curative cancer chemotherapy1 · cancer chemotherapy provides variably effective treatment for the...

[CANCER RESEARCH 45, 6523-6537, December 1985]

Position Paper

Curative Cancer Chemotherapy1

Emil Frei III

Dana Farber Cancer Institute, Boston, Massachusetts 02115

ABSTRACT

Cancer chemotherapy provides variably effective treatment forthe majority of forms of human cancer and curative treatmentfor some 12 categories of cancer. Curative treatment is definedas the proportion of patients who survive beyond the time afterwhich the risk of treatment failure approaches zero, i.e., thedisease-free survival plateau. This progress has resulted from a

closely integrated scientific effort, including drug development,pharmacology, preclinical modeling, experimental design withrespect to clinical trials, quantitative criteria for response, and aseries of clinical trials (initially in children with acute lymphocyticleukemia) in which the importance of complete remission, ofdose and schedule, of sequencing chemotherapeutic agents, ofpharmacological sanctuaries, and particularly of combinationchemotherapy was studied. The principles derived from thesestudies, particularly those relating to combination chemotherapy,resulted in curative treatment for disseminated Hodgkin's disease, non-Hodgkin's lymphoma, pediatrie solid tumors, testicular

cancer, and limited small cell lung cancer. Many patients withcertain stages of solid tumors, such as breast cancer and osteo-

genic sarcoma, are at high risk of having disseminated microscopic disease. Experimental studies indicate that treatmentwhich is only partially effective against macroscopic disease ismuch more effective against microscopic tumors. Thereforechemotherapy is administered immediately following control ofthe primary tumor in patients at high risk of having disseminatedmicroscopic disease, a treatment known as adjuvant chemotherapy. This program has been highly successful in increasingthe cure rate in patients with pediatrie solid tumors and inprolonging disease-free survival in patients with premenopausal

breast cancer. Given dissemination of the technology, it is estimated that 15,000-30,000 patients per year are potentially

curable in the United States. Curability of cancer by chemotherapy generally is inversely related to age, i.e., the above tumorsare most common in children and young adults. There are newand promising treatment strategies, such as neoadjuvant chemotherapy and autologous bone marrow transplantation. The revolution in molecular and cellular biology is providing an increasein targets, rationale, and opportunity for more effective and novelchemotherapeutic approaches.

INTRODUCTION

This paper will describe the major conceptual and clinicalinvestigational advances that have led to the cure of certain

Received 3/14/85; revised 7/25/85, 8/15/85; accepted 9/10/85.1A position paper of the American Association for Cancer Research, Inc.,

commissioned by the Association's Scientific and Public Affairs Committee.

Requests for reprints for both individual and bulk orders should be addressedto: American Association for Cancer Research, Inc., Temple University School ofMedicine, West Building, Room 301, Philadelphia, PA 19140.

forms of cancer by chemotherapy. Basic science has contributedto this progress in terms of the synthesis, development, andpreclinical studies of the active chemotherapeutic agents. However, the major thrust of this presentation will deal with theintegrated clinical and basic science efforts that have taken thesetools (active chemotherapeutic agents) and constructed progressively effective and finally definitive treatment for a number ofneoplastic disease categories. It will be organized primarily bydisease category, historical sequence, and three strategies: (a)chemotherapy only; (b) adjuvant chemotherapy; and (c) neoadjuvant chemotherapy.

The term "cure" is a sensitive one and subject to several

definitions. In a strict sense, a representative sample of patientswith a given disease must survive a normal life span. In anoperational sense, this would be counterproductive, since itwould take, for example, 60 years to determine whether a giventreatment program for childhood leukemia was curative. Somephysicians deliberately avoid using the word "cure," preferringthe expression "long-term disease-free survival." We think this

inappropriate if the evidence for cure is compelling (see below).The well-being and compliance of patients are substantially

improved if they are aware that they are being treated withcurative intent. To the extent that physicians and investigatorsare ambivalent with respect to the use of the term "cure," patients

and the medical community will be skeptical. One of the obstaclesto progress in cancer therapy generally and in cancer chemotherapy specifically has been the presence of such skepticism.

For most categories of tumors, the cure rate can be securelyand operationally defined as the disease-free survival plateau

(69,168). Thus following potentially definitive treatment, the riskof relapse is major at an early stage and decreases with time;then there is a point in time (1 to 4 years, depending upon thekinetics of the tumor) after which the risk of relapse is minimal(<10%). Thus the disease-free survival from that point is essen

tially flat (plateau). Confidence in the delivery of curative treatment by this definition is based on the number of patients andthe duration of survival on that plateau. Breast cancer is the onlymajor exception to the application of this operational definitionfor cure. This is because the risk of failure in breast cancer, whileit decreases with time, continues beyond 5 and even 10 and 15years (93). Thus except for breast cancer, the disease-free

survival plateau will define cure in this paper.While declining mortality from a tumor must be the ultimate

parameter of curative treatment, its operational utility is limited.Thus the time required from the introduction of curative treatmentfor a given tumor to the recognition and confirmation that curativetreatment has, in fact, been delivered is substantial. Additionaltime is required for the transfer of such technology to thecommunity such that a decrease in mortality occurs. For example, curative combination chemotherapy for Hodgkin's disease

CANCER RESEARCH VOL. 45 DECEMBER 1985

6523

Research. on November 15, 2020. © 1985 American Association for Cancercancerres.aacrjournals.org Downloaded from

http://cancerres.aacrjournals.org/

CURATIVE CANCER CHEMOTHERAPY

was introduced in 1963 (37, 62). Since the risk period for failureafter treatment of Hodgkin's disease is 4 years, it was 7 years

(1970) before the first full publication appeared which indicatedthe probability that Hodgkin's disease was curable by chemo

therapy (38). Further follow-up of that study and other studies

provided extension and confirmation of the results so that, bythe mid-1970s, it was generally appreciated that patients withdisseminated Hodgkin's disease could be treated with curative

intent. However, not until the mid-1970s and later was there asignificant decline in mortality for Hodgkin's disease based on

national mortality statistics. This time lag was shorter for testic-ular cancer, which is a more dynamic disease; I.e., the disease-free survival plateau begins as early as 1 year following treatment. The time lag is much longer for diseases such as breastcancer, ovarian cancer, and small cell lung cancer, wherein thedynamics of the disease are much slower and/or the cure ratesattributable to chemotherapy substantially lower. It is not surprising, therefore, that in the main the curative treatment whichdeveloped between 1970 and 1975 may not yet have had animpact on national mortality statistics. Indeed, curative treatmentdeveloped after that time and, particularly after 1980, might notyet be wholly recognized as such because there has beeninsufficient time for the development of a secure disease-free

survival plateau (60).

CHEMOTHERAPY

Gestational Choriocarcinoma

This tumor produces a marker, HCG,2 in the serum, which in

the individual patient is a precise measure of tumor burden,including microscopic tumor burden, down to as few as perhaps1000 cells. It was observed in the 1950s that antifolates interfered with the estrogen effect on the oviduct and that serumhuman chorionic gonadotropin decreased in a patient receivingmethotrexate (98, 119).

In 1956, after a pilot clinical pharmacological study was observed to diminish HCG, an intensive intermittent methotrexateprogram was developed for gestational Choriocarcinoma (119).A prompt decrease in human chorionic gonadotropin followed bya decrease in tumor size was observed in the first and subsequently in almost all patients. As complete clinical remissionswere achieved, treatment was continued in an effort to reducethe microscopic tumor burden. This could be measured by serumHCG levels and such treatment was continued for one to twocourses beyond the point where the HCG had reached normallevels (99,118).

This observation has been widely confirmed, and currentlymethotrexate alone, or more commonly methotrexate combinedwith actinomycin D, produces cure rates in over 90% of patientswith low or intermediate tumor burdens at the time of diagnosis.Even in patients with high tumor burden, as measured clinically,

2The abbreviations used are: HCG, human chorionic gonadotropin; ALL, acute

lymphocytic leukemia; CMS, central nervous system; VAMP, vincristine, amethop-terin, Oncovin, and prednisone; ara-C, 1-/3-o-arabinofuranosylcytosine; MOMP,mustargen, Oncovin, methotrexate, and prednisone; MOPP, mustargen, Oncovin,procarbazine, and prednisone; ABVD, Adriamycin, bleomycin, vinblastine, anddacarbazine; DHL, diffuse histiocytic lymphoma; CHOP, cycloheximide, hydroxy-daunorubicin, Oncovin, and prednisone; AML, acute myelogenous leukemia; cis-platin, c/s-diamminedichloroplatinum(ll); VBP, vinblastine, bleomycin, and cisplatin;CMF, cyclophosphamide, methotrexate, and fluorouracil; PROMACE-MOPP, prednisone, methotrexate, Adriamycin, cyclophosphamide, etoposide, mustargen, vincristine, prednisone, and procarbazine.

radiographically, and by tumor markers, cure rates of greaterthan 60% can be achieved in the majority of cases (118,156).

A benign, but potentially malignant, precursor of Choriocarcinoma is the hydatidiform mole, which when locally invasive inthe uterus requires hysterectomy. Surgical removal of the uteruscompromises the quality of life in young women. Accordinglymethotrexate has been used in selected patients and has beenfound to be highly effective in providing a nonsurgical approachto eradicating invasive and metastatic moles. Subsequent fertilityand normal pregnancy in such patients have not been impaired(104).

ALL in Children

The sequential studies leading to the development of curativetreatment for ALL deserve attention, since many of the studiesrelating to experimental design, criteria for response, the importance of preclinical modeling, cytokinetics, pharmacology, andparticularly the importance of dose, schedule, and combinationchemotherapy were major targets of quantitative and often original studies in this disease (57).

Chemotherapeutic Agents

The folie acid antagonists were introduced in 1947; the glu-cocorticoids and adrenocorticotrophic hormone in 1951; 6-mer-captopurine in 1953; vincristine and cyclophosphamide in 1961;and, more recently, asparaginase, anthracyclines, and 1-0-D-arabinofuranosylcytosine.

In 1955, a quantitative, prospective (scientific) clinical trial wasfirst applied to cancer (66), specifically to acute lymphocyticleukemia in children, with emphasis on precisely defining thefollowing in advance: the therapeutic hypothesis; selection ofpatients; treatment strategy and tactics; quantitative criteria forresponse; and major biostatistical input concerning experimentaldesign, including, where appropriate, randomization and stratification, quality control, and mechanisms for data collection andanalysis (66,196).

Complete Remission

Complete remission consists of the complete clinical and he-matological disappearance of disease. It was found in the abovequantitative study that the most powerful discriminant for prognosis in terms of survival was the attainment of complete remission (66, 71).

Increasing the Complete Remission Rate

Given the importance of complete remission, emphasis wasgiven to increasing the complete remission rate. This was mostreadily achieved with combination chemotherapy. Single agentsproduced complete remission rates varying from 20 to 50%,whereas combinations of Chemotherapeutic agents, particularlyvincristine and prednisone, produced complete remission ratesof 80-90% (63, 67,167). These studies were the first to under

score the importance of combination chemotherapy.The fundamental rationale for combination chemotherapy is

tumor cell heterogeneity, indicating the need for multitargetedtherapy (116). Agents with qualitatively different mechanisms of


6524




action are, for the most part, not associated with cross-resist

ance. Thus combination chemotherapy reduces the risk of emergent drug-resistant tumor cells (116). In parallel studies wheredose was investigated as an independent variable, the dose-

response curve was steep for both tumor and host (83). Agentswhich had nonmyelosuppressive dose-limiting toxicity could be

used in combination at full doses and hence accrue the effectiveness of the combination without compromise in dose (59). Inretrospect, the ultimate rationale for combination chemotherapyis the pragmatic one, i.e., essentially all highly effective andcurative chemotherapeutic regimens represent combinations.Combination chemotherapy has become a highly sophisticatedbasic and clinical research discipline and has been the subjectof in-depth reviews (8).

Treatment during Remission

With the high complete remission rate achieved as above,survival was somewhat improved, but all patients relapsed fromremission. Accordingly treatment during remission was essential.Experimentalists, particularly Skipper ef al. (171), had demonstrated the first order kinetic effect of chemotherapeutic agents.Given a homogeneous population of cells, the fractional reductionof tumor cells was constant, independent of tumor burden.Hence complete remission of the tumor represented "the tip ofthe iceberg" in an exponential sense and substantially further

treatment (treatment during remission) was required to eradicatemicroscopic disease (63).

The signal studies addressed to the biology of the microscopictumor burden as defined by chemotherapy were as follows.

Prolongation of Remission. It was demonstrated that theantileukemic agent 6-mercaptopurine significantly prolonged the

duration of complete remission as compared to a placebo. Thisestablished the importance of treatment during remission andalso represented the first "adjuvant" study (70).

Effect of Schedule. Methotrexate was the best single agentfor treatment during remission, but relapse invariably occurred.Experimental studies in transplanted leukemias indicated thatthe intermittent administration of methotrexate was superior todaily administration of methotrexate (83). A study comparingtwice weekly methotrexate with daily methotrexate in ALL incomplete remission indicated a marked prolongation of remissionwith the former program (167). This established the premise thatschedule could influence the therapeutic index and started thetrend towards intermittent treatment. While the rationale for thisapproach was obscure at the time, it probably relates to therecently demonstrated evidence that in vitro drug resistance tomethotrexate occurs much more readily with continuous treatment as compared to intermittent selection pressure (166).

Dose. In a randomized comparative study, it was found thata 2-fold difference in dose of agents used during remission

resulted in a significant improvement of duration of remission forthe higher dose (142).

Combinations. As with remission induction, combinations ofchemotherapeutic agents, including, in particular, intermittentmethotrexate and continuous 6-mercaptopurine administration,

significantly prolonged the duration of remission as compared tosingle agents (64, 103).

Meningeal Leukemia

With the above high rate of complete remission and increasingduration of remissions, there occurred an increasing frequencyof meningea! leukemia in patients in complete remission to thepoint where >50% of patients relapsed with meningea! leukemia(49). Detailed clinical studies, as well as studies of an experimental model, indicated that the central nervous system was involvedwith microscopic disease in the majority of patients at the timeof diagnosis (78). Pharmacological studies indicated that theantileukemic agents used systemically did not pass the blood-

brain barrier (146). Thus the central nervous system was apharmacological sanctuary wherein leukemia could progress inpatients in otherwise complete systemic remission.

Brain irradiation and intrathecally administered methotrexatehad definite, albeit limited, effectiveness in patients with overtmeningeal leukemia. It was therefore applied in quantitativestudies immediately following remission induction in an effort toeradicate microscopic disease (so-called CNS prophylaxis). This

resulted in a reduction of meningeal leukemia from in excess of50% of patients in complete remission to <10% in most and<5% in some studies (3, 4, 67,141).

The VAMP Program

A number of experimental studies indicated, and clinical studies implied, that optimal treatment would consist of maximal,intensive, intermittent "up front" combination chemotherapy. This

led to the development of the VAMP program, which produceda high complete remission rate and long durations of remissionbut was limited by the absence of CNS prophylaxis (63,73, 91).Nevertheless, the VAMP program served as a stimulus andprototype for subsequent combination chemotherapy studies,such as those in the lymphomas.

The Cure of ALL

The integration of the aforementioned strategies, i.e., combination chemotherapy for complete remission induction; followedby CNS prophylaxis; followed by combination systemic treatmentduring remission, resulted in a long-term disease-free survival(cure rate) in 40-50% of patients (102,103,141,160).

The Last 10 Years. The addition of asparaginase and/or ananthracycline to vincristine and prednisone for remisssion induction produces complete remission rates approaching 100% andfurther prolongs the duration of remission (102,141,160).

The use of asparaginase i.m. weekly and Adriamycin duringthe first 6 months of remission, on a background of 6-mercap

topurine and intermittent methotrexate administration, adaptedto prognostic factors has resulted in disease-free survival forstandard-risk patients approaching 100% and 70% for poor-risk

patients, with an overall survival of 85% (161).Intensive multiple combination "up front" therapy, involving the

intensive use of multiple agents (vincristine, prednisone, dauno-rubicin, Adriamycin, asparaginase, dexamethasone, cyclophos-phamide, and ara-C) during the first 8 weeks of therapy, hasalso provided disease-free survival curves in the range of 70-

80% (95).CNS prophylaxis with radiotherapy has been associated with

mild (about 10%) deficits in mentation, attention span, and other


6525




aspects of central nervous system function (78, 133, 157). Thishas led to investigation of alternative approaches to CNS prophylaxis. High-dose methotrexate with leucovorin rescue supplies therapeutic levels of methotrexate to the cerebrospinal fluid,providing effective prophylaxis of CNS leukemia, particularly instandard-risk patients. The issue as to its relative effectivenesscompared to brain irradiation with intralumbar intrathecally administered methotrexate is to some extent determined by riskfactors (56,143,157).

Prognostic Factors and Tumor Biology. Prognostic factorssuch as age, pretreatment white blood cell count, and mediastinalmass have provided for the stratification of patients into high-and low-risk groups.

These interrelated prognostic factors have been variably powerful, depending upon the treatment. More recently, a morefundamental pathobiological classification has been made possible by immunological phenotyping. These findings are consistent with the thesis that T-cell leukemias, and probably also theB-cell leukemias, represent monoclonal expansion of a givendifferentiation step. Cytogenetic studies are consistent with theclonal origin of leukemia and show reciprocal translocations thatmay affect the activity of oncogenes. Molecular biological studiesof immunoglobulin gene rearrangement indicate monoclonal arrest in patients with B-cell disease. Such changes demonstratethe B-cell origin, even of tumors that lack surface B-cell immu

nological phenotypes (113, 134, 149). Almost all patients cannow be categorized by cell lineage and differentiation levels.Various categories may demonstrate major differences in response to treatment and prognosis.

Acute Lymphocytic Leukemia in Adults

Acute lymphocyte leukemia in adults resembles high-risk ALL

in children in terms of clinical behavior, immunological phenotyping, and cytogenetics. The application of the aforementionedprinciples for ALL in children to ALL in adults include, in particular,the use of an anthracycline and/or asparaginase with vincristineand prednisone to achieve a high complete remission inductionrate and the use of combination chemotherapy during remission.This includes alternation between cell cycle-nonspecific and cellcycle-specific agents; the use of an anthracycline early in remission; and related approaches. Disease-free survival plateaushave been achieved in 40-60% of patients, a range approacningthat of high-risk ALL in children. This is particularly true of the

younger adult patients who tend to have more favorable prognostic factors (7,107,125,165).

Disseminated Hodgkin's Disease

Alkylating agents were found to be effective in producing tumorregression in Hodgkin's disease in World War II. Methotrexate

and vinblastine were observed to be effective by the early 1960s,and vincristine and prednisone were separately found to beeffective and, importantly, nonmyelosuppressive.

In comparative studies, Vinca alkaloids and alkylating agentswere found individually to produce partial responses in 50% andcomplete responses in 10% of patients. Responses were slowin developing and relatively brief (2-4 months) (23).

Dose. This first randomized trial wherein dose was an independent variable was conducted in Hodgkin's disease and non-Hodgkin's lymphoma patients using alkylating agents and meth

otrexate (16, 69). Full doses of these agents produced responsein 60% of the patients, whereas the random sample of patientswho received one-half of the full dose had marginal antitumoreffects. A simiiar steep dose-response relationship held for sys

temic toxicity.MOMP. Given the aforementioned and the ALL experience,

the four-drug combination chemotherapy study (MOMP) was

initiated in 1963 (37, 62,197). It was based on the rationale that:(a) the agents had different mechanisms of action and presumably were not cross-resistant; (b) two of the agents were non

myelosuppressive and thus dose modifications for the combination should be minimal; (c) cytokinetic modeling and experimental in vivo studies of first order kinetic effect of single agents,drug resistance, and combination chemotherapy suggested thatagents with the aforementioned activity in combination might becapable of achieving a 10-12-log cell kill, which might be sufficient to eradicate the Hodgkin's disease (59,63,72); and (d) the

drugs were given in combination in 10-14-day courses every 4

weeks based on experimental and clinical evidence that myeloidand immunological recovery occurred during that interval. Suchintermittent treatment tended to be superior to continuous treatment not only for methotrexate but also for alkylating agents,and this effect perhaps can be generalized in experimentalsystems (97).

MOPP. In 1964, procarbazine, a nonclassical alkylating agentwhich had proved effective for the treatment of Hodgkin's dis

ease in Europe and in preliminary studies in the United States,was substituted for methotrexate (resulting in MOPP). Both theMOMP and the MOPP programs produced complete remissionin 60-80% of the patients. These remissions, in contrast to the

use of single agents, occurred rapidly and, most importantly,they were durable with an overall cure rate with very adequatefollow-up of 40-50% (38, 39).

Clinical trials indicated that maintenance treatment with MOPPdid not increase the cure rate, but that the duration of treatmentwith MOPP could be operationally determined by the rapiditywith which complete remission occurred and the results ofintensive (including pathological) staging prior to treatment cessation (191).

ABVD. Subsequent to the mid-1960s, additional agents werefound to be active in patients with Hodgkin's disease, including

dacarbazine, Adriamycin, and bleomycin. Accordingly, Adriamy-cin-based combinations, such as ABVD, were developed. These

combinations produced variable complete remission rates inpatients refractory to MOPP in the United States, but in largequantitative studies in Italy they produced response and curerates comparable to those achieved with MOPP (15). In a comparative study, MOPP alternated with ABVD produced a 75%disease-free survival estimate, compared to 50% for MOPP only(15). Noncontrolled studies of the MOPP-ABVD regimen with or

without radiation to pretreatment sites of bulk disease haveproduced similar cure rates (15,173).

Studies of treatment failure in patients achieving completeremission with MOPP indicated a remarkable pattern of relapse.As might be predicted from cytokinetic analyses, relapses occurred quite reproducibly at pretreatment sites of bulk disease.This might have major implications for treatment, particularlywith respect to follow-up radiotherapy (68,192).

Late Effects. In addition to the acute toxic effects that arewell known to cancer chemotherapy, the Hodgkin's chemother-


6526




apy experience produced two chronic effects worthy of note.Acute myelogenous leukemia occurred with a latent period of atleast 2 years following MOPP treatment in 5% of patients. Onthe basis of experimental studies, including mutagenicity and invivo studies, it is concluded that procarbazine in particular, andalkylating agents as well, are the major contributors to thisleukemogenesis. Of note is the fact that ABVD and programsfor ALL which do not use procarbazine or alkylating agents donot show an increase in secondary acute myelogenous leukemia.With a relatively large number of active agents for Hodgkin's

disease, it should be possible to structure treatment programswith high cure rates which factor out agents known to be potentmutagens and carcinogens (21, 35).

The above figures for complete response and cure rates (60-80%) for Hodgkin's disease relate to patients with advanced

disease, i.e., Stages 1MBand IV. A number of clinical trials indicatethat combination chemotherapy plus limited-field radiotherapy ishighly effective for patients with Stages I and IIA disease andthat combinations of chemotherapeutic regimens with radiotherapy may improve disease-free survival in certain intermediatestages of Hodgkin's disease (154). The interpretation of these

studies, however, has been complicated by improvement insalvage therapy. Thus total nodal radiotherapy plus MOPP issuperior to MOPP alone in certain studies of intermediate-stageHodgkin's disease in terms of the initial disease-free survival, but

the difference disappears with long-term follow-up because sal

vage therapy with radiotherapy and ABVD is superior in patientswho have received one rather than two modalities as initialtreatment (154).

Non-Hodgkin's Lymphoma

Shortly after the demonstration that combination chemotherapy could produce high initial complete response rates in Hodgkin's disease, the MOPP program, with cyclophosphamide as

the alkylating agent (C-MOPP), was used in the treatment ofnon-Hodgkin's lymphoma. In diffuse histiocytic lymphoma, a 40-

50% complete response rate was achieved. Essentially all ofthese patients remained in remission, with a cure rate of approximately 40% (36). This reaffirmation of the importance of an initialcomplete remission led to a sequence of studies of combinationchemotherapy designed to (a) increase the complete remissionrate and (b) improve the durability of complete remissions.

Adriamycin had major single agent activity in non-Hodgkin's

lymphoma, including particularly DHL; the CHOP regimen, whichincludes Adriamycin, produced response rates of 60% and long-term disease-free survivals in the range of 30-40% (110,128).

Subsequent studies resulted in further modifications of combination chemotherapy designed to: (a) add effective agentswithout compromising the dose rate of the basic CHOP components (e.g., bleomycin, high-dose methotrexate with rescue); (b)

control the proliferate thrust between courses of chemotherapyfor this aggressive tumor (distribute the administration of vincris-tine and high- or intermediate-dose methotrexate with rescue tothe interface between combination chemotherapy courses); (c)add other agents of known effectiveness but which might compromise the dose of cyclophosphamide and Adriamycin (VP16,procarbazine); and (cf) cycle combinations of chemotherapeuticagents (PROMACE-MOPP), with a rationale comparable to thatof MOPP-ABVD for Hodgkin's disease. Perhaps the two most

novel recent contributions to the combination chemotherapy ofDHL were: (a) cytokinetically based adjustments in the durationof courses of treatment in the PROMACE-MOPP program; and(b) the demonstration that high-dose methotrexate with leuco-

vorin rescue maintained the full antitumor activity of methotrexate but (with appropriate pharmacological monitoring) resulted inmuch reduced toxicity, thus making it ideal for combined therapy(40, 55, 61, 169, 175). Other combinations, such as COMLA(ara-C, vincristine, methotrexate with rescue, and cyclophospha

mide) also produced good results. It is difficult to compare theseprograms across institutions, but at least four of them, (PROMACE-MOPP, M-BACOP, COP-BLAM, CHOP Â±bleomycin Â±

VP16) produce initial complete remission rates approaching 80%and long-term disease-free survival plateaus of 50-60% (18,55,

115,169).Non-Hodgkin's lymphoma is an extraordinary heterogeneous

group of diseases; it has been the subject of a sequence ofhematopathologic classifications, of which the Rappoport hasbeen the most durable and the working formulation the mostrecent. Pathologically the intermediate or large cell group with adiffuse pattern is cytokinetically the most aggressive and alsothe most subject to curative treatment with chemotherapy. However, while the cure rate for DHL is in the range of 50%, it issubstantially lower for the less common forms such as diffusepoorly differentiated lymphoma and diffuse mixed cell lymphoma.

Approximately one-half of non-Hodgkin's lymphomas com

prise the nodular, indolent category. While these respond initiallyto single agent or combination chemotherapy with good remission rates and reasonable durability, the force of relapse andfailure is constant over time. With the possible exception ofnodular mixed lymphoma, there is no evidence that presentchemotherapy is curative.

Burkitt's Lymphoma

Whether epidemic in Africa or endemic in the United States,Burkitt's lymphoma is curable by chemotherapy. Burkitt dem

onstrated that single-agent cyclophosphamide was curative for

patients with Stage I and II disease. Relatively high cure rateshave been achieved with combination chemotherapy for Stage Iand II disease, with lower but definite cure rates for Stage IIIdisease (17,195).

Similarly lymphoblastic lymphoma, which is a T-cell disease

occurring primarily in adolescents and young adults, has curerates in the range of 40-70%, with treatment based on programssimilar to those for high-risk acute lymphocytic leukemia and/or

diffuse histiocytic lymphoma (184).

Acute Myelogenous Leukemia

Supportive Care. The dose-response curve for most chemotherapeutic agents is steep, and myelosuppression is the mostcommon form of dose-limiting toxicity. Therefore the develop

ment of blood product support and antibiotics for the control ofthrombocytopenia and for the prevention and treatment of infections has had a major impact on the effectiveness of chemotherapy in terms of safety and therefore in terms of dosing, withrespect to both unit dose and interval between treatments. Bonemarrow transplantation may be viewed, in part, as the ultimatein bone marrow support. Much of the research in blood productsupport and marrow transplantation began with and had its


6527




major impact on AML (reviewed in Ref. 88).Remission induction. ara-C was the first agent with substan

tial activity in AML. When given daily, complete response ratesin the range of 10-15% were achieved (47). Skipper ef al. (172)

in a series of elegant experimental studies in mouse L1210leukemia demonstrated a marked influence of schedule on thetherapeutic index, probably related to the cytokinetics of thetumor as compared to the bone marrow. In summary, they foundthat courses of ara-C which lasted twice the generation time ofthe leukemic cells provided substantial cytoreduction and suchcourses could be repeated without compromise every 4 days,an interval sufficient to allow for complete recovery from myelo-

suppression in the mouse. Comparative cytokinetics of AML andthe normal marrow in humans indicated that the appropriateextrapolation would be 5-day courses of continuous infusion,with a 9-10-day interval between such courses (139, 172). In

comparative and noncomparative studies, it was found that suchintermittent treatment produced significantly higher completeremission rates (35-40%), as compared to daily treatments

(15%) and significantly prolonged the duration of remission (10).The activity of the anthracyclines was demonstrated (181).

Daunorubicin is probably superior to Adriamycin because ofsomewhat lesser side effects relating to the gastrointestinal tract(190). When daunorubicin was combined with 5-day courses ofara-C, remission rates of 50% were achieved. Based on cytoki-netic considerations, 7-day infusions of ara-C were studied, andit was found that 7 days of continuous infusion of ara-C plus

three daily injections of daunorubicin (the 7 & 3 program) produced complete remission rates of 70% (145). Substantial complete remission rates were achieved in patients over 50 years ofage. As with ALL 15 years earlier, the stage was set for approaches involving treatment during remission designed to prolong the duration of remission and ultimately to eradicate themicroscopic tumor burden.

Early Intensification. The rationale for early intensificationwas based on the fact that the potential for cytoeradication wasmaximal immediately after complete remission induction when amicroscopic, minimally drug-exposed tumor burden existed, and

before the ravages of clonal evolution developed, particularlyspecific or pleiotropic drug resistance (96,121).

Single, highly intensive courses of ara-C given during remission

induction were attended not only by a high complete remissionrate but also by a prolonged duration of unmaintained remissions(22,25,52,179,187,188). ara-C exhibited a steep concentration

viability curve against AML cells in culture (127). Such was alsotrue in in vivo experimental animal studies. Moreover because ofthe cell cycle specificity and the presumed lack of stem cell effectof ara-C, bone marrow recovery tended to occur quickly (within

3 weeks) and increasing doses, which increased the magnitudeof myelosuppression, did not increase the duration of myelo-

suppression (158, 183,188).Late Intensification. The rationale for late intensification with

combination chemotherapy 6-12 months after treatment during

remission related to the expectation that a minimal tumor burdenmight exist at this time and thus provide maximal opportunity forcytoeradication (11). In addition, there is evidence for delayedcytokinetic recovery of tumor cells following treatment. Suchcytokinetically active cells should be more susceptible to chemotherapy (137).

In addition to the two primary agents, agents with limited but

definite effectiveness have been identified; these include 6-mer-

captopurine or thioguanine, azacytidine, probably vincristine andprednisone and, more recently, amsacrine and mitoxantrone.Accordingly combinations of agents which were rotated at appropriate intervals to minimize the emergence of drug-resistant

lines were used (183).Based on the above, several studies emphasizing high doses

of ara-C for remission induction and/or early intensification and

often including the sequencing of other active agents wereundertaken during remission. These trials, in younger patients,produced complete remissions approaching 80% with continuous, complete remission curves (long-term disease-free survival)

as high as 50% in pediatrie AML patients (22, 183). In adults,late relapses still occur, but survival plateaus in the range of20% have been achieved in a number of studies (28, 111, 126,144,182).

AML Prognostic Factor Analysis. Using multistep regressionanalysis over a series of studies, prognostic factor profiles forcomplete remission induction and for duration of remission measured from different time points were identified (76). Of considerable interest was the fact that prognostic profiles for completeremission induction differed substantially from those for durationof remission (112). With such information, patients could besegregated with respect to treatment regimens; I.e., patientswith the expectation of poor response to conventional treatmentcould be started on new treatment. Perhaps the most compellinghas been the correlation of cytogenetic abnormalities with prognosis. For example, inversion in chromosome 16 in AML isassociated with an improved survival (median survival time, 25months). Trisomy 8 has an intermediate prognosis (median survival time, 10 months), but complex chromosomal changes indicative of two or more stem lines and therefore clonal evolutionand heterogeneity have a markedly adverse effect on prognosis(median survival time, 2.5 months) (194).

AML Biochemical Pharmacology. Detailed studies of thebiochemical pharmacology of ara-C in patients with AML have

provided significant variations which may predict prognosis onthe one hand and influence the choice, dose, and duration ofara-C on the other hand. These include studies of ara-C triphos-phate pool concentrations and half-times, DMA polymerase inhibition, and ara-C incorporation into DNA (114,159,106).

In the latter studies, it was observed that ara-C at high

concentrations produced chain termination of DNA synthesis,precluding recovery of DNA synthesis, and therefore causingmajor cytotoxicity. At low concentrations in the HL-60 cell line,

chain elongation was slowed, and differentiation of this humanacute promyelocytic leukemia line in vitro was demonstrated.This was confirmed by morphological and myeloid antigen studies and was associated with a marked decrease in expressionof the myc gene. Thus clinical trials designed to induce maturation have been undertaken (186).

Very high doses of ara-C have, in preliminary studies, pro

duced substantial remission rates in patients with refractory AMLand lymphoma (22).

Testicular Cancer

In the 1950s, it was demonstrated that actinomycin D produced a significant response rate in patients with disseminatednonseminomatous testicular cancer. Combinations of actinomy-


6528




ein D, methotrexate, and chlorambucil were equally and possiblymore effective than was actinomycin D alone, and some 5-10%of patients thus treated had long-term complete remissions

consistent with cure (120).In the mid-1960s, vinblastine was found to produce partial

responses in a substantial proportion of patients. It was demonstrated that higher doses of vinblastine, particularly whengiven in combination with bleomycin, produced significant complete response rates, some of which were durable (163).

In preclinical toxicological studies, cisplatin was demonstratedto be selectively toxic to the male gonad. Clinical trials indicatedsubstantial activity against refractory testicular cancer (100). Thestage was set for multidrug therapy.

As with all of the aforementioned studies, major attention toclinical pharmacology, toxicology, dose scheduling, and durationof treatment was essential before the optimal program, VBP,was identified. These drugs have differing dose-limiting toxicity

and thus can be used in combination at full dose. It has nowbeen widely confirmed that this combination produces a highinitial complete remission rate and durable remissions in 50-70%

of patients in most studies and in upwards of 90% of patients insome studies (45, 46, 75, 180). Cure is generally achieved afterfour courses of VBP. Patients either show evidence of refractorydisease by that time or more commonly are free of clinical andmarker evidence of disease and do not relapse. Testicular canceris an aggressive disease such that relapse of patients in completeremisssion after cessation of treatment usually occurs within thefirst year, and it almost always occurs by 24 months.

Partial responses to VBP can be converted in many instancesto complete responses by surgical extirpation of regressed butpersisting lesions. The durability of such remissions approachesthat of de novo complete remissions (41). This important treatment strategy is consistent with other evidence that high-risk

sites of relapse (pretreatment sites of bulk disease and incompletely regressed lesions) after chemotherapy may be definitivelycontrolled by surgery and/or radiotherapy.

This highly effective and curative combination chemotherapyfor advanced testicular cancer raises the question as to its utilityas adjuvant therapy. Patients with Stage I disease have a 10%risk, and those with Stage II disease have a 50% risk for relapseafter local therapy. It was found in both comparative and non-

comparative studies that two courses of VLB following localtreatment produced essentially a 100% cure rate for Stage I andII disease. In order not to treat patients who do not requiretreatment, a sample of patients with locally controlled Stage Iand II disease was followed closely, particularly by the use oftumor markers and chest film. Early relapse was identified. Thecure rates for such patients with four courses of VLB approach100%. Thus adjuvant chemotherapy is probably not required,except in high-risk patients or in patients where compliance is

suspect (45).The development of radioimmunoassays for measuring nano-

gram quantities of human chorionic gonadotropin and other testistumor markers has been of critical importance in the evaluationand particularly in the tactics of treating and following patientswith testicular cancer.

Major advances have been achieved in the control of centralnausea and vomiting induced by chemotherapy. This is a majorproblem with respect to cisplatin and often precluded the deliveryof adequate doses. The development of new and increasingly

effective antiemetics for the control of cisplatin-induced emesis

was an important step in the evolution towards curative chemotherapy for testicular cancer.

The above figures apply to patients with classical, nonsemi-

nomatous testicular cancer. Patients with extremely high hormone titers and tumor burdens and patients with extragonadalgerm cell primary tumors do not respond as well, and differenttreatment strategies are indicated.

ADJUVANT CHEMOTHERAPY

The above studies and results relate to the use of chemotherapy against established clinically evident disseminated disease.Evidence in experimental in vivo tumors indicates that a givenchemotherapy which is marginally effective against macroscopic,clinically overt disease may be highly effective and indeed curative against a microscopic burden of the same tumor (82, 170).Essentially all studies relating to the science of tumor biology,including cytokinetics, heterogeneity, and tumor neovasculari-zation, strongly support the thesis that the potential for cyto-

eradicative chemotherapy should be far greater against themicroscopic (<109) tumor burden as compared to clinically evident (>1011) tumor burden in humans (80, 96). There are many

clinical circumstances wherein the nature and the extent of theprimary tumor are such that a high probability exists that disseminated micrometastases are present at the time when localcontrol is achieved with surgery and/or radiotherapy. In suchcircumstances where chemotherapy has proven of moderate butlimited benefit in clinically overt metastatic disease, such treatment has been moved "up front" immediately behind local control

in an effort to eradicate micrometastatic disease. This is calledadjuvant chemotherapy, i.e., adjuvant to local treatment withsurgery and/or radiotherapy. Historically the first studies of adjuvant chemotherapy and, indeed, many of the principles ofadjuvant chemotherapy were initially applied, developed, andsubjected to quantitative clinical trials in the pediatrie solid tumors.

Pediatrie Solid Tumors

This heterogeneous group of relatively rare tumors includesWilm's tumor, embryonal rhabdomyosarcoma, and Ewing's sar

coma. These tumors have been the subject of a common multi-

disciplinary definitive treatment strategy. Actinomycin D addedto localized treatment of Wilm's tumor with surgery and/or

radiotherapy increases the cure rate from 40 to 80% and wasthe first demonstration of the effectiveness of adjuvant chemotherapy (50). It is in these tumors that neoadjuvant chemotherapy; i.e., chemotherapy used initially to reduce local disease,was first shown to be effective in increasing the subsequentcurability of radiation and/or surgery (33). For Wilm's tumor,

actinomycin D and vincristine are the most effective combination;for embryonal rhabdomyosarcoma and Ewing's tumor, vincris

tine, actinomycin D, and cyclophosphamide, with or withoutAdriamycin, are the most effective (26, 89).

In a series of comparative studies, it has been establishedthat: (a) localized treatment, including surgery and/or radiation,may be used initially if local control can be achieved; (b) chemotherapy, as above, should be applied initially if stage reductionis required for local control by surgery and/or radiotherapy; and


6529




(c) chemotherapy following surgery and/or radiotherapy is required in the majority of patients to eradicate microscopic and,in some instances, macroscopic mÃ©tastases.As a generalizationfor these tumors, radiation and surgery would be expected tocure some 30%; and with multimodality therapy, including chemotherapy, the figures approach 80% (26). Neuroblastoma is lessresponsive, although recent evidence with combined modalitytherapy featuring alkylating agents indicates that durable complete remissions can be achieved, particularly in Stage III patients(150).

Breast Cancer

Breast cancer is the most common cause of death from cancerin women. The risk of ultimate treatment failure and death inpatients with breast cancer (and in other neoplastic diseases aswell) can be determined by evaluating the extent of the diseasefollowing diagnosis (staging). The principal prognostic discriminant for patients with localized disease is axillary lymph nodeinvolvement. Thus local treatment with surgery and/or radiotherapy provides a 75% 10-year survival for node-negative patients.For node-positive patients, the respective figures are 15-35%

(54, 93).The lack of a disease-free survival plateau and therefore an

operational definition of cure for breast cancer has been presented. Thus, the risk for failure after treatment of primary breastcancer, while it decreases with time, continues beyond 5 andeven 10 and 15 years. Nevertheless some of the randomizedtrials of adjuvant chemotherapy for breast cancer show significant differences in favor of chemotherapy in long-term disease-

free and overall survival (up to 10 years) (12,14, 53, 92).Axillary node-positive breast cancer patients are at high risk

of having disseminated micrometastatic disease, as evidencedby the fact that usually within 1 to 3 years, but often later, themajority (70-90%) of patients who will relapse do so with clinically overt disease. Clinically overt metastatic disease can betreated effectively with chemotherapy or hormonal therapy, buttreatment failure eventually occurs and the patient is destined todie of the disease.

There are a number of chemotherapeutic agents, includingalkylating agents, antimetabolites such as methotrexate andfluorouracil, and Adriamycin, which individually produce responserates in 25-50% of patients. Combinations of chemotherapeutic

agents in comparative and noncomparative studies producehigher response rates (in the range of 50%), with combinationsinvolving Adriamycin being perhaps superior; i.e., they produceresponse rates in the range of 60-70% (93). This degree of

responsiveness of clinically overt disease (high tumor burdendisease) would suggest that such treatment applied to low tumorburden disease (micrometastases immediately following controlof the primary tumor in patients with Stage II disease, adjuvantchemotherapy) might be capable of eradicating the tumor. Inexperimental transplanted tumors, there is definitive and widelyconfirmed evidence that a chemotherapy program which is onlypartially effective against a high tumor burden has a much higherprobability of being curative against a low tumor burden (81, 82,170). Moreover the effectiveness, in terms of producing tumorregression in the high tumor burden setting, correlates withcurability for the same treatment in the low tumor burden setting.

As a result of the above, adjuvant chemotherapy for patients

with node-positive breast cancer in studies using modern tumor

biological, chemotherapeutic, pharmacological, and experimentaldesign concepts and techniques was begun in the early 1970s.These early studies, where chemotherapy was compared to notreatment, indicate that, particularly for premenopausal women,disease-free survival is significantly improved as a result of

adjuvant chemotherapy (12, 14, 53, 92). Combination chemotherapy, usually CMF or close analogues thereof, is superior tosingle-agent therapy (31,93). The initial concept of maintenance

treatment carried out for 2 years is probably inappropriate,inasmuch as there is experimental (Skipper) and now clinicalevidence that more short-term treatment is equally effective.

Thus where duration of treatment was an independent variable,CMF for 6 months proved as effective as CMF for 12 months(176), and a combination of Adriamycin and cyclophosphamidefor 4 months was as effective as the same regimen deliveredover an 8-month period (94).

Retrospective analysis of clinical studies (13), as well as numerous experimental studies, suggest that dose, or more properly dose rate, correlates with the capacity of the treatmentregimen to control micrometastatic disease; however, someother clinical studies have not confirmed this. Thus high prioritymust be given to prospective studies where dose is the independent variable. Hormone therapy, when added to chemotherapy, in postmenopausal, estrogen receptor-positive women, inrelatively short-term studies, further improved disease-free sur

vival (52). Whether combinations including Adriamycin are superior to those without and whether relatively recently introducedstrategies, such as the rotation of non-cross-resistant combina

tions, will improve effectiveness remain to be determined.The most important, but also the most difficult, question is

whether adjuvant chemotherapy has significantly increased thecure rate. Two of the best designed studies, which also havethe longest follow-up (10 years), are the melphalan versus control

(NSABP) (53) and the CMF versus control (Milan) (14) studies.Here disease-free survival, particularly in premenopausal pa

tients, is clearly superior in patients receiving chemotherapy.More important, overall survival is significantly superior at the11-year (maximum) follow-up point (a 20% improvement) for

premenopausal patients. This improvement in survival appearsearly and progresses with time. Two other major studies demonstrate improved disease-free and overall survival for adjuvantchemotherapy in both pre- and postmenopausal patients with 8-and 15-year follow-up (79, 136). Several reports, however, do

not confirm the effectiveness of adjuvant chemotherapy in postmenopausal patients.

Small Cell Lung Cancer

This cytokinetically aggressive tumor is responsive to a varietyof chemotherapeutic agents. For patients with clinically limiteddisease (;'.e., disease limited to the chest), complete response

rates of 40-60% can be achieved with combination chemother

apy (29, 123).Relapse in the central nervous system is common, occurring

in 25% or more of patients. This can be reduced to <5% bycranial irradiation early in complete remission (123). A morecommon site of relapse in patients entering complete remissionis at the pretreatment site of bulk disease in the chest. Irradiationhere will also reduce the risk of local, thoracic relapse from 60%


6530




to as low as 15-25% (105). Remission induction with combina

tion chemotherapy and particularly the rotation of combinationsof chemotherapeutic agents during remission for up to 1 yearhave markedly improved disease-free and overall survival for this

disease (29, 124). While the majority of patients relapse, some10-20% of patients with limited, small cell lung cancer will

continue disease free beyond 3 or 4 years (29,123,124). Whilethe risk of relapse markedly decreases after 2 years, 19 of 97patients disease free at 2.5 years subsequently relapsed, 2 after8 years (6).

Osteogenic Sarcoma

Local control can almost always be achieved for this tumor byamputation. Nevertheless the survival rate for the 30 yearspreceding the 1970s was in the range of 20% largely becauseof the development of lung mÃ©tastases(74,129).

In the early 1970s, it was demonstrated that high-dose meth-

otrexate with rescue produced rÃ©ponsesin a small proportion ofpatients with advanced disease and, when used as adjuvantchemotherapy immediately following surgery, produced a disease-free survival plateau of 40% (108). At about the same time,

Adriamycin was found to be comparably effective (32). Thecombination of high-dose methotrexate and Adriamycin in the

adjuvant setting, particularly where dose rate of the individualagents was preserved, produced the expected additive rate, i.e.,disease-free survival plateaus between 50 and 60% (84). These

agents in various combinations with cisplatin and other agentsin a variety of studies produce disease-free survival plateaus inthe range of 50-70% (24), and in a more complex combination,but featuring, in particular, high-dose methotrexate and Adriamycin, a disease-free survival plateau of 70-80% has been

achieved (151,185).In the mid-1970s, stimulated by the capacity of chemotherapy

to produce tumor regression, limb-preserving surgery was de

veloped. Chemotherapy before surgery, i.e., neoadjuvant chemotherapy, often resulted in cytoreduction in the primary tumor,providing an improved opportunity for local bone tumor resectionand endoprosthesis insertion (43,109,152).

In addition, preoperative chemotherapy provides an opportunity to evaluate the effectiveness of high-dose methotrexate with

or without Adriamycin against overt disease and to correlate thiswith subsequent survival which is a function of the capacity ofchemotherapy to control micrometastatic disease. It was foundthat cytoreduction by chemotherapy of the primary tumor wascorrelated with eradication of micrometastatic disease, mainly inthe lungs, when the same chemotherapy was continued aftercontrol of the primary tumor. Accordingly response of the primarytumor was used as a measure of effectiveness of chemotherapy,and major adjustments were made in the adjuvant program forpatients in whom primary tumor regression was suboptimal (151,185).

Osteogenic sarcoma is a rare disease, such that comparativestudies are difficult, if not impossible, to conduct in single institutions. Clinicians at the Mayo Clinic noted a progressive increasein disease-free survival of osteogenic sarcoma into the early

1970s in the absence of adjuvant chemotherapy. Therefore, theyconducted a study in the mid-1970s, wherein patients, followingcontrol of the primary tumor, were randomly allocated to high-

dose methotrexate with leucovorin rescue or to an untreated

control group (42). In a relatively small sample of patients (only30% of eligible patients agreed to randomization), there was nodifference between the two groups, both having disease-freesurvival plateaus in the range of 40% (42).

Does adjuvant chemotherapy indeed improve the cure rate ofpatients with osteogenic sarcoma, or have we been a victim ofthe vagaries of early diagnosis, evaluation, and other factorswhich might change the natural history? To answer this question,two randomized studies were undertaken, one a single institution(UCLA) study, and the other in a cooperative group (POG).Following surgical control of the primary tumor, patients wererandomly allocated to combination chemotherapy, featuring high-dose methotrexate with rescue and Adriamycin, or were allocated to no-treatment control groups. These studies have beencompleted, and a highly significant difference in 2-year disease-free survival in favor of the chemotherapy arm was observed inboth studies (44, 122).

Soft-Tissue Sarcomas in Adults

Metastatic soft-tissue sarcoma is responsive to Adriamycin,

which produces partial responses in approximately 30% of patients (138). In most studies, this is increased to 40 to 60%by the addition of dimethyltriazinoimidazolecarboxamide, cyclo-

phosphamide, and perhaps vincristine (9, 85, 86). From 10 to15% of such patients with overt metastatic soft-tissue sarcomaachieved complete remission, about one-third of which (3 to 4%

of the total) are durable (189).Adriamycin and Adriamycin combinations were therefore eval

uated in the adjuvant treatment of high-grade soft-tissue sarco

mas, where local control had been achieved. In randomizedstudies, both positive and negative results have been reported(2,155). Improved overall survival for all patients in recent years,probably because of better control of the primary tumor throughintegrated surgery and radiotherapy, has complicated the designand interpretation of adjuvant studies (174). A large controlledintergroup study of the role of adjuvant chemotherapy in soft-tissue sarcomas is ongoing.

Gastric and Rectal Carcinoma

Gastrointestinal carcinoma is generally poorly responsive tochemotherapy. While response rates of up to 40% for gastriccarcinoma using combination chemotherapy have beenachieved, the figures for the remainder of nonesophageal gastrointestinal carcinomas are in the range of 20% (132). Nevertheless major multiinstitutional adjuvant chemotherapy trials havebeen undertaken.

For Stage II, a regional gastric carcinoma, a multiinstitutionalstudy has compared fluorouracil plus methylcyclohexylnitrosou-rea to a no-treatment control arm following surgery. There wasa significant (approximately 20%) improvement in disease-free

and overall survival in the adjuvant arm (30). However, negativestudies have been reported (101 ).

In a study of high-risk localized rectal carcinoma conducted by

the same multiinstitutional group (Gastrointestinal Tumor StudyGroup), the addition of postoperative radiotherapy increasedlocal control as compared to a randomized control group. Theaddition of fluorouracil plus methylcyclohexylnitrosourea produced a further and significant (20%) improvement in disease-


6531




free and overall survival (131 ). These studies of gastric and rectalcarcinoma await confirmation and extension.

Bone Marrow Transplantation

Bone marrow transplantation exploits the dose effect, both forradiotherapy and for chemotherapy (usually cyclophosphamide).It has been most effective when used in patients with acuteleukemia in the minimal tumor burden setting that is presentearly in complete remission (177). A low cure rate was achievedfor acute myelogenous leukemia with total body radiation only.Cyclophosphamide, when added to total body radiotherapy,increased the cure rate. In AML, some 50% of patients treatedearly in complete remission and supported by histocompatiblebone marrow transplantation are cured (177). Thirty % die,largely of graft-versus-host disease. Only 20% have relapse of

leukemia. Comparable figures have been achieved with combinations of intensive cyclophosphamide and busulfan (164). Similar programs with matched allogeneic or autologous bone marrow (with or without chemotherapy or immunological approachesto controlling bone marrow "contamination") have provided a

variable proportion of long-term disease-free survivors in patients

with acute lymphocytic leukemia in second or subsequent remission (147,177), patients with acute myelogenous leukemia (177),selected patients with chronic myelogenous leukemia in stablephase (confirmed by eradication of the Philadelphia chromosome)(51), and in patients with various types and stages of high-risknon-Hodgkin's lymphoma (135,140).

Ovarian Cancer

Cytoreductive surgery (debulking) improves response to subsequent chemotherapy in terms of duration of disease control(87). Thus, surgery plays a relatively novel role for Stage III andIV ovarian cancer in terms of reducing the tumor burden inpreparation for systemic treatment and also is used in endstaging (second look) to determine the effectiveness of systemictreatment following debulking. The alkylating agents have longbeen known to be effective in producing tumor regression inperhaps 50% of patients with ovarian cancer. The addition ofAdriamycin and of cisplatin has increased the overall responserate and particularly has resulted in complete clinical tumorregression in 40% of patients (27, 193). Up to 50% of Stage IIIand IV disease patients who achieve complete clinical tumorregression will, with end staging (second look operations), bemicroscopically disease free. In those studies using this approachwith 5-year or greater follow-up, there is evidence that 15-20%

of all patients with Stage III and IV disease so treated are clinicallyand microscopically disease free (27, 47,193). Whether this canbe improved upon by more effective chemotherapy (34), by moreeffective initial surgery, by monitoring ovarian antigen, and bymonitoring with second-look operations, intraperitoneal chemo

therapy, and/or immunological approaches remains to be determined (27, 34, 147,193).

NEOADJUVANT CHEMOTHERAPY

The improved effectiveness of chemotherapy in squamous cellcarcinoma, largely as a result of the use of platinum-based

combinations, has reopened these diseases to approaches involving initial chemotherapy in an effort to reduce the size of the

primary tumor (stage reduction), such that the primary tumorbecomes operable and/or treatable with radiotherapy with curative intent. In addition, disseminated micrometastatic disease,the risk of which will depend on the primary site, type, and extent(stage), will also be addressed initially (58). This is of importancein view of the fact that micrometastatic disease is probablykinetically more aggressive than overt disease and thus at considerable risk of mutation to drug resistance. Mutation theory,modeling, and experimental studies suggest that the risk ofmicrometastatic disease developing resistant cell lines over arelatively short time period (several months) may be major (80,168). To this extent, the initiation of systemic treatment in theform of neoadjuvant chemotherapy avoids the 1- to 2-monthdelay which is likely to occur if the primary tumor is treatedinitially with surgery and/or radiotherapy. Neoadjuvant chemotherapy with respect to childhood tumors and osteogenic sarcoma has already been discussed. The development of increasingly effective agents and combination chemotherapy for squamous cell carcinomas has suggested that the neoadjuvant approach may be an idea whose time has come.

In head and neck cancer, in which neoadjuvant chemotherapyis under the most intensive study, several combination regimens,which include cisplatin, can produce initial tumor regression ratesof 70 to 90%, with complete response occurring in 20 to 50%of patients (1, 48, 77). Following chemotherapy, such patientsare treated with surgery and/or radiotherapy with curative intent.Whether surgery should be decreased in terms of extent ofresection and radiotherapy reduced in terms of field size anddose because of prior tumor reduction with chemotherapy response remains controversial. What seems clear in some studiesis that survival after surgery and radiotherapy correlates with thedegree of response to neoadjuvant chemotherapy. Thus patientswho achieve complete remission after chemotherapy have relatively high survival rates, as compared to those who achievepartial responses (1, 48). It remains to be determined whetherthis approach will in fact increase the cure rate in patients withadvanced (Stage III and IV) head and neck cancer. Other tumorsfor which neoadjuvant chemotherapy is the subject of studyinclude Stage III regional non-small cell lung cancer, Stage III

breast cancer, esophageal cancer, bladder cancer, anal carcinoma, and, as above, osteogenic sarcoma.

CONCLUDING AND SUMMARY REMARKS

The final arbiter of advances in curative treatment for a givendisease must be reduction in national mortality attributable tosuch treatment. As indicated in the introduction, it may take 5 to20 years from the time of introduction of curative treatment torecognize its impact on national mortality. For certain diseaseswhere there has been a major impact of curative cancer chemotherapy, where such treatment has been in effect for a substantial number of years, and where the disease is dynamic, asignificant reduction in mortality has, in fact, occurred. For example, this has been conclusively demonstrated for acute lymphocytic leukemia in children, Hodgkin's disease, diffuse histio-

cytic lymphoma, pediatrie solid tumors, testicular cancer, andgestational trophoblastic cancer (117,130).

A more current and therefore relevant measure of the impactof curative treatment is presented in Table 1. Even here, the timelag and some of the other problems mentioned in the introduction


6532




Table 1

Curability of cancer by chemotherapy (1983)

PotentialcurabilityEstablishedType

ofcancerALL

(pediatrie)ALL(adult)AML(pediatrie)AML(adult)Breast(premenopausal)Breast(postmenopausal)Gastric

(StageI)Hodgkin's(StagesIIIand

IV)Lung,smallcellUmitedAdvancedLymphoma,non-Hodgkin'sOvarian

Pediatrie solidtumorsTesticularTrophoblastic

diseaseTotalIncidence

(â€”)"2,000

(2,000)3,600(3,600)350

(350)6,000(4,500)41

,500(20,750)72,500(26,100)24,500

(8,085)7,100(4,260)18,005(15,188)18,005(9,315)23,000(9,315)23,000

(7,000)2,250(2,135)5,400(3,240)1,000(1,000)%50202010100040100400

25-7560>80No.1,000720704502,075001,7041,51903,72601,0741,94494815,230Putative%8040402020151580205651060-9690>80No.1,6001,4401409004,1503,9151,2133,4083,0387596,5217001,6382,91694833,286

a (â€”), subset appropriate for curative intent chemotherapy (see text) (3). For

references, see text." Includes Wilms', rhabdomyosarcoma, Ewing's, lymphoma, and osteosarcoma.

are pertinent, but they are not as restrictive as those relating tomortality. In the first column of Table 1 are listed the 11 (or 14 ifpediatrie solid tumors are divided into their components) tumorswhich can be cured by chemotherapy (see above). The incidencefigures are the number of new patients diagnosed with thatdisease in 1983 by American Cancer Society statistics (19). Thenumbers in parentheses represent the subset of the total incidence appropriate to curative intent chemotherapy. For example,in breast cancer, only patients with Stage II disease (<50% ofthe total) are candidates for adjuvant chemotherapy.

Curability is divided into established and putative. The "established" column represents figures based on multiple studies

conducted in centers and cooperative groups which are wellestablished in time, numbers of patients, and confirmation. In the"putative" column, the percentage of cure rate represents more

recent studies, the majority of which had been confirmed or arein the process of being confirmed by ongoing studies. (For detailsand references above, see text with respect to specific disease.)While it takes time to disseminate the curative treatment technology to the community, there is substantial evidence that oncesuch treatment is well established, it can be effectively appliedin the community (5). Hence the word "potential" relates to the

number of patients cured by multiplying percentage cured by thenumber of patients treated (in parentheses under "incidence").

The total number of patients, by these estimates, comes to15,000-30,000 per year. While this represents only approximately 10% of the annual mortality from cancer, it is importantto emphasize that curative treatment by chemotherapy is inversely related to age. Thus the diseases wherein a high curerate is achieved are disproportionately represented in the pediatrie and young adult population. Hence the overall impact onsurvival is substantially greater than the figures in Table 1 indicate.

With rapid advances in basic tumor biology and clinical investigation, it is probable that advances in curative treatment willcontinue. New strategies relating to chemotherapy and hormonaltherapy, the rapidly emerging field of tumor immunology, and

refinements in surgery and radiotherapy are under development.The in vitro tumor stem cell assay may allow for assessingpatient responsiveness to antitumor agents and thus the in-

dividualization and optimization of treatment (162). Basic sciencestudies relating to oncogene products, differentiation, immuno-

toxins, microenvironmental signals, and drug resistance, to mention a few, provide new targets, strategies, and tactics for theimmediate future. Therapeutic ferment has led to the expectationby many experts that progress in the curative treatment of headand neck cancer, selected stages of lung cancer, esophagealcancer, rectal cancer, bladder cancer, anal cancer, and cervicalcancer may be under way.

Long-term disease-free survival (cure) for patients with cancer

is increasing. This has led to increasing emphasis on the qualityof life. In contrast to some chronic diseases, the vast majority ofpatients cured of cancer return to full activity with little or nocompromise in the quality of life. Emphasis on less radicalprocedures for breast cancer (90) and limb preservation procedures for extremity cancers (152,153) are representative of suchefforts. The potential long-term adverse effects of chemotherapy,

such as the increased risk of leukemia, are being intenselystudied, particularly by the deletion of those chemotherapeuticagents which have major mutagenic and carcinogenic activity,where this can be accomplished without significantly compromising the cure rates (20).

Thirty years ago it was widely held that cancer could not becured by chemotherapy. Ten years ago it was conceded thattumors of hematological and embryological origin might be curable, but the more common epithelial tumors would not yield tochemotherapy. Progress has been steady and has acceleratedas such dire predictions have been progressively set aside. Whileprogress has been substantial and real, we still have a long wayto go. The current revolution in basic tumor biology, continuingclinical innovations, and the interaction between the two providerealistic optimism for continuing progress in the curative treatment of cancer.

REFERENCES1. Al-Sarraf, M., Binns, P., Vaishampayan, G., Loh, J., and Weaver, A. The

adjuvant use of c/s-platinum, oncovin, and bleomycin (COB) prior to surgeryand/or radiotherapy in untreated epidermoid cancer of the head and neck. InS. E. Salmon and S. E. Jones (eds.), Adjuvant Therapy of Cancer II, pp. 103-108. New York: GruÃ±e& Stratton, 1979.

2. Antman, K., Suit, H., Amato, D., Corson, J., Wood, W., Proppe, K., Harmon,D., Carey, Ft., Greenberger, J., Blum, R., and Wilson, R. Preliminary resultsof a randomized trial of adjuvant doxorubicin for sarcomas: lack of apparentdifference between treatment groups. J. Clin. Oncol., 2: 601-608,1984.

3. Aur, R. J. A., Simone, J. V., Hustu, H. O., Walters, T., Borella, L., Pratt, C.,and Pinkel, D. Central nervous system therapy and combination chemotherapy of childhood lymphocytic leukemia. Blood, 37: 272-281,1971.

4. Aur, R. J. A., Simone, J. V., Hustu, H. O., and Verzosa, M. S. A comparativestudy of central nervous system irradiation and intensive chemotherapy earlyin remission in childhood acute lymphocytic leukemia. Cancer (Phila.), 29:381-391,1972.

5. Begg, C. B., Carbone, P. P., Elson, P. J., and Zelen, M. Participation ofcommunity hospitals in clinical trials. N. Engl. J. Med., 306:1076-1080,1982.

6. Bergsagel, D., and Feld, R. Small-cell lung cancer is still a problem. J. Clin.Oncol., 2. 1189-1191,1985.

7. Blacklock, H. A., Matthews, J. R. D., Buchanan, J. G., Ockelford, P. A., andHill, R. S. Improved survival for acute lymphoblastic leukemia in adolescentsand adults. Cancer (Phila.), 48:1931-1935. 1981.

8. Blum, B., and Frei, E., III. Combination chemotherapy. Methods Cancer Res.,77:215, 1979.

9. Blum, R. H., Corson, J. M., Wilson, R. E., Greenberger, J. S., Canellos, G.P., and Frei, E., III. Successful treatment of metastatic sarcomas withcyclophosphamide, Adriamycin, and DTIC (CAD). Cancer (Phila.), 46: 1722-1726,1980.

10. Bodey, G. P., Coltman, C. A., Hewlett, J. S., and Freireich, E. J. Progress in


6533




the treatment of adults with acute leukemia: review of regimens containingcytarabine studied by the Southwest Oncology Group. Arch. Intern. Med.,736:1383-1388, 1976.

11. Bodey, G. P., Freireich, E. J, Gehan, E., McCredie, K. B., Rodriguez, V.,Gutterman, J., and Burgess, M. A. Late intensification therapy for acuteleukemia in remission. Chemotherapy and immunotherapy. J. Am. Med.Assoc., 235. 1021-1025,1976.

12. Bonadonna, G., and Valagussa, P. Adjuvant systems therapy for resectablebreast cancer. J. Clin. Oncol., 3: 259, 1985.

13. Bonadonna, G., and Valagussa, P. Dose response effect in adjuvant chemotherapy in breast cancer. N. Engl. J. Med., 304: 10-15, 1981.

14. Bonadonna, G., Rossi, A., Tancini, G., ef al. Adjuvant chemotherapy trials inresectable breast cancer with positive axillary nodes. The experience of theMilan Cancer Institute. In: S. E. Jones and S. E. Salmon, (eds.), AdjuvantTherapy of Cancer IV, p. 195. New York: GruÃ±e& Stratlon, 1984.

15. Bonadonna, G., Santoro, A., Bonfante, V., and Valagussa, P. Cyclic deliveryof MOPP and ABVD combinations in Stage IV Hodgkin's disease: rationale,background studies and recent results. Cancer Treat. Rep., 66: 881-887,1982.

16. Brindley, C. O., et al. Further comparative trial of thio-TEPA and mechloreth-amine in Hodgkin's diseaseand melanoma.J. Chronic Dis., 17:19-30,1964.

17. Burkitt, D. P. Long-termremissionsfollowing one andtwo dose chemotherapyfor African lymphoma. Cancer (Phila.),20: 756-759,1967.

18. Cabanillas,F., Burgess, M. A., Bodey, G. P., and Freireich, E. J. Sequentialchemotherapyand late intensificationfor malignant lymphomasof aggressivehistologie type. Am. J. Med., 74: 382-388,1983.

19. Cancer Statistics, 1983. CA-CancerJ. Clin., 33: 16, 1983.20. Canellos, G. P. Therapy-related leukemia: a necessary complication of suc

cessful systemic chemotherapy?J. Clin. Oncol., 2: 1077-1079, 1984.21. Canellos,G. P.,Come, S. E., and Skarin,A. T. Chemotherapyin the treatment

of Hodgkin's disease. Semin. Hematol., 20:1-24,1983.

22. Capizzi, R. L., and Cheng, Y. C. Sequential high dose cytosine arabinosideand asparaginasein refractory acute leukemia.Med. Pediatr.Oncol. (Suppl.),7. 221-228, 1982.

23. Carbone, P. P., Spurr, C., Schneiderman, M., Scotta, J., Holland,J. F., andShnider,B. Managementof patients with malignantlymphoma:a comparativestudy with cyclophosphamide and Vinca alkaloids. Cancer Res., 28: 811-822, 1968.

24. Carter, S. K. Adjuvant chemotherapy in osteogenic sarcoma: the triumph thatisn't? J. Clin. Oncol., 2: 147-148,1984.

25. Cassileth, P., Begg, C., Bennett, J., Burkart, P., Keller, A., Knospe, W.,Mazza, J., Scharfman,W., Spiers, A., Weiler, C., and O'Connell, M. Intensiveconsolidation therapy with high-dose cylosine arabinoside (Ara-C) and am-sacrine (AMSA) in adults with acute nonlymphocytic leukemia (ANLL). Proc.Am. Soc. Clin. Oncol., 3: 194, 1984.

26. ChildhoodSolid Tumors. In: Cancer Medicine:J. Hollandand E. Frei III. (eds.),pp. 2181-2220. Philadelphia:Lea and Febiger, 1983.

27. Cohen, C. J., Goldberg, J. D., Holland, J. F., Bruckner, H. W., Deppe, G.,Gusberg,S. B., Wallach,R. C., Kabakow, B., and Rodin,J. Improvedtherapywith cisplatin regimens for patients with ovarian carcinoma (FIGDStages IIIand IV) as measured by surgical end-staging (second-lookoperation).Am. J.Obstet. Gynecol., 745: 955-967, 1983.

28. Coliman, C. A., Savage,R. A., and Gehan,E. A. Long-term survival of adultswith acute leukemia. Proc. Am. Assoc. Cancer Res., 20: 389, 1979.

29. Comis, R. L. Small cell carcinoma of the lung. Cancer Treat. Rev., 9: 237-258, 1982.

30. Controlled trial of adjuvant chemotherapy following curative resection forgastric cancer. The Gastrointestinal Study Group. Cancer (Phila.),49:1116-1122,1982.

31. Cooper, R. G.Combinationchemotherapyin hormoneresistant breastcancer.Proc. Am. Assoc. Cancer Res., 70: 15, 1969.

32. Cortes, E. P., Holland, J. F., Wang, J. J., Sinks, L. F., Blom, J., Senn, H.,Bank, A., and Glidewell, D. Amputation and Adriamycin in primary osteosar-coma. N. Engl. J. Med., 297: 998-1000,1974.

33. D'Angio, G. J., Evans, A. E., Breslow, N., Beckwith, B., Bishop, H., Feigl, P.,

Goodwin, W., Leape, L. L., Sinks, L. F., Sutow, W., Tefft, M., and Wolff, J.The treatment of Wilms' tumor: results of the national Wilms' tumor study.Cancer (Phila.),38: 633-646, 1976.

34. Dembo,A. J. Spontaneousmutation to chemotherapyresistance:implicationsof the Goldie Goldmanmodel for the managementof ovarian cancer. J. Clin.Oncol., 2: 1311-1316,1984.

35. DeVita, V., Jr. The consequencesof the chemotherapyof Hodgkin's disease:the 10th David A. Kamofsky Memorial Lecture. Cancer (Phila.),47: 1-13,1981.

36. DeVita, V. T., Canellos, G. P., Chabner, B. A., Schein, P., Hubbard, S. P.,and Young, R. C. Histiocytic lymphoma,a potentiallycurabledisease.Lancet,7:248-250, 1975.

37. DeVita, V. T., Jr., Moxley, J. H., Ill, Brace, K. C., and Frei, E., III. Intensivecombination chemotherapy and x-irradiation in the treatment of Hodgkin's

disease. Proc. Am. Assoc. Cancer Res., 6: 15, 1965.38. DeVita, V. T., Serpick, A. A., and Carbone, P. Combinationchemotherapy in

the treatment of Hodgkin's disease. Ann. Intern. Med., 73: 881-895,1970.

39. DeVita, V. T., Jr., Simon, R. M., Hubbard, S. M., Young, R. C., Berard, C.W., Moxley, J. H., Ill, Frei, E., Ill, Carbone,P. P., and Canellos,G. P.Curabilityof advanced Hodgkin's disease with chemotherapy. Long-term follow-up ofMOPP-treated patients at the National Cancer Institute. Ann. Intern. Med.,92: 587-595,1980.

40. Djerassi,I. Highdose methotrexate andcitrovorum factor rescue:backgroundand rationale. Cancer Chemother. Rep., 6: 3,1975.

41. Donohue,J. P., Einhorn, L. H., and Williams,S. D. Cytoreductive surgery formetastatic testis cancer: considerations of timing and extent. J. Urol., 723:876-880,1980.

42. Edmonson, J. H., Green, S. J., Ivins, J. C., Gilchrist, G. S., Creagan, E. T.,Pritchard,D. J., Smithson,W. A., Dahlin,D. C., and Taylor,W. F. A controlledpilot study of high-dosemethotrexate as postsurgical adjuvant treatment forprimary osteosarcoma.J. Clin. Oncol., 2: 152-156, 1984.

43. Eilber, F. R., Morton, D. L., Eckardt, J., Grant, T., and Weisenburger,T. Limbsalvage for skeletal and soft tissue sarcomas: multidisciplinarypreoperativetherapy. Cancer (Phila.),53: 2579-2584,1984.

44. Eilber, F. R., and Eckhardt, J. Adjuvant therapy for osteosarcoma:a randomized prospective trial. Proc. Am. Soc. Clin. Oncol., 4: 144,1985.

45. Einhorn, L. H. (ed.). Testicular Tumors: Management and Treatment. NewYork: Masson Publishing, Inc., 1980.

46. Einhorn, L. H., and Donohue, J. Cisplatin, vinblastine and bleomycin combination chemotherapy in testicular cancer. Ann. Intern. Med., 87: 293-298,1977.

47. Ellison, R. R., Holland,J. F., Weil, M., Jacquillat, C., Boiron, M., Bernard, J.,Sawitsky, A., Rosner, F., Gussoff, B., Silver, R. T., Karanas,A., Cuttner, J.,Spurr, C. L, Hayes, D. M., Blom, J., Leone, L. A., Haurani, F., Kyle, R.,Hutchinson,J. L., Forcier, R. J., and Moon, J. H. Arabinosylcytosine: a usefulagent in the treatment of acute leukemiain adults. Blood, 32:507-523,1968.

48. Ervin, T. J., Weichselbaum, R. R., Miller, D., Meshad, M., Posner, M., andFabian,R. Treatment of advancedsquamous cell carcinomaof the head andneck with cisplatin, bleomycin and methotrexate (PBM).Cancer Treat. Rep.,65:787-791,1981.

49. Evans, A. E., Gilbert, E. S., and Zandstra, R. The increasing incidence ofcentral nervous system leukemiain children.(Children'sCancer Study GroupA). Cancer (Phila.),26: 404-409,1970.

50. FÃ¤rber,S. Chemotherapy in the treatment of leukemiaand Wilm's tumor. J.Am. Med. Assoc., 798: 826-836,1966.

51. Fefer, A., Cheever, M. A., Greenberg, P. D., Appelbaum, F. R., Boyd, D. N.,Buckner, C. D., Kaplan, H. G., Ramberg, R., and Sanders, J. E. Treatmentof chronic granulocytic leukemiawith chemoradiotherapyand transplantationof marrow from identical twins. N. Engl. J. Med., 306: 63-68, 1982.

52. Fisher, B., Redmond,C., Brown, A., Wickerham, D. L., Wolmark, N., Allegra,J., Escher, G., Ã¼ppman,M., Savlov, E., Wittliff, J., ef al. Influenceof tumorestrogen and progesteronereceptor levelson the responseto tamoxifen andchemotherapy in primary breast cancer. J. Clin. Oncol., 7: 227-241,1983.

53. Fisher, B., Redmond, C., and Fisher, E. R. A summary of findings fromNSABPtrials of adjuvant therapy for breast cancer. In: S. E. Jones and S. E.Salmon (eds),Adjuvant Therapy of Cancer IV. New York: GruÃ±e& Stratton,1984.

54. Fisher, B., and Carbone, P. P. Breast Cancer. In: J. F. Hollandand E. Frei III(eds.),CancerMedicine,Ed. 2, pp. 2025-2056. Philadelphia:Leaand Febiger,1982.

55. Fisher, R. l., DeVita, V. T., Jr., Hubbard, S. M., Longo, D. L., Wesley, R.,Chabner, B. A., and Young, R. C. Diffuse aggressive lymphomas: increasedsurvival after alternating flexible sequencesof proMACE and MOPP chemotherapy. Ann. Intern. Med., 98: 304-309, 1983.

56. Freeman,A. L,Weinberg,V., Brecher,M. L., et al.Comparisonof intermediatedose methotrexate with cranial irradiation for the post-induction treatment ofacute lymphocytic leukemia in children. N. Engl. J. Med., 308: 477-484,1983.

57. Frei, E., III.Acute leukemiain children:model for the developmentof scientificmethodology for clinical therapeutic research in cancer. General MotorsCancer Research Foundation Prizes: Charles F. Kettering Prize Address.Cancer (Phila.),53: 2013-2025,1984.

58. Frei, E., III. Clinical cancer research: an embattled species. Cancer (Phila.),50:1979-1992, 1982.

59. Frei, E., III. Combinationcancer therapy: PresidentialAddress. Cancer Res.,32:2593-2607, 1972.

60. Frei, E., III. Letter to the Editor. Science(Wash. DC), 220: 254-256,1983.61. Frei, E., Ill, Blum, R. H., Pitman, S. W., ef al. High dose methotrexate with

leucovorinrescue. Rationaleand spectrum of antitumor activity. Am. J. Med.,68:370-376,1980.

62. Frei, E., Ill, DeVita, V. T., Moxley, J. H., Ili, et al. Approaches to improvingthe chemotherapyof Hodgkin's disease.CancerRes., 26:1284-1289,1966.

63. Frei,E., Ill, and Freireich,E.J. Progressand perspectivesin the chemotherapyof acute leukemia.Adv. Chemother., 2: 269-298,1965.

64. Frei, E., Ill, Freireich, E. J., Gehan, E., ef al. Studies of sequential andcombinationantimetabolitetherapy in acute leukemia:6-mercaptopurineandmethotrexate. Blood, 78: 431-454,1961.

65. Frei, E., Ill, and Gehan,E. A. Definitionof cure for Hodgkin's disease. CancerRes., 37: 1828-1833,1971.

CANCER RESEARCH VOL 45 DECEMBER 1985

6534




66. Frei, E., Ill, Holland, J. F., Schneiderman,M. A., et al. A comparative studyof two regimensof combination chemotherapy in acute leukemia. Blood, 73:1126-1148,1958.

67. Frei, E., III. Karon, M., Levin, R. H., ef al. The effectiveness of combinationsof antileukemicagents in inducing and maintainingremission in children withacute leukemia. Blood, 26. 642-656,1965.

68. Frei, E., Ill, Luce, J. K., Gamble, J. F., ef al. Combination chemotherapy inadvanced Hodgkin's diseaseâ€”inductionand maintenanceof remission.Ann.Intern. Med., 79: 376-382, 1973.

69. Frei, E., Ill, Spurr, C. L, Brindley, C. O., ef al. Clinical studies of dichloro-methotrexate (NSC 29630). Clin. Pharmacol.Ther., 6. 160-171,1965.

70. Freireich, E. J., Gehan, E., Frei, E., Ill, ef al. The effect of 6-mercaptopurineon the duration of steroid-induced remissions in acute leukemia:a model forevaluation of other potentially useful therapy. Blood, 21: 699-716,1963.

71. Freireich, E. J., Gehan, E. A., Sulman, D., Boggs, D. R., and Frei, E., III. Theeffect of chemotherapy on acute leukemia in the human. J. Chronic Dis., 74:593-608,1961.

72. Freireich,E. J., Henderson,E. S., Karon, M. R., and Frei, E., III.The treatmentof acute leukemia considered with respect to cell population kinetics. Proliferation and Spread of Neoplasie Cells, 21st Annual Symposium on Fundamental Cancer Research, 1967. The University of Texas, M. D. AndersonHospital and Tumor Institute at Houston, Texas. Austin, TX: The Universityof Texas Press, 1967.

73. Freireich, E. J., Karon, M., and Frei, E., III. Combination chemotherapy ofchildhood leukemiawith vincristine, amethopterin, mercaptopurineand pred-nisone (VAMP). Proc. Am. Asssoc. Cancer Res., 5: 50, 1964.

74. Friedman, M. A., and Carter, S. K. The therapy of osteogenic sarcoma:current status and thoughts for the future. J. Surg. Oncol.,4:482-510,1972.

75. Gamick, M. B., Canellos, G. P., and Richie, J. P. Treatment and surgicalstaging of testicular and primary extragonadalgerm cell cancer. J. Am. Med.Assoc., 250. 1733-1741,1983.

76. Gehan, E. A., Smith, T. L., Freireich, E. J., Bodey, G., Rodriguez, V., Speer,J., and McCredie, K. Prognostic factors in acute leukemia. Semin. Oncol., 3:271-282,1976.

77. Click, J. H., and Taylor, S. G., IV. Integrationof chemotherapyinto a combinedmodality treatment plan for head and neck cancer: a review. Int. J. RadiÃ¢t.Oncol. Biol. Phys., 7: 229-242, 1981.

78. Goff, J. K., Anderson, H. R., Jr., and Cooper, P. F. Distractabilityand memorydeficits in long-term survivors of acute lymphoblastic leukemia. Dev. Behav.Pediatr., 7. 158-163, 1980.

79. Glucksberg, H., Rivkin, S. E., Rasmussen,S., Tranum, B., Gad-EI-Mawla,N.,Costanzi, J., Hoogstraten, B., Athens, J., Maloney, T., McCracken, J., andVaughn, C. Combination chemotherapy (CMFVP)versus phenylalaninemustard (L-PAM)for operable breast cancer with positive axillary nodes. Cancer(Phila.),50: 423-434, 1982.

80. Goldie. J. H., and Goldman, A. J. A mathematic model for relating the drugsensitivity of tumors to their spontaneous mutation rate. CancerTreat. Rep.,63. 1727-1733, 1979.

81. Goldie, J. H., and Coldman, A. J. Quantitative model for multiple levels ofdrug resistance in clinical tumors. Cancer Treat. Rep., 67: 923-931,1983.

82. Goldin, A., Venditti, J., Humphreys, S., and Mantel, N. Influence of concentration of leukemic inoculum on the effectiveness of treatment. Science(Wash. DC), 723: 840, 1956.

83. Goldin, A., Venditti, J. M., Humphreys, S. B., and Mantel, N. Modification oftreatment schedules in the management of advanced mouse leukemia withamethopterin. J. Nati. Cancer Inst., 77: 293,1956.

84. Goorin, A. M., Frei, E., Ill, and Abelson, H. T. Adjuvant chemotherapy forosteosarcoma: a decade of experience. Surg. Clin. N. Am., 67: 1379,1984.

85. Gottlieb, J. A., Baker, L. H., O'Bryan, R. M., Sinkovcs, J. G., Hoogstraten,

B., Quagliana, J. M., Rivkin, S. E., Bodey, G. P., Sr., Rodriguez, V. T.,Blumenschein,G. R., Saiki, J. H., Coltman, C., Jr., Burgess, M. A., Sullivan,P., Thigpen, T., Bottomtey, R., Balcerzak, S., and Moon, T. E. Adriamycin(NSC-123127) used alone and in combination for soft tissue and bonysarcomas. Cancer Chemother. Rep. Part 3, 6: 271-282, 1975.

86. Gottlieb, J. A., Baker, L. H., and Quagliana,J. M. Chemotherapyof sarcomawith a combination of Adriamycin and OTIC. Cancer (Phila.),20:1632,1972.

87. Griffiths, C. T., Parker, L. M., and Fuller, A. F., Jr. Role of cytoreductivesurgical treatment in managementof advancedovariancancer.CancerTreat.Rep., 63. 235-240, 1979.

88. Higby, D. J. Transfusion therapy. In: E. W. Gunz and E. S. Henderson(eds.),Leukemia, Ed. 4, pp. 843-863. New York: GruÃ±e& Stratton, 1983.

89. Hartmann, J. R. The role of combined chemotherapy in the treatment ofrhabdomyosarcomain children. Cancer (Phila.),34: 2128-2142,1974.

90. Hellman,S. Principlesof radiation therapy. In: V. T. DeVita, S. Hellman,andS. A. Rosenberg (eds.), Cancer: Principles and Practice of Oncology, pp.103-131. Philadelphia:J. B. Uppincott, 1982.

91. Henderson, E. S. Combinationchemotherapy of acute lymphocytic leukemiaof childhood. Cancer Res., 27: 2570-2572,1967.

92. Henderson, I. C. Editorial: adjuvant chemotherapy of breast cancer: a promising experiment or standard practice? J. Clin. Oncol., 3:140-143,1985.

93. Henderson, I. C., and Canellos, G. P. Cancer of the breast: the past decade.N. Engl. J. Med., 302: 17-30, 78-90, 1980.

94. Henderson, I. C., Gelman, R., Parker, L. M., Skarin, A. J., Mayer, B. J.,Gamick, M. B., Canellos, G. P., and Frei, E. 15 vs. 30 weeks of adjuvantchemotherapy for breast cancer patients with a high risk of recurrence: arandomizedtrial. Proc. Am. Soc. Clin. Oncol., 7: 75, 1982.

95. Henze, G., Langermann, H. J., Ritter, J., Schellong, G., and Riehm, H.Treatment strategy for different risk groups in childhood acute lymphoblasticleukemia:a report from the BFM study group. Haematol. Blood Transf., 26:87-93,1981.

96. Heppner, G. H., Dexter, D. L., DeNucci, T., Miller, F. R., and Calabresi, P.Heterogeneityin drug sensitivity among tumor cell subpopulationsof a singlemammarytumor. Cancer Res., 30: 3758-3763,1978.

97. Hersh. E. M., Whitecar, J. P., Jr., McCredie, K. B.. Bodey, G. P., Jr., andFreireich,E. J. Chemotherapyimmunocompetence,immunosuppressionandprognosis in acute leukemia.N. Engl. J. Med., 285:1211-1216, 1971.

98. Hertz, R. Interferencewith estrogen inducedtissue growth in the chick genitaltract by a folie acid antagonist. Science(Wash. DC), 707: 300,1948.

99. Hertz, R., Lewis, J., and Lipsett, M. B. Five years experience with thechemotherapyof metastatic trophoblastic diseasesin women. Am. J. Obstet.Gynecol.,86: 808-814,1963.

100. Higby, D. J., Wallace, H. J., Jr., Albert, D. J., and Holland,J. F. Diammodi-chloroplatinum: a phase I study showing responses in testicular and othertumors. Cancer (Phila.),33:1219-1225, 1973.

101. Higgins,G. A., Amadeo,J. H., Smith, D. E., Humphrey,E. W., and Keehn, R.J. Efficacyof prolonged intermittent therapy with combined 5-FUand methyl-CCNU following resection for gastric carcinoma. A Veterans AdministrationSurgicalOncology, Group report. Cancer (Phila.),52: 1105-1112, 1983.

102. Holland,J. F. Breaking the cure barrier. Kamofsky Memorial Lecture. J. Clin.Oncd., 7:75-90,1983.

103. Holland,J. F.E.pluribus unum: PresidentialAddress. Cancer Res.,37:1319-1329,1971.

104. Hreshchyshyn, M. Trophoblastic neoplasia. In: J. F. Holland and E. Frei III(eds.),CancerMedicine,Ed. 2, pp. 2014-2024. Philadelphia:Leaand Febiger,1983.

105. Ihde, E. C., Dunn, P. Aâ€žLichter, A. S., Cohen, M. H., Makuch, R. W., Carney,D. M., Johnston-Early,A., Minna,J. D., and Glatstein, E. Randomizedtrial ofchemotherapy with or without adjuvant breast or radiation in limited smallcell cell lung cancer. In: S. E. Jones and S. E. Salmon (eds.), AdjuvantTherapy of Cancer IV, pp. 147-155. New York: GruÃ±e& Stratton, 1984.

106. lacobini, S., Estey, E., Danhauser, L., Liliemark, J. 0., Keating, M. J., andPlunkett, W. Pharmacologicallydirected ara-C therapy for refractory leukemia. Semin.Oncol., 72 (Suppl. 3V 20-30,1985.

107. Jacobs, A. D., and Gale, R. P. Recent advancesin the biology and treatmentof acute lymphoblasticleukemiain adults. N. Engl. J. Med., 377:1219-1231,1984.

108. Jaffe, N., Frei, E., Ill, Traggis, D., and Bishop, Y. Adjuvant methotrexate andcitrovorum-factor treatment of osteogenic sarcoma. N. Engl. J. Med., 297:994-997,1974.

109. Jaffe, N., Knapp,J., Chuang,V. P., Wallace,S., Ayala, A., Murray, J., Cangir,A., Wang, A., and Benjamin, R. S. Osteosarcoma: intra-arterial treatment ofthe primary tumor with c/s-diamine-dichloroplatinumII: angiographie,pathologic, and pharmacologiestudies. Cancer (Phila.),57: 402-407,1984.

110. Jones, S. E., Grozea, P. N., Metz, E. N., ef al. Superiority of Adriamycin-containing combination chemotherapy in the treatment of diffuse lymphoma:A Southwest Oncology Group study. Cancer (Phila.),43: 417-425,1979.

111. Keating, M. J., McCredie, K. B., Bodey, G. P., Smith, T. L., Gehan, E., andFreireich,E. J. Improved prospects for long-term survival in adults with acutemyelogenousleukemia.J. Am. Med. Assoc., 248: 2481-2486, 1982.

112. Keating, M. J., Smith, T. L., Gehan,E. A., McCredie,K. B., Bodey, G. P., andFreireich, E. J. A prognostic factor analysis for use in development ofpredictive models for response in adult acute leukemia. Cancer (Phila.),50:457-465,1982.

113. Korsmeyer, S. J., Arnold, A., Bakhshi, A., ef al. Immunoglobulingene rearrangement and cell surface antigen expression in acute lymphocytic leuke-miasof T cell and B cell precursororigins. J. Clin. Invest., 77:301-313,1983.

114. Kufe, D. W., Major, P. P., Egan, E. M., and Beardsley, G. P. Correlation ofcytotoxicity with incorporationof ara-C into DNA.J. Biol. Chem., 255: 8997-9000,1980.

115. Laurence, J., Coleman, M., Allen, S. L., Silver, R. T., and Pasmantier, M.Combination chemotherapy of advanced diffuse histiocytic lymphoma withthe six-drug COP-BLAM regimen. Ann. Intern. Med., 97:190-195, 1982.

116. Law, L. W. Effects of combinations of antileukemic agents on an acutelymphocytic leukemiain mice. Cancer Res., 72: 871-878, 1952.

117. Li, F. P., Connelly,R. R., and Myers, M. Improved survival rates among testiscancer patients in the United States. J. Am. Med. Assoc., 247: 825-826,1982.

118. Li, M. C. Trophoblastic disease; natural history, diagnosis and treatment.Ann. Intern. Med., 74: 102-112, 1971.

119. U, M. C., Hertz, R., and Spencer, D. B. Effect of methotrexate uponchoriocarcinomaand chorioadenoma.Proc. Soc. Exp. Biol. Med., 93: 361-366,1956.

120. U, M. C., Whitmore,W. F., Golbey,R., and Grahstald, H. Effects of combineddrug therapy on metastatic cancer of the testis. J. Am. Med. Assoc., 774:


6535




1291-1299,1960.121. Ling, V., Kartner, N., Sudo, T., Simonovitch, L., and Riordan,J. R. Multidrug-

resistance phenotype in Chinese hamster ovary cells. Cancer Treat. Rep.,67:869-874, 1983.

122. Link, M., Goorin, A., Miser, A., ef al. The role of adjuvant chemotherapy inthe treatment of osteosarcomaof the extremity: preliminaryresults of a multi-institutional osteosarcoma study (MÃ•OS).Proc. Am. Soc. Clin. One., 4: 237,1985.

123. Livingston, R. Small cell carcinoma of the lung. Blood, 56: 575-584, 1980.124. Mathews, M. J., Rosencweig, M., Staquet, M. H., Minna, J. D., and Muggia,

F. M. Long term survivors with small cell carcinoma of the lung. Eur. J.CancerClin. Oncol., 16: 527-531,1980.

125. Mayer, R. J., Coral, F. S., Rosenthal, D. S., Sallan,S. E., and Frei, E., III. Thetreatment of non-T, non-B cell acute lymphocytic leukemia in adults. Proc.Am. Soc. Clin. Oncol., 1: 126, 1982.

126. Mayer, R. J., Weinstein, H. J., Coral, F. S., Rosenthal, D. S., and Frei, E., III.The role of intensive post-induction chemotherapy in the treatment of my-elogenous leukemia.Cancer Treat. Rep., 66: 132, 1982.

127. McCultoch,E. A., Buick, R. N., Curtis, J. E., Messner, H. A., and Senn,J. S.The heritablenature of clonal characteristics in acute myeloblastic leukemia.Blood, 50:105-109, 1981.

128. McKelvey, E. M., Gottlieb, J. A., Wilson, H. E., ef a/. Hydroxyldaunomycin(Adriamycin) combination chemotherapy in malignant lymphoma. Cancer(Phila.),38. 1484-1493, 1976.

129. Mike, V., and Marcove, R. Osteogenic sarcoma under the age of 21: experience at Memorial Sloan-Kettering Cancer Center. In: W. T. Terry and D.Windhorst (eds.), Immunotherapyof Cancer: Present Status of Trials in Man,Vol. 6, pp. 283-292. New York: Raven Press, 1978.

130. Miller, R. W., and McKay, F. W. Decline in U.S. childhood cancer mortality:1950 through 1980. J. Am. Med. Assoc., 25?: 1567-1570,1984.

131. Mittelman, A., Holyoke, P. L. M., and Moertel, C. G. Adjuvant chemotherapyand radiotherapyfollowing rectal surgery: an interimreport from the Gastrointestinal Tumor Study Group (GITSG).In: S. E. Salmonand S. E. Jones (eds.),Adjuvant ChemotherapyIII, pp. 547-559. New York: GruÃ±e& Stratton, 1981.

132. Moertel, C. G. Alimentary tract cancer. In: J. F. Holland and E. Frei (eds.),CancerMedicine,Ed. 2, pp. 1753-1863. Philadelphia:Leaand Febiger,1983.

133. Moss, H. A., Nannis, E. D., and Poplack, D. G. The effects of prophylactictreatment of the central nervous system on the intellectual functioning ofchildrenwith acute lymphocytic leukemia.Am. J. Med., 71: 47-52, 1981.

134. Nadler, L. M., Ritz, J., Bates, M. P., Park, E. K., Anderson, K. C., Sallan,S.E., and Schlossman, S. F. Induction of human B cell antigens in non-T cellacute lymphoblastic leukemia.J. Clin. Invest., 70: 433-442,1982.

135. Nadler, L. M., Takvorian, R., Botnick, L, Bast, R. C., Finberg, R., Hellman,S., Canellos,G. P., and Schlossman, S. F. Anti-B1 monoclonalantibody andcomplement treatment in autologous bone-marrow transplantation for relapsed B-cell non-Hodgkin's lymphoma. Lancet, 2: 427-430,1984.

136. Nissen-Meyer,R. In: Baum, Kay, and Scheurien(eds.),ClinicalTrials in EarlyBreast Cancer, p. 571. Basel: Pirhauser, 1982.

137. Norton, L., and Simon, R. Tumor size, sensitivity to therapy, and design oftreatment schedules. Cancer Treat. Rep., 61: 1307-1317,1977.

138. O'Bryan, R. M., Baker, L. H., Gottlieb, J. E., Rivkin, S. E., Balcerzak, S. P.,

Grumet, G. N., Salmon, S. E., Moon, T. E., and Hoogstraten, B. Doseresponse evaluation of Adriamycin in human neoplasia. Cancer (Phila.),39:1940-1948,1977.

139. Ogava, M., Fried, J., Sakai, Y., Strife, A., and Clarkson, B. D. Studies ofcellular proliferation in human leukemia.VI. The proliferativeactivity, generation time, and emergence time of neutrophilicgranulocytes in chronic granu-locytic leukemia.Cancer (Phila.),25: 1031-1049, 1970.

140. Phillips, G. L., Herzig, R. H., Lazarus, H. M., et al. Treatment of resistantmalignantlymphomawith cyclophosphamide,total body irradiationand transplantation with cryopreserved autologous marrow. N. Engl. J. Med., 370:1557-1561,1984.

141. Pinkel, D. The Ninth Annual David Kamofsky Lecture: Treatment of acutelymphocytic leukemia.Cancer (Phila.),48: 1128-1137, 1979.

142. Pinkel, D., Hernandez, K., Borella, L., Holton, C., Aur, R., Samey, G., andPratt, C. Drug dosage and remission duration in childhood lymphocyticleukemia.Cancer (Phila.),27: 247-256,1971.

143. Poplack, D. G., Reaman,G. H., Bleyer, W. A., Miser, J., Feusner,J., Wesley,R., and Hammond,D. Central nervous system (CNS)preventivetherapy withhigh dose methotrexate (HDMTX) in acute lymphoblastic leukemia (ALL):preliminaryreport. Proc. Am. Soc. Clin. Oncol., 3: 204, 1984.

144. Preisler, H. D., Brecher, M., Browman, G., Early, A. P., Walker, I. R., Raza,A., and Freeman,A. The treatment of acute myelocytic leukemia in patients30 years of age and younger. Am. J. Hematol., 73: 189-198,1982.

145. Rai, K., Holland,J. F., Glidewell,O. J., et al. Treatment of acute myelogenousleukemia:a study by Cancer and LeukemiaGroup 8. Blood, 58:1203,1981.

146. Rail, D. P., Stabenau,J. R., and Zubrod, C. G. Distribution of drugs betweenblood and cerebrospmal fluid: general methodology and effect of pH gradients. J. Pharmacol.Exp. Ther., 725: 185-193,1959.

147. Richardson, G. S., Scully, R. E., Nikrui, N., and Nelson, J. H. Commonepithelial tumors of the ovary. N. Engl. J. Med., 372: 415-423, 474-483,1985.

148. Ritz, J., Sallan, S. E., Bast, R. C., Jr., Lipton, J. M., ClaveÂ«,L. A., Feeney,M., Hercend, T., Nathan, D. G., and Schlossman, S. F. Autologous bone-marrow transplantation in CALLA-positiveacute lymphoblasticleukemiaafterin vitro treatment with J5 monoclonal antibody and complement. Lancet, 2:60.1982.

149. Romain, P. L., and Schlossman, S. F. Human T lymphocyte subsets: functional heterogeneity and surface recognition structures. J. Clin. Invest., 74:1559-1565,1984.

150. Rosen, E., Cassady, J. R., Frantz, C. N., Kretschmar, C., Levey, R., andSallan,S. E. Neuroblastoma:The Joint Center for RadiationTherapy/Dana-Farber Cancer Institute/Children's Hospital experience. J. Clin. Oncol., 2:719-732,1984.

151. Rosen, G., Marcove, R. C., Huvos, A. G., Caparros, B. I., Lane, J. M.,Nirenberg, A., Cacavio, A., and Groshen, S. Primary osteogenic sarcoma:eight year experience with adjuvant chemotherapy. J. Cancer Res. Clin.Oncol., 706: 55-67,1983.

152. Rosen, G., Murphy, M. L., Huvos, A. G., ef al. Chemotherapy, and blockresection, and prosthetic bone replacement in the treatment of osteogenicsarcoma. Cancer (Phila.),37:1-17,1976.

153. Rosenberg,S. A. Principlesof surgicaloncology. In: V. T. DeVita,S. Hellman,and S. A. Rosenberg (eds.), Principles and Practice of Oncology, p. 93.Philadelphia:J. B. Uppincott, 1982.

154. Rosenberg, S. A., Kaplan, H. S., Hoppe, R. T., ef al. An overview of therationaleand results of Stanford randomizedtrials in the treatment of Hodg-kin's disease. 1957-1980. In: S. E. Jones and S. E. Salmon(eds.),AdjuvantTherapy of Cancer III, pp. 65-78. New York: GruÃ±e& Stratton, 1981.

155. Rosenberg,S. A., Kent, H., Costa, J., ef al. Prospective randomizedevaluation of the role of limb-sparing surgery, radiation therapy, and adjuvantchemoimmunotherapyin the treatment of adult soft-tissue sarcomas. Surgery, 84: 62-69, 1978.

156. Ross, G. T., Goldstein, D. P., Hertz, R., Lipsett, M. D., and Oddi, W. D.Sequential use of methotrexate and actinomycin D in the treatment ofmetastatic choriocarcinoma and related trophoblastic disease in women.Amer. J. Obstet. Gynecol.,93: 233,1965.

157. Rowland, J. H., Glidewell,0. J., Sibley, R. F., Holland,J. C., ef al. Effects ofdifferent forms of central nervous system prophylaxis on neuropsychiatriefunction in childhood leukemia.J. Clin. Oncol., 2: 1327, 1984.

158. Rudnick, S. A., Cadman, E. C., Capizzi, R. L, Skeel, R. T., Bertino, J. R.,and Mclntosh, S. High dose cytosine arabinoside (HDARAC) in refractoryacute leukemia.Cancer (Phila.),44:1189-1193,1979.

159. Rustum, Y. M., and Preisler,H. D. Correlationbetween leukemiccell retentionof 1-/3-D-arabinofuranosylcytosine5'-triphosphate and response to therapy.Cancer Res., 39: 42-49, 1979.

160. Sallan,S. F., Cammita, B. M., Cassady,J. R., Nathan, D. G., and Frei, E., III.Intermittent combination chemotherapy with Adriamycin for childhood acutelymphoblasticleukemia:clinical results. Blood, 57: 425-433, 1978.

161. Sallan, S. E., Hitchcock-Bryan, S., Gelber, R., Cassady, J. R., Frei, E., Ill,and Nathan, D. G. Influence of intensive asparaginase in the treatment ofchildhood non-T-cellacute lymphoblastic leukemia. Cancer Res., 43: 5601-5607, 1983.

162. Salmon, S. E., Hamburger,A. W., Soehnten,B., Durie, B. G., Alberts, D. S.,and Moon, T. E. QuantitÃ¤tenof differential sensitivity of human-tumor stemcells to anticancer agents. N. Engl. J. Med., 298:1321-1327, 1978.

163. Samuels, M. L., Johnson, D. E., and Holyoke, P. Y. Continuous intravenousbleomycmtherapy with vinblastine in Stage III testicular neoplasia. CancerChemother. Rep. I, 59: 563,1975.

164. Santos, G. P., Tutschka, P. J., Prookmeyer,R., ef al. Marrow transplantationfor acute non-lymphoblastic leukemia after treatment with busulphan andcyclophosphamide.N. Engl. J. Med., 309: 1347-1353,1983.

165. Schauer, P., Arlin, Z. A., Mertelsmann,R., ef a/. Treatment of acute lymphoblastic leukemia in adults: Results of the L-10 and L-10M protocols. J. Clin.Oncol., 7: 462-470,1983.

166. Schimke,R. T. Geneamplification,drug resistance,and cancer. CancerRes.,44:1735-1742, 1984.

167. Selawry, 0. S., Hananian,J., Wolman, I. J., ef al. New treatment scheduleswith improved survival in childhood leukemia. Intermittent parenteralvs. dailyoral administration of methotrexate for maintenance of induced remission.Acute leukemiagroup B. J. Am. Med. Assoc., 794: 75-81,1965.

168. Shackney, S. E., McCormack, G. W., and Cuchural, G. J., Jr. Growth ratepatterns of solid tumors and their relationship to responsivenessto therapy.Ann. Intern. Med., 89. 107-121, 1978.

169. Skarin, A. T., Canellos, G. P., Rosenthal, D. S., Case, D. C., Jr., Maclntyre,J. M., Pinkus, G. S., Moloney, W. C., and Frei, E., III. Improved prognosis ofdiffuse histiocytic and undifferentiatedlymphoma by use of high dose methotrexate alternatingwith standard agents (M-BACOD).J. Clin. Oncol., 7: 91-98.1983.

170. Skipper, H. E. Adjuvant chemotherapy.Cancer (Phila.),47: 936-940, 1978.171. Skipper, H. E., Schabel, F. M., Jay, R., and Wilcox, W. S. Experimental

evaluation of potential antitumor agents: on the criteria and kinetics associated with curability of experimental leukemia. Cancer Chemother. Rep., 35:1,1964.

172. Skipper, H. E., Schabel, F., and Wilcox, W. Experimental evaluation of


6536




potential anticancer agents. XXI. Scheduling of arabinosyl cytosine to takeadvantage of its S-phase specificity against leukemic cells. Cancer Chemo-ther. Rep., 51: 125,1976.

173. Straus, D., Myers, J., Passe, S., et al. The 8 drug/radiation program foradvanced Hodgkin's disease. A follow-up report. Cancer (Phila.),46: 233-

240,1980.174. Suit, H. D., Proppe, K. H., Mankin, H. J., and Wood, W. C. Radiationtherapy

and conservative surgery for sarcoma and soft tissue. In: I. M Ariel (ed.),Progressin ClinicalCancer,Vol. 8, pp. 311-318. New York: GruÃ±e& Stratton,1982.

175. Sweet, D. L, Golomb, H. M., Ultmann, J. E., et al. Cyclophosphamide,vincristine, methotrexate with leucovorin rescue and cytarabine (COMLA)combination sequential chemotherapy for advanced diffuse histiocytic lym-phoma. Ann. Intern. Med., 92: 785-790, 1980.

176. Tancini, G., Bonadonna, G., Valagussa, P., Marchini, S., and Veronesi, U.Adjuvant CMF in breast cancer: Comparative five-year results of 12 vs. 6cycles. J. Clin. Oncol., 1: 2.1983.

177. Thomas, E. D. Kamofsky Memorial Lecture. Marrow transplantation formalignant disease.J. Clin. Oncol., 1: 517-531,1983.

178. Thomas, L. B., Skirigas, M. A., Hymphreys,S. R., and Goldin,A. Pathologicalspread of L1210 leukemia in the central nervous system of mice and effectof treatment with Cytoxan. J. Nati. Cancer Inst, 28:1355-1389,1962.

179. Vaughan, W. P., Karp, J. E., and Burke, P. J. Two-cycle timed-sequentialchemotherapyfor adult acute nonlymphocyticleukemia.Blood, 64:975-980,1984.

180. Vugrin, D., er al. VAB6 combination chemotherapy in the treatment ofmetastatic testicular tumors. Cancer (Phila.),47: 833, 1981.

181. Weil, M., Glidewell, O. J., Jacquillet, C. et al. (Acute Leukemia Group B).Daunorubicinin the therapy of acute granulocytic leukemia.Cancer Res., 33:921-928,1973.

182. Weinstein, H. J., Mayer, R. J., Rosenthal, D. S., Coral, F. S., Camilla, B. M.,and Gelber, R. D. Chemotherapyfor acute myelogenousleukemiain childrenand adults: VAPA update. Blood, 62:315-319,1983.

183. Weinstein, H. J., Mayer, R. J., Rosenthal, D. S., Camilla, B. M., Coral, F. S.,Nalhan, 0. G., and Frei, E., III. Treatment of acute myelogenousleukemia inchildren and adulte. N. Engl. J. Med. 303: 473-478,1980.

184. Weinstein, H. J., Vance, Z. B., Jaffe, W., BueÂ«,D., Cassady, J. R., andNathan,D. G. Improved prognosis for patients with mediastinallymphoblastic

lymphoma.Blood, 53: 687-694,1979.185. Winkler, K., Bertn, G., Katz, R., ef al. Neoadjuvantchemolherapy for osleo-

sarcoma: resulls of a cooperalive German/Auslrian study. J. Clin. Oncol., 2:617-624,1984.

186. Wisch, J., Griffin, J., and Kufe, D. Response of preleukemic syndromes toconlinuous infusion of low-dose cytarabine. N. Engl. J. Med., 309: 1599-1602, 1983.

187. Wolff, S. N., Marion, J., Stein, R. S., Flexner, J., Lazarus, H., Herzig, R.,Phillips,G. L., and Herzig, G. P. High-dose(HD)cylosine arabinoside(ara-C)and daunorubicin (D) for acute non-lymphocytic leukemia (ANLL) in firstremission.Proc. Am. Soc. Clin. Oncol., 3: 193,1984.

188. Wolff, S. N., Marion,J., Slein, R., Flexner,J. M., et al. Therapy of acute non-lymphocytic leukemiain first remission:brief intensiveconsolidationwilh highdose ara-C (HDA-RAC).Blood, 60 (Suppl. 1). 1591,1982.

189. Yap, B. S., Sincovics,J. G., Burgess, M. A., Benjamin,R. S., and Bodey, G.P. The curability of advancedsoft tissue sarcomas in adults with chemotherapy. Proc. Am. Soc. Clin. Oncol., 2: 239, 1983.

190. Yales, J., Glidewell,O., Wiemik, P., ef al. Cylosine arabinoside with daunorubicin or Adriamycin for therapy of acute myetocytic leukemia: a CALGBstudy. Blood, 60:454-462,1982.

191. Young, R., Canellos, G., Chabner, B., et al. Maintenancechemotherapy foradvanced Hodgkin's disease in remission. Lancet, 7:1339-1343,1973.

192. Young, R., Canellos,G., Chabner, B., ef al. Patterns of relapse in advancedHodgkin's disease treated with combination chemotherapy. Cancer (Phila.),42: 1001-1007, 1978.

193. Young, R. C., Knapp, R. C., and Perez, C. A. Cancer of the ovary. In: V. T.DeVita, S. Hellman, and S. A. Rosenberg (eds.), Cancer: Principles andPractice of Oncology, pp. 884-913. Philadelphia:J. B. Ã¼ppincotl,1982.

194. Yunis, J. J. The chromosomal basis of human neoplasia. Science (Wash.DC),221: 227-236,1983.

195. Ziegler, J. L. Burkitt's lymphoma. N. Engl. J. Med., 305: 735-744,1981.

196. Zubrod, C. G., Schneiderman,M., Frei, E. Ill, ef al. Appraisalof melhods forIhe study of chemotherapyof cancer in man: comparative therapeutic trial ofnitrogen muslard and Iriethylene thiophosphoramide.J. Chronic Dis., 11: 7-33,1960.

197. Moxley, J. H., DeVita, V. T., Brace, K., Frei, E., III. Intensive combinationchemotherapyand X-irradiationin Hodgkin's disease.CancerRes.,27:1258-

1263, 1967.


6537



1985;45:6523-6537. Cancer Res Emil Frei III Curative Cancer Chemotherapy

Updated version

http://cancerres.aacrjournals.org/content/45/12_Part_1/6523

Access the most recent version of this article at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected] at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerres.aacrjournals.org/content/45/12_Part_1/6523To request permission to re-use all or part of this article, use this link



http://cancerres.aacrjournals.org/cgi/alerts

mailto:[email protected]



curative cancer chemotherapy1 · cancer chemotherapy provides variably effective treatment for the...

Documents