CancerInvestigation
`
`
`
`EDITORIAL BOARD
`
`Editor-in-Chief:
`
`7
`Deputy Editor:
`
`Senior Editors:
`
`YASHAR HIRSHAUT,M.D.
`Yeshiva University
`2495 Amsterdam Avenue
`New York, New York 10033
`
`:
`Joseph R. Bertino, M.D.
`MemorialSloan-Kettering CancerCenter
`
`Ronald B. Herberman, M.D.
`Pittsburgh Cancer Center
`Morton K. Schwartz, Ph.D.
`MemorialSloan-Kettering Cancer Center
`Alan S. Rabson, M.D.
`National CancerInstitute
`
`e
`
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`
`Managing Editor:
`
`Ora J. Baer
`
`Promotions Assistant:
`
`Jaclyn Silverman
`
`Departments:
`OriginalArticles:Clifford A. Hudis, Melvin Spigelman, and
`David C. Smith
`Clinical Science Reviews; Malcolm S. Mitchell
`Clinical Trials: Douglass C. Tormey 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 Reviews in Surgery: Frederick L. Moffat
`Miniseries/SpecialArticles: Alan S. Rabson
`New Drugs: Hira Gurtoo
`Op-Ed: Ezra Greenspan
`Psychosocial Issues:Jimmie C. Holland
`Bioethics: Joseph J. Fins
`Assistant Editor for Bioethics: Matthew Bacchetta
`Biostatistics: Larry R. Muenz
`
`Public Issues. B. J. Kennedy
`Report trom Congress: Roger C. Herdman
`Pain Management: MarcL. Citron
`Hematology: Morton Coleman and Hans W.Grunwald
`Neuro-Oncology: Stuart A. Grossman
`Pediatric Oncology: MichaelB. Harris
`Art andArchitecture in Medicine: Charles Gianfagna
`Hematopoietic Stem Cell Transplantation: Subhash C.
`Gulati
`Funding: William J. McLoughlin
`Epidemiology: Henry T. Lynch
`Genetics: John J. Mulvihill
`Radiation Therapy: Florence Chu andEli Glatstein
`Veterinary Oncology: William D. Hardy, Jr.
`Infectious Complications of Cancer: Ron Feld
`Environmental Carcinogenesis:F. William Sunderman,Jr.
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`Abstracts
`
`59
`
`Table I
`
`
`Gr. 4
`
`thrombocytopenia/
`Gr. 4
`
`Level No.of pts/cycle—_neutropenia/cycleTaxol dose, mg/m? cycle Otherside effects (grade)
`
`
`
`
`
`
`
`I
`II
`
`120
`135
`
`3/14
`3/17
`
`1/14
`WT
`
`0
`4/17
`
`1 pneumonia(2)
`1 C. diff. (2);
`1
`fever
`1 leucopenic fever
`2/15
`5/15
`3/15
`150
`Ill
`
`
`
`
`
`IV 1 N/V (4) 175 6/18 5/18 1/18
`
`leucopenic
`
`from analysis due to lack of information. A total of 64
`cycles have been givento 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
`samelevel of Taxol. The side effect profiles of the 15
`patients are shownin 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
`other4 patients did not respond. In summary, ICE-Tis 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, BorosL, Asbury R: PhaseII study ofifosfam-
`ide, carboplatin, and etoposide in patients with advanced non-small
`cell lung cancer. Am J Clin Oncol 17:509-513, 1994,
`Loehrer PJ, Lauer R, Roth BJ: Salvage therapy in recurrent germ cell
`cancer:ifosfamide andcisplatin pluseither vinblastine or etoposide.
`Ann Intern Med 87:540—547, 1988.
`Rowinsky EK, Cazenave LA, DonehowerRC: Taxol: a novel investiga-
`tional antimicrotubule agent. J Nat! Cancer Inst 82:1247—1259, 1990.
`Smith IE, Perren TJ, Ashley SA, et al: Carboplatin, etoposide, and
`ifosfamide as intensive chemotherapy for small-cell lung cancer. J
`Clin Oncol 8:899-905, 1990.
`Van Zandwijk N, ten Bokkel Huinink WW, WandersJ, et al: Dose
`finding studies with carboplatin, ifosfamide, etoposide and mesna
`in non-small cell
`lung cancer. Semin Oncol 17(suppl 2):16-19,
`1990.
`
`53. CHEMOIMMUNOTHERAPY OF
`LOW-GRADE LYMPHOMAWITH THE
`ANTI-CD20 ANTIBODY IDEC-C2B8 IN
`COMBINATION WITH CHOP
`CHEMOTHERAPY
`
`M.S. Czuczman,A.J. Grillo-Lopez, C. Jonas, L. Gordon,
`M. Saleh, C. A. White, C. Varns, and B. K. Dallaire
`Roswell Park CancerInstitute, Buffalo, New York; IDEC
`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 occurin the U.S. for 1995,
`with approximately 42% of these cases being of a low-
`grade orfollicular 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 withtotal-
`bodyirradiationin the setting of purged autologous bone
`marrow transplantation (ABMT)produce recurrence-free
`survival in only 40-75% ofpatients (Gribbenet al; John-
`son et al) with a median follow-up of approximately 4
`years. Molecular research has identified the bcl-2 pro-
`tooncogeneas being associated with the t(14;18) chromo-
`somaltranslocation of follicular, low-grade lymphomas.
`This t(14;18) leads to movementof the bcl-2 gene from
`18q21 to 14q32 (immunoglobulin heavy chain locus) and
`results in increased transcription and accumulationof high
`levels of bcl-2 protein. Recent research has demonstrated
`that bel-2 overexpression may lead to multidrug resis-
`tance, independentof the P170 glycoprotein, by causing
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`

`60
`
`Abstracts
`
`BIBLIOGRAPHY
`
`resistance to apoptosis by a variety of chemotherapeutic
`CNSdisease,the secondrefused further therapy following
`agents including certain alkylating agents, doxorubicin,
`5 cycles of CHOP and 4 doses of IDEC-C2B8 due to
`glucocorticoids, and vincristine (Hsu et al). For patients
`steroid-induced severe depression (achievedapartial re-
`with low-grade lymphoma,bcl-2 status posttherapy may
`mission—PR), and the third was taken off study after 2
`not only have prognostic value, but may also serve as a
`cycles of CHOP and 2 doses of IDEC-C2B8 following
`marker to monitor minimal residual disease. Extensive
`surgery for cervical osteomyelitis (achieved a PR). Char-
`research by Gribbenet al has demonstrated thatno patient
`acteristics of these 14 patients include: 6 males/8 females,
`cleared bcl-2 positivity in marrow following induction or
`80% stage III/IV at diagnosis, median age 59 (range of
`salvage chemotherapy (including 6 cycles of standard-
`35-75), 12 previously untreated, IWF A = 4, IWF B = 4,
`dose CHOP), and that residual bcl-2 positive cells in
`IWF C =5,other low-grade = 1. Adverse events included
`reinfused purged autologous bone marrow appear to be
`nausea, neutropenia,pain, fatigue, vomiting, fever, alope-
`associated witha 7.5-fold risk of relapse in patients under-
`cia, constipation, and peripheral neuropathy. Sixty-one
`going ABMTfor low-grade lymphoma. Unfortunately a
`events were attributed to CHOP (80% grade 3 and 20%
`large numberof patients with low-grade lymphoma are
`grade 2) and 18 to IDEC-C2B8 (25% grade 2 and 75%
`elderly or have bone marrow whichis unable to be purged
`grade 1). The latter consisted primarily of flulike symp-
`to polymerase chain reaction (PCR)negativity and would
`toms,usually associated with thefirst of six infusions. No
`therefore not be optimal candidates for ABMT. Because
`human anti-mouse or anti-chimeric antibody responses
`of this, new therapeutic strategies with improved antitu-
`(HAMA/ HACA)nor unexpected toxicities have been
`moractivity and acceptable toxicity need to be developed
`observed for the combination of CHOP and antibody.
`with the goal being achievementof a molecular complete
`Overall response rate for the 11 patients completingall
`remission with no detectable bcl-2 rearrangementin mar-
`scheduled therapy is 100% (8 complete remission—CR
`row orblood by sensitive PCR methods. Preliminary data
`and 3 PR). These responses are ongoing with a median
`from a novel chemoimmnotherapeutic approachoftreat-
`observation time of 9 months. Four patients found to be
`ing low-grade lymphomawith standard-dose CHOP and
`positive for bcl-2 by PCRprior to therapy (3 in peripheral
`IDEC-C2B8(a chimeric anti-CD20 antibody) is being
`blood and bone marrow,
`1
`in peripheral blood alone)
`presented at this time. IDEC—C2B8 haspreviously been
`converted to bcl-2 negativity by completion of therapy.
`shownto have antitumoractivity with mild to moderate
`The three patients achieving PCR negativity in marrow
`toxicity as a single agent in patients with relapsed low-
`have undergone unpurged autologous bone marrow har-
`grade and follicular lymphoma. In a recent IDEC-C2B8
`vesting at time of count recovery with the pooled bone
`multidose (375mg/ m* q week x 4) phase II trial, a 50%
`marrow specimens confirming bcl-2 negativity. Current
`responserate (17 of 34 relapsed patients) lasting 4.4 to
`efficacy and toxicity data appear encouraging and the
`greater than 15.5 months was achieved (Maloneyetal.).
`finding of molecular remissions by PCR suggeststhat the
`Mechanismsof action of IDEC-C2B8 include comple-
`antitumor activity of CHOP and IDEC-C2B8 is superior
`ment-mediated cytotoxicity, antibody-dependentcellular
`to CHOPtherapyalone. This study is onging and accrual
`cytotoxicity, induction of apoptosis (in vitro data), and
`of 30 evaluable patients is planned.
`synergistic antitumoractivity with certain chemotherapeu-
`tic agents (including doxorubicin). The rationale for com-
`bination of IDEC-C2B8 with CHOPincludes: non-cross-
`resistant mechanisms of action,
`individual efficacy,
`nonoverlapping toxicities, and known synergy with
`doxorubicin. In the current trial, IDEC-C2B8is given at
`a dose of 375 mg/m? on weeks1 (2infusions), 7, 13, 20,
`and 21 fora total of 6 doses. CHOP chemotherapy (cyclo-
`phosphamide 750 mg/m?i.v. x 1, doxorubicin 50 mg/m?
`iv. x 1, vincristine 1.4 mg/m?i.v. x 1 (up to maximum of
`2 mg), prednisone 100 mg/m?/day p.o. for 5 days) is given
`on weeks 2, 5, 8, 11, 14, and 17 for a total of 6 cycles.
`Currently 27 patients have entered on this study and data
`are available for 14 patients, 11 of whom have completed
`all scheduled therapy. Of the 3 remaining patients, one was
`registered but never treated secondary to rapid onset of
`
`CzuczmanM,Grillo-Lopez AJ, Saleh M,et al: Phase II clinicaltrial of
`IDEC-C2B8/CHOPcombination therapy in low-grade lymphoma:
`preliminary results, Proc ASCO 14:401 (#1261), 1995.
`DemidemA, Hanna N,Hariharan H, et al: Chimeric anti-CD20 antibody
`(IDEC-C2B8) is apoptotic and sensitizes drug resistant human B-cell
`lymphomasand AIDSrelated lymphomastothe cytotoxic effect of
`CDDP, VP-16, and toxins. FASEB 9: A206, 1995.
`Gribben JG, Freedman AS, Neuberg D,et al: Immunologic purging of
`marrow assessed by per before autologous bone marrow transplan-
`tation for B-cell lymphoma. N Engl J Med 325:1525—1533,1991.
`Gribben JG, Freedman AS, Woo SD,et al: All advanced stage non-
`Hodgkin’s lymphomaswith a polymerase chainreaction amplifiable
`breakpoint of bel-2 have residual cells containing the bel-2 rear-
`rangementat evaluation and after treatment. Blood 12:3275-3280,
`1991.
`
`Gribben JG, Neuberg D, Freedman AS, et al: Detection by polymerase
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`
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`Abstracts
`
`chain reaction of residual cells with the bcl-2 translocation is as-
`sociated with increased risk ofrelapse after autologous bone marrow
`transplantation for B-cell lymphoma. Blood 81: 3449-3457, 1993.
`Hsu B, Marin M,BrisbayS, et al: Expression ofbcl-2 gene confers mullti-
`drug resistance to chemotherapy-induced cell death. Cancer Bull
`46:125-129, 1994.
`Johnson PWM, Price CGA,Smith T,et al: Detection ofcells bearing
`the t(14;18) translocation following myeloablative treatment and
`autologous bone marrowtransplantation for follicular lymphoma.
`J Clin Oncol 12:798-805, 1994.
`Maloney DG,Bodkin D,Grillo-Lopez AJ,et al: IDEC-C2B8:final report
`on a phase II trial in relapsed non-Hodgkin’s lymphoma. Blood
`84:169a (#661), 1994.
`MaloneyDG,Liles TM, Gzerwinski DK,et al: Phase I clinicaltrial using
`escalating single-dose infusion of chimeric anti-CD20 monoclonal
`antibody (IDEC-—C2B8) in patients with recurrent B-cell lymphoma.
`Blood 84:2457-2466, 1994.
`
`
`
`54. USE OF RADIOIMMUNODETECTION
`WITH CEA-SCAN IN THE PREOPERATIVE
`EVALUATIONOFPATIENTS WITH
`COLORECTAL AND BREAST CANCER
`
`K. Hughes,! C. Pinsky,” N.Petrelli, Y. Z. Patt,’ H. Nabi,
`B. Barron,A.Serafini, B. Line, L. Hammershaimb,” andD.
`M. Goldenberg”
`‘Lahey Clinic, Burlington, Massachu-
`setts 01805; 2 the Immunomedics Clinical Study Group,
`Morris Plains, New Jersey 07950; Roswell Park Cancer
`Institute, Buffalo, New York 14263; and 4University of
`Texas M.D. Anderson Cancer Center, Houston, Texas
`77030,
`
`The ability of CEA-Scan™ to detect CEA-expressing
`tumorssuchas colorectal, breast, and lung cancer has been
`investigatedin clinicaltrials over the past few years. The
`results of two multicentertrials (2) are discussed in this
`paper, one whichevaluates the role of CEA-Scanin plan-
`ning for resection of recurrent colorectal cancer (CRC);
`andthe other, the safety and efficacy of CEA-Scanin the
`preoperative evaluation of breast and axillary nodes in
`breast cancer (BC). CEA-Scan wasprovidedas an instant,
`ready-to-labelkit. Patients with colorectal cancer and pri-
`mary operable breast cancer were injected with 1
`mg”Tc-labeled Fab’ fragmentof the murine anti-CEA
`IMMU-4 monoclonalantibody (CEA-Scan, Immunomed-
`ics, Inc., Morris Plains, NJ) labeled with 20-30 mCi?"Tc.
`Planar imaging was performedat 4-8 and 18-24 h post-
`injection. SPECT wasperformed at 4-8 h postinjection.
`Serum for HAMAanalysis was obtained at baseline, 4-6
`weeks, and 3-4 monthspostinjection.
`Colorectal cancer: Curative resection of recurrent or
`metastatic CRCresults 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
`undertakenin patients with CRC to determinethe imaging
`efficacy, clinical utility, and safety of RAID using CEA-
`Scan. Ten adverseevents were reported, only one of which
`waspotentially 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-
`mal roughness, and “upset” stomach—were transient,
`mild, and judged remotely ornot related to the antibody
`infusionbythe investigator.
`The ability to predict tumorresectability was studied
`in 208 of 210 patients with known or suspected CRC,
`whohadthe results of CT or CEA-Scan imaging corre-
`lated with surgery. Curative resectability (R) was based
`on the presence of <4 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
`disease by either CT, CEA-Scan, or surgery.
`In 208
`assessable patients, overall accuracy for predicting R,
`NR, or NED washigher for CEA-Scan, 124/208 (60%),
`than CT scan, 97/208 (47%), p = 0.0014, McNemar’s
`test. In 50 patients in whom CT 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 NRat 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 commonsite for me-
`tastases in CRC, the subgroup of patients who might
`benefit from detection of resectable liver lesions was
`also examined. CEA-Scan was more accuratein 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 knownoroccult colorectal cancer.(b)
`Using CEA-Scanin conjunction with CTresults in statis-
`tically significant superiorpredictions of surgical outcome
`comparedto CT alone. (c) Based onthis analysis, certain
`decision rules for the managementofpatients with poten-
`tially resectable 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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