Cancer Investigation
`
`
`
`EDITORIAL BOARD
`
`Editor-rn-Ch/etf-
`
`.
`Deputy Eo’iton
`
`SeniorEd/tors:
`
`YASHAR HIRSHAUT, M.D.
`Yeshiva University
`2495 Amsterdam A venue
`New York, New York 10033
`
`.
`Joseph R. Bertino, MD.
`Memorial Sloan-Kettering Cancer Center
`
`Ronald B. Herberman, MD.
`Pittsburgh Cancer Center
`
`Morton K. Schwartz, Ph.D.
`Memorial Sloan-Kettering Cancer Center
`Alan s. Rabson, MD.
`National Cancer institute
`
`E
`c 2
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`82.2:
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`9;”
`5‘;
`
`a:
`it
`
`Managing Editor:
`
`Ora J. Baer
`
`Promotions Assistant
`
`Jaclyn Silverman
`
`Departments:
`
`Ong/nalAn/oles.'Clifford A. Hudis, Melvin Spigelman, and
`David C. Smith
`Ci/n/cal Science Reviews: Malcolm S. Mitchell
`Clinical Trials: Douglass C. Tonney and Peter C. Raich
`Basic Science Reviews'Jeffrey Schlom
`Controversies in Patient Management: Dennis Cooper
`Controversies in Basic Science: Michael Lieberman
`Technology'T. Ming Chu
`Brief Clinical Reports: Ephraim S. Casper
`Concise He views in Surgery: Frederick L. Mofiat
`Min/ser/es/Spec/a/Adie/es: Alan S. Rabson
`New Drugs: Hira Gurtoo
`Op—Ed: Ezra Greenspan
`Psychosocial issues: Jimmie C. Holland
`B/oeth/cs:Joseph J. Fins
`Assistant Editor for Bioethics: Matthew Bacchetta
`Biostat/st/cs: Larry R. Muenz
`
`Public issues: 8. J. Kennedy
`Report from Congress: Roger C. Herdman
`Pain Management: Marc L. Citron
`Hematology'Morton Coleman and Hans W. Grunwald
`Neuro—Onco/ogy.’ Stuart A. Grossman
`Pediatric Oncology: Michael B. Harris
`Art andArch/lecture in Med/tine: Charles Gianfagna
`Hematopoiet/c Stem Cell Transplantation: Subhash C.
`Gulati
`
`Funding-William J. McLoughIin
`Epidemiology: Henry T. Lynch
`Genetics:John J. Mulvihill
`Radiation Therapy: Florence Chu and Eli Glatstein
`Veterinary Oncology'William D. Hardy, Jr.
`infectious Complications of Cancer: Ron Feld
`Environmental Caro/nogenesis: F. William Sunderman. Jr.
`
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`Abstracts
`
`59
`
`Table I
`
`
`Gr. 4
`
`Gr. 4
`thrombocytopenia/
`
`Level
`Taxol dose, mg/m2
`No. of pts/cycle
`neutropenia/cycle
`cycle
`Other side effects (grade)
`
`I
`II
`
`120
`135
`
`3/14
`3/17
`
`1/14
`7/17
`
`0
`4/17
`
`l pneumonia (2)
`1 C. diff. (2);
`l
`fever
`
`leucopenic
`
`1 leucopenic fever
`2/15
`5/15
`3/15
`150
`III
`
`IV INN (4) 175 6/18 5/18 1/18
`
`
`
`
`
`from analysis due to lack of information. A total of 64
`cycles have been given to the patients. The dose-limiting
`toxicity was defined as grade 3 or worse nonhematologic
`toxicity or neutropenic sepsis, or grade 4 neutropenia
`greater than 5 days. If any patient developed a dose-lim-
`iting toxicity, subsequent patients were entered to the
`same level of Taxol. The side effect profiles of the 15
`patients are shown in the table.
`Alopecia was universal. Nausea/vomiting was usually
`mild or moderate except for 1 patient. Myelosuppression
`was accumulative. No toxic death was observed. There
`
`was 1 complete remission (CR), 5 partial remission (PR)
`in 6 breast cancer patients; 3 CR and 1 PR in 4 sarcoma
`patients; PR in 1 patient with adenoidcystic carcinoma; the
`other 4 patients did not respond. In summary, ICE—T is a
`very active and well-tolerated regimen. The study is con-
`tinuing.
`
`BIBLIOGRAPHY
`
`Fields KK. Elfenbein GJ. Saleh RA. et al: Ifosfamide, carboplatin, and
`etoposide for induction and high-dose chemotherapy: Focus on
`breast cancer and lymphoma. Hematol Oncol 10:61—74, 1992.
`Hsieh R-K, Chang AY-C, Boros L, Asbury R: Phase ll study of ifosfam-
`ide, carboplatin, and etoposide in patients with advanced non-small
`cell lung cancer. Am I Clin Oncol 17:509-513. 1994.
`Loehrer PJ. Lauer R, Roth 8]: Salvage therapy in recurrent germ cell
`cancer: ifosfamide and cisplatin plus either vinblastine or etoposide.
`Ann Intern Med 87:540—547. 1988.
`Rowinsky EK, Cazenave LA. Donehower RC: Taxol: a novel investiga-
`tional antimicrotubule agent. J Natl Cancer Inst 82:1247-1259, 1990.
`Smith IE, Perren TJ, Ashley SA, et a1: Carboplatin. etoposide, and
`ifosfamide as intensive chemotherapy for small-cell lung cancer. J
`Clin Onc0182899—905, 1990.
`Van Zandwijk N. ten Bokkel Huinink WW. Wanders I. et al: Dose
`finding studies with carboplatin, ifosfamide, etoposide and mesna
`in non-small cell
`lung cancer. Semin Oncol 17(suppl 2):]6—19,
`1990.
`
`53. CHEMOIMMUNOTHERAPY OF
`LOW-GRADE LYMPHOMA WITH THE
`ANTI-€020 ANTIBODY IDEC-C2B8 IN
`COMBINATION WITH CHOP
`CHEMOTHERAPY
`
`M. S. Czuczman, A. I. Grille—Lopez, C. Jonas, L. Gordon,
`M. Saleh, C. A. White, C. Vams, and B. K. Dallaire
`
`Roswell Park Cancer Institute, Buffalo, New York; [DEC
`Pharmaceuticals Corporation, San Diego, California,
`Northwestern University, Chicago, Illinois; University of
`Alabama, Birmingham, Alabama; Sharp Health Care and
`Sidney Kimmel Cancer Center, San Diego, California
`
`The incidence of non-Hodgkin’s lymphoma (NHL) is
`increasing in the United States. More than 50,000 new
`cases of NHL are projected to occur in the U.S. for 1995,
`with approximately 42% of these cases being of a low-
`grade or follicular histology (International Working For-
`mulation A, B, C, or D). Although low-grade lymphomas
`are responsive to standard chemotherapy, the majority of
`patients are not cured by this approach. In fact, the best
`results from high-dose systemic chemotherapy with total-
`body irradiation in the setting of purged autologous bone
`marrow transplantation (ABMT) produce recurrence-free
`survival in only 40—75% of patients (Gribben et al; John-
`son et al) with a median follow-up of approximately 4
`years. Molecular research has identified the bcl-2 pro-
`tooncogene as being associated with the t(14;18) chromo-
`somal translocation of follicular, low-grade lymphomas.
`This t(14;18) leads to movement of the bcl-2 gene from
`18q2l to l4q32 (immunoglobulin heavy chain locus) and
`results in increased transcription and accumulation of high
`levels of bcl-2 protein. Recent research has demonstrated
`that bcl-2 overexpression may lead to multidrug resis-
`tance, independent of the P170 glycoprotein, by causing
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`60
`
`Abstracts
`
`resistance to apoptosis by a variety of chemotherapeutic
`agents including certain alkylating agents, doxorubicin,
`glucocorticoids, and vincristine (Hsu et al). For patients
`with low-grade lymphoma, bcl-2 status posttherapy may
`not only have prognostic value, but may also serve as a
`marker to monitor minimal residual disease. Extensive
`
`research by Gribben et al has demonstrated that no patient
`cleared bcl-2 positivity in marrow following induction or
`salvage chemotherapy (including 6 cycles of standard-
`dose CHOP). and that residual bcl-2 positive cells in
`reinfused purged autologous bone marrow appear to be
`associated with a 7.5-fold risk of relapse in patients under-
`going ABMT for low-grade lymphoma. Unfortunately a
`large number of patients with low-grade lymphoma are
`elderly or have bone marrow which is unable to be purged
`to polymerase chain reaction (PCR) negativity and would
`therefore not be optimal candidates for ABMT. Because
`of this, new therapeutic strategies with improved antitu-
`mor activity and acceptable toxicity need to be developed
`with the goal being achievement of a molecular complete
`remission with no detectable bcl-2 rearrangement in mar-
`row or blood by sensitive PCR methods. Preliminary data
`from a novel chemoimmnotherapeutic approach of treat-
`ing low-grade lymphoma with standard-dose CHOP and
`IDEC—CZB8 (a chimeric anti-CD20 antibody) is being
`presented at this time. lDEC—C2B8 has previously been
`shown to have antitumor activity with mild to moderate
`toxicity as a single agent in patients with relapsed low-
`grade and follicular lymphoma. In a recent IDEC—CZBS
`multidose (375mg in2 q week x 4) phase II trial, a 50%
`response rate (17 of 34 relapsed patients) lasting 4.4 to
`greater than 15.5 months was achieved (Maloney et al.).
`Mechanisms of action of lDEC-C2B8 include comple-
`ment-mediated cytotoxicity, antibody-dependent cellular
`cytotoxicity, induction of apoptosis (in vitro data), and
`synergistic antitumor activity with certain chemotherapeu-
`tic agents (including doxorubicin). The rationale for com-
`bination of lDEC—C2B8 with CHOP includes: non-cross-
`
`individual efficacy,
`resistant mechanisms of action,
`nonoverlapping toxicities, and known synergy with
`doxorubicin. In the current trial, IDEC—CZB8 is given at
`a dose of 375 mg/m2 on weeks 1 (2 infusions), 7, 13, 20,
`and 21 for a total of 6 doses. CHOP chemotherapy (cyclo-
`phosphamide 750 mg/m2 i.v. x 1, doxorubicin 50 mg/m2
`i.v. x 1, vincristine 1.4 mg/m2 i.v. x 1 (up to maximum of
`2 mg), prednisone 100 mg/mzlday p.o. for 5 days) is given
`on weeks 2, 5, 8, ll, 14, and 17 for a total of 6 cycles.
`Currently 27 patients have entered on this study and data
`are available for 14 patients, 1 l of whom have completed
`all scheduled therapy. Of the 3 remaining patients, one was
`registered but never treated secondary to rapid onset of
`
`CNS disease, the second refused further therapy following
`5 cycles of CHOP and 4 doses of IDEC—CZB8 due to
`steroid-induced severe depression (achieved a partial re-
`mission—PR), and the third was taken off study after 2
`cycles of CHOP and 2 doses of lDEC—CZBS following
`surgery for cervical osteomyelitis (achieved a PR). Char—
`acteristics of these 14 patients include: 6 males/8 females,
`80% stage III/IV at diagnosis, median age 59 (range of
`35-75), 12 previously untreated, IWF A = 4, IWF B = 4,
`IWF C = 5, other low-grade = l. Adverse events included
`nausea, neutropenia, pain, fatigue, vomiting, fever, alope-
`cia, constipation, and peripheral neuropathy. Sixty-one
`events were attributed to CHOP (80% grade 3 and 20%
`grade 2) and 18 to [DEC—C238 (25% grade 2 and 75%
`grade 1). The latter consisted primarily of flulike symp-
`toms, usually associated with the first of six infusions. No
`human anti-mouse or anti-chimeric antibody responses
`(HAMA/ HACA) nor unexpected toxicities have been
`observed for the combination of CHOP and antibody.
`Overall response rate for the 1] patients completing all
`scheduled therapy is 100% (8 complete remission—CR
`and 3 PR). These responses are ongoing with a median
`observation time of 9 months. Four patients found to be
`positive for bcl-2 by PCR prior to therapy (3 in peripheral
`blood and bone marrow,
`1
`in peripheral blood alone)
`converted to bcl-2 negativity by completion of therapy.
`The three patients achieving PCR negativity in marrow
`have undergone unpurged autologous bone marrow har-
`vesting at time of count recovery with the pooled bone
`marrow specimcns confirming bcl-2 negativity. Current
`efficacy and toxicity data appear encouraging and the
`finding of molecular remissions by PCR suggests that the
`antitumor activity of CHOP and IDEC—CZBS is superior
`to CHOP therapy alone. This study is onging and accrual
`of 30 evaluable patients is planned.
`
`BIBLIOGRAPHY
`
`Czuczman M, Grille-Lopez A], Salch M, et a]: Phase II clinical trial of
`IDEC—CZB8/CHOP combination therapy in low-grade lymphoma:
`preliminary results. Proc ASCO 14:40] (#1261), 1995.
`Demidem A, Hanna N, Hariharan H, ct al: Chimeric anti—CD20 antibody
`(lDEC—CZB8) is apoptotic and sensitizes drug resistant human B-cell
`lymphomas and AIDS related lymphomas to the cytotoxic effect of
`CDDP, VP-16, and toxins. FASEB 9: A206, 1995.
`Gribben JG, Freedman AS. Neuberg D, et a1: Immunologic purging of
`marrow assessed by per before autologous bone marrow transplan-
`tation forB-cell lymphoma. N Engl J Med 325: 1525-1533, 1991.
`Gribben JG, Freedman AS. Woo SD. et a]: All advanced stage non-
`Hodgkin’s lymphomas with a polymerase chain reaction amplifiable
`breakpoint of bcl-2 have residual cells containing the bcl-2 rear-
`rangement at evaluation and after treaunent. Blood 123275—3280.
`1991.
`
`Gribben JG, Neuberg D. Freedman AS, et al: Detection by polymerase
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`
`
`Abstracts
`
`chain reaction of residual cells with the bcl-2 translocation is as-
`sociated with increased risk of relapse after autologous bone marrow
`transplantation for B-cell lymphoma. Blood 81: 3449—3457, 1993.
`Hsu B, Marin M, Brisbay S, et al: Expression ofbcl-2 gene confers multi-
`drug resistance to chemotherapy-induced cell death. Cancer Bull
`46:125—129, 1994.
`Johnson PWM. Price CGA, Smith T, et al: Detection of cells bearing
`the t(l4;l8) translocation following myeloablative treatment and
`autologous bone marrow transplantation for follicular lymphoma.
`.1 Clin Oncol 12:798-805. 1994.
`Maloney DG, Bodkin D, Grillo—Lopez A], et a]: [DEC—C2138: final report
`on a phase II trial in relapsed non-Hodgkin's lymphoma. Blood
`84:169a (#661), 1994.
`Maloney DG, Liles TM. Gzerwinski DK, et a1: Phase I clinical trial using
`escalating single-dose infusion of chimeric anti-CD20 monoclonal
`antibody “DEC-(3238) in patients with recurrent B-cell lymphoma.
`Blood 84:2457-2466. 1994.
`
`
`
`54. USE OF RADII‘OIMIWUNODETECTION
`WITH CEA—SCAN IN THE PREOPERATIVE
`EVALUATION OF PATIENTS WITH
`COLORECTAL AND BREAST CANCER
`
`K. Hughes,‘ c. Pinsky,2 N. Petrelli,3 Y. z. Pan,4 H. Nabi,
`B. Barron, A. Serafini, B. Line, L. Hammershaimb,2 and D.
`M. Goldenberg2
`lLahey Clinic, Burlington, Massachu-
`setts 01805; 2the Immunomedics Clinical Study Group,
`Morris Plains, New Jersey 07950; 3Roswell Park Cancer
`Institute, Buflalo, New York 14263; and 4University of
`Texas MD. Anderson Cancer Center, Houston, Texas
`77030;
`
`The ability of CEA-ScanTM to detect CEA-expressing
`tumors such as colorectal, breast, and lung cancer has been
`investigated in clinical trials over the past few years. The
`results of two multicenter trials (2) are discussed in this
`
`paper, one which evaluates the role of CEA-Scan in plan-
`ning for resection of recurrent colorectal cancer (CRC);
`and the other, the safety and efficacy of CEA-Scan in the
`preoperative evaluation of breast and axillary nodes in
`breast cancer (BC). CEA-Scan was provided as an instant,
`ready-to-label kit. Patients with colorectal cancer and pri-
`mary operable breast cancer were injected with 1
`mg99mTc-labelcd Fab’ fragment of the murine anti-CEA
`IMMU-4 monoclonal antibody (CEA-Scan, Immunomed-
`ics, lnc.. Mom's Plains, NJ) labeled with 20—30 mCi99"’Tc.
`
`Planar imaging was performed at 4—8 and 18—24 h post-
`injection. SPECT was performed at 4—8 h postinjection.
`Serum for HAMA analysis was obtained at baseline, 4—6
`weeks, and 3—4 months postinjection.
`Colorectal cancer: Curative resection of recurrent or
`
`metastatic CRC results in a 5-year survival rate of 25—30%
`
`61
`
`(4). While radioimmunodetection (RAID) has been re-
`ported to accurately image CRC, its role in the preop-
`erative patient evaluation for resection has not been estab-
`lished. A 20—center prospective clinical
`trial was
`undertaken in patients with CRC to determine the imaging
`efficacy, clinical utility, and safety of RAID using CEA-
`Scan. Ten adverse events were reported, only one of which
`was potentially serious (seizure in a patient with a long-
`standing history of hypertension, 1 day post-antibody in-
`fusion). The other adverse events—chills, eosinophilia,
`bursitis, nausea, low-grade fever, headache, rash, subder-
`ma] roughness, and “upset" stomach—were transient,
`mild, and judged remotely or not related to the antibody
`infusion by the investigator.
`The ability to predict tumor resectability was studied
`in 208 of 210 patients with known or suspected CRC,
`who had the results of CT or CEA-Scan imaging corre-
`lated with surgery. Curative resectability (R) was based
`on the presence of S4 liver lesions and <2 regions of
`involvement. Nonresectability (NR) was based on >4
`liver lesions or 22 regions of involvement (1—4). No
`evidence of disease (NED) was based on the absence of
`
`In 208
`disease by either CT, CEA-Scan, or surgery.
`assessable patients, overall accuracy for predicting R,
`NR, or NED was higher for CEA-Scan, 124/208 (60%),
`than CT scan, 97/208 (47%), p = 0.0014, McNemar’s
`test. In 50 patients in whom CI‘ and CEA-Scan were
`concordant for R,
`the prediction of R was accurate in
`31 patients (61%); and in 16 patients in whom both tests
`were concordant for NR, 15 patients (94%) were con-
`firmed NR at surgery, thus obviating the need for addi-
`tional diagnostic modalities. In 71 patients in whom the
`two tests were discordant, CEA-Scan was correct more
`
`often than CT; CEA-Scan: 49/71 (69%) versus CT:
`22/71 (22%). Since the liver is a common site for me-
`
`tastases in CRC, the subgroup of patients who might
`benefit from detection of resectablc liver lesions was
`
`also examined. CEA-Scan was more accurate in predict-
`ing R, NR, NED overall than CT, 47/100 (47%) versus
`33/100 (33%), p = 0.016, McNemar’s test.
`In conclusion, (a) CEA-Scan more accurately predicted
`resectability, nonresectability, and disease-free status than
`CT in patients with known or occult colorectal cancer. (b)
`Using CEA-Scan in conjunction with CT results in statis-
`tically significant superior predictions of surgical outcome
`compared to CT alone. (c) Based on this analysis, certain
`decision rules for the management of patients with poten-
`tially resectablc colorectal cancer can be proposed: When
`both CT and CEA-Scan are positive for a lesion or are
`confirmatory in establishing nonresectability, the manag-
`ing physician can proceed with confidence in assuming
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