[CANCER RESEARCH 50, 3473-3486, June 15, 1990]

Review Antineoplastic Activity of the Combination of Interferon and Cytotoxic Agents against Experimental and Human Malignancies: A Review1

Scott Wadler2 and Edward L. Schwartz

Department of Oncology; Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467

Abstract drugs (4). The incorporation of biological agents, often termed biological response modifiers, into combination regimens with The combination of Interferon (IFN) and conventional chemotherapeu- standard chemotherapeutic agents offers an important chal tic agents offers a promising therapeutic approach for the treatment of cancer. However, there is as yet no consensus on optimal strategies for lenge to the medical oncologist since the assumptions for their combining this family of compounds with other cancer therapies. While use likely differ from those for chemotherapeutic agents. These in vitro studies have demonstrated both direct cytotoxic and cytokinetic agents, which include the interferons, the interleukins, tumor effects for IFN, a more interesting role derives from its ability to necrosis factor and other cytokines, and colony-stimulating and synergistically potentiate the activity of a wide variety of cytotoxic agents other growth factors, have diverse physiological actions and against multiple human and rodent tumors, both in vitro and in animal interactions. Factors impeding the development of rational models. The interaction between IFN and cytotoxic agents in vitro is strategies for incorporation of these compounds into clinical complex and depends not only on the choice of cytotoxic agent but also regimens include: (a) their poorly understood mechanism of on the concentrations, ratios, duration, and sequence of exposure to the action (5); (¿>)theirrelatively weak or absent cytotoxic activities two drugs. Preliminary data suggest that some combinations are not (6); (c) a novel spectrum of toxicities (7); (d) a wide range of merely additive but rather that IFN may biochemically modulate the cellular uptake or metabolism of the cytotoxic agent resulting in syner- biologically effective doses (8); and (e) the absence of a clear gistic antineoplastic activity. In vivo interactions between IFN and cyto correlation between maximum tolerated dose and optimal ther toxic agents involve an additional layer of complexity because of the apeutic effect (9). Thus, it is far from clear what the optimal potential effects of the biological agent on the host immune system and strategy for combining cytotoxic agents and biologies might be. drug-metabolizing enzymes. Furthermore, IFN may have a protective The IFNs3 are a family of naturally occurring glycoproteins effect on normal host tissues which theoretically could allow for the which share antiviral, immunomodulatory, and antiproliferative delivery of higher doses of cytotoxic agents. The results of early clinical effects. Discovered in 1957 by Isaacs and Lindenmann (10), trials using combinations of IFN with chemotherapeutic agents have their antitumor activity has been the most thoroughly studied generally been disappointing. This may be due to the inability of preclin- of the biological response modifiers. Early clinical trials estab ical models to accurately predict the clinical situation or alternatively lished activity for IFNs as single agents against two relatively from a failure to incorporate information on dose, scheduling, and se uncommon malignancies, hairy cell leukemia and acquired im quence of drug administration into clinical trials. Preliminary clinical munodeficiency syndrome-related Kaposi's sarcoma (11, 12). studies with IFN-a and the fluorinated pyrimidine, 5-fluorouracil, in patients with advanced colorectal carcinoma suggest that IFN may en Activity has also been reported against nodular lymphomas, hance the effects of the antimetabolite. Confirmatory trials are in prog renal cell carcinoma, melanoma, and multiple myeloma; how ress. Further trials designed to exploit the preclinical experience with ever, objective response rates remain less than 30% and dura combinations of IFN and cytotoxic agents are warranted. tions of response are generally short (13-16). While the IFNs have been studied for over 30 years, the Introduction mechanism of their antitumor activity remains poorly under stood. The 3 classes of IFN can be distinguished by their acid Combination chemotherapy has a recognized role in the cure stability, their cell surface receptors, their primary sequence, of such disseminated neoplasms as testicular cancer, lym- and their chromosomal location and organization. IFNs have a phoma, Hodgkin's disease, and acute leukemia. A standard number of biochemical actions, many of which can be attributed strategy for the design of regimens containing multiple cyto to gene activation and the stimulation of the synthesis of several toxic agents is based on the following premises: the drugs used proteins of known and unknown functions. One of the predom have direct actions on the tumor cells, with some selectivity inant cellular effects noted in vitro is the inhibition of cell cycle compared to normal cells (1); efficacy is likely directly corre progression, with partial block in either the transition from G0- lated with the intensity and duration of drug exposure, and Gi to S, progression through S, or even generalized inhibition therefore drugs should be used at or near their maximal toler of cell cycle traverse (17). Because of the latter findings and the ated dose (2); optimal combinations utilize agents with different relatively weak cytotoxic effects of the IFNs, it has been pos mechanisms of action (3); and drug combinations should be tulated that they may be best used in combination with other selected to minimize any overlapping toxicities of the individual cytotoxic agents (18). This review will summarize and evaluate the clinical and preclinical studies that have used IFNs in Received 11/7/79; revised 2/2/90. The costs of publication of this article were defrayed in part by the payment combination with cytotoxic drugs. of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Supported in part by American Cancer Society Research Grant CH-479, by 3The abbreviations used are: IFN, interferon; BCNU, carmustine [1.3-bis(2- Cancer Center Core Grant P30CA13330-16 awarded by the National Cancer chloroethyl)-l-nitrosourea]; 5-FUra, 5-fluorouracil; ADA, adenosine deaminase; Institute, and by a grant from the Mathers Foundation. DCF, 2'-deoxycoformycin; rIFN-a, recombinant human a-interferon; DFMO, 2 Recipient of a Career Development Award from the American Cancer Soci difluoromethylornithine; VP16, etoposide; MP, melphalan-prednisone; MU, IO6 ety. To whom requests for reprints should be addressed, at Department of units; ACNU, 1-(4-amino-2-methylpyrimidine-5-y 1)methyl-3-(2-chloroethyl)-3- Oncology. Montefiore Medical Center, 111 East 210th Street. Bronx. NY 10467. (2-chloroethyl)-3-nitrosourea; MGBG, mitoguazone. 3473 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1990 American Association for Cancer Research. INTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY

Table 1 Interactions oflFN and chemotherapeulic agents: in vitro clonogenic and proliferation assays, tumor stem cell assays, and animal studies The extent of antineoplastic activity of combined IFN-anticancer drug treatments is indicated. The nature of the interaction as shown may not have been observed at all dose levels or schedules tested. "Inactive" means that neither component nor the combination had activity; "none" means that one component had no activity and had no effect when used in combination with an active agent: "additive" indicates that the antitumor effect of the combination was equal to that predicted from the use of individual active agents. Synergistic interactions were assessed by a variety of methods, including a combined effect greater than that predicted from the individual agents, and by isobologram analysis. Except when indicated as recombinant (Recomb.), IFN was purified or semipurified. Human IFN-aUu was purified from normal human leukocytes, and human IFN-«Lywas purified from Namalwa lymphoblastoid cells. Human tumor stem cell assays (HTSCA) measured clonogenicity of primary human tumor cells in vitro', the number of responses and total number of tumors tested is indicated. In vivo assays measured tumor growth, animal survival or extent of métastasesafter tumor inoculation into syngeneic animals, or immunocompromised or nude mice. NSCLC. non-small cell lung carcinoma; ALL. acute lymphocytic leukemia. InterferonCisplatin lineBG-1 or cell +Recomb. «2bHuman carcinomaRPMIhuman ovarian a^,,Recomb. myelomaHuman8226 human «2bRecomb. tumorsHuman (2/2)Additive a2bRecomb. tumorsHuman (4/5)SynergisticSynergisticNoneAdditive/synergisticSynergisticSynergistic/additiveAdditiveSynergisticAdditiveAdditiveAdditiveAdditiveSubadditiveAdditive/synergistic a2.Murine vivoIn xenograftsP388mesothelioma a/ßRecomb. vivoIn leukemiaMBT-2murine aHuman murine vivoIn carcinomaHumanmurine bladder aL>Recomb. vivoProliferationCloningCloningCloningCloningCloningCloningCloningCloningHTSCAHTSCAInxenograftsACHNNSCLC fis«Human carcinomaHeLahuman renal cell ßRecomb. cervicalKO-RCC-1human yRecomb. carcinomaRCC-nu-1human renal 7Recomb. carcinomaBG-1human renal 7Recomb. carcinomaSK-MEL-28human ovarian yRecomb. melanomaME human 7Recomb. carcinomaMCF-7180 human cervical 7Recomb. carcinomaHEC1Ahuman breast yRecomb. carcinomaHumanhuman endometrial 7Cyclophosphamide carcinomaHumanrenal cell (7/10)SynergisticSynergisticSynergisticNoneSynergisticSynergisticSynergisticSynergisticNoneNoneSynergisticSynergisticAdditiveAdditiveSynergistic*SynertisticAdditiveSubadditiveSynergistic

+Recomb. «2bMurine tumorsAKRovarian cellMurineC-243 vivoIn lymphomaCmurine L-cellMurine vivoIn neuroblastoma1121(11300 murine L-cellMurine vivoIn leukemiaP388murine a/fiHuman vivoIn leukemiaHumanmurine uL>Human vivo"In xenograftHumanbreast carcinoma «L,Human vivoIn xenograftTBDNSCLC «AHuman vivoIn lymphosarcomaHT1932 hamster OL.URatfJDoxorubicin vivo"In lymphomaLSI17 human vivoProliferationCloningCloningCloningCloningCloningCloningCloningHTSCAHTSCAProliferationIn75 ratliposarcomaCA46 -+-Recomb. lymphomaBG-1human Burkitt's o2bRecomb. a2bHuman carcinomaMCF-7human ovary aAHuman carcinomaRPMIhuman breast aARecomb. myelomaBG-18226 human a2bRecomb. carcinomaMCF-7human ovarian a2bRecomb. carcinomaCaSkihuman breast «2bRecomb. carcinomaSK-MEL-28human cervical «2bRecomb. melanomaMultiplehuman a2bHuman tumorsMultiplehuman 3)Additive/synergistic(9/1 ->•Human tumorsMOLT-4human (3/10)Synergistic'SynergisticAdditiveInactiveNoneNone oLyHuman lymphomaHumanhuman T-cell «LyMurine vivo"ProliferationIn xenograftMBT-2breast a/ßMurine tumorMBT-2murine bladder a/ßMouse vivoIn tumorLI murine bladder L-cellRecomb. vivoHTSCACloningProliferationProliferationInleukemiaMultiple2 10 murine ßs^.Human tumorsHeLahuman (0/25)Synergistic/additive'SynergisticAdditiveAdditiveAdditiveAdditiveAdditiveAdditiveSubadditiveAdditiveAdditiveSynergisticSynergisticSynergisticSynergistic .;Human carcinomaH.Ep2human cervical 70,74747434757575757575757777437743134135135135135135136, ßHuman carcinomaDaudihuman laryngeal .Human lymphomaHumanhuman .;Recomb. vivoaCloningCloningCloningCloningCloningCloningCloningCloningCloningCloningHTSCAInglioblastomasBG-1 7Recomb. carcinomaSK-MEL-28human ovarian 7Recomb. melanomaME human 7Recomb. carcinomaCaSki180 human cervical 7Recomb. carcinomaHEChuman cervical 7Recomb. endometrialMCF-71A human 7Recomb. carcinomaRPMIhuman breast 7Recomb. myelomaKO-RCC-18226 human 7Recomb. carcinomaRCC-nu-1human renal 7Recomb. carcinomaRPMIhuman renal 7Recomb. carcinomaHuman4788 human colon 7Recomb. carcinomasRPMIrenal cell (8/11)SynergisticSynergisticAdditiveAdditiveSynergisticSynergisticSynergisticNoneAdditiveRef.6261636231251303013132,70777775757575757763222423132293028332713363606063,6463,6463,6463,646263134296868237669, y5-Fluorouracil vivo"ProliferationProliferationProliferationProliferationProliferationProliferationProliferationProliferationTumorcarcinomaMOLT-44788 human colon +Human nL>Recomb. ALLDaudihuman «2.Recomb. lymphomaMOLT-3human B-cell «2mRecomb. lymphomaMOLT-4human T-cell o2.Recomb. lymphomaK562human T-cell a2.Recomb. leukemiaHT-29human a2-Recomb. carcinomaDF-48human colon aRecomb. carcinomaMKN-28pancreatic 137136, «AssayCloningCloningHTSCAHTSCAIn and 74 human gastric carcinomaInteractionSynergisticSynergisticSynergistic 137 3474

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Table 1—Continued InterferonMurine lineMurine or cell a/ßReeomb. adenocarcinomaHL-60colon »Recomb. leukemiaHT-29human «Reeomb. adenocarcinomaMultipleand SW-480 colon a2llRecomb. tumorsMBT-2human (2/5)NoneAdditiveAdditiveAdditiveSynergisticAdditive/synergisticNoneSynergisticSynergisticAdditiveNoneNoneSynergisticNoneSynergisticSynergisticSubadditiveSynergisticSynergisticAntagonisticAdditiveAdditiveNoneNoneAdditiveSynergisticNoneSynergistic «Recomb.murine vivoIn carcinomaCOLOmouse bladder nRecomb. vivo"ProliferationProliferationCloningCloningCloningCloningProliferationProliferationCloningHTSCAInadenocarcinomaDF-48205 human colon rfRecomb. carcinomaMKN-28pancreatic 137136, ßRecomb. carcinomaHT-29and 74 human gastric 13710432.7072. iiHuman adenocarcinomaHeLaand SW-480 colon fiHuman carcinomaWI-38human cervical ßHuman fibroblastsWI-38-CTnormal human 13972, tiHuman fibroblastsKMM-1transformed 13971,72, à Human myelomaRajihuman 139,71,72, lymphomaMCF-7human Burkitt's ßHuman 139,71,72, fiRecomb. carcinomaMultiplehuman breast 139,76139141142136, ßs,.Human tumorsHeLahuman ßRat/3Recomb. vivo"In carcinomaCC351human cervical vivoCytolysisProliferationProliferationProliferationCloningCloningCloningProliferationProliferationInratadenocarcinomaHT-29 7Recomb. carcinomaDF-48human colon yRecomb. carcinomaMKN-28pancreatic 137136. yRecomb. carcinomaMurineand 74 human gastric 13746104777739393939642863767064136, 7Recomb. adenocarcinomaHT-29colon yRecomb. carcinomaKO-RCC-1and SW-480 colon 7Recomb. carcinomaRCC-nu-1human renal yHuman carcinomaKMhuman renal yMurine recomb. carcinomaKM12 human colon yHuman recomb. carcinomaKM12 human colon yMurine recomb. vivo"In carcinomaKM12 human colon yMelphalanrecomb. vivo"CloningIn carcinomaRPM112 human colon

+Human «2bHuman myelomaTBD8226 human «ARecomb. vivoHTSCAHTSCACloningCloningProliferationInlymphosarcomaHuman932 hamster «2bRecomb. tumorsMultiplelung (1/2)None ii„.Human tumorsHeLahuman (0/26)AdditiveSynergisticNoneAdditiveAdditiveNoneAdditiveSynergisticAntagonisticAdditiveAdditiveAdditiveNoneSynergisticSynergisticAdditiveAdditiveSynergisticSynergisticSynergisticSynergisticSynergisticSynergisticSynergisticSynergisticNone tiMethotrexate carcinomaBG-Icervical

+Recomb. i»2bRecomb. carcinomaDF-48human ovarian aMouse carcinomaLIpancreatic 13723136, L-cellRecomb. vivoProliferationProliferationProliferationInleukemiaDF-48210 murine 7Recomb.ßor carcinomaMKN-28pancreatic 137136.

C+Recomb. «¡.Murine vivo"ProliferationProliferationProliferationCloningCytolysisCloningProliferationProliferationProliferationProliferationProliferationCloningCloningCloningCloningInxenograftMBT-2mesothelioma a/ßHuman tumorH.Ep2mouse bladder .Human carcinomaDaudihuman laryngeal .;Human lymphomaHeLahuman fiRecomb. carcinomaHT-29human cervical 7Recomb. carcinomaKO-RCChuman colon 7Nitrogen renalHT-29and RCC-nu-1 human

+Recomb.mustard «2.Recomb. carcinomaDaudihuman colon a2-Recomb. lymphomaMOLT-3human B-cell o2«Recomb. lymphomaMOLT-4human T-cell «2.Recomb. lymphomaKS62human T-cell n2.Vinblastine leukemiaRPMIhuman

+Human nAHuman myelomaMCF-78226 human «AHuman carcinomaWiDrhuman breast nARecomb. carcinomaBG-1human colon «2bMurine carcinomaP388human ovarian a/0Recomb. vivoProliferationHTSCACloningCloningCloningCloningCloningCloningCloningHTSCAProliferationCloningProliferationProliferationProliferationTumorleukemiaACHNmurine ß„.Recomb. renalMultiplehuman 14376777575757575757713470, ß„.Recomb. tumorsKO-RCChuman (0/26)SubadditiveAdditiveSubadditiveSubadditiveSubadditiveAdditiveSubadditiveAdditive/synergistic 7Recomb. renalBG-1and RCC-nu-1 human 7Recomb. carcinomaSK-MEL-28human ovarian 7Recomb. melanomaCaSkihuman 7Recomb. carcinomaME180human cervical 7Recomb. carcinomaMCF-7human cervical 7Recomb. carcinomaHEC1Ahuman breast 7Recomb. carcinomaHumanhuman endometrial 7Vincristine carcinomasMOLT-4renal cell (4/6AdditiveAdditive/synergisticAdditiveAdditiveSynergisticRef.464610463130138136,

+Human «LïHuman ALLHeLa human .;Human cervicalDaudihuman 74747474140140140 rfHuman lymphomaM14Burkitt's ..'Human melanomaH.Ep2human ;AssayProliferationProliferationCloningHTSCAIn human laryngeal tumorInteractionSynergisticSynergisticSynergisticSynergistic 3475

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Table rontinued InterferonActinomycin lineHeLa or cell +Human D ¡iRccomb. carcinomaRCC-nu-lcervical •>Recomb. carcinomaKO-RCC-Irenal cell •)ACNU carcinomaHeLarenal cell +HumanHuman carcinomaGL-2-JCKcervical ,1BCNU vivo"In gliomaA375 +Recomb. «C243 rivoIn melanomaLSTRAand HM7 cellBleomycin vivoCloningCloningCloningCloningInleukemiaKS62 +Human nL,Recomb. leukemiaBG-1human albMurine carcinomaLI210ovarian a/ßHumanM leukemiaHeLa carcinomaLIcervical (il-/í-D-Arabinofur-anosylcytosineHumanin nu a/ viroProliferationIn 210leukemiaMOLT-4

«LxMouse ALLLI human L-cellHuman riroProliferationCloningCloningIn2 10leukemiaACHN £?s«rHuman carcinomaHeLarenal cell .DFMO carcinomaJDFIcervical +Human Mercaptopurine tumors11:111human +Mouse L-cellHumanHuman vivoProliferationProliferationCloningCloningCloningProliferationProliferationProliferationTumorleukemiaH.Ep2 carcinomaDaudilaryngeal ßNeocarzinostatin lymphomaHeLa +Human ßPeplomycin carcinomaW1-38-CTcervical +Human AHuman fibroblastsHeLatransformed ..Prednisone carcinomaMOLT-4cervical +Human .Thioguanine-, ALL1 human +Recomb. a.nThiotepa 11 (.11leukemiaMBT-2 +Murine a/ßAssayCloningCloningCloningCloningIn bladder tumorInteractionNoneSynergisticSubadditiveSynergisticAdditiveSynergisticSynergisticSynergisticSynergisticSynergisticSynergisticSynergisticSynergisticNoneAntagonisticNoneSynergisticAdditiveSynergisticAdditiveAdditiveAdditiveAdditiveNoneNoneNoneSubadditiveSubadditiveSynergisticSynergisticSynergisticSynergisticSynergisticAntagonisticRef.707777703414321586458139581342313170111Ml1281281281451451457623777769139321346768 flAssayed in nude mice. * Similar results observed with 4'-deoxydoxorubicin, 4'-epidoxorubicin, and 4'-demethoxydoxorubicin. c Similar results observed with aclacinomycin A.

Studies in Animal Tumor Models in Combination with Antican- not potentiate the activity of 6-mercaptopurine, doxorubicin, cer Drugs 1-ß-D-arabinofuranosylcytosine, or cyclophosphamide against L1210 cells in vivo, despite the fact that these agents alone had Studies evaluating the antitumor activity of IFN in combi some activity (23). IFN did not potentiate the activity of cyclo nation with cytotoxic agents were begun shortly after it was phosphamide against a spontaneous liposarcoma in rats (27) recognized that IFN possessed antitumor activity in experimen and at high doses actually abrogated the antitumor efficacy of tal animal tumor systems (19, 20). The earliest studies against cyclophosphamide in hamsters bearing TBD 932 lymphosar- murine leukemias were largely empirical in design and were coma cells (28). based on the assumption that cytotoxic agents were most useful The studies cited above demonstrated the value of IFN in for debulking large tumor volume and that the resultant micro enhancing the activity of chemotherapeutic agents in vivo scopic residual disease would best be eradicated with IFN against rodent tumors, although those studies which used rela "immunotherapy" (9). The efficacy of this approach was judged tively crude preparations of IFN must be interpreted with by comparing survival of animals treated with the combination caution. More recently these observations have been extended of a single dose of cytotoxic agent and multiple doses of IFN to human tumor xenografts and human tumor cells implanted with that of animals treated with either agent alone (Table 1). in nude mice (Table 1). Many of these studies also used highly Initial studies reported activity of murine IFN when it was purified natural or recombinant IFN. Human IFN-«was found administered in combination with BCNU, cyclophosphamide, to increase the antitumor activity of cyclophosphamide, doxo or methotrexate to mice bearing spontaneous or implanted rubicin, cisplatin, and mitomycin C (29-31). Activity was ob leukemia and lymphomas (21-23). Murine IFN also increased served in human breast tumor (29), non-small cell lung cancer survival in mice with neuroblastoma cells after administration (30), and human mesothelioma xenografts (31). Human fibro- of cyclophosphamide (24) and in mice with P388 leukemia cells blast IFN-/3 enhanced the growth inhibition of 5-fluorouraciI after treatment with cisplatin (25) or vinblastine (26). Not all against implanted human cervical carcinoma (HeLa) cells (32). studies yielded positive results, however. For example, IFN did Other studies failed to show any significant potentiation by 3476 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1990 American Association for Cancer Research. INTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY

IFN-a of the activity of cyclophosphamide against a variety of activity of the chemotherapeutic agents against the human human xenografts (testicular, colonie, squamous cell, and renal xenografts (41). Conversely, murine IFN did not potentiate the cell carcinomas; melanoma; and non-Hodgkin's lymphoma) antitumor activity of the same drugs against the xenografts, (33), although in the latter trials IFN was administered 24 h despite the fact that it presumably produced multiple host- after the alkylating agent, suggesting that schedule and se dependent effects (42). It is likely that both direct antitumor quence may be of critical importance. Interestingly, IFN also effects and host-mediated actions occur in vivo, but the relative enhanced the activity of radiation against human glioma xeno contribution of each may vary depending upon the species of grafts and monolayer cultures (34, 35). IFN used. These studies indicated that IFN potentiates the activity of a Undoubtedly interactions of IFN and anticancer agents in number of clinically useful drugs against a variety of human vivo are complex and multifaceted. For example, daily injec tumors in many but not all possible combinations and tumor tions of IFN-7 did not affect the s.c. growth of human colon models. In most of the cases where potentiation was observed, carcinoma cells in nu/nu mice but did synergistically enhance IFN alone had only weak antitumor activity; however, IFN the antitumor activity of doxorubicin when the two were used seemed to be most effective in combination with drugs that simultaneously (43). However, when the cells were inoculated alone possessed substantial activity against the specific tumor i.V., IFN-7 had both activity alone and also enhanced the (31). The experiments described above cannot resolve the ques activity of doxorubicin against the formation of pulmonary tion of the mechanism of interaction between IFN and the métastasesinthis tumor model. Other studies suggest that IFN cytotoxic agents. It seems likely that the interactions observed may be particularly active against experimental métastasesafter were not solely the consequence of the combined effect of two i.v. inoculation of mice with melanoma or erythroleukemia cells cytoreductive agents, since the enhanced activity of the drug- (44, 45). In the latter study, although both the IFN and several IFN combination was observed even in instances where IFN cytotoxic agents were active against tumor inoculated i.p., only alone lacked activity, and IFN also failed to potentiate the the IFN was active against the i.v.-inoculated tumor, suggesting activity of other efficacious drugs. At least two broadly defined that the efficacy of IFN-drug combinations may reflect actions alternative modes of interaction can be envisioned: IFN might on different populations of tumor cells or on tumor cells at biochemically modulate the activity of anticancer drugs by, e.g., different anatomical sites. Of interest in this regard is the affecting critical target enzymes, repair mechanisms, or detox observation that IFN had a selective growth-suppressive effect ification pathways within the tumor cell; alternatively IFN on the hyperdiploid compartment of a murine colon adenocar- could have actions on the host animal that could affect the cinoma cell line (46). Further investigations into the effect of activity of the anticancer agent, either directly or indirectly. IFN on aneuploid cells and micrometastases in combination These may include actions on drug-metabolizing enzymes that with anticancer drugs would be very useful. activate or inactivate the drugs, protective effects on normal host tissues which enhance the usefulness of the cytotoxic agent, Host Protective Effects and effects on the immune system which produce synergistic An alternative indirect mechanism for the interaction of IFN antitumor actions when used in combination with other chem- and anticancer drugs was reported by Stolfi et al. (47). Partially otherapeutic drugs. purified or recombinant IFN-t* was found to protect mice from the toxic effects of 5-fluorouracil (47, 48). This protection was manifested as decreases in body weight loss, leukopenia, and Indirect Antitumor Effects in Vivo mortality. The schedule of administration of the two agents, 5- The earliest evidence for an indirect antitumor effect of IFN FUra followed by multiple injections of IFN, is similar to that was combined in vitro-in vivo studies with mouse LI210 cells. used in many of the in vivo studies described above. These IFN directly inhibited the proliferation of L1210 cells in vitro, investigators suggest that the mechanism for the protective and a variant cell line that was resistant to this effect was effect of the IFN was the suppression of proliferation of the isolated. When tested in vivo, IFN had activity against both the normal bone marrow cells of the host, thus rendering them less sensitive and resistant cell lines, suggesting that IFN was acting sensitive to the cytotoxic actions of the 5-FUra. Presumably in vivo by a host-mediated action (36, 37). Similar conclusions the protective effect of IFN would allow higher doses of cyto were reached using IFN-resistant B-cell lymphoma cells (38). toxic drugs to be used, thus increasing their antitumor activity Another approach to demonstrate indirect host-mediated anti- (48). tumor effects is based on the species specificity of some IFN Effects on Drug-metabolizing Enzymes actions. For example, human colon carcinoma cells were im planted in nude mice which were then treated with 5-FUra in One potential source of indirect interaction of interferons combination with either human or mouse IFN--y. Synergistic with cytotoxic agents is via the hepatic microsomal enzymes, antitumor activity was observed with the mouse IFN, which which mediate the activation or detoxification of a wide variety had no direct effect on the growth of the human tumor cells of chemotherapeutic agents. IFN-inducing agents, such as tila- but had immunological effects in the mouse, while the human rone, have inhibitory effects on hepatic cytochrome P-450 IFN had no effect on tumor growth in vivo, despite having a monooxygenase activity (49-51). In addition, partially purified direct antitumor effect in vitro (39). or recombinant IFN-a and IFN-7 preparations are capable of IFN has well documented immunomodulatory actions in significantly reducing the activity and/or concentrations of cluding augmentation of antibody-dependent cell-mediated cy- microsomal cytochrome P-450, cytochrome P-450 reducíase, totoxicity and human natural killer cell activity (40). However, cytochrome b5, and cytoplasmic glutathione 5-transferase (52- as indicated above, IFN retained activity when used in combi 54). The effects on the microsomal enzyme system appear nation with chemotherapeutic agents in immunocompromised complex. Sodium dodecyl sulfate-polyacrylamide gel electro- nude mice bearing human tumor xenografts. Furthermore, the phoresis analysis of murine hepatic microsomal enzymes re human IFN used in these studies had no effect on the natural vealed that treatment with murine IFN results in either an killer cells of the host mice yet potentiated the antitumor increase or a decrease in five different P-450 isozymes (53). 3477 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1990 American Association for Cancer Research. INTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY

The limited data available suggest that these effects do not sure (59-61) and others showing that brief exposures may be contribute to the antitumor activity of IFN. In a nu/nu mouse equally efficacious (62, 63) to continuous exposure. bearing human tumor expiants, human lymphoblastoid IFN, which had no effect on murine hepatic enzymes, augmented the In Vitro Growth Inhibition Studies activity of doxorubicin and cyclophosphamide, drugs signifi cantly metabolized by the cytochrome P-450 system. In con The ability of IFN to directly modulate the biochemical trast, murine IFN suppressed the cytochrome P-450 activity effects of cytotoxic agents independent of immunomediated or host-protective effects has been evaluated in a variety of in vitro but did not alter the antitumor activity of the two anticancer drugs (53). In other studies, recombinant IFN-a abrogated the systems. Combinations of recombinant IFN with anticancer efficacy of high dose cyclophosphamide, but not that of mel- drugs have been tested against human cell lines using clonogenic assays to assess the cytotoxic actions of IFN-drug combinations. phalan, in hamsters bearing the TBD 932 lymphosarcoma (28). Using the BG-1 ovarian carcinoma line, synergistic (greater This effect, however, was likely not due to the modulation of drug metabolism, since the IFN did not affect cytochrome P- than additive) cytotoxicity was observed for IFN-a combina tions with doxorubicin, cisplatin, vinblastine, methotrexate, 450 activity or alter the formation of alkylating metabolites bleomycin, and mitoxantrone, but not with 5-FUra (64, 65). after cyclophosphamide treatment. Evidence suggesting that IFN effects on hepatic microsomal Synergy in the RPMI 8226 myeloma cell line was seen in enzymes can be clinically important is supplied by the case of combination with cisplatin and vinblastine but not doxorubicin (61) and in the MCF-7 breast line with vinblastine but not a patient receiving both high dose human lymphoblastoid IFN doxorubicin or cisplatin (61, 65). Synergy between 5-FUra and and phénobarbital. Initiation of IFN therapy resulted in a IFN-a or IFN-a//3 was observed in a human salivary gland dramatic increase in serum phénobarbitallevels with resultant lethargy and stupor, which was reversed when the IFN was adenocarcinoma cell line, in the mouse colon adenocarcinoma 38 cell line, and in the HL-60 human promyelocytic leukemia discontinued (55). cell line (46, 66). Additive growth inhibition in the HL-60 cells was also reported for IFN-a and 6-thioguanine (67). Additional Schedule and Sequence Dependence of in Vivo Effects conclusions from the above studies include the findings that The optimal timing for administration of IFN in combination higher concentrations of interferon were more effective in pro with cytotoxic agents has been studied in preclinical systems. ducing additive or synergistic effects, and both 1-h exposures Three major questions need to be addressed from both a theo and continuous IFN treatments were effective. retical and practical point of view: (a) when to administer IFN Not all in vitro studies have yielded positive evidence for the in relation to the tumor inoculation; (b) when to administer potentiation of cytotoxic activity by IFN-a (56, 62, 65). Fur IFN in relation to the cytotoxic agent; and (c) the optimal thermore, a positive interaction in an in vitro assay was not length of exposure to IFN. The first and second questions always predictive of activity in vivo. An additive or synergistic address issues of tumor burden: whether biologies are more effect of mouse IFN-a/0 in vitro was observed in combination effective against small volume disease. The second question with doxorubicin (but not with mitomycin C or thiotepa) in the also addresses the issue of sequence: whether IFN should be mouse bladder tumor cell line MBT-2 (68). However, in vivo administered prior to, concurrently with, or subsequent to studies on MBT-2 tumors implanted intravesically showed no cytotoxics. The third question addresses the issue of brief antitumor activity for the doxorubicin-IFN combination. exposure versus continuous exposure to IFN. The analysis of Modulating activity has also been noted for IFN-/3. Human these questions requires a more complete understanding than fibroblast IFN-/3 was found to produce a synergistic antiprolif- is currently available regarding the mechanism of action of erative effect on HeLa cells when combined with bleomycin, IFN, the mechanism of interaction of IFN with cytotoxics, and neocarzinostatin, or 5-FUra but had only an additive effect on the degree to which IFN exerts direct antitumor versus host- these cells in combination with doxorubicin or mitomycin C mediated effects. Each question has important practical impli (69-72). Synergy in combination with 5-FUra was also observed cations for the design of clinical treatment regimens. in KMM-1 myeloma cells and Raji Burkitt's lymphoma cells, In early combination studies a sequential design with the but not with MCF-7 cells (72). Human IFN-/3 substantially cytotoxic agent followed by IFN was used, based on the hy enhanced the antiproliferative effect of actinomycin D in both pothesis that the actions of the cytotoxic agent and IFN were normal and transformed human fibroblasts, while having a independent, but that IFN is most effective when the tumor weaker effect on cisplatin cytotoxicity and no effect on cyclo burden is low (25). However, this schedule would also be active phosphamide, methotrexate, or vincristine cytotoxicity (73). if IFN directly modulated the cell-killing effect of the cytotoxic As with IFN-a, the modulating effects of IFN-/3 are complex agent. In several earlier studies (21, 22, 25), synergy between and not readily predictable a priori. For example, IFN-/8 was IFN and various cytotoxic drugs was demonstrated with admin found to additively inhibit the proliferation of laryngeal tumor istration of drugs in sequence. Later studies (23, 56), however, (H.Ep-2) cells in combination with mitomycin C and neocar used concurrent scheduling of IFN and a cytotoxic agent or zinostatin. It had a greater than additive effect with doxorubicin compared concurrent with sequential scheduling, and failed to and vincristine and a less than additive effect in combination demonstrate a benefit for sequential administration, suggesting with 6-mercaptopurine (74). The specificity of the IFN species, that tumor burden is not the primary determinant of IFN the antitumor drug, the cell line, and the schedule were further activity. More recent studies (57, 58) demonstrate a complex examined in these studies. The critical determinant for dem relationship between the timing of administration of IFN with onstrating additive or greater than additive interactions was the a cytotoxic agent, the doses used, and the efficacy of the appropriate combination of cell line and antitumor agent. For regimen. example, vincristine did not enhance the activity of IFN in The question of brief exposure versus continuous exposure to Daudi (Burkitt) lymphoma cells, was additive when tested in interferon is of importance because of the well-described cyto- M-14 melanoma cells, and had greater than additive activity in kinetic effects of IFN (17). Unfortunately, the preclinical data HeLa and H.Ep-2 cells. In combination with vincristine, IFN- fail to answer this question, with some studies demonstrating a and IFN-/3 produced identical effects on the proliferation of that continuous exposure is more efficacious than brief expo the H.Ep-2 cells. Scheduling appeared to be important, since 3478 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1990 American Association for Cancer Research. INTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY treatment with IFN followed by vincristine was more effective antibiotic, aclacinomycin A (67, 89). In addition, 6-thioguanine then the reverse order (74). abrogated IFN-induced stimulation of natural killer cell activ Synergistic antiproliferative activity of IFN-7 has been re ity. While possibly not directly applicable to the mechanisms ported when used in combination with 5-FUra in MCA 38 and for the Synergistic cytotoxicity of IFN-drug combinations, these HT-29 colon adenocarcinoma cells and HL-60 leukemia cells studies do demonstrate that the modulation of IFN actions by (46). In contrast, no synergy was observed for recombinant other agents can occur. IFN-7 when used in combination with doxorubicin, cisplatin, There is also evidence suggesting that IFN can biochemically or vinblastine in the cell lines BG-1, SK-MEL-28, ME-180, modulate the activity of an anticancer drug. Recombinant IFN- CaSki, MCF-7, or RPMI 8226 (75). 7 and higher concentrations of purified IFN-a/ß caused a In vitro studies have also utilized cells from primary human Synergistic growth inhibition of MCA-38 colon adenocarci tumors in clonogenic assays. Synergistic interactions were re noma cells when used in combination with 5-FUra (46). The ported for the combination of doxorubicin and IFN-a in 8 of synergy was schedule dependent, with the sequence of IFN 19 tumors representing a variety of tumor types (62, 63). Most followed by fluoropyrimidine being most effective, suggesting of the synergies were observed in breast tumors (4 of 6). Synergy that the IFN caused a modulation of the 5-FUra effect (46). In was not observed in 5 primary tumors treated with cisplatin a subsequent study treatment of HL-60 cells with recombinant and IFN-a (62). In contrast to these findings with IFN-a, IFN-a resulted in a decrease in the catalytic activity of the 5- recombinant IFN-ßwas neither additive nor Synergistic in FUra target enzyme, thymidylate synthase, and a 10-fold in combination with doxorubicin, 5-FUra, vinblastine, melphalan, crease in the levels of the active 5-FUra metabolite, fluorodeox- or MGBG when tested using 114 primary human tumor sam yuridylate (90). The suggestion that IFN acts to increase the ples in a colony-forming assay (76). Differences in the nature inhibitory effects of 5-FUra on DNA synthesis by enhancing its of the assay could possibly account for the opposite results conversion to the active compound, fluorodeoxyuridylate, with observed using IFN-a and -ß.Treatment using doxorubicin, consequent augmentation of thymidylate synthase inhibition, cisplatin, or vinblastine and recombinant IFN-7 synergistically was supported by the observation that thymidine, which circum inhibited colony formation in 11 of 16 human renal cell carci vents the inhibition of thymidylate synthase, reversed the syn- noma tumors (77). ergistic interaction of fluorodeoxyuridine and IFN (46). IFN has also been shown to inhibit thymidine uptake and thymidine Growth Inhibition in Vitro: Mechanisms kinase activity in several cell types, reducing the utilization of exogenous thymidine by the cells (91-94). Hence IFN may both The in vitro studies described above clearly demonstrate that directly enhance the actions of 5-FUra on de novo thymidylate combinations of interferon and anticancer drugs have direct synthesis and complement the actions of 5-FUra by its effects cytotoxic interactions in malignant cells. Little is known about on thymidine salvage. It is possible that neither of these bio the nature of these interactions, but based on the observed chemical actions alone is sufficiently growth inhibitory but synergy in many of the studies, it is likely there is a modulation rather that the combination is required for antitumor activity. of the antiproliferative activity of either the cytotoxic or the As described in Table 2, additional sources of interaction of 5- biological agent (or possibly both). Although multiple biochem FUra and IFN have been described, including complementary ical actions of IFN have been described, including the antago effects on natural killer cell activity (95). It remains to be nism of the actions of growth factors and inhibition of oncogene determined what the relative contributions of the biochemical expression (18, 78-81), those responsible for inhibition of cell interactions and those on the host defense mechanisms are for growth remain to be determined. Furthermore, IFN potentiated the observed clinical antitumor activity of the combination. the actions of a range of cytotoxic agents with multiple and Because both IFN and the adenosine deaminase (ADA) in varying mechanisms. This suggests that no single interaction is hibitor, DCF, have clinically important antiproliferative effects operative but rather that the synergy observed results from a against hairy cells in patients with hairy cell leukemia, the combination of two broadly defined areas of interaction: an effects of IFN on ADA have been investigated. In Daudi cells, enhancement of the activity of IFN or the anticancer agent by incubation with IFN results in a 2-3-fold increase in ADA a specific biochemical interaction, relevant only to a particular activity, an increase which prevents inhibition by DCF. Despite combination; or potentiation due to specific actions on cell growth, replication, differentiation, or the response to cellular Table 2 Summary of potential mechanisms of interaction of interferon damage, which potentiate the activity of many antiproliferative and 5-fluorouracil agents. Ref. The possibility that the actions of IFN can be modified by 1. Direct but separate antiproliferative actions. See Table 1 anticancer agents was suggested by a report that vincristine 2. Increased formation of active metabolite (fluoro- 90 inhibited the antiviral activity of IFN in human fibroblasts (82). deoxyuridylate) by IFN, enhancing inhibition of critical enzyme activity (thymidylate synthase) In contrast, bleomycin, vincristine, and mitomycin C increased by cytotoxic agent (5-FUra). the growth-inhibitory effects of IFN-/3 in HeLa cells without 3. Complementary inhibition: IFN-mediated de- 91-94 affecting the antiviral actions of IFN (83). In this study, the crease in uptake of substrate (thymidine) and anticancer drugs did not affect the stimulation of 2'-5'-oligoad- reduction in enzyme activity (thymidine kinase). further depleting cellular thymidylate in con enylate synthetase activity or double-stranded RNA-dependent junction with action of cytotoxic agent (5- FUra). protein kinase activity produced by IFN. It has been reported 4. Cell cycle effects leading to enhanced antiprolifer- 104 that induction of differentiation of HL-60 human promyelocy- ative actions. tic leukemia cells causes a 2- to 3-fold increase in cell surface 5. Protective effect against normal host tissue by 47, 48 receptors for IFN-a and IFN-7 and increases the antiprolifer IFN permitting use of higher dose of cytotoxic agent. ative activity of IFN (84-87). Several reports have demon 6. Combined cytotoxic action (5-FUra) and activated 39 strated that recombinant IFN-a, -ß,and 7 can substantially host defense mechanisms (IFN). 7. Augmentation of host immunomodulatory actions 95 enhance the induction of differentiation of HL-60 cells pro by complementary effects of both the cytotoxic duced by either retinoic acid or actinomycin D (88-89), al agent (5-FUra) and IFN on natural killer cell though not that caused by 6-thioguanine or the anthracycline activity. Downloaded from cancerres.aacrjournals.org on September3479 30, 2021. © 1990 American Association for Cancer Research. INTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY these opposite interactions, both agents inhibit growth of Daudi in this trial were acceptable, with no instances of life-threaten cells, and their effects are not negated by use of both IFN and ing myelosuppression (Table 3). DCF in combination (96). Based on preclinical investigations demonstrating enhance IFN-7 has been reported to increase the number of DNA ment of the antitumor effect of cisplatin by IFN (62), a phase I strand breaks in treated cells (97), providing a theoretical basis clinical trial combined rIFN-a, 5 MU/m2 s.c. three times for interaction with cytotoxic agents that produce similar ef weekly, with cisplatin, 5-30 mg/m2 weekly for three doses fects. IFN may also affect the cellular response to the damage (101). The dose-limiting toxicity was fatigue resulting in a caused by cytotoxic agents, including DNA repair enzymes. decrease in performance status. Renal toxicity occurred in only Human IFN potentiated the cytotoxicity of yV-methyl-/V'-nitro- two patients and was reversible. Furthermore, the maximal soguanidine in vitro (98). This action was not due to an effect tolerated dose of weekly cisplatin, 25 mg/m2, was equivalent to on 06-methylguanine repair, however, since the Mer+ pheno- therapeutic doses administered in the absence of IFN, suggest type was not required for the IFN enhancement of cell killing ing that the addition of IFN did not require dose reduction of by W-methyl-W-nitrosoguanidine. the cytotoxic agent. One responder was noted among 26 pa tients entered into this trial. Locoregional administration of the combination of rIFN-a Combinations of IFN and Chemotherapeutic Agents: The Tran and cisplatin was used with the goal of increasing the effective sition from Preclinical to Clinical Investigations drug concentrations at the tumor and with reducing systemic Translating preclinical data into clinical regimens has proved toxicities (102). Patients with persistent ovarian carcinoma difficult, and this accounts for the relatively few clinical trials following conventional therapy received i.p. therapy with IFN, using IFN in combination with chemotherapeutic agents. Prob day 1, followed by i.p. cisplatin, day 2, every 14-21 days for 12 lems in the design of combination regimens include the novel cycles. Nausea, vomiting, and a flu-like syndrome occurred spectrum of toxicities observed with IFN, conceptual questions despite locoregional administration. Of 14 évaluablepatients, that relate to the role of IFN as both an immunomodulator and 5 achieved an objective response. a biochemical modulator, and the traditional questions in the Based on studies demonstrating efficacy for the combination design of combination regimens that include dose, schedule, of IFN and cisplatin in explanted human non-small cell lung and host tolerance. Attention has appropriately focused on cancer (30), 33 patients with non-small cell lung cancer were phase I trials to assess the optimal doses to be used in phase II treated with rIFN-a, 3 MU s.c. three times weekly, and cispla tin, 100 mg/m2, day 8, then every 4 weeks (103). Of 26 évaluable trials and to anticipate the spectrum of toxicities. Phase II and III trials combining IFN and chemotherapeutic agents have patients, 6 achieved an objective response lasting for up to 40 also been initiated to evaluate the efficacy of combination weeks. A total of 5 of 11 patients with squamous cell histology regimens against solid and hematopoietic malignancies. This responded, a number higher than might be expected based on section will discuss combinations of IFN and single cytotoxic historical controls. Gastrointestinal and constitutional symp drugs; the subsequent section will focus on combinations of toms were predominant, and 12 patients experienced a decrease IFN and multiple cytotoxic drugs. in creatinine clearance. While few chemotherapeutic agents have single agent activity against renal cell carcinoma, both IFN and the Vinca alkaloid, IFN and Single Cytotoxic Agents vinblastine, induced objective responses in approximately 20% Few clinical trials have sought to exploit early preclinical of patients with this malignancy (14). This has stimulated observations demonstrating synergy between IFN and alkylat- interest in both preclinical and clinical investigations examining ing agents, particularly cyclophosphamide. Two trials with cy- the activity of the combination. Studies of the combination of clophosphamide plus IFN have focused on the immunological vinblastine with either IFN-7 or recombinant IFN-/3 against effects of the latter drug and have attempted to use low-dose three human renal cell carcinoma cell lines have demonstrated cyclophosphamide as an inhibitor of suppressor cell activity, a greater than additive effect for the combinations (Table 1). thus as an immunoadjuvant. In one phase II trial with cyclo Six phase I-II or II studies of combined IFN and vinblastine phosphamide, 25 mg p.o. twice daily, in combination with therapy for advanced renal cell carcinoma have been reported rIFN-tt, response rates in melanoma and renal cell carcinoma (Table 3). A summary of these suggests that the combination, were only 4 and 6% (99). A phase I trial of low-dose cyclo while active, was not clearly better than either agent alone and phosphamide and IFN is in progress with assessment of sup was more toxic. Similar studies were performed in patients with pressor cell activity as a biological end point (100). acquired immunodeficiency syndrome-related Kaposi's sar Based on preclinical data demonstrating synergy in vitro and coma, where both IFN and Vinca alkaloids have demonstrated in nude mice bearing explanted human tumors (29, 62, 64), two activity. phase I trials studied the combination of rIFN-a, administered Interest in the interaction of 5-FUra and IFN derives from s.c. three times per week, and doxorubicin, administered either the protective effect attributed to IFN in a murine model (47, weekly for three doses or every 3 weeks (Table 3). The weekly 48), from synergy documented in in vitro systems (46, 66, 104), schedule allowed delivery of nearly twice the cumulative dose and from a possible combined cytotoxic and immunotherapeu- of doxorubicin as the every-3-week schedule and demonstrated tic effect for the combination (39). The results of preliminary less myelosuppression and fewer nonhematological toxicities. clinical trials have suggested a benefit for the combination of Objective responses were noted on both schedules. These stud recombinant IFN-a and 5-FUra (105). In a pilot phase II ies formed the impetus for a broad-based phase II trial con clinical trial, a total of 20 of 32 (63%) of patients with advanced ducted primarily in patients with gynecological malignancies. colorectal carcinoma achieved an objective response to the Response rates greater than expected with single agent therapy combination. 5-FUra was administered at 750 mg/m2 daily for were reported in patients with ovarian and cervical carcinomas. 5 days, then as weekly bolus therapy. In contrast, in a trial in In addition, there were 7 responses among 24 patients who had which 5-FUra was administered at 250-500 mg/m2 with high- failed conventional therapy for ovarian carcinoma. Toxicities dose daily IFN-a, the response rate was only 4% in patients 3480

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Table 3 Interactions oflFN and chemotherapeutic agents: clinical investigations"

DrugsAlkylating (%)332784NS64756362.1141014029Ref.14610060147999914S101102103144150151152153 cisplatinCY*CYfCYCY"CY'L-PAM7CDDP*CDDP*CDDP'AnthracyclinesADR'ADR*ADR'ADR"ADR"IFNree-«ree-«ree-«ree-«ree-«ree-«ree-«ree-«ree-«ree-«ree-«ree-«ree-«ree-«No.915NS604030181433142071724PhaseIII-IIliIIl-III1IIIIIIIIITumorMyelomaNHLRCCMelanomaMyelomaOvaryNSCLCRCCOvaryDLTFatigueNSFatigueNSWBCWBCFatigueORagents and

17 Cervix 35 153 9 Breast O 153 ADR° IX RCC O 153 24 Gì o 153 8 Melanoma o 153 29 Other 10 153 DHAD NS 21 NS o 154

VincaalkaloidsVBI/VBLVBL"VBLVBL'VBL'VBL'VBL"5-Fluorouracil5-FUra'5-FUra"5-FUra*5-FUra'5-FUra5-FUraOther

fatigueWBCFatigueFatigueFatigueFatigueFatigueFatigueHearing?WBCWBC8136164331447019204632570818II22678155156157I5X15916(1161162108109107105163163164165166144167168169

agentsDFMO-"DFMO°°DFMOBCNUBCNUHU**VP16CCaaaree-«ree-«ree-«NSaree-«ree-«rec-oree-«rec-irec-7aaNSaNSNSree-«23NSIX5740169152752832163024251718181526III-III-IIII1-11III-IIIIII-IIIIIII111II-IIIIIIIIIRCCRCCRCCRCCRCCRCCRCCKSColonColonColonColonColonColonMelanomaBrainCMLKSWBC.

" DLT. dose-limiting toxicity; OR. objective response; CY, cyclophosphamide; L-PAM, melphalan: CDDP. cisplatin; rec-a. recombinant «-interferon;NHL, non- Hodgkin's lymphoma; RCC. renal cell carcinoma; NSCLC. non-small cell lung carcinoma; NS. not stated; ADR, doxorubicin (Adriamycin); DHAD. mitoxantrone: GI, gastrointestinal tumors; WBC. myelosuppression; VBL. vinblastine: «.human leukocyte or lymphoblastoid interferon; KS, acquired immunodeficiency syndrome- related Kaposi's sarcoma; HU, hydroxyurea; CML. chronic myelogenous leukemia. *CY P.O., days 2-5; IFN, days 1-5 then every other day at 3-15 MU. ' Low-dose CY prior to IFN to enhance natural killer cell/lymphokine-activating activity. ''Low-dose IFN 3 times/week. CY, 100 mg/mVday P-"-; 46% OR in previously untreated patient. ' Low-dose CY (25 mg p.o. 2 times/day) and IFN (10 MU/m2 3 times/week). One OR each in melanoma and RCC. 'Escalating IFN. 0.5-10 MU. days 1-14. L-PAM. prednisone p.o.. days 2-5. * IFN, 5 MU/m2 3 times/week; CDDP, 5-30 mg/m i.v. weekly for 3 weeks. * i.p. therapy. ' Five of 11 OR in patients with squamous cell carcinoma. •'Twoof14 Eastern Cooperative Oncology Group grade 4 myelosuppression. * Both responses in melanoma. ' Response in hepatoma which failed chemotherapy. m Myelosuppression noted in only 2 of 17 patients after 81 courses. " IFN i.v. and s.c. followed l h later by ADR, 20 mg/m2. " IFN, 10 MU/m2 i.v. over 30 min. then i.m. Peak serum levels. 600-1200 IU; 24-h serum level. 75-150 IU. "IFN, 8 MU daily. * High-dose IFN, continuous infusion VBL. ' High-dose IFN, 3 times/week. ' High-dose IFN (36 MU i.m. 3 times/week). ' Intermediate dose IFN. " Intensive regimen with high-dose IFN administered daily and VBL every other week. " 28% OR in previously untreated patients. * One of 5 OR in patients failing prior 5-FUra therapy. * High-dose IFN daily for 5 days; 5-FUra, 250-500 mg/m2 for 5 days. y 5-FUra by continuous infusion then weekly bolus therapy; IFN, 9 MU 3 times/week. 1 Hearing loss was significant toxicity. *°Bothresponses in melanoma. **Five of 8 previously untreated and 5 of 7 previously treated patients had a cytogenetic response. " No difference between sequential and concurrent treatment.

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1990 American Association for Cancer Research. INTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY with advanced colorectal carcinoma (106, 107). Lower doses of with multiple myeloma. One study combining IFN with com IFN may be more efficacious than higher doses; in a phase I bination chemotherapy (VMCP) demonstrated an increased clinical trial, 5 of 9 (56%) previously untreated patients with objective response rate of borderline statistical significance with colorectal carcinoma responded to the combination of 5-FUra the addition of IFN as compared to cytotoxic agents alone and and IFN-tt, 6-9 MU daily, whereas 0 of 9 responded to the no improvement in overall survival (118, 119). A phase II study same dose of 5-FUra with IFN-«12-18 MU daily (108). In the by the Eastern Cooperative Oncology Group of VBMCP with same study 1 of 8 patients who had previously failed a 5-FUra- IFN suggested an improvement in the quality and duration of containing regimen responded. In a small study with only 5 objective responses as compared with historical controls not previously treated patients, 1 responded to the combination of receiving IFN (120). The NCI-Canada Clinical Trials Group is 5-FUra and IFN suggesting there may be a small subset of currently conducting a study of MP versus MP plus IFN in patients failing 5-FUra alone who will respond to the combi patients who have previously responded to MP. nation (109). Multiple studies investigating the treatment of In addition to combining IFN with chemotherapy for induc solid tumors with the combination of 5-FUra and IFN are in tion therapy of multiple myeloma, interest has also been gen progress. erated in the use of IFN as maintenance therapy following Following reports of a synergistic inhibition of tumor cell chemotherapy induction, prompted by the findings from a large growth by the combination of IFN and the ornithine decarbox- study from Italy which has demonstrated a significant increase ylase inhibitor, DFMO (110, 111), phase I trials have combined in remission duration and nearly significant (P = 0.058) in IFN and DFMO (Table 3). The toxicities noted included fa crease in median survival with IFN maintenance (121). Three tigue, myelosuppression, and reversible hearing loss. Based on other studies of IFN maintenance are under way from the NCI- objective responses in patients with melanoma, renal cell car Canada, the Southwest Oncology Group, and the Myeloma cinoma, and colon cancer, further clinical trials are in progress. Group of Western Sweden. A variety of antitumor antibiotics, including actinomycin D, In chronic myelogenous leukemia IFN has been combined neocarzinostatin, mitomycin C, bleomycin, and pepleomycin, with single agent therapies, including hydroxyurea, busulfan, have demonstrated synergy or additivity with interferon in and l-/3-D-arabinofuranosylcytosine (122). A study investigat preclinical studies (Table 1). The nitrosoureas, BCNU and ing the role of IFN-«maintenance following induction therapy ACNU, while less thoroughly studied, have also demonstrated with cytotoxics has demonstrated prolongation of Philadelphia a positive interaction. Combination therapy with antimetabo- chromosome suppression in 8 patients ranging from 22 to 42+ lites, with the exception of 5-FUra, appears less efficacious. In months (123). For the 32 patients studied, the projected 3-year clinical trials, combinations of IFN with BCNU or VP16 have survival is 84%. not demonstrated an advantage over single agent therapy (Table Because both IFN and DCF have clinical activity in hairy 3); however, the combination of IFN and VP16 in patients with cell leukemia, the combination has been investigated. The drugs Kaposi's sarcoma was much more myelosuppressive than would were administered at full dose, but alternating every other have been predicted with VP16 or IFN alone. month. Of 13 évaluablepatients, all improved with therapy; 12 of 12 patients undergoing bone marrow biopsy had reduction in the population of hairy cells to <5% (124). IFN and Combination Chemotherapy Two studies of IFN maintenance in low-grade non-Hodgkin's Hematological Malignancies. Initial clinical trials demon lymphoma are in progress. The EORTC Lymphoma Coopera strated the single agent activity of IFN in the treatment of tive Group is examining the role of maintenance therapy fol chronic hematological malignancies (112, 113). Because IFN lowing induction with cyclophosphamide, vinblastine, and pred- has a nonoverlapping spectrum of toxicities with standard nisone in a randomized phase III trial. At M. D. Anderson chemotherapeutic agents, various combinations of IFN and Hospital, a clinical trial is under way to examine the effects of chemotherapy have been used against the chronic hematological combined therapy with chemotherapy and radiation followed malignancies. by maintenance with interferon and corticosteroids. In patients with multiple myeloma, important activity has Solid Tumors. Few clinical trials have sought to incorporate been identified for IFN both in combination with chemotherapy IFN into combination chemotherapy regimens against solid as induction therapy and following chemotherapy as mainte tumors. In a phase III trial in patients with osteosarcoma, IFN nance therapy. In a pilot clinical trial in patients with multiple maintenance therapy produced no improvement in survival myeloma the addition of IFN-«, 2 MU/m2 three times per following induction with combination chemotherapy (125). In week, did not diminish the doses of melphalan/prednisone (MP) a phase III trial comparing IFN-/8/-y therapy followed by con that could be delivered (114). This has encouraged investigators ventional chemotherapy versus chemotherapy alone in patients to combine IFN with either single alkylator induction therapy with non-small cell lung cancer, there was no difference in or more aggressive therapy with multiple alkylating agents. A objective response rates or survival (126). phase III trial by the Myeloma Group of Sweden comparing Two phase I trials with IFN with cytotoxic agents are of MP versus MP-IFN demonstrated increased objective response interest. The National Cancer Institute is conducting a trial of rates for the latter combination (82% versus 52%, P < 0.01) interleukin 2-cyclophosphamide with either tumor-infiltrating (115). A recent update with 220 patients accrued confirms the lymphocytes or IFN-cv in patients with advanced refractory improvement in objective responses initially noted but demon cancer. The second is a clinical trial of IFN-n plus cisplatin and strates no survival benefit. Similar results have been found in a radiotherapy in patients with advanced cancer. phase III study from Argentina (116). A phase III trial by the Cancer and Leukemia Group B has been initiated to confirm Conclusions these results; however, preliminary results indicate that the addition of IFN has required a 20% decrease in the dose of MP With few exceptions, enthusiastic reports of synergy between delivered (117). IFN and chemotherapeutic agents in preclinical systems have Various studies have compared therapy with multiple alkyl not translated into an important benefit in clinical trials. This ating agents versus the same treatment with IFN in patients may result from the failure of the preclinical systems studied to 3482 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1990 American Association for Cancer Research. INTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY

accurately reflect the clinical setting, or alternatively a failure (éd.).Pharmacologie Principles of Cancer Treatment, pp. 3-14. Philadel phia: W. B. Saunders Co.. 1982. to accurately translate the findings of the preclinical setting to 2. Hryniuk. W. The importance of dose intensity in outcome of chemotherapy. the clinic. The latter may result from a reliance on models for In: S. Hellman, V. DeVita, and S. Rosenberg (eds.). Advances in Oncology, drug combinations that fail to account for the differences in pp. 121-141. Philadelphia: J. B. Lippincott Co.. 1988. 3. Goldie. J. H.. and Coldman. A. J. The genetic origin of drug resistance in mechanism of action between IFN and conventional agents. neoplasms: implications for systemic therapy. Cancer Res.. 44: 3643-3653, For example, in combination with cytotoxic agents, sequence 1984. 4. Tannock, I. F. Experimental chemotherapy. In: I. F. Tannock and R. P. and duration of exposure to IFN may play as significant a role Hill (eds.). The Basic Science of Oncology, pp. 308-325. Elmsford. NY: as dose and dose intensity, and the maximum tolerated dose of Pergamon Press, 1987. 5. Dinarello, C. A., and Mier, J. W. Lymphokines. N. Engl. J. Med.. 317: IFN may not be the most biologically effective dose. 940-945. 1987. The early impetus to the study of IFN-cytotoxic combinations 6. Pfeffer. L. A. Cellular effects of interferons. In: L. A. Pfeffer (ed.). Mecha derived from the theory that chemotherapy was more effective nisms of Interferon Actions. Vol. 2. pp. 2-18. Boca Raton, FL: CRC Press. against bulky disease than immunotherapy, which was presum Inc.. 1987. 7. Quesada. J. R., Talpaz. M., Rios, A., et al. Clinical toxicity of interférons ably overwhelmed by massive quantities of antigen; but that in cancer patients: an overview. J. Clin. Oncol., 4: 234-243. 1986. immunotherapy, with its high degree of specificity, was more 8. Krown, S. E. Interferons in malignancy: biological products or biological response modifiers? 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Scott Wadler and Edward L. Schwartz

Cancer Res 1990;50:3473-3486.

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