High-Intensity Chemotherapy
`with Hematopoietic Support
`in Breast Cancer’
`
`JOHN CROWN,’ LINDA VAHDAT,
`DAVID FENNELLY, PRUDENCE FRANCIS,
`CAROLYN WASSERHEIT, CLIFFORD HUDIS,
`ALAN KRITZ, JEFFREY SCHNEIDER,
`NICOLA HAMILTON, TERESA GILEWSKI,
`AND LARRY NORTON
`
`Breast and Gynecologic Cancer Medicine Service
`Diviston ofSolid Tumor Oncology
`Department ofMedicine
`Memorial Sloan-Kettering Cancer Center
`1275 York Avenue, New York, New York 10021
`
`INTRODUCTION
`
`Chemotherapy produces frequent objective responses in patients with
`metastatic breast cancer. The majority of these responses are incomplete, and
`virtually all are temporary, with a median duration of response of approxi-
`mately 12 months. Chemotherapy-induced complete remissions that are
`durable beyond five years are extremely rare. While many patients derive sub-
`stantial palliation ofdistressing symptoms, and individual women who appear
`to be in imminent danger of death are restored to periods of improved health
`with apparent prolongation ofsurvival, proof that the introduction of such
`“effective” chemotherapy has significantly increased the median survival of
`patients with metastatic disease has not been demonstrated.!
`The paradoxical observation that the substantial cell kill achieved by
`chemotherapyhaslittle impact on survival can be explained on the basis of
`tumorkinetics. According to the Gompertzian model proposed by Norton,
`residual populationsofcancercells that have survived massive, but noneradica-
`tive cell kill, can undergo accelerated regrowth. The amountofcell kill pro-
`
`# Dr. Crown is supported by an American Cancer Society Clinical Oncology Career Devel-
`opment Award.
`Address for correspondence: John Crown, M.D., Memorial Sloan-Kettering Cancer
`Center, 1275 York Avenue, New York, New York 10021.
`
`378
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`Genentech Exhibit 2066
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`duced can result in substantial palliation during the period of reduced tumor
`burden, but the tumorwill achieve lethal volume at approximately the same
`time that it would have in the absence of therapy. More effective therapies
`would produce greatercell kill per treatment, and shorter intervals between
`treatments would decrease the interval regrowth.? Attempts to increase the
`efficacy of chemotherapyby increasing the administered dose continue to be
`the focus of a substantial research effort.
`
`DOSE INTENSITY
`
`Laboratory models suggest that some componentof the resistance of
`cancercells to cytotoxic drugs can be overcomebydoseescalation.’ In single-
`arm studies, high responserates have been reported for higher-dose administra-
`tions of doxorubicin.Prospective randomizedtrials of higher- versus lower-
`dose chemotherapy have yielded mixed results, but seem to indicate a trend
`toward improved response for the higher dose.®® Several reach statistical
`significance. Tannock and colleagues demonstrated survival and quality of
`life advantages for a higher-dose cyclophosphamide-methotrexate-fluorouracil
`(CMF) regimen compared to a lower dose. In a study from Denmark, patients
`with metastatic breast cancer were randomly assignedto oneoffour dose levels
`of epirubicin chemotherapy. Statistically significant trends for improved re-
`sponse and time to progression were obtained. In general, for dose escalation
`studies within the “standard” dose range (i.e., doses not requiring autologous
`bone marrow transplant), higher doses produce improved response rates and
`palliation, but have modest survival impact.
`For the alkylating agents and other chemotherapeutic drugs that have
`limited nonhematologic toxicity, a much more substantial degree ofdose esca-
`lation can be facilitated by the use of autologous bone marrow transplanta-
`tion.? This modality is emerging as a valid curative strategy for patients with
`lymphoma!® andpossibly testicular carcinoma! whose cancer has progressed
`ontraditional dose therapies. The partial chemotherapy sensitivity of meta-
`static breast cancerhas led to extensive investigation of this approach. As the
`literature ofthis field is extremely heterogeneous, it is necessary to examine
`the developments in a step-wise fashion.
`
`HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS
`BONE MARROW TRANSPLANTATION
`IN BREAST CANCER
`
`Early studies involved patients with advanceddisease that had been refrac-
`tory to conventional-dose treatment. The Dana-Farber group studied high-
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`ANNALS NEW YORK ACADEMY OF SCIENCES
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`dose BCNU,cisplatin, and cyclophosphamide (CPB) in this setting and
`reported a high frequency ofrelatively short-lived responses.!2 The use of
`high-dose chemotherapy with autologous bone marrowtransplantationis not
`favoredas a salvage strategy for patients with refractory disease. Several groups
`of investigators have subsequently tested this modality in patients with newly
`diagnosed metastatic disease without prior chemotherapy.
`Investigators at
`Dukestudied the CPB regimenin this patient population and reported a com-
`plete response rate of 54%, with 25% of these complete responders surviving
`progressionfree at five years.!3 Louieet al. and Kaiseret al. also reported high
`complete response rates in previously untreated patients. '*!5
`Subsequentresearchefforts have focused onthestrategy of using high-dose
`therapy as a form of consolidation in patients with breast cancer whose disease
`wasin a state of ongoing complete orpartial response to prior conventionally
`dosed induction therapy. It was hoped that substantially increased antitumor
`activity would be achieved, as patients would be treated at a time of decreased
`tumor burden, when the high-dose consolidation would have greater poten-
`tial for disease eradication. This approach wouldalso allow patients whosedis-
`ease is not responsive to chemotherapy to be excluded from toxic treatment
`programs where thelikelihood of benefit is small.
`The group at Dukeused an intensive doxorubicin-based approach followed
`by CPB consolidation for responders and reported a combined complete re-
`sponse rate of 68%, with again approximately 25% of complete responders
`remaining disease-free at five years.'© Dunphy,Spitzer, and colleagues havere-
`ported that approximately 18% ofpatients achieve long-term disease-free sur-
`vival with a program consisting of induction chemotherapy followed by con-
`solidation with tandem courses of high-dose cyclophosphamide, cisplatin,
`and etoposide.” These investigators report that for the subset of patients
`treated for metastases confined to the lung or lymph nodes, the durable
`complete response rate may be higher.!® Antman and colleagues at Dana-
`Farber used a combination of carboplatin, thiotepa, and cyclophosphamide
`in patients who were in a state of ongoing complete orpartial responseto in-
`duction chemotherapy and reported 20% durable complete remissions 17-43
`months from transplantation.'? Kennedy and colleagues at Johns Hopkins
`used cyclophosphamide/thiotepaas consolidation therapy in patients respond-
`ing to a prior intensive outpatient doxorubicin-based regimen and reported
`that approximately 18% of patients achieved prolonged disease-free survival.”
`Unfortunately, these results are not substantially better than those that are
`achieved with high-dose chemotherapy as initial treatment for metastases.
`While the numbersare small, there is as yet no conclusive evidence that prior
`induction chemotherapy improves the outcome following subsequent high-
`dose therapy. The usual outcomefollowing conventional-dose chemotherapy
`is a partial response, which likely represents between oneandthreelogs ofcell
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`kill for most patients. It is possible that in attempting to devise curative strate-
`gies involving high-dose chemotherapy, suchrelatively modest degreesofcell
`kill achieved over several months of conventional-dose chemotherapy might
`not have substantial impact on the ultimate eradication of a tumor comprising
`10 to 12 logs ofcells. The numberof procedures required to achieve the same
`CRrate, however, may be reduced, thus sparing patients whoare destined not
`to have a good result from undergoing a potentially morbid procedure.
`
`CURRENT STATUS
`
`High-dose chemotherapy produces complete and partial response rates that
`are higher than those achieved with more conventionally dosed chemotherapy.
`Approximately 10-20% of patients treated with high-dose chemotherapy for
`metastatic disease that was notrefractory to prior induction chemotherapy
`achieve long-term disease-free survival. As this outcomeis achieved by only
`approximately 1~2% ofpatients treated with conventional-dose chemotherapy,
`it appears that superiorresults are achieved with high-dose chemotherapy.?!-??
`Treatment-related mortality, which was a very substantial problem in earlier
`studies, has become much less common.?4
`Thelack of prospective data derived from random-assignmenttrials, how-
`ever, has led other commentators to suggest that case selection has been an
`important factor in producing these outcomes. Eddy has suggested that
`median survival is similar for patients treated with high-dose chemotherapy
`and those treated with more traditional schedules.2* Eddy’s data set, how-
`ever, comprised both optimal studies conducted in patients meeting modern
`eligibility criteria for this modality and older trials, which included patients
`with refractory breast cancer, a group knownto havevirtually no prospect for
`benefit from high-dose chemotherapy.
`While there are undoubted case selection biases in many of the studies of
`high-dose chemotherapy, several would, in fact, have the effect of undermin-
`ing any benefit of this modality. As an example,patients accrued to the studies
`with long-term follow-up had hormone-refractory or hormone receptor-
`negative cancers, a known adverse prognostic factor.!3-!7 In addition, docu-
`mentation of responsiveness to chemotherapy is required to enter most high-
`dose chemotherapy programs. The responsiveness of bony metastases is
`difficult to document, and hence most patients with metastases confined to
`the bones are excluded from these protocols. Yet patients with bone-only
`metastasis have relatively favorable prognoses.?*
`In summary, this treatment can induce complete remissions in manypa-
`tients, at the cost of substantial toxicity. While the majority of these patients
`will relapse within five years, a sizable minority do not.
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`ANNALS NEW YORK ACADEMY OF SCIENCES
`
`STRATEGIES TO IMPROVE THE OUTCOME
`
`There is an inverse relationship between the numberofcells in a tumor
`andits curability.*© This suggests that the benefits of high-dose chemotherapy
`might be higher if it was applied to patients earlier in the natural history of
`poor-prognosis breast cancer, at a time when the tumor burdenis less. Pa-
`tients found at definitive local surgery to have metastatic involvement of 10
`or more axillary nodes have a very poor prognosis with local therapy alone.
`Approximately 90% will
`relapse with disseminated cancer.2” Adjuvant
`therapy has altered this outlook somewhat, but the majority ofpatients still
`develop metastases. The Cancer and Leukemia Group B conductedasingle-
`arm prospective study of induction chemotherapy with cyclophosphamide,
`doxorubicin, and 5-fluorouracil, followed by intensification with a single
`course ofCPB with autologousstem cell support. With a maximum follow-up
`of nearly five years, 72% of patients remain progression free.*® This group is
`currently conducting a national random-assignmentstudy of high-dose CPB
`versus lower-dose CPB as consolidation in patients with 10 or more lymph
`nodes treated with cyclophosphamide, doxorubicin, and 5-fluorouracil che-
`motherapy. Gianni and colleagues studied a novel sequential program in
`which high doses of myelosuppressive agents were alternated with agents that
`induce less profound myelosuppression. At two years offollow-up, 90% of
`patients remain disease free.?°
`In metastatic disease one possible explanation for the high rate ofrelapse
`from complete remission following high-dose chemotherapy might be that
`the intrinsic drug resistance (i.c., due to enzymatic mechanisms or to the
`multidrug resistance phenotype) of the surviving clones could not be over-
`comeby doseescalation, and that the chemotherapeutic agents that are cur-
`rently available are not active enough toeradicate the cancer in any dose. Al-
`ternatively, further dose intensification might be of value. The regimens
`currently in use in high-dose chemotherapy/autologous marrow transplanta-
`tion, however, are being applied at doses that are producing limiting non-
`hematologic toxicity. An alternative method ofdose intensification would be
`to apply multiple courses of high-dose therapy. The rapid regrowth of sur-
`viving populations that the Norton-Simon model predicts would, however,
`undermine much of the advantage of multiple-course high-dose chemother-
`apy if the interval between treatments were prolonged. Dunphy, Spitzer, and
`colleagues used tandem courses ofcisplatin, etoposide, and cyclophospha-
`mide in their study.!? Bezwoda randomlyassigned patients with previously
`untreated metastatic disease to receive two courses ofhigh-dose cyclophospha-
`mide and etoposide with standard-dose mitoxantrone and reported a 50%
`complete response rate, compared to 8% for patients receiving conventionally
`dosed therapy.*° In this trial, the retreatmentinterval was approximately four
`weeks. All of the agents in these programs have, however, been given in high
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`doses without any form of hematopoietic cell support, and thus are not
`“marrow ablative”! In situations where multiple treatments with agents
`requiring marrow support have been performed,rapid treatmentis difficult
`to achieve. 3?
`
`IMPROVEMENTS IN HEMATOLOGIC SUPPORT
`
`The major advancein the field of high-dose chemotherapy over the last
`several years has been the dramatic reduction in toxicity consequentto devel-
`opmentsin the area of hematopoietic support technology. The introduction
`of the colony-stimulating factors G-CSF (granulocyte colony-stimulating
`factor) and GM-CSF(granulocyte-macrophage colony-stimulating factor) has
`been shownin prospective randomized trials to shorten the period of neutro-
`penia following high-dose chemotherapy and autologous bone marrowtrans-
`plantation.?3-34 Platelet effects have been less consistent. The CALGB
`demonstrated that multiple courses of high-dose cyclophosphamide could be
`administered using GM-CSFto accelerate hematopoietic recovery.*5 In our
`group’s early studies of multiple-cycle high-dose chemotherapy, we demon-
`strated the feasibility of using a similar sequence of high-dose cyclophospha-
`mide courses as crossover consolidation following induction chemotherapy
`with single-agent doxorubicin. The regimen, although myelosuppressive, was
`feasible, and more than 90% of cyclophosphamide courses were administered
`on schedule.**.37 Attempts to intensify other drugs, (e.g., carboplatin and
`thiotepa) with colony-stimulating factors alone are complicated by thrombo-
`cytopenia and cumulative myelosuppression.38.39
`The colony-stimulating factors also mobilize hematopoietic progenitors
`into the peripheral blood,either at steady state or during the hematologicre-
`bound following chemotherapy.*° These progenitors can be harvested by
`leukapheresis for subsequentreinfusion as rescuefollowing high-dose chemo-
`therapy. Several groups have reported excellent hematologic recovery using
`peripheral progenitors either alone or in combination with autologous
`marrow. Recovery, especially of platelets, appears to be faster with the use of
`peripheral blood progenitors,4!-43 In a small randomized study in Memorial
`Sloan-Kettering, patients receiving peripheral blood progenitors plus GM-CSF
`had substantially faster recovery with decreased morbidity compared to pa-
`tients receiving the same chemotherapy with GM-CSFalone.
`These advances appearto havetranslated into reduced morbidity and mor-
`tality for patients undergoing high-dose chemotherapy. In the earlier studies
`involving the CPB regimen, mortality rates in excess of 20% were reported.
`Later-generation studies in which patients receive colony-stimulating factors
`and peripheral progenitors are associated with reduced regimen-related mor-
`tality.?3 In Memorial Sloan-Kettering Cancer Center we have now performed
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`88 high-dose chemotherapy treatments rescued with peripheral blood progen-
`itors in 54 patients and have not had any treatment-related deaths. Nopatient
`has required ventilatory support.
`While this welcome reduction in mortality may ofitself improve the out-
`comefollowing high-dose chemotherapy, the majorcause oftreatmentfailure
`remains relapse of cancer. We hypothesize that these new forms of hemato-
`poietic support might possibly contribute to an improvementin this out-
`come, too, as the decreased toxicity mightfacilitate multiple, timely courses
`of therapy.
`
`MEMORIAL SLOAN-KETTERING CANCER STUDIES
`OF MULTIPLE-CYCLE HIGH-DOSE CHEMOTHERAPY
`
`The ability to deliver multiple courses of high-dose cyclophosphamide
`with colony-stimulating factors together with the description of enhanced
`mobilization of hematopoietic progenitors into the peripheral blood fol-
`lowing such treatment led us to develop intensive sequential regimens. In
`these regimenspatients receive multiple courses ofcyclophosphamiderescued
`by G-CSF, followed by multiple peripheral blood leukaphereses to harvest pro-
`genitors and are then crossed overto intensified treatment with agents that,
`due to the profound myelosuppression that they induce, require hemato-
`poietic cell support. We studied a sequence consisting of two courses ofcyclo-
`phosphamide 3.0 gm/m? followed by a single course of high-dose carbo-
`platin, cyclophosphamide, and etoposide. The median interval between
`treatment courses was 15 days. The median time to recovery of neutrophil
`count to >0.5 x 10°/L andofplatelets to >20 x 109/L, respectively, were
`9 and 14 days after progenitor cell rescue. Two offive patients entering the
`study with measurable metastases ofbreast cancer that were partially respond-
`ing to prior induction chemotherapy were converted to complete response
`(manuscript submitted).
`In an ongoing phase I trial, patients without prior chemotherapy are
`treated with two courses of induction cyclophosphamide followed bya series
`of rapidly cycled high-dose carboplatin courses rescued by peripheral blood
`progenitorcells. We have succeeded in administering carboplatin doses of
`1000 mg/m? approximately every 15 days in this fashion.*> We are currently
`conductinga similar trial in metastatic breast cancer where patients receive
`two courses of cyclophosphamide, followed by two coursesof escalating-dose
`thiotepa. Preliminary data show that tandem courses of thiotepa in doses of
`500-600 mg/m? can be administered on an approximately 15-day schedule.
`Dose escalation in this study is continuing.
`It is clear from these studies that the application of the hematopoietic sup-
`port technologies is allowing a redefinition of dose-limiting toxicity, maxi-
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`mum tolerated dose, and maximum doseintensity for a variety ofchemothera-
`peutic agents that produce prominent hematologic toxicity. We are currently
`attempting to include other agents both in the induction/mobilization phase
`and in the high-dose consolidation/progenitor-supported phase of our pro-
`grams. The regimens that emerge from this process will be subjected to
`prospective controlled evaluations in an attemptto define the precise role of
`very intensive therapy in human cancer.
`
`SUMMARY
`
`Chemotherapy can produce excellent palliation for many patients with
`metastatic breast cancer. Survival impact is, however, limited, and permanent
`remission is extremely rare. There is increasing evidence that dose and dose
`intensity may be important determinants of outcome in the chemotherapy
`ofbreast cancer. Single courses ofchemotherapy in doses requiring autologous
`bone marrow support produce high rates of objective response in patients
`with metastatic disease that was refractory to prior standard-dose therapy.
`Whenusedasfirst chemotherapy for metastases or as consolidation in patients
`whose disease is responding to lower-dose therapy, high-dose chemotherapy
`can result in prolonged disease-free survival for some patients. The major
`cause of treatmentfailure is relapse from a chemotherapy-induced complete
`response. Kinetic models suggest that multiple, rapidly cycled courses ofhigh-
`dose chemotherapy might be superior to single applications or to multiple
`treatmentsthat are widely spaced in time. Heretofore, the substantial toxicity
`of high-dose chemotherapy (up to 20% mortality in someearly trials) has
`largely precluded the consideration of timely retreatment; however, the risk
`appears to have been reduced through the use of hematopoietic growth factors
`and peripheral blood progenitorcells. Our group has used these new technol-
`ogies to develop regimensconsisting of multiple cycles of high-dose chemo-
`therapythatare rapidly administered. We are currently refining these regimens
`in preparation for phase II and III studies.
`
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