to establish optimal toxicity predictiverelationships. Continued refinement of dosimetry techniques and standardization is expected to increasethe accuracy and comparability of radiation dose reports between institutions as well as improve dose/re-sponse correlation.

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INTRODUCTION

Although the major utilization of radionuclidesin medicine has been for diagnostic purposes,there has been increasing interest in therapeuticapplications for malignancy in the past twodecades. The hope that targeted delivery of ra-dionuclides to tumor sites via conjugation of ra-dionuclides to an antibody or other molecules thatspecifically attach to tumor cells will allow ef-fective, well-tolerated systemic therapy has re-sulted in the development and testing of multipleagents. Fewer studies have been reported on nor-mal tissue tolerance and anti-tumor efficacy ofradionuclide therapy than from external beam ra-diation. Prior studies have considered a number

of radiobiologic factors in the comparison of ef-fects from radionuclides versus external beam ra-diation.1,2,3,4,5,6 The following review describes:1. the usual toxicity and efficacy scoring systemsused in clinical trials of radionuclide agents, 2.comparison of normal tissue tolerance reportedfor radionuclides versus that established for ex-ternal beam radiation, 3 considerations on the accuracy and comparability of radionuclide doseestimates between studies, and 4. examples ofanti-tumor efficacy reports.

Toxicity Scoring

The limitation of radionuclide therapy as givenfor most malignant diseases is the tolerance ofnon-targeted normal tissues. As experiencegrows, more information about the tolerance ofthe various normal tissues for radionuclide ther-apy is accumulated to direct future administra-tions and clinical trial design. The toxicities ofnormal tissue are tracked acutely as well as long

Address reprint requests to Ruby Meredith, M.D., Ph.D.,University of Alabama at Birmingham, Department of Ra-diation Oncology, WTI #T117, 1824 6th Ave. South, Birm-ingham, Alabama 35233-1932

term after radionuclides in the development of ra-dionuclide therapies. This is similar to that ofother therapeutic agents but the spectrum of nor-mal tissues at risk may vary. Standard toxicityscoring systems are used in the design of clinicaltrials. Frequently used scoring tabulations includethe Common Toxicity Criteria serving in Na-tional Cancer Institute supported clinical trialsand a related system associated with the WorldHealth Organization. Guidelines for CommonToxicity Criteria recommended by the NationalCancer Institute can be downloaded from the In-ternet at http://ctep.info.nih.gov. These criteriause a grading system from 0 to 4.

Grade 0 5 no clinically significant toxicity.For toxicities tracked by laboratory values thisusually means the result has not fallen out of thenormal range even though there may have beensome change from baseline that is due to the treat-ment. For instance, if a patient had a baselineplatelet count of 300,000/ml that fell to 150,000/mlafter treatment this represents a 50% decline butis still within the normal range and is Grade 0.Grade 1 5 mild toxicity,Grade 2 5 moderate toxicity,Grade 3 5 severe toxicity,Grade four 5 potentially life threatening toxicity.

In some systems, a Grade 5 is used to indicatea fatal complication. This basic grading from 0–4 can be used to score an observed toxicity thatis not listed in the Common Toxicity Criteria ta-bles. The criteria for grading toxicity may varywith different clinical circumstances. For exam-ple, in a non-stem cell rescue regimen wherehematologic toxicity may be the dose-limitingtoxicity, a Grade 1 platelet toxicity 5 75,000/ml-normal, with normal in most laboratories being$150,000/ml. In the stem cell rescue criteria,Grade 1 platelet toxicity is defined as 1 platelettransfusion in 24 hours. In this circumstance, thenumber of platelets is expected to be in the rangeof Grade 4 for a non-stem cell rescue set of cri-teria. Some scales such as the Radiation TherapyOncology Group use different criteria for acute(which may be defined as # 90 days after treat-ment) versus those for late toxicity. As an exam-ple of acute versus late toxicity, hematuria and/ordysuria within days after radionuclide adminis-tration would be an acute urinary system toxicitywhereas fibrosis leading to bladder contraction 9months later would be considered a type late tox-icity.7 There are a number of other indicators oftoxicity that can be monitored but are not re-flected in the grading such as the time to the de-

velopment of moderate to severe toxicity, the du-ration of severe toxicity and the effect of toxicityon other factors such as performance status. Asan example, Figure 1 compares post-treatmentdepression in platelet counts among three patientsreceiving increasing administered activity of177Lu-CC49. Typical for radionuclide therapy,the highest 177Lu-CC49 activity resulted in alower nadir, a greater percent decrease from base-line at nadir and longer recovery than that for thelower doses.

Many studies now incorporate quality of life(QOL) indicators as an integral part of the clini-cal trial design. A patient’s sense of well-beingstems from their satisfaction with aspects that areimportant to them. Some of these QOL assess-ment instruments incorporate a pain scale or usea pain scale in addition to other quality of lifequestions such as fatigue level, mood, and activ-ity level.8 A placebo controlled study of stron-tium-89 showed improved QOL for several cat-egories among patients who received the activeagent compared to those who received theplacebo.9 These QOL categories included suchitems as pain, use of analgesics, constipation,mood, fatigue, and measures of performance sta-tus such as physical activity. Some studies nowlook at quality adjusted time also. For example,if a particular agent when given one day a monthprolongs survival by 6 months but with each ad-ministration the patient has 3 days of severe painand vomiting, the days of decreased quality oflife are taken into account when assessing the sur-vival benefit. An example of an agent that wasapproved for the treatment of pancreas cancer dueto improved symptom relief, rather than im-proved tumor regression or longer survival com-pared to other therapies, is the chemotherapeuticGemcitabine.10

Clinical Trial Design

New agents being developed for therapy are usu-ally evaluated in a progressive series of study de-signs. The FDA regulates biomedical researchand requires that standards for the design, con-duct, monitoring, recording, and reporting arefollowed. These standards assure that the resultsreported are accurate, and that the safety andrights of human trial participants is protected.11

Department of Health and Human Services reg-ulations for the protection of human research trialparticipants is subject to periodic amendment.Vriesendorp et al.12 have suggested that altered

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sequential study phases for radioimmunotherapyagents may be preferable to classical phase I andII studies used to evaluate chemotherapeutics.After therapeutic potential of an agent is identi-fied by basic science, as well as often human cellculture and animal model studies, the first clini-cal trial (Phase I) is designed to determine safetyand what toxicities are associated with its use.Phase I studies often establish pharmacologiccharacteristics in parallel with other biologicstudies. A Phase I clinical trial is often designedto determine the maximum tolerated dose, orsome other measure of optimum dose if this isless than the maximum dose tolerated. The defi-nition of maximum tolerated dose (MTD) variesbut usually is the dose that results in moderate tosevere toxicity in the majority of a cohort of atleast 5 patients. Grade 4 toxicity may be observedin the cohort but will not be present in the ma-jority of the patients. Although there are com-monly used definitions of MTD, the definition inany given study will be defined in that study andmay or may not be identical to that in similar stud-ies. There are several options for dose escalationof radionuclide therapies. These include a fixedincrease per dose group. In this case a 20–25%increase is usual, at least when the study is in thedose range that results in significant toxicity.

Options for dose escalation based on some pa-tient specific variables are common. This may useadministered activity per m2 of body surface area,per kilogram of body weight, area under the curveof plasma pharmacokinetics, or to deliver a de-fined radiation dose to normal organs or thewhole body. Some examples are presented inTable 1.

Although therapeutic efficacy is often moni-tored in a phase I study, a low response rate doesnot halt further investigation of the agent sincemost patients may have received a smaller dosethan needed for efficacy.

Phase II studies have the goal of determiningthe response rate at a dose that would be tolera-ble by most patients. The dose in a phase II trialis often not the full maximum tolerated dose thatwas established in the phase I trial but reducedby a modest amount such as 80% of the MTD orthe next lower dose from the MTD. Phase II on-cology trials usually not only look at the objec-tive response rate but also the duration or re-sponse, progression free survival and overallsurvival after therapy. These trials are often setup on a two-stage design such that if no responsesare achieved among the initial 14 patients, thetrial will be terminated because the probability ofa response rate of 20% or greater is less than 0.05.If there are several responses among the initialpatients, the number of patients required to de-termine that the response rate is at least 20% issmaller than initially planned and can be esti-mated from the fraction of those responding, i.e.,the number of patients accrued in the secondstage depends on the number of responses ob-served in the first stage and the desired standarderror. If there is at least one response among thefirst 14 patients, the trial may proceed to accrue25 patients to provide an estimate of the responserate. Patients entering Phase I and II trials usu-ally have failed standard therapies or have prog-nosis/circumstances such that standard or alter-native therapies are judged not to have substantialimpact on their disease outcome. Although pa-

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Figure 1. Comparison of depression and recovery of platelet counts as a function of time after escalating doses of 177Lu-CC49.

tients participating in these trials have failed othertherapies, the number and type of previous thera-pies may be restricted by trial design. In addition,patients are usually required to have a high per-formance status to be eligible for participation.

A Phase III trial is a definitive study. This of-ten adds the new agent to standard care or com-pares it directly with the current standard in or-der to determine if the new agent is superior inefficacy or has other advantages such as de-creased toxicity for equivalent therapeutic bene-fit. Some examples of definitive radionuclidestudies are presented in Table 2. These includethe addition of strontium–89 as an adjunct to ex-ternal beam radiation for painful bone metastasiscompared to similar administration of a placebo.With positive reports of radiolabeled antibodiesfor B-cell non-Hodgkin’s lymphoma (NHL), de-

finitive studies have been conducted comparingthe radiolabeled antibody with unlabeled anti-body alone, or comparing the response rate, du-ration of response and other factors with the his-tory of each patient’s course after their pastchemotherapy.13,14,15

Although not reported to be a Phase III design,the addition of 89SrCl was also studied in patientswith advanced androgen-independent prostatecancer receiving chemotherapy. Those random-ized to receive 89Sr-Cl in addition to their dox-orubicin chemotherapy had improved survivalcompared to those receiving chemotherapyonly.16

Response Evaluation

Many early studies such as Phase I trials often

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monitor for anti-tumor effects even though theirmain objective is not determination of tumor re-sponse rates. For Phase II and III studies objec-tive criteria for response are needed. Althougheach study defines its criteria for response, thereare standardly accepted criteria used in most stud-ies.17 Bidimensional measures of masses withsharply defined borders are desirable for assess-ing response, but lesions that can only be mea-sured in single dimension can be evaluated also.Measurements of bidimensional lesions are usu-ally recorded as the product of the longest diam-eter multiplied by the greatest perpendicular di-ameter as determined by physical examinationand/or imaging studies. Non-measurable disease,which includes malignant disease found to be sur-gically unresectable but not clinically detectable,usually cannot be assessed by objective mea-surement criteria but response may be assessableby biochemical markers. Patients who have non-measurable disease may be evaluated in Phase Istudies for toxicity and can be followed for timeto progression and survival as indicators of anti-tumor effects but they are usually not candidatesfor Phase II trials where objective measurementsare needed. The following represent objective re-sponse definitions commonly used.

Complete response 5 disappearance of all clini-cal evidence of active tumor (objectively mea-surable and non-measurable tumor sites) for aminimum of 4 weeks. The patient must be freeof any symptoms related to cancer.

Partial response 5 fifty percent or greater de-crease in the sum of the products of the perpen-dicular diameters of all objectively measurablelesions, .30% decrease in linear measurement of

unidimensional lesions and stable status or im-provement in all non-measurable tumor sites.When patients have multiple lesions, 3 or moretarget lesions may be measured for response.However, there can be no simultaneous increasein the size of any lesion or the appearance of newlesions. The remission must be maintained for atleast 4 weeks.

Stable disease 5 steady state or response lessthan partial remission, or progression of less than25% for a minimum of 4 weeks. There may beno appearance of new lesions and no worseningof the symptoms.

Progression 5 an increase of at least 25% in thesize of any measured lesions or the appearanceof new lesion(s).

Duration of response, time to need for more ther-apy, and QOL improvement are also indicatorsof therapeutic effects.

What is the tolerance of normal organs toradiation?

A number of human cell culture and animalmodel studies have been designed to determinedifferences between radiation effects from ra-dionuclide therapy and external beam radia-tion.1-6,18 Several studies directly comparing theefficacy of radionuclides, or similar exponen-tially decreasing low dose rate radiation, withhigh dose rate external beam radiation haveshown variable results. As expected based on alow dose rate effect and other radiobiologic fac-tors,1-6,19 many organs appear to have more tol-erance for radionuclides than external beam ra-diation. In the dose rate range between ,0.1 Gy/

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hour to several Gy/minute,3 the lethal effects ofradiation on cells diminishes with dose rate andthe rate of this decrease is determined by the sizeof the shoulder on the radiation survival curve.An inverse dose rate effect is also possible whenthe radiation results in a block at G2, a portionof the cell cycle characterized by increased radi-ation sensitivity.3,4 Other factors to consider inthe comparison of radiobiologic effects from ex-ternal beam radiation include the overall treat-ment time, reoxygenation during radiation, cellproliferation during the radiation course, andnon-uniform distribution of radionuclide thatcould be more damaging by concentration at vas-culature.

Mechanisms explaining some of these differ-ences in radiation sensitivity for radionuclidesand external beam radiation among tumor lines(in addition to G2 block effects) include tumordoubling time,18 the size of the shoulder of thesurvival curve,1 and the induction of apoptosisversus classical radiation induced cellular necro-sis.20,21

To date, direct comparison of the effects onnormal organs between external beam radiationand radionuclide therapy in clinical trials havenot been reported. Thus, comparisons are basedon toxicities reported separately for each type ofradiation and may also be influenced by the factthat the patient groups studied differ. Consider-able external beam normal organ tolerance datahave been compiled from analysis of literaturethat deals mainly with irradiation using $ 1 MEVenergy treatment of the whole organ, in adults notreceiving chemotherapy, and at 2 Gy/fraction,one fraction per day, 5 days/week. The total timeof treatment is # 8 weeks.22,23,24 For this data,the dose rate is considered high, with the usualdose rate . 100 cGy/minute. The radiation toler-ance doses tabulated are categorized as TD5/5 orTD50/5.23 The TD5/5 indicates a 5% risk of severecomplications by 5 years and a TD50/5 indicatesa 50% probability of severe complications by 5years. Since the dose/response curve for normaltissues is steep, the TD50/5 is sometimes reachedwith , 20% dose increment above the TD5/5. Ad-ditional information has shown that higher dosesare tolerated for partial, as opposed to the wholeorgan, radiation.22 However, for comparison onlywhole organ tolerance doses are presented inTable 4. Although partial organ tolerance for ra-dionuclides has not been frequently considered,Bouchet et al.30 have recently provided dosime-try models for sub-regions of the kidney and

MIRD pamphlet #17 addresses dosimetry of non-uniform activity distribution.26 Yorke et al.32 an-alyzed dose volume histograms for human liverafter 90Y-microsphere therapy. Their results wereconsistent with increased tolerance when much ofthe organ receives less than the mean calculateddose. In practice, radionuclides administered di-rectly into tumor masses or resection cavities,which provides a high dose to a small rim of sur-rounding normal tissue, have been well toler-ated.28,29 A device for infusional radionuclide,Gliasite from Proxima Therapeutics, Inc. has beendeveloped to facilitate treatment of brain lesionswhile minimizing radiation dose to normal tissues.

There is usually less tolerance for single dosecompared to fractionated radiation. 1000 cGy 1chemotherapy has been tolerated by normal or-gans as a preparative regimen for bone marrowtransplantation. However, without dose reductionor fractionation the risk of pneumonitis is.25%.30,31 Also, most tissues are less tolerantwhen therapy is combined with other modalitiessuch as nephrotoxicity at 12–14 Gy fractionatedexternal beam radiation to kidneys in bone mar-row transplant patients who also received busul-phan.32

Tissues for which no definite tolerance is listedin Table 4 such as meninges and bowel serosaare felt to have a higher tolerance than the adja-cent more radiosensitive tissues such as bowelmucosa and brain. Column 3 of Table 4 listssome doses calculated from radionuclide thera-pies for which no significant toxicity was re-ported, while column 4 provides some doses as-sociated with toxicity. The radiation toxicity forradionuclides includes both acute and late tox-icity whereas that for external beam data in-cluded here applies to late effects. While sometolerance doses for external beam radiation wereestablished from a large patient experience, thedata listed for radionuclides is derived from arelatively small number of patients. Also, col-umn 4 lists any toxicity reported even if it af-fects only a small fraction of the patients in aparticular study. For instance, renal toxicity isreported for 90Y-DOTA-biotin after pretargetedNR-LU-10/SA but this only affected two patientswhile other patients treated with the same or otherradionulcide agents were reported to receivemuch higher doses without toxicity manifesta-tions.33,34,35 The tolerance for an individual pa-tient to radionuclide therapy may be considerablyhigher or lower than reported. A number of fac-tors have been identified that may influence tol-

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erance. Thus, it should not be surprising that thereare some apparent contradictions between thevalues in column 3 and column 4 in Table 4.These apparent discrepancies may reflect a num-ber of factors including differences in calculatedvs. biologic dose, dose rate effects, other modi-fying factors, different calculation methods orvariation due to the characteristics of the ra-dionuclide agent.36 Compared to data from ex-ternal beam, which was primary treatment, or af-ter surgery, radionuclide tolerance data (with theexception of thyroid) has been derived from pa-tients who have failed chemotherapy and/or havewidespread disease. Much of the radionuclidedata is for a single administration, which wouldbe expected to have a lower tolerance than re-

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peated dosing at non-maximum levels for a cu-mulated higher dose. For instance, a cumulativerenal dose of 33 Gy was tolerated for 90Y-DOTA-TYR-Octreotide given as repeat therapies every6 weeks plus intravenously administered aminoacids compared to toxicity noted in some patientsat lower doses after a single administration of ra-dionuclide therapy.37

How accurate are radionuclide doseestimates and comparison between studies?

1.) Radionuclide dosimetry is less accuratethan external beam. Compared to methodsfor measuring radiation delivered to human

tissues by external beam radiation, those fromradionuclide therapy are less precise. For ex-ample, dosimetry methods for a parenchymallung tumor treated with a radionuclide con-jugate usually will not take into account thedifference in attenuation between lung andmore dense tissue as is common with exter-nal beam radiation dosimetry. The currentlimitations in obtaining accurate three-di-mensional localization of non-uniform ra-dionuclide distribution hamper precise dosecomputations.

2.) How accurate are tracer studies? On a the-oretical basis one would predict that tracerstudies using a small amount of the same ra-dionuclide agent would be the most accuratecurrently available method to estimate organdoses for a larger therapeutic administration.Many studies have been designed such that atracer dose of the radioactive agent was giveninitially for biodistribution/dosimetry datacollection that would determine administra-tion of the therapeutic level of the radioac-tive agent. This allowed individualization ofadministered activity and, in some cases, pa-tient exclusion from therapeutic administra-tion based on results of the tracer study show-ing an unfavorable biodistribution. Doseestimates predicted from tracer studies haveshown considerable variation compared tothose obtained after therapeutic dose admin-istration in the same patient. Several reportsthat allow this comparison are briefly sum-marized in Table 5. The comparison for the

first two reports in Table 5 is given as a ra-tio of the dose to normal organs predictedfrom the tracer study to that obtained whenimaging and dosimetry were repeated afteradministration of the therapeutic level of ra-dioimmunoconjugates.

As dosimetry techniques become more accu-rate, it is anticipated that dose estimate concor-dance between tracer and therapy administrationswill further improve.38

3.) Calculated dose is not equal to biologicdose. There are differences in clinical resultsof various radionuclides due to non-uniformdistribution of the radiation within normal or-gans and tumors, dose rate effects, the effec-tive range of radiation, relative biologic ef-fectiveness (RBE), and other characteristics.19

For instance, alpha emitters with high linearenergy transfer (LET) may provide an ad-vantage when tumor is more radioresistantthan normal tissues while beta particles pro-vide an advantage when tumor is less ra-dioresistant than normal tissues.2 However,these advantages vary as the ratio of the doseto tumor relative to dose to normal tissue in-creases. Biologic factors that affect toleranceof normal tissues may depend on age, priortherapies, the time since prior therapies, dis-ease status-e.g., anemia of chronic disease ormarrow replacement by malignancy; geneticfactors and/or physiologic conditions such ashypoxia that affect radiosensitivity and re-

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pair. Biologic effectiveness of radionuclidetherapy is also influenced by additionalagents/factors that do not contribute to the ra-diation dose estimates. These factors can in-clude chemotherapy, other biologic responsemodifiers such as radiosensitizers, cytokines,and growth factor inhibitors (e.g., anti-EGFrantibody).69–72 For instance, DeNardo et al.109

demonstrated that the addition of paclitaxelcan improve efficacy of radioimmunotherapyin an animal model without substantially in-creasing the toxicity. In their study usingbreast cancer xenografts, 79% of tumor-bear-ing animals responded to 90Y-ChL6 alone butnone were cured whereas 100% of animalsresponded when paclitaxel was given 6 or 24hours after the same dose of 90Y-ChL6 and48% were cured.

4.) How accurate are comparisons of ra-dionuclide dose estimates? There are a num-ber of factors that need to be considered inattempts to compare dosimetry among stud-ies. For most studies to date, precise com-parisons will not be meaningful, sometimeseven between different protocols of the sameagent at a single institution. Due to variationsin data collection and processing, cautionneeds to be applied to comparisons. Some as-pects for consideration for variance indosimetry methods include:a) Measured organ volume such as used in

myeloablative studies at the University ofWashington44 versus phantom models

b) Do calculations use computer programssuch as MIRDOSE 2 or MIRDOSE 345

c) Was attenuation correction applied for re-gions of interest observed on gamma cam-era imaging or a transmission scan tech-nique used46,47

d) Was background subtraction performed?Was scatter correction performed?

e) What was the frequency and appropriate-ness of the data collection time points. Forinstance, with a limited number of sampletimes for data collection such as gammacamera images, the peak concentration maybe missed. This would result in a lowerdose estimate than actually delivered.

Variability for marrow dose computation hasimproved greatly over the past two decades butstill could be further reduced. In the 1980s vari-ability for marrow dose computation was 700%.This improved to ,200% in the 1990s and re-

cent analysis shows a yet smaller range. For thisanalysis, Wessels et al.78 collected data from non-myeloablative radioimmunotherapy trials in 7 in-stitutions, using radionuclide conjugates of 131Ior 186Re that did not target the marrow. The bloodmethod for marrow dosimetry49 was used and theresults of bone marrow radiation doses comparedwith marrow suppression toxicity. Data were re-analyzed at a central facility using methods sim-ilar, but not identical, to those at each participat-ing institution. The absolute value of the marrowdose computed by the central facility had an av-erage variation of 215% from that of the con-tributing institutions (range 235 to 16%). Theimplementation of biologic markers to dosimetrymethods such as quantitation of chromosomaltranslocations in blood cells after radionuclidetherapy may provide insight to improved accu-racy and standardization for some dosimetrymethods.50

What radiation doses have been delivered totumors and how effective have they been?

Table 681–92 shows a large range of administeredactivity of radionuclides in a variety of tumorsvarying in radiosensitivity. In general, there havebeen responses to solid glandular or other com-mon adult tumors and pediatric malignancies thatare considered more radioresistant than hemato-logic malignancies. Responses have been morereadily achieved in pediatric malignancies thansome adult tumors. This should not be surprisingsince in general doses that control pediatric non-CNS solid tumors are less than required for com-parable results in adults. Of adult tumors, al-though some studies do not show responses evenwith high doses of administered activity, re-sponses have been noted in other studies. Suchresponses have been more frequent when ra-dionuclide therapy was used in conjunction withother modalities for hepatoma but the combina-tion therapy makes it difficult to determine howmuch of the effect was due to the radionuclideconjugate portion of the therapy.52 In the rela-tively radioresistant adenocarcinoma of theprostate, radionuclides have been successful inpalliation of bone pain but objective responsesare not usually reported for bone seeking ra-dionuclides 89Sr and 153Sm, or with antibody-tar-geted radionuclides 131I-CC49, 90Y-Cyt356, or90Y-K4C alone.63,64 However, when 131I-CC49was given with interferon enhancement and/or aspart of a combined modality regimen, objectiveresponses were observed.64,65 When radionuclide

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therapy can be given in a non-systemic mannersuch as local/regional administration into theCSF, cranial tumor cavity, or peritoneal cavityhigher activities can be tolerated than when givensystemically. The higher administered activity ofradionuclides may account for the improved re-sponse rates observed with non-systemic admin-istrations. In some instances, response rates mayalso be influenced by more radiosensitive types

of disease and smaller tumor deposits. As ex-pected, smaller tumor masses have a higher prob-ability of response for both solid non-hemato-logic malignancies and NHL. Press et al.39

showed that response rates were less for NHL pa-tients receiving 131I-antiB1 therapy who hadsplenomegaly and/or tumor burden . 500 ml.Similarly, using an alternate anti-CD20 antibodycarrying 90Y, more than double the response rate

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was observed among patients with tumormasses , 7 cm. (86%) compared to the 41% re-sponse rate for those with larger tumor masses.81

For solid non-hematologic malignancies, Behr et

al. have shown excellent response rates amongpatients with limited tumor burden.96 More de-tails of radionuclide clinical studies are presentedin recent reviews.67,68,69,70

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Figure 2. Longer response duration for patients achieving a CR compared to all patients receiving treatment.

Some of the best response rates have beenachieved in NHL, which is considered a relativelyradiosensitive malignancy, and may be effec-tively treated with low dose rate radiation as pro-vided by radionuclide therapy.67 Table 7 lists sev-eral selected studies from a few of the promisingradioimmunoconjugates currently under investi-gation. Although there is a range of response from54% to 100%, the patient eligibility criteria andother prognostic factors varied such that thesestudies should not be directly compared for effi-cacy. However, compared to many new singleagents that are developed for cancer therapy, aresponse rate of . 50%, as seen in all of theseselected studies, is very favorable. The dose totumor masses varies widely from 16 – 14,000cGy. Although there is a trend for a dose responserelationship, this has usually not reached statisti-cal significance with relatively small numbers ofpatients in each study. Some of the potential dif-ficulties in the relationship may be the heteroge-neous nature of the radiation deposition. Whereasthe radiation dose is reported as the mean to a tu-mor mass, the region that receives the lowest dosemay be the area determining efficacy. As indi-cated in Table 7 and other reports, there is a ten-dency for more complete responses with in-creasing dose and these responses achieved withhigher doses tend to be more durable. This is il-lustrated in Figure 2 which shows a much longerduration of remission among patients receivinghigh dose radioimmunoconjugate therapy fol-lowed by stem cell rescue than in non-myeloab-lative studies with 131I-antiB1 whether conductedat the University of Michigan or as part of amulti-institutional effort.15,35,71 A trend of doseresponse is also noted with analysis of non-my-eloablative studies with 131I where 30 tumors inPR patients had a mean 5 369 1/2 54 cGy com-pared to 56 tumors in CR patients having amean 5 7201/2 80 cGy.72

Improved dose/response relationships betweenthe bone marrow toxicity and dosimetry estimatesof radiation to the bone marrow have improvedwhen biologic factors have been taken into ac-count or individualized marrow measurementswere performed.73 Considerations for biologicfactors that have improved correlation includesprior chemotherapy and/or radiation, time sinceprior chemotherapy, age, and gender.74,75,76 Forinstance, Wessels et al. found that the correlationcoefficient between marrow toxicity and marrowdose improved from r 5 0.57 to r 5 0.80 by ad-justing for age, gender and prior therapy. Further

improvement in correlation may result from ad-ditional analysis of biologically relevant factorsin addition to more precise physical methods ofdosimetry calculations.77

SUMMARY/CONCLUSION

Information on normal tissue toxicity from ra-dionuclide therapy is more limited than for ex-ternal beam irradiation and appears more vari-able, as expected, due to a number of biologicand physical factors.1-6,19 However, with the in-creasing expansion of agents being developed fortargeted radionuclide therapy more accurate ra-diation dose estimates and improved dose-re-sponse correlations are expected. More refine-ment in dosimetry techniques as well asstandardization for data collection and process-ing should increase the accuracy and compara-bility of radiation dose estimates. Additionalknowledge about biologic modifiers of radionu-clide effects such as chemotherapy or other ra-diosensitizing agents that increase response with-out changing dose calculations can be applied toimprove dose-response correlation for normal or-gans and targeted masses.

ACKNOWLEDGMENTS

Discussions with Susan Knox, Barry Wessels andHazel Breitz are appreciated as well as assistancein manuscript preparation from Susan Melat andJoey Slatsky.

REFERENCES

1. Knox SJ, Levy R, Miller RA, Uhland W, Schiele J,Ruehl W, Finston R, Day-Lollini P, Goris ML. Deter-minants of the anti tumor effect of radiolabeled monoclonal antibodies. Can Res 1990;50:4935–4940.

2. Langmuir VK, Fowler JF, Knox SJ, Wessels BW,Sutherland RM, Wong JYC. Radiobiology of radiola-beled antibody therapy as applied to tumor dosimetry.Med Phys 1993;20:601–610.

3. Hall EJ, Brenner DJ. The dose-rate effect revisited: ra-diobiological considerations of importance in radio-therapy. Int J Radiat Oncol Biol Phys 1991;21:1403–1414.

4. Williams JR, Zhang YG, Dillehay LE. Sensitizationprocesses in human tumor cells during protracted ir-radiation: Possible exploitation in the clinic. Int J Ra-diat Oncol Biol Phys 1992;24:699–704.

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5. Murtha AD, Review of low-dose-rate radiobiology forclinicians. Sem Radiat Oncol 2000;10(2):133–138.

6. Knox SJ, Goris ML, Wessels B. Overview of animalstudies comparing radioimmunotherapy with doseequivalent external beam irradiation. Radiother Oncol1992;23:111–117.

7. WWW.RTOG.ORG.8. Cella DF, Tulsky DS, Gray G, et al. The functional as-

sessment of cancer therapy scale: Development andvalidation of the general measure. J Clin Oncol 1993;11:570–579.

9. Porter AT, McEwan AJ, Powe JE, Reid R, McGowanDG, Lukka H, Sathyanarayana JR, Yakemchuk VN,Thomas GM, Erlich LE, et al. Results of a randomizedphase-III trial to evaluate the efficacy of strontium-89adjuvant to local field external beam irradiation in themanagement of endocrine resistant metastatic prostatecancer. Int J Radiat Oncol Biol Phys 1993;25:805–813.

10. Burris HA 3rd. Objective outcome measures of qual-ity life. Oncology (Huntington), 1996; 10(11suppl):131–5.

11. WWW.FDA.GOV/OC/GCP/.12. Vriesendorp HM, Quadri SM, Jaeckle KA, Freedman

RS, Cromeens DM. Proposal for translational analysisand development of clinical radiolabeled immuno-globulin therapy. Radiotherapy and Oncology 1996;11:1829–1834.

13. Kaminski MS, Zasadny KR, Francis IR, Fenner MC,Ross CW, Milik AW, Estes J, Tuck M, Regan D,Fisher S, Glenn SD, Wahl RL. Iodine-131-Anti-ANTI-B1 radioimmunotherapy for B-cell lymphoma. J ClinOncol 1996;14:1974–81.

14. Press OW. Prospects for the management of non-Hodgkin’s lymphomas with monoclonal antibodiesand immunoconjugates. The Cancer Journal 1998;4 (2 Suppl.):S19–S26.

15. Knox SJ, Goris ML, Trisler K, Negrin R, Davis T,Liles TM, Grillo-Lopez A, Chinn P, Varns C, NingSC, Fowler S, Deb N, Becker M, Marquez C, Levy R.Yttrium-90-labeled anti-CD20 monoclonal antibodytherapy of recurrent B-cell lymphoma. Clin CancerRes 1996;Mar,2:457–470.

16. Witzig TE, White CA, Wiseman GA, Gordon LI, Em-manouilides C, Raubitschek A, Janakiraman N,Gutheil J, Schilder RJ, Spies S, Silverman D, ParkerE, Grillo-Lopez AJ. Phase I/II trial of IDEC-Y2B8 ra-dioimmunotherapy for treatment of relapsed or refrac-tory CD201 B-cell non-Hodgkin’s lymphoma. J ClinOncol 1999;Dec.,17(12),3793–3803.

17. Laing AH, Ackery DM, Bayly RJ, Buchanan RB, Lew-ington VJ, McEwan AJB, Macleod PM, ZivanovicMA. Strontium-89 chloride for pain palliation in pro-static skeletal malignancy. The British Journal of Ra-diology 1991;64:816–822.

18. Witzig TE, White CA, Gordon LI, Murray JL, Wise-man GA, Emmanouilides C, Czuczman MS, Shen D,Multani P, Grillo-Lopez AJ. Final results of a ran-domized controlled study of the Zevalin™ radioim-

munotherapy regimen versus a standard course of rit-uximab immunotherapy for B-cell NHL. Blood 2000;96(11),831a.

19. Knox SJ, Goris ML, Davis TA, Trisler KD, Saal J,Levy R. Randomized controlled study of 131I-anti-B1versus unlabeled-anti-B1 monoclonal antibody in pa-tients with chemotherapy refractory low-grade non-Hodgkin’s Lymphoma. Int J Radiat Oncol Biol Phys1997;39(Suppl 2),326.

20. Vose JM, Wahl RL, Saleh M, Rohatiner AZ, Knox SJ,Radford JA, Zelenetz AD, Tidmarsh GF, Stagg RJ,Kaminski MS. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-related/refractorylow-grade and transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol 2000;Mar,18(6),1316–1323.

21. Tu SM, Millikan RE, Mengistu B, Delpassand ES,Amato RJ, Pagliaro I, Daliana D, Papandreou CN,Smith TL, Kim J, Podoloff DA, Logothetis C. Bone-targeted therapy for advanced androgen-independentcarcinoma of the prostate: a randomized phase II trial.Lancet 2001;357(Feb 3):326–327.

22. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J,Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M,van Oosterom AT, Christian MC, Gwyther SG. Newguidelines to evaluate the response to treatment in solidtumors. J Natl Cancer Inst 2000;92:205–216.

23. Wong JYC, Williams LE, Demidecki AJ, WesselsBW, Yan XW. Radiobiologic studies comparing yt-trium-90 irradiation and external beam irradiation invitro. Int J Radiat Oncol Biol Phys 1990;20:715–722.

24. O’Donoghue JA. Dosimetric Principles of TargetedRadiotherapy In: Radioimmunotherapy of Cancer.Fritzberg A, Abrams P (Eds), Marcel Dekker, Inc.,New York, chapt 1, 2000; pp. 1–20.

25. Macklis RM, Beresford BA, Palayoor S, Sweeney S,Humm JL. Cell cycle alterations, apoptosis, and re-sponse to low-dose-rate radioimmunotherapy in lym-phoma cells. Int J Radiat Oncol Biol Phys 1993;27:643–650.

26. Knox SJ, Sutherland W, Goris ML. Correlation of tu-mor sensitivity to low-dose-rate irradiation withG2/M-phase block and other radiobiological parame-ters. Radiat Res 1993;35:24–31.

27. Emami B, Lyman J, Brown A, Cioa L, Goitein M,Munzenrider JE, Shank B, Solin LJ, Wesson M. Tol-erance of normal tissue to therapeutic irradiation. IntJ Radiation Oncology Biol Phys 1991; May, 21(1),109–122.

28. Rubin P, Cassarett G. A direction for clinical radiationpathology. In: Vaeth JM, et al., eds. Frontiers of radi-ation therapy and oncology VI. Baltimore: UniversityPark Press, 1972;1–16.

29. Committee on Self-Evaluation and Testing, AmericanCollege of Radiology. Radiation Biology and Radia-tion Pathology Syllabus. American College of Radiol-ogy, Chicago, Illinois, 1975.

30. Bouchet LG, Blanco HP, Rajon DA, Clairand I, BolchWE, Wessels BW, Konijnenberg MW. MIRD Pam-

95

phlet No. 19: Absorbed fractions and radionuclidesvalues for six age-dependent multi-region models ofthe kidney. [In press].

31. Bolch WE, Bouchet LG, Robertson JS, Wessels BW,Siegel JA, Howell RW, Erdi AK, Aydogan B, CostesS, Watson EE. MIRD Pamphlet No. 17: The dosime-try of nonuniform activity distributions-radionuclide Svalues at the voxel level. J Nucl Med 1999;40:11S–36S.

32. Yorke ED, Jackson A, Fox RA, Wessels BW, GrayBN. Can current models explain the lack of liver com-plications in Y-90 microsphere therapy? Clin CancerRes 1999;5:3024s–3030s.

33. Order SE, Siegel JA, Principato R, Zeigler LE, John-son E, Lang P, Lustig R, Wallner PE. Selective tumorirradiation by infusion brachytherapy in non-resectablepancreas cancer: a phase I study. Int J Radiat OncolBiol Phys 1996;36(5):1117–1126.

34. Brown MT, Coleman RE, Friedman AH. Intrathecal131I-labeled anti-tenascin monoclonal antibody 81C6treatment of patients with leptomeningeal neoplasmsor primary brain tumor resection cavities with sub-arachnoid communication: Phase I trial results. ClinCancer Res 1996;2:963–972.

35. Thomas ED, Sanders JE, Flournoy N, Johnson FL,Buckner CD, Clift RA, Fefer A, Goodell BW, StorbR, Weiden PL. Marrow transplantation for patientswith acute lymphoblastic leukemia in remission. Blood1979;54:468.

36. Wara WM, Phillips TL, Margolis LW, Smith V. Ra-diation pneumonitis: A new approach to the derivationof time-dose factors. Cancer 1973;32:547–552.

37. Lawton CA, Cohen EP, Murray KJ, Derus SW, CasperJT, Drobyski WR, Horowitz MM, Moulder JE. Long-term results of selective renal shielding in patients un-dergoing total body irradiation in preparation for bonemarrow transplantation. Bone Marrow Transplant1997;20(12):1069–74.

38. Breitz HB, Fisher DR, Goris ML, Knox S, Radliff B,Murtha AD, Weiden PL. Radiation absorbed dose es-timation for 90y-DOTA-biotin with pretargeted NR-LU-10/streptavidin. Cancer Biother Radiopharm1999;14(5):381–395.

39. Press OW, Eary JF, Appelbaum FR, Martin PJ, Bad-ger CC, Nelp WB, Glenn S, Butchko G, Fisher D,Porter B, Matthews DC, Fisher LD, Bernstein ID. Ra-diolabeled-antibody therapy of B-cell lymphoma withautologous bone marrow support. N Eng J Med 1993;329:1219–1224.

40. Liu SY, Eary JF, Petersdorf SH, Martin PJ, MaloneyDG, Appelbaum FR, Matthews DC, Bush SA, DurackLD, Fisher DR, Gooley TA, Bernstein ID, Press OW.Follow-up of relapsed B-cell lymphoma patientstreated with iodine-131-label anti-CD20 antibody andautologous stem-cell rescue. J Clin Oncol 1998; Oct,16(10),3270.

41. Behr TM, Behe M, Lohr M, Sgouros G, AngersteirnC, Wehrmann E, Nebendahl K, Becker W. Therapeu-tic advantages of Auger electron-over beta-emitting ra-

diometals or radioiodine when conjugated to internal-izing antibodies. Eur J Nucl Med 2000;27:753–65.

42. Valkema R, Jamar F, Jonard P, Bakker WH, Noren-berg J, Hadley J, Smith C, Kvols L, Pauwels S, Kren-ning EP. Targeted radiotherapy with 90Y-DOTA-TUR3-Octreotide (90Y-SMT487; Octreother™): APhase I Study. J Nucl Med 2000s;41(5):111P.

43. Meredith R, Partridge E, Alvarez R, Khazaeli MB,Plott G, Russell C, Wheeler R, Liu T, Grizzle W,Schlom J, LoBuglio A: Intraperitoneal radioim-munotherapy of ovarian cancer with 177Lu-CC49. JNucl Med 1996;37:1491–1496.

44. Liu T, Meredith R, Saleh M, Wheeler R, Khazaeli MB,Plott W, Schlom J, LoBuglio A. Correlation of tox-icity with treatment parameters for 131I-CC49 ra-dioimmunotherapy in three Phase II clinical trials.Cancer Biother Radiopharm 1997;12(2):79–87.

45. Akabani G, Cokgor I, Coleman RE, Gonzalez TD,Wong TZ, Friedman HS, Friedman AH, Garcia-TurnerA, Herndon JE, DeLong D, McLendon RE, Zhao XG,Pegram CN, Provenzale JM, Bigner DD, Zalutsky MR.Dosimetry and dose-response relationships in newlydiagnosed patients with malignant gliomas treated withiodine-131-labeled anti-tenascin monoclonal antibody81C6 therapy. Int J Radiat Oncol Biol Phys 2000;46:947–58.

46. Riva P, Arista A, Franceschi G, Frattarelli M, SturialeC, Riva N, Casi M, Rossitti R. Local treatment of ma-lignant gliomas by direct infusion of specific mono-clonal antibodies labeled with 131I: comparison of theresults obtained in recurrent and newly diagnosed tu-mors. Cancer Res 1995;55(23 Suppl):5952s–5956s.

47. Paganelli G, Bartolomei M, Ferrari M, Cremonesi M,Broggi G, Maira G, Sturiale C, Grana C, Prisco G, GattiM, Caliceti P, Chinol M. Pre-targeted locoregional ra-dioimmunotherapy with 90Y-biotin in glioma patients:Phase I study and preliminary therapeutic results. Can-cer Biotherapy Radiopharm 1999;14(4):318.

48. Pizer BL, Papanastassiou V, Mosley R. Meningealleukemia and medulloblastoma: Preliminary experi-ence with intrathecal radioimmunotherapy. AntibodyImmunoconj Radiopharm 1991;4:753–761.

49. Riva P, Arista A, Tison V, Sturiale C, Franceschi G,Spinelli A, Riva N, Casi M, Moscatelli G, FrattarelliM. Intralesional radioimmunotherapy of malignantgliomas. An effective treatment in recurrent tumors.Cancer 1994;73:1076–1082.

50. Richardson RB, Kemshead JT, Davies AG, StaddonGE, Jackson PC, Coakham HB, Lashford LS. Dosime-try of intrathecal iodine131 monoclonal antibody incases of neoplastic meningitis. Eur J Nucl Med 1990;17:42–48.

51. Kemshead JT, Hopkins K, Pizer B, Papanastassiou V,Coakham H, Bullimore J, Chandler C. Dose escalationwith repeated intrathecal injections of 131I-labelledMAbs for the treatment of central nervous system ma-lignancies. Br J Cancer 1998;77(12):2324–30.

52. Breitz HB. Dosimetry in a myeloablative setting. Can-cer Biother Radiopharm 2002;17:119–127.

96

53. Knox SJ, et al. Phase II trial of yttrium-90-DOTA-bi-otin pretargeted by NR-LU-10 antibody/streptavidin inpatients with metastatic colon cancer. Clin Cancer Res2000;6(2):406–14.

54. Buckman R, De Angelis C, Shaw P, Covens A, Os-borne R, Kerr I, Reed R, Michaels H, Woo M, ReillyR, Law J, Baumal R, Groves E, Marks A. Intraperi-toneal therapy of malignant ascites associated with car-cinoma of ovary and breast using radioiodinated mono-clonal antibody 2G3. Gynecol Oncol 1992;47:102–109.

55. Walton LA, Yadusky A, Rubinstein L. Intraperitonealradioactive phosphate in early ovarian carcinoma: Ananalysis of complications. Int J Radiat Oncol Biol Phys1991;20:939–944.

56. Spanos WJ, Day T, Abner A, Jose B, Paris K, PursellS. Complications in the use of intra-abdominal 32P forovarian carcinoma. Gyn Oncol 1992;45:243–247.

57. Epenetos AA, Munro AJ, Stewart S, Rampling R,Lambert HE, McKenzie CG, Soutter P, Rahemtulla A,Hooker G, Sivolapenko GB, Snook D, Courtenay-Luck N, Dhokia B, Krausz T, Taylor-Papadimitrou J,Durbin H, Bodmer WF. Antibody-guided irradiationof advanced ovarian cancer with intraperitoneally ad-ministered radiolabeled monoclonal antibodies. J ClinOncol 1987;5:1890–1899.

58. Stewart JSW, Hird V, Snook D, Sullivan M, HookerG, Courtenay-Luck N, Sivolapenko G, Griffiths M,Myers MJ, Lambert HE, Munro AJ, Epenetos AA. In-traperitoneal radioimmunotherapy for ovarian cancer:Pharmacokinetics, toxicity, and efficacy of I-131 la-beled monoclonal antibodies. Int J Radiat Oncol BiolPhys 1989;16:405–413.

59. Tempero M, et al. High-dose therapy with 90Yttrium-labeled monoclonal antibody CC49: a phase I trial.Clin Cancer Res 2000;6(8):3095–102.

60. Breitz HB, Weiden PL, Vanderheyden JL, AppelbaumJW, Bjorn MJ, Fer MF, Wolf SB, Ratliff BA, SeilerCA, Foisie DC. Clinical experience with rhenium-186-labeled monoclonal antibodies for radioimmunother-apy: results of phase I trials. J Nucl Med 1992 Jun;33(6):1099–1109.

61. Matthews DC, Appelbaum FR, Eary JF, Fisher DR,Durack LD, Bush SA, Hui TE, Martin PJ, Mitchell D,Press OW, et al. Development of marrow transplantregimen for acute leukemia using targeting hemato-poietic irradiation delivered by 131I-labeled anti-CD45antibody, combined with cyclophosphamide and totalbody irradiation. Blood 1995;85:1122–1131.

62. Carabasi MH, Meredith RF, Khazaeli MB, Tilden AB,Brezovich IA, Scholm J, LoBuglio AF. Combined mo-dality radiation using radioimmunotherapy and exter-nal beam radiation (TBI) for breast and prostate can-cer. Cancer Biotherapy Radiopharm 1999;14(4):318.

63. Gray BN, Fracs M, Burton B, Kelleher D, Klemp P,Matz L. Tolerance of the liver to the effects of yttrium-90 radiation. Int J Radiat Oncol Biol Phys 1989;18:619–623.

64. Meredith RF, Khazaeli MB, Plott G, Wheeler R, Rus-

sell C, Shochat D, Norvitch M, Salatan S, LoBuglio A.Comparison of diagnostic and therapeutic doses of 131I-LYM-1 in patients with non-Hodgkin’s lymphoma. An-tibody Immunoconj Radiopharm 1993;6(1):1–11.

65. Eary JF, Pollard KR, Durack LD, Bice AN, LewellenTK, Matthews D, Press OW, Nelp WB, AppelbaumFR, Bernstein I. Post therapy imaging in high dose I-131 radioimmunotherapy patients. Med Phys 1994;21:1157–62.

66. Clarke KG, Odom-Maryon TL, Williams LE, Liu A,Lopatin G, Chou J, Farina GM, Raubitschek AA,Wong JY. Intrapatient consistency of imaging biodis-tributions and their application to predicting therapeu-tic doses in a phase I clinical study of 90Y-based ra-dioimmunotherapy. Med Phys 1999;26(5):799–809.

67. Macey DJ, Grant EJ, Kasi L, Rosenblum MG, ZhangHZ, Katz RL, Rieger PT, LeBherz D, South M, GreinerJW, Scholm J, Podoloff DA, Murray JL. Effect of re-combinant alpha-interferon on pharmacokinetics,biodistribution, toxicity, and efficacy of 131I-labeledmonoclonal antibody CC49 in breast cancer: A phaseII trial. Clin Cancer Res 1997;3(9):1547–55.

68. DeNardo GL, Juweid ME, White CA, Wiseman GA,DeNardo SJ. Role of radiation dosimetry in radioim-munotherapy planning and treatment dosing. CriticalRev Onc Hematol 2001;Aug,39(1–2):203–18.

69. Evans MJ, Kovacs CJ, Gooya JM, Harrell JP. Inter-leukin-1a protects against the toxicity associated withcombined radiation and drug therapy. Int J Radiat On-col Biol Phys 1991;20:303–306.

70. Saleh MN, Raisch KP, Stackhouse MA, Grizzle WE,Bonner JA, Mayo MS, Kim H-G, Meredith RF,Wheeler RH, Buchsbaum DJ. Combined modalitytherapy for the treatment of A431 human epidermoidcancer using the anti-EGFR antibody C225 and radi-ation – in vivo and in vitro effects. Cancer Brother Ra-diopharm 1999;14:451–463.

71. DeNardo GL, DeNardo SJ, Lamborn KR, et al. En-hancement of tumor uptake of monoclonal antibody innude mice with PEG-IL-2. Antibody ImmunoconjugateRadiopharm 1991;4:859–870.

72. Buchsbaum DJ, Khazaeli MB, Davis MA, et al. Sen-sitization of radiolabeled monoclonal antibody therapyusing bromodeoxyruidine, Cancer 1994;73:999–1005.

73. DeNardo SJ, Kukis DL, Kroger LA, O’Donnell RT,Lamborn KR, Miers LA, DeNardo DG, Meares CF,DeNardo GL. Synergy of Taxol and radioim-munotherapy with yttrium-90-labeled chimeric L6 an-tibody: efficacy and toxicity in breast cancer xeno-grafts. Proc Natl Acad Sci 1997;94:4000–4004.

74. Eary JF, Krohn KA, Press OW, Durack L, BernsteinID. Importance of pre-treatment radiation absorbeddose estimation for radioimmunotherapy of non-Hodg-kin’s lymphoma. Nucl Med Biol 1997;24:635–638.

75. Stabin MG. MIRDOSE: Personal Computer Softwarefor Internal Dose Assessment in Nuclear Medicine. JNucl Med 1996;37:538–546.

76. Siegel JA, Thomas SR, Stubbs JB, Stabin MG, HaysMT, Koral KF, Robertson JS, Howell W, Robertson

97

JS, Wessels BW, Fisher DR, Weber DA, Brill AB.MIRD Pamphlet No. 16: Techniques for quantitativeradiopharmaceutical biodistribution data acquisitionand analysis for use of human radiation dose estimates.J Nucl Med 1999;40:37S–61S.

77. Thomas SR, Maxon HR, Kereiakes JG. In vivo quan-titation of lesion radioactivity using external countingmethods. Med Phys 1976;3:252–255.

78. Wessels BW, Bolch WE, Breitz HB, Meredith RF,Sharkey RM, DeNardo GL. Bone marrow dosimetryfor radionuclide therapy-a multi-institutional compar-ison. J Nucl Med 2001;42(5suppl):22.

79. Siegel JA, Wessels BW, Watson EE, Stabin MG,Vriesendorp HM, Bradley EW, Badger CC, Brill AB,Kwok CS, Stickney DW, Eckerman KF, Fisher DR,Buchsbaum DJ, Order SE. Bone marrow dosimetryand toxicity for radioimmunotherapy. Antib Immuno-con Radiopharm 1990;3(4):213–233.

80. Wong JY, Wang J, Liu A, Odom-Maryon T, ShivelyJE, Raubitschek AA, Williams LE. Evaluation changesin stable chromosomal translocation frequency in pa-tients receiving radioimmunotherapy. Int J Radiat On-col Biol Phys 2000;46(3):599–607.

81. Lashford L, Jones D, Pritchard J, et al. Therapeutic ap-plication of radiolabeled monoclonal antibody UJ13Ain children with disseminated neuroblastoma. NCIMonogr 1987;3:53.

82. Order SE, Stillwagon GB, Klein JL, et al. Iodine-131-antiferritin, a new treatment modality in hepatoma: ARadiation Therapy Oncology Group study. J Clin On-col 1985;3:1573–1582.

83. Schroff RW, Weiden PL, Appelbaum F, et al. Rhe-nium-186 (186Re) labeled antibody in patients withcancer: Report of a pilot phase I study. Antibody Im-munoconjugate Radiopharm 1990;3:99–110.

84. Breitz HB, Weiden PL, Vanderheyden J-L, Appel-baum JW, Bjorn MJ, Fer MF, Wolf SB, Ratliff BA,Seiler CA, Foisie DC, Fisher DR, Schroff RW,Fritzberg AR, Abrams PG. Clinical experience withrhenium-186-labeled monoclonal antibodies for ra-dioimmunotherapy: Results of phase I trials. J NuclMed 1992;33:1099–1112.

85. Epenetos AA, Courtenay-Luck N, Pickering D, et al.Antibody guided irradiation of brain glioma by arter-ial infusion of radioactive monoclonal antibody againstepidermal growth factor receptor and blood group Aantigen. Br Med J 1985;290:1463–1466.

86. Brady LW, Woo DV, Markoe A, et al. Treatment ofmalignant gliomas with 125I labeled monoclonal anti-body against epidermal growth factor receptor. Anti-body Immunoconjugate Radiopharm 1990;3:169–179.

87. Reardon D, Akabani G, Freidman A, Freidman H,Herndon J, Cokgor I, McLendon R, Quinn J, Rich J,Regalado L, Sampson J, Shafman T, Wong T, Zalut-sky M, Bigner D. Outcome of newly diagnosed pa-tients with high-grade glioma treated with Iodine-131murine anti-tenascin monoclonal antibody 81C6 viasurgically created resection cavities in a phase II trial.Proc Am Soc Clin Oncol 2001;20(212):542.

88. Salk D, Lesley T, Wiseman G, et al. A phase I clini-cal trial of a fractionated dose intraperitoneal admin-istration of rhenium-186 (186Re) monoclonal antibod-ies in ovarian cancer. Antibody ImmunoconjugateRadiopharm 1992;5:359.

89. Meredith R, Alvarez R, Khazaeli MB, LoBuglio A. In-traperitoneal radioimmunotherapy for refractory ep-ithelial ovarian cancer with 177Lu-CC49. MinervaBiotechnological 1998;10:100–107.

90. Hird V, Maraveyas A, Snook D, et al. Adjuvant ther-apy of ovarian cancer with radioactive monoclonal an-tibody. Br J Cancer 1993;68:403–406.

91. Young RC, Walton LA, Ellensburg SS, et al. Adjuvanttherapy in stage I and stage II epithelial ovarian can-cer. Results of two prospective randomized trials. NEng J Med 1990;322(15):1021–1027.

92. Vergote IB, Vergote-De Vos LN, Abeler VM, Aas M,Lindegaard MW, Kjorstad KE, Trope CG. Random-ized trial comparing cisplatin with radioactive phos-phorus or whole-abdomen irradiation as adjuvant treat-ment of ovarian cancer. Cancer 1992;69(3):741–749.

93. Deb N, Goris M, Trisler K, Fowler S, Saal J, Ning S,Becker M, Marquez C, Knox S. Treatment of hor-mone-refractory prostate cancer with 90Y-CYT-356monoclonal antibody. Clin Can Res 1996;2:1289–1297.

94. Meredith RF, Khazaeli MB, Carabasi MH, LoBuglioAF. Radioimmunotherapy of prostate cancer. In: Ther-apy of Malignancies with Radioconjugate MonoclonalAntibodies: Present Possibilities and Future Perspec-tives. Riva P (Ed), Harwood Academic pp. 321–331,1999.

95. Meredith RF, Khazaeli MB, Macey DJ, Grizzle WE,Mayo M, Schlom J, Russell CD, Wheeler RH,LoBuglio AF. Phase II study of interferon enchanted131I-labeled high affinity CC49 monoclonal antibodytherapy in patients with metastatic prostate cancer. ClinCancer Res 1999;5(10):3254s–3258s.

96. Behr TM, Salib AL, Liersch T, Behe M, AngersteinC, Blumenthal RD, Fayyazi A, Sharkey RM, Ringe B,Becker H, Wormann B, Hiddemann W, GoldenbergDM, Becker W. Radioimmunotherapy of small vol-ume disease of colorectal cancer metastatic to the liver:preclinical evaluation in comparison to standard che-motherapy and initial results of a phase I clinical study.Clin Cancer Res 1999;5(10suppl):3232s–3242s.

97. Meredith RF, Knox SJ. Radioimmunotherapy of B-cell. NHL Current Biopharm Technol 2001;2(4):327–339.

98. Knox S, Meredith R: Clinical Radioimmunotherapy.Seminars in Radiation Oncology 2000;10(2):73–93.

99. McDougall IR. Systemic radiation therapy with un-sealed radionuclides. Seminars in Radiation Oncology2000;10(2):94–102.

100. McEwan AJB. Use of radionuclides for the palliationof bone metastases. Seminars in Radiation Oncology2000;10(2):103–114.

101. Kaminski MS, Estes J, Zasadny KR, Francis IR, RossCW, Tuck M, Regan D, Fisher S, Gutierrez J, Kroll S,

98

Stagg R, Tidmarsh G, Wahl RL. Radioimmunotherapywith iodine 131I tositumomab for relapsed or refrac-tory B-cell non-Hodgkin lymphoma: Updated resultsand long-term follow-up of the University of Michi-gan experience. Blood 2000;Aug,15:96(4),1259–1266.

102. Koral KF, Dewaraja Y, Clarke LA, Lui J, Zasadny KR,Rommelfanger SG, Francis IR, Kaminski MS, WahlRL. Tumor-absorbed-dose estimates versus responsein tositumomab therapy of previously untreated pa-tients with follicular non-Hodgkin’s lymphoma: pre-liminary report. Cancer Biother Radiopharm 2000;Aug,15(4),347–355.

103. Shen S, Meredith RF, Duan J, Brezovich IA, RobertF, LoBuglio AF. Improved prediction of myelotoxic-ity using imaging dose estimate for non-marrow tar-geting 90Y-Antibody therapy. J Nucl Med 2001;42(5suppl):22.

104. Wessels B, Breitz H, Meredith R, Juweid M, PastorM, Colburn M, DeNardo G. Bone marrow dosimetrymodel adjustments based on age, gender, and priortherapy. J Nucl Med 2000;41(5):83p.

105. Robinson SN, Freedman AS, Neuberg DS, Nadler LM,Mauch PM. Loss of marrow reserve from dose-inten-sified chemotherapy results in impaired hematopoieticreconstruction after autologous transplantation:CD341, CD34138-, and week-6 CAFC assays predictpoor engraftment. Exper Hematol 2000;28:1325–1333.

106. Juweid ME, Zhang CH, Blumenthal RD, Hajjar G,Sharkey RM, Goldenberg DM. Prediction of hemato-logic toxicity after radioimmunotherapy with (131) I-labeled anticarcinoembryonic antigen monoclonal an-tibodies. J Nucl Med 1999;40(10):1609–16.14(4):318.

107. Wessels BW, Bolch WE, Breitz HB, Meredith RF,Sharkey RM, DeNardo GL. Bone marrow dosimetry

for radionuclide therapy - A multi-institutional com-parison. J Nucl Med 2001;42(5):22p.

108. Lamborn KR, DeNardo GL, DeNardo SJ, GoldsteinDS, Shen S, Larkin EC, Kroger LA. Treatment-relatedparameters predicting efficacy of Lym-1 radioim-munotherapy in patients with B-lymphocytic malig-nancies. Clin Cancer Res 1997;3:1253–1260.

109. DeNardo GL, DeNardo SJ, Kukis DL, O’Donnell RT,Shen S, Goldstein DS, Kroger LA, Salako Q, DeNardoDA, Mirick GR, Mausner LF, Srivastava SC, MearesCF. Maximum tolerated dose of 67Cu-2IT-BAT-LYM-1 for fractionated radioimmunotherapy of non-Hodgkin’s lymphoma: A pilot study. Anticancer Res1998;18:2779–88.

110. Wiseman GA, White CA, Stabin M, Dunn WL, ErwinW, Dahlbom M, Raubitschek A, Karvelis K,Schultheiss T, Witzig TE, Belanger R, Spies S, Sil-verman D, Berifein JR, Ding E, Grillo-Lopez AJ.Phase I/II 90Y-Zevalin (yttrium-90 ibritumomab tiux-etan, IDEC-Y2B8) radioimmunotherapy dosimetry re-sults in relapsed of refractory non-Hodgkin’s lym-phoma. Eur J Nuc Med 2000;27:766–77.

111. Knox SJ, Goris ML, Trisler K, Negrin R, Davis T,Liles TM, Grillo-Lopéz A, Chinn P, Varns C, NingSC, Fowler S, Deb N, Becker M, Marquez C, Levy R.90Y-labeled anti-CD20 monoclonal antibody therapyof recurrent B-cell lymphoma. Clin Cancer Res 1996;2:457–470.

112. Weiden PL, Breitz HB, Press O, Appelbaum JW,Bryan JK, Gaffigan S, Stone D, Axworthy D, FisherD, Reno J. Pretargeted radioimmunotherapy (PRITTM)for treatment of non-Hodgkin’s lymphoma (NHL): Ini-tial phase I/II study results. Cancer Bio & Rad 2000;15(1):15–29.

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