radioimmunotherapy of small cell lung carcinoma with the...

Vol. 5, 3259s-3267s, October 1999 (Suppl.) Clinical Cancer Research 3259s

Radioimmunotherapy of Small Cell Lung Carcinoma with the Two- Step Method Using a Bispecific Anti-Carcinoembryonic Antigen/ Anti-Diethylenetriaminepentaacetic Acid (DTPA) Antibody and Iodine-131 Di-DTPA Hapten: Results of a Phase I/II Trial 1

Jean-Phi l ippe Vui l lez , 2 Fran~oise Kraeber-Bod~r~ ,

Denis M o r o , M a n u e l Bardi~s,

Jean-Yves Doui l lard , E m m a n u e l Gautherot ,

Eric Rouvier , Jacques Barbet , Freder ic Garban ,

Phi l ippe M o r e a u , and J e a n - F r a n c o i s Chatal Nuclear Medicine Department [J. P. V.], Pneumology Department [D. M.], and Hematology Department [F. G.], University Hospital, 38000 Grenoble; Nuclear Medicine Department IF. K-B., M. B., J-F. C.], Oncology Department [J-Y. D.], and Hematology Department [P. M.], Cancer Center and University Hospital, 4400 Nantes; and Immunotech Co., 13276 Marseille [E. G., E. R., J. B.], France

Abstract As small cell lung carcinoma (SCLC) is frequently a

widespread disease at diagnosis, highly radiosensitive and often only partially responsive to chemotherapy, radioimmunotherapy (RIT) would appear to be a promising technique for treatment. We report the preliminary results of a Phase I/II trial of RIT in SCLC using a two-step method and a myeloablative protocol with circulating stem cells transplantation. Fourteen patients with proved SCLC relapse after chemotherapy were treated with RIT. They were first injected i.v. with a bispecific (anti-carcinoembryonic antigen/anti-diethylenetriaminepentaacetic acid) monoclonal antibody (20-80 mg in 100 ml of saline solution) and then 4 days later with di-(In-diethylenetriaminepentaacetic acid)- tyrosyl-lysine hapten labeled with 1.48-6.66 GBq (40-180 mCi) of 1-131 and diluted in 100 ml of saline solution. In patients receiving 150 mCi or more, circulating stem cells were harvested before treatment and reinfused 10-15 days later. Treatment response was evaluated by CT and biochemical data during the month before and 1, 3, 6, and 12 months after treatment. All patients received the scheduled dose without immediate adverse reactions to bispecific antibody or 1-131 hapten. Toxicity was mainly hematological, with two cases of grade 2 leukopenia and three cases of grade 3 or 4 thrombopenia. Body scanning 8 days after injection of the radiolabeled hapten generally showed good uptake at the tumor sites. Esti-

1 Presented at the "Seventh Conference on Radioimmunodetection and Radioimmunotherapy of Cancer," October 15-17, 1998, Princeton, NJ. Supported by a grant from the "Program Hospitatier de Recherche Clinique" 1996 conducted by the French Ministry of Health. 2 To whom requests for reprints should be addressed, at Laboratoire d'Etude de Radiopharmaceutiques Unite Propre de Recherche de l'Enseignement Superieur Associ6. Centre National de la Recherche Scientifique 5077, Facult6 de M6decine, 38700 La Tronche, France.

mated tumor dose was 2.6-32.2 cGy/mCi. Among the 12 patients evaluated to date, we have observed 9 progressions, 2 partial responses (one almost complete for 3 months), and 1 stabilization of more than 24 months. Efficiency and toxicity were dose-related. The maximal tolerable dose without hematological rescue was 150 mCi. These preliminary results are encouraging, and dose escalation is currently continuing to reach 300 mCi. RIT should prove to be an interesting therapeutic method for SCLC, although repeated injections and hematological rescue will probably be required, as well as combination with other treatment modalities.

Introduction SCLC 3 represents 15-20% of all bronchogenic carcinoma

diagnosed in France (1) and the United States (2). Over the past 15 years, multimodality treatment, including multiagent chemotherapy, has led to an improvement in survival, but the efficacy of SCLC treatment remains limited despite high response rates to chemotherapy and radiotherapy. The use of combined chemotherapy and thoracic radiation therapy for limited SCLC en- hances local control and improves survival (3); prophylactic cranial irradiation reduces the frequency of clinically significant brain metastases and should be proposed to patients achieving a complete response (4), whereas surgery may benefit a small number of patients with stage 1 tumor (5). However, 2-year survival is usually less than 25%, even in limited disease, and fewer than 10% of patients are alive and tree of disease at 5 years (6-8) .

RIT is an internal radiotherapy approach in which radio- nuclide-labeled monoclonal antibodies recognizing tumor-asso- ciated antigens are administered systemically for selective targeting of radioactivity to tumor cells. Very encouraging results have already been obtained in N H M L with or without myeloa- blation with iodine-13 I-labeled anti-CD20 monoclonal antibodies (9-12).

However, some well-known limitations of RIT are mostly problematic for solid tumor. In particular, nonspecific activity in normal tissues is usually too high compared to tumor uptake, providing an inadequate tumor:nontumor ratio that limits the rate of injected activity (13, 14). The AES has been proposed to increase the tumor:nontumor ratios. AES consists in a two-step

3 The abbreviations used are: SCLC, small cell lung carcinoma; RIT, radioimmunotherapy; AES, affinity enhancement system; Bs, bispecific; Ab, antibody; MAb, monoclonal Ab; HAMA, human antimouse antibodies; CEA, carcinoembryonic antigen; BMT, bone marrow transplantation; NHML, non-Hodgkin malignant lymphoma; DTPA, diethylenetriaminepentaacetic acid; CT, computed tomography.

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3260s Two-Step Radioimmunotherapy for SCLC

Table 1 Eligibility of patients

Inclusion criteria Exclusion criteria

Histologically confirmed diagnosis of SCLC CEA expression by primary tumor ~>40% of tumor cells Documented known recurrence(s) No alternative treatment Bone scan within the last 3 months Serum bilirubin and serum creatinine level < 1.5• normal value Leukocyte count >4000/mm ~ Platelet count > 100,000/mm 3 Age -> 18 years and --<75 years Karnofsky index >60% Life expectancy >9 weeks Signed informed consent form

Known intercurrent cancer Psychiatric disorders Previous injected murine monoclonal antibody with positive HAMA External radiotherapy and chemotherapy within the last month Unstable condition not allowing isolation therapy Pregnancy or breast-feeding No informed consent

method using a BsAb and a bivalent radiolabeled hapten (15, 16). Dosimetric studies in patients have confirmed the possible therapeutic benefit of this method (17).

The present Phase I/II dose escalation trial was undertaken to evaluate the feasibility and toxicity of the method. Response to treatment was evaluated as a secondary goal of the study.

Patients and Methods Patients. Eligible patients were adults with histologically

proved SCLC expressing the CEA antigen (at least 40% of tumor cells expressing CEA on a biopsy specimen), who had failed at least on one prior chemotherapy regimen and had assessable and measurable disease. Detailed patient selection criteria are indicated in Table 1.

Reagents. A Bs anti-CEA/anti-DTPA-indium Ab (BsMAb anti-CEA/anti-DTPA-In) designated F6-734 was obtained by coupling an equimolar quantity of a Fab' fragment of anti-CEA MAb F6 (murine IgG1 K, specific for human CEA) to a Fab fragment of anti-DTPA-In MAb 734 (murine IgG1M specific for DTPA-In complexes) previously activated by o- phenylenedimaleimide.

The bivalent DTPA hapten N-oL-DTPA-tyrosyl-n-e-DTPA- lysine (di-DTPA) was obtained by reaction of DTPA dianhy- dride with tyrosyl-lysine diacetate (18). 131I -bivalent hapten (13JI -di-DTPA-In) was provided by Cis Bio-International (Saclay, France). Before labeling, DTPA bivalent hapten was saturated with indium in an indium chloride solution because MAb 734 only recognizes the DTPA-In complex.

AES Therapeutic Protocol and Dose Escalation Proto- col. The aim of this Phase I/II study was mainly to determine the maximal tolerated dose. For this purpose, dose escalation was performed, starting from 1.85 GBq (50 mCi) of 131I -di- DTPA-In and increasing by 1.85-GBq steps.

The two-step method has been described elsewhere (15). Briefly, during the first step at day 0 (DO), nonlabeled Bs anti-CEA/anti-DTPA Ab was injected at a dose of 1 mg of Ab for 4 nmol (74 MBq) of 131I-hapten in a 100 ml serum saline infusion. Four days later (day 4), the second step consisted in injecting di-DTPA-tyrosyl-lysine bivalent hapten labeled with iodine-131. The 131I -hapten was injected in serum saline through a radioprotected device (Perfucis, Cis Bio-Internation- al). Infusion was performed inside a lead-protected room in which patients remained until the dose rate became less than 20

txSv at 1 m. To protect the thyroid gland from inappropriate irradiation, the patient received 30 drops of saturated solution of potassium iodine p.o. three times daily, beginning 3 days before injection of 131I -hapten and then for 14 days after therapy.

Toxicity Monitoring. Toxicity was assessed from clinical and biological data, i.e., blood cell count, liver enzyme level (aspartate aminotransferase, alanine aminotransferase, y glu- tamyl transpeptidase, alkaline phosphatase, and lactate dehydro- genase), blood biochemistry (urea, creatinine, glucose, total bilirubin, total proteins, and albumin), and urine parameters (protein, WBCs, and RBCs).

Hematological Rescue. During the first course of the protocol, it appeared that hematological toxicity was problematic for injected activities above 5.55 GBq (150 mCi). Thus, the protocol was modified, with the approval of the local ethics committee, to perform autologous BMT with peripheral stem cells. Stem cells obtained by cytapheresis after stimulation by granulocyte macrophage colony-stimulating factor (10 txg/kg of body weight for 5 days) were systematically harvested before RIT for doses of 150 mCi or more. RIT was then performed if more than 1.5 • 106 stem cells (CD34+)/kg were obtained; if not, the injected activity was reduced to 100 mCi. When BMT was scheduled, stem cells were reinjected as soon as blood activity became lower than 1 bLCi/ml.

Treatment Effectiveness. Response to treatment was evaluated by clinical data, morphological imaging (CT, ultra- sound, and sometimes magnetic resonance imaging), and biological data (CEA and neuron-specific enolase serum levels). Response categories were defined as follows. A complete response (CR) was defined as the disappearance of all clinical and radiological evidence of disease, together with negative CEA and neurone-specific enolase serum blood levels, lasting a min- imum of 1 month. A partial response (PR) was defined as a decrease of 50% or more in the size of all of the measurable lesions lasting at least 1 month. A minor response (PR) was defined as a decrease of less than 50% and more than 25% in the size of all of the measurable lesions, lasting for at least 1 month. Stable disease (SD) was defined as a less than 25% decrease or a less than 25% increase in size lasting for at least 1 month. Disease progression (PD) was defined as an increase of greater than 25% of the cross-sectional area of one or more lesions or the occurrence of new lesions irrespective of response elsewhere.



Clinical Cancer Research 3261s

Patient Disease [ACE] [NSE] no. Sex Age spread ng/ml ng/ml

Table 2 Patient characteristics

Previous treatments Residual disease

01 M 65 D a 135.1 19.5

02 F 61 D 1.7 20

03 M 46 D 1.6 8.5

04 M 59 D 4.5 74.7

05 F 67 D 4.3 9.6

06 M 66 L 19.4 18.2

07 M 56 L 0.8 5.8

08 M 50 D 264. l 16.7

09 M 60 D 4.4 19.5 10 M 71 D 6.4 12 11 M 63 L 1,015 5.3

12 F 50 D 1,280 137.9

13 M 64 L 3 28.1 14 M 48 L 3.5 7

(Cisplatin-VP 16) • 6 (Adria-cyclophosphamide-vincristine) • 2 (Cisplatin-VP 16) • 6 (Adria-cyclophosphamide-vincristine) X4 V P l 6 p e r o s • 4 (Cisplatin-VP16) • 3 (Epirubicin-ifosfamide-vepeside) • 4 (Adria-cisplatin-VP16-cyclophosphamide) x 6 (ifosfamide-uromitexan) • 3 Radiotherapy (Adria-cisplatin-VP16-cyclophosphamide) • 5 (Ifosfamide-uromitexan) • 3 Radiotherapy (Adria-cisplatin-VP16-cyclophosphamide) • 6 Radiotherapy (Adria-cisplatin-VP16-cyclophosphamide) X 6 Radiotherapy (Cisplatin-VP16) • 6 Radiotherapy (Cisplatin-VP16) X 6 (Cisplatin-VP16) X 6 (Adria-cisplatin-VP16) • 12 Radiotherapy (Farmorubicin-cisplatin-VP16-

cyclophosphamide) • 6 (Adria-cyclophosphamide-VP16) • 6 (Cisplatin-VP16) • 6 Taxotere X 3 Radiotherapy

D, diffuse; L, localized disease, limited to the thorax.

Right lung, mediastinal mass and lymphnodes

Left lung, mediastinum, liver

Mediastinum, lungs, liver

Mediastinum Neck lymphnodes Liver, bone metastases Right lung mass Bone metastases

Left lung mass

Left lung mass

Bone, neck and mediastinal mass

Liver metastases Mediastinal lymphnodes, liver Mediastinal lymphnodes and tumor mass

Mediastinum and lung tumor mass Liver and bone metastases Mediastinum and lung tumor mass Neck lymph nodes

Dosimetr ic Studies . The radiation dose delivered to tu-

mor sites and normal organs was est imated by daily serial

whole-body scanning. Cumulat ive activity in whole-body, tu-

mor, liver, and kidneys was determined by whole-body quanti-

tative scintigraphy performed with a double-headed Sopha Med-

ical camera (DHD Body Track) equipped with a high-energy

collimator, as proposed by DeNardo et al. (19). Whole-body

scintigraphic images (anterior and posterior views) were re-

corded 5 min after injection of 131I -labeled hapten and then at

days 1, 2, 3, 4, and 7, using a 20% window set on the ~3~I

photopeak (364 keV). The posit ioning of the patient was done in a reproducible manner using a system based on laser sources.

The attenuation correction factor was determined f rom a transmission image. A coll imated linear source perpendicular to the direction of scanning movemen t was attached to the lower camera head. To define the geometrical parameters for record- ings, acquisition was performed in the presence and then the

absence of the patient on the day of nonradiolabeled F6-734 BsMAb injection.

The geometrical mean of each acquisition was calculated and mult ipl ied by the attenuation correction factor to obtain the resulting image. During each acquisition, a known activity

standard was placed on the examinat ion table at the level of the patient 's feet to determine the calibration factor for the camera (in counts per MBq in the air). The activities calculated at the different t ime points were transferred to a pharmacokinet ic study program (Siphar, Simed) to determine the effective half-

lives of 131I -labeled hapten in the regions defined and then the

cumulat ive activity.

The doses absorbed by tumor targets and normal tissues

after injection of 13 ~I -labeled hapten were calculated according

to the medical internal radiation dose scheme (20).

Dosimetry was performed on scintigraphically visualized

tumors for which it was possible to define a target vo lume (and

thus estimate the mass) f rom CT scan sections. Regions of

interest were defined on the liver and left k idney of each patient

to estimate the doses delivered to these organs.

The calculation of the bone-marrow dose was performed

according to the technique of DeNardo et al. (21) by summing

a "whole-body" componen t of the bone-marrow dose (only

penetrating radiations were taken into account) and a blood

componen t (only nonpenetrat ing radiations were taken into ac-

count).

Bioethical Cons iderat ions . All patients received de-

tailed informat ion and gave their signed written consent before

being included. The protocol was approved by the local ethics committee, according to European regulations.

R e s u l t s

Fourteen patients were included and comple ted the treatment. All patients had previously received at least one course of chemotherapy and were in relapse of the disease. Patient char-

acteristics are shown in Table 2.




Fig. 1 Patient 8. Whole-body scan at day 7 after RIT (50 mCi of ~31I -hapten), showing excellent targeting in all tumor sites in this very widespread recurrence of SCLC.

o

ANT POST

D 7 (50 mCi)

Tumor Targeting and Dosimetry. Tumor targeting was generally excellent, all tumoral sites being visualized with high contrast, even in case of very widespread disease (Fig. 1). The retention time of radioactivity in the tumor was good and, in some cases, excellent; indeed, the biological half-life of radioactivity in the tumor was between 4.5 and 22 days. Tumor:blood ratios ranged between 0.64 and 5.8, and tumor:liver ratios ranged between 0.46 and 6.6 at day 7.

Dosimetric data were available for six patients. Mean dosimetric values are indicated in Table 3. The estimated tumor dose was between 1.81 and 32.19 cGy/mCi, depending on tumor

mass and tumor uptake, but also on the biological half-life of radioactivity in the tumor. The maximum dose (32.2 cGy/mCi) delivered to the tumor in terms of cGy/mCi was obtained with the first level of activity in patient 5, who received 1.55 GBq (42 mCi) of hapten, producing a calculated total tumor dose of only 13.5 Gy.

For other tissues, greater doses were given to kidneys, according to the elimination of the radiolabeled hapten, and to red bone marrow, which accounted for the toxicity.

Toxicity. Limiting toxicity was hematological (Table 4). We observed four cases of grade III or IV leukopenia and 7




Table 3 Toxicity

Patient no. Injected activity,

GBq (mCi) Bone marrow

transplant Red marrow dose (cGy) Myelotoxicity grade

Nadir (days)

Grade 3 or 4 duration (days)

02 1.18 (32) - NA a 04 1.61 (43.6) - 19 05 1.55 (42) - 73 08 1.86 (50.3) - NA 01 3.58 (96.8) - NA 03 3.64 (98.3) - NA 06 3.90 (105.5) - 123 07 4.76 (128.8) - 117 09 5.03 (136) + NA 10 4.62 (125) + NA 11 5.91 (159.7) + 264 12 2.78 (75.1) - NA 13 5.74 (155.2) + NA 14 6.66 (180) +

1 (Plat.) 0 1 (Plat.) 0 0 2 (Plat.) 3 (Plat.), 2 (WBC) 0 4 (Plat.), 3 (WBC) 4 (Plat.), 4 (WBC) 4 (Plat.), 3 (WBC) 4 (Plat.), 3 (WBC) 4 (Plat.), 3 (WBC) 3 (Plat.), 2 (WBC)

3O

3O

30 33, 46

19, 23 24, 32 25, 24 14, 26 21, 24 23, 30

40, 5 31, 32 28, 7

ND 20

2,2

a NA, not applicable; plat., platelet count.

Table 4 Dosimetry

Patient no. Injected activity, GBq (mCi) Tumor

Dose (cGy) Dose/activity (cGy/mCi)

Total body Red marrow Liver Kidney

04 1.61 (44) 79/469 1.8/10.8

05 1.55 (42) 1352 32.2

06 3.90 (106) 274 2.6

07 4.76 (129) 2283 17.7

11 5.91 (160) 3655 22.9

13 5.74 (155) 1706/2181 11/14

13 19 182 ND" 0.3 0.4 4.2

41 73 210 ND 0.97 1.7 5.0

65 123 ND ND 0.62 1.2

68 117 227 501 0.5 0.9 1.8 3.9

140 161 258 ND 0.9 1.0 1.6

171 251 320 767 1.1 1.6 2.1 5.0

a ND, not determined.

cases of grade III or IV thrombopenia. Typically, thrombopenia occurred earlier and persisted longer than leukopenia. No other

significant adverse events were observed. Response to T r e a t m e n t . Twelve patients were fully

evaluated (for the other 2 patients, fol low-up was less than 3 months). A m o n g these 12 patients, we observed 9 progressions,

2 partial responses (1 almost complete, but unfortunately lasting only 3 months), and 1 stabilization of more than 24 months. One

patient (patient 12) was enrolled on a compassionate basis and thus was not taken into account for evaluation of efficacy.

The patient who presented disease stabilization for more than 24 months (patient 3, Fig. 2) was a 46-year-old male. Pulmonary and mediastinal lesions, which were in progression

before RIT, as compared to previous CT, were unchanged 1 year after RIT was performed.

In the first patient who presented a partial response (patient

7, Fig. 3), lesions had decreased by more than 60% 3 and 6 months after RIT. This effect occurred quite late, differing from effects usually obtained with conventional radiotherapy, and persisted after 17 months, at which t ime the patient died from heart failure without evidence of disease progression.

The patient who exhibited almost complete response for 3

months (patient 9) had residual disease consisting only in sev-

eral small liver metastases (less than 1 cm in diameter). Most of

these lesions had disappeared 6 weeks after RIT (Fig. 4). Un-

fortunately, reccurrences were detected after 3 months in liver

and brain.

H A M A Response . In most cases, survival was too short

to allow a good evaluation of H A M A occurrence. A m o n g five

complete evaluations, one patient showed significant H A M A levels after 2 months, which persisted at 12 months.

Discussion RIT is a new potentially useful method of treating dissem-

inated, radiosensit ive tumors for which chemotherapy, despite significant responses, cannot provide a complete cure. Impres- sive results have been obtained in NHMLs using anti-CD20

antibodies labeled with iodine-131 (9-11) . An overall and complete response rate of respectively 79 and 50% was obtained with nonmyeloabla t ive activities of 1311 -labeled anti-CD20 Ab.

SCLC is another type of cancer for which RIT could




Table 5 Response to treatment and clinical outcome

Patient Injected activity, Estimated no. GBq (mCi) tumor dose Tumor response and clinical outcome

Survival after RIT

(days)

01 3.58 (96.8) NA" 02 1.18 (32) NA 03 3.64 (98.3) NA 04 1.61 (43.6) 80/473 05 1.55 (42) 1352 06 3.90 (105.5) 274 07 4.76 (128.8) 2286 08 1.86 (50.3) NA 09 5.03 (136) NA

10 4.62 (125) NA 11 5.91 (159.7) 3664 12 2.78 (75.1) NA 13 5.74 (155.2) NA 14 6.66 (180) NA

Progression: death 109 Progression: death 63 Stable (>24 months) >800 Progression: death 48 Progression: death 92 Progression: death 193 Partial response: 60% decrease of tumor size (20 months) 583 Progression: death 34 D30: partial response (>50%) of multiple liver metastases; occurrence of brain 165

metastases M3: partial response (liver metastases); external beam radiation of brain; death Progression: death 78 Rapidly growing tumor before inclusion; progression: death 127 Enrolled on a compassionate basis (life expectancy <9 weeks); progression: death 30 Progression >60 D30: minimal response (-20%) >50

a NA, not applicable.

Ju ly 29, 1996 - M o n t h 2 P R E - R I T

M a r c h 19, 1997 - M o n t h 6 P O S T - R I T

S e p t e m b e r 22, 1997 - M o n t h 12 P O S T - t i l T

Fig. 2 Patient 3. This patient experienced disease stabilization for more than 12 months. Lesions that were in progression before RIT, as compared to previous CT, were unchanged in subsequent examinations after RIT was performed. After 24 months, the clinical status of this patient was unchanged.

provide beneficial additional treatment. Despite a high response

rate since the introduction of platinum and multidrug regimens, chemotherapy has led to durable complete remission in less than

20% of cases, even in localized intrathoracic forms (22).

Preliminary studies have been conducted with various antibodies, such as anti-GD2 ganglioside MAb 3F8 (23), MOC-31

(24), and anti-neural cell adhesion molecule antibodies (25, 26). However, no clinical results appear to have been reported with RIT for SCLC.

Toxicity. The AES method provided high tumor:whole- body, tumor:liver, and tumor:blood ratios, as well as a favorable tumor:red marrow ratio, whereas limiting toxicity was hematological with severe leukopenia and thrombopenia occurring when injected activity was greater than 5.55 GBq (150 mCi), which required autologous BMT. This hematological toxicity could be partially explained by bone marrow tumor involve- ment, which is frequent at advanced stages of the disease.

Dosimetry and Clinical Response. Three significant responses were obtained in 12 evaluable patients. The total tumor dose, which depended on injected activity as well as tumor uptake and the retention time of radiolabeled hapten, was significant, but probably not sufficient for a tumoricidal effect (the maximum calculated dose was 36 Gy).

At least three parameters may account for the dose received by the tumor, i.e., tumor uptake and the tumor:nontumor ratio, retention time of radioactivity in the tumor, and injected activity. In solid tumors (with the exception of lymphoma), RIT is generally limited by a low tumor:tissue uptake ratio, which reduces injected activity and the dose delivered to tumor to spare other tissues from excessive toxicity. Moreover, in many cases, the retention time of radiolabeled antibodies in tumor is of short duration. The AES method improves both of these limiting parameters (15). The tumor:nontumor tissue ratio is increased, mainly because nonspecific activity is reduced, which has been demonstrated with radioimmunodetection using l~In-labeled bivalent hapten for immunoscintigraphy of medullary thyroid carcinoma (27) and non-SCLC (28), and in animal studies (29). In addition, the retention time in tumor is increased, which, in



Clinical Cancer Rcsearch 3265s

Fig. 3 a, left, this patient (patient 7) had a left pulmonary residual tumor before RIT (arrow). Right, after RIT, a significant decrease (greater than 50%) in the tumor mass was observed, and the case was considered as a partial response. This effect occurred late, reached 60% of decrease at 6 months, and persisted after 17 months (arrow). b, control scan performed 3 days after injection of the labeled hapten, showing the good targeting of the tumoral site, providing a dose of 17.7 cGy/mCi. This patient received 129 mCi; thus, the total dose to the tumor could be estimated as 22.8 Gy

December 20, 1996 PRE-RIT

dune 22, 1998 Month 17 POST-RIT

ANT POST

the present study, was especially favorable in some cases, reach-

ing 32.2 days. In the present Phase I/II trial, treatment efficiency was not

the main objective, and only three responses were obtained,

probably because of the low injected activities. In terms of cGy/mCi, the m a x i m u m dose delivered to tumor was obtained with 1.55 GBq (42 mCi) of hapten, providing a total tumor dose of only 13.5 Gy, which probably accounted at least in part tor

the observed progression of disease in this patient. Conversely, the three significant responses we observed were all obtained for

injected activities greater than 3.7 GBq (100 mCi). If only patients injected with a dose of 3.7 GBq or more are considered, the response rate was three of seven evaluable patients (42.8%).

Such results are satisfactory in a Phase I/II trial and justify the continuation of this therapeutic approach, to improve the

dose delivered to tumor. If sufficient dose levels are obtained, the therapeutic benefit of internal irradiation could be extrapo- lated f rom that of external beam radiation on the thorax, which

provides an increase of 5 -15% in relapse-free survival in localized forms (3, 22). For this purpose, two complementary strat- egies may be proposed. First, injected activity could be increased. Our study shows that in cases in which circulating stem

cells could be harvested (in fact, bone marrow is often impaired after chemotherapy) , more than 200 mCi could be given without

significant nonhematologica l adverse effects. Thus, dose escalation studies are cont inuing to reach a level of 300 mCi.




Before RIT 6 weeks after RIT Fig. 4 Patient 9. Almost complete response for 3 months. Residual disease in this patient consisted only small liver metastases (arrows), most of which disappeared 6 weeks after RIT. Unfortunately, recur- rences were detected after 3 months, in liver and brain.

Second, injections could be repeated, as in NHML. The possi- bility of repeating injections depends on the absence of HAMA. However, in the present study, fol low-up was too short in most

cases to have a correct evaluation of the frequency of H A M A occurrence. In another study concerning medullary thyroid carcinoma, H A M A was found in 9 of 17 patients (53%). In any

event, BsAb will be totally humanized in the near future, so that H A M A should no longer be a problem with repeated injections.

RIT, like internal radiotherapy in general, is more efficient when tumor targets are smaller, i.e., less than 1 cm in diameter

(13). For this reason, patients enrolled in the present Phase I study, who generally had a large tumor burden after proved

chemotherapy failure, did not represent the best populat ion for the RIT success. The method would probably be more efficient

if applied together with chemotherapy (either at the same time or immediately after), to eradicate microscopic or subclinical residual disease. Interestingly, the best response in our study was obtained for minimal residual lesions (liver metastases less than 1 cm in diameter). Unfortunately, the patient who had no

prophylactic brain irradiation died from brain metastases that appeared 1 month after RIT.

Our study confirms the putative interest of RIT in SCLC

and indicates that the AES method could contribute to better efficacy by providing lower toxicity together with high tumor uptake, thereby allowing injection of activities that produce a

significant tumoricidal effect. The AES method will probably prove useful in the future in association with other modalities.

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1999;5:3259s-3567s. Clin Cancer Res Jean-Philippe Vuillez, Françoise Kraeber-Bodéré, Denis Moro, et al. I/II TrialAntibody and Iodine-131 Di-DTPA Hapten: Results of a Phase Antigen/Anti-Diethylenetriaminepentaacetic Acid (DTPA)Two-Step Method Using a Bispecific Anti-Carcinoembryonic Radioimmunotherapy of Small Cell Lung Carcinoma with the

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