High-dose chemotherapy and autologous bone marrow or stem cell reconstitution for solid tumors

High-Dose Chemotherapy and Autologous Bone Marrow or Stem Cell Reconstitution for Solid Tumors Abstract--High-dose chemotherapy--in conjunction with the transplantation of either mononuclear cells harvested from the marrow or CD 34+ cells harvested from the peripheral blood---has proved effective in curing certain patients with leukemia, lymphoma, and, to a lesser extent, multiple myeloma. Though the CD 34+ therapy is a relatively new treatment and the mononuclear cell therapy is more standard, both have been successfully used to reconstitute lethally damaged hematopoietic stem cells. Allogeneic transplants have been more effective than autologous transplants against tumors, but they also pose a greater hazard of death from complications, graft-versus-host disease, and infections. More currently, this approach has been used in patients with certain solid tumors, either in a metastatic or recurrent disease setting or as an adjuvant to surgery and/or standard doses of chemotherapy in patients with a known high risk of recurrence. Unfortunately, the majority of the studies about the impact of this therapy have been small and nonrandomized against standard therapy, and they have encompassed diverse populations of patients. This makes comparisons with contemporary standard-dose approaches--already problematic from a statistical point of view---even more dangerous because of the dissimilarity of the groups being compared. Particularly in the high-risk adjuvant setting, data suggest that those patients that meet the eligibility criteria for high-dose therapy and transplantation exhibit the prognostic factors for a positive outcome. When one compares these results with those of a more heterogeneous group of patients treated with conventional therapy, the conclusion might be drawn that high-dose therapy is superior to standard therapy, when a longer follow-up of the 138

Curr Probl Cancer, May/June 1998

patients in the study will show this to be untrue. Thus there is a plea from clinicians and physicians conducting trials for prospective, randomized trials that would allow a fair comparison between high-dose therapy in combination with transplant procedures and a more conventional, standard chemotherapy, which is often less toxic and definitely less expensive. This article reviews the data for transplantation in four tumors: breast cancer, ovarian cancer, small-cell lung cancer, and germ cell testis cancer. There is such a small number of randomized trials that an attempt must be made to compare these small high-dose therapy studies with similar, though not identical, large studies of conventional therapy. This article attempts to make those comparisons, and several conclusions are drawn, which are detailed below. First, few data support the use of high-dose chemotherapy in any patient with recurrent and drugresistant breast cancer or ovarian cancer. Similarly, few data support the use of high-dose approaches for patients with extensive small-cell lung cancer. For patients with metastatic breast cancer that has responded completely to conventional chemotherapy, no data suggest a survival advantage for the immediate consolidation of that response with high-dose chemotherapy. The only trial addressing this issue found that immediate transplantation led to a better disease-free survival rate, but overall survival, as compared with that of patients who received transplants at relapse, was not affected, and the study did not address the issue of the relative merits of conventional chemotherapy in either case. The only study of high-dose versus conventional chemotherapy was statistically underpowered, and it showed poorerthan-anticipated outcomes in the patients who received conventional therapy. Ongoing or recently completed trials will, it is hoped, address the many unanswered questions in this area. For patients with high-risk, non-metastatic breast cancer, no completed and analyzed phase HI randomized studies address the relative merits of conventional versus high-dose therapy. Early results from Curr Probl Cancer, May/June 1998

139

high.dose approaches suggest a better disease-free survival than has typically been observed with standard chemotherapy, but the patients who have received transplants are often highly selected and may have favorable prognostic factors as compared with the more heterogeneous groups that have received conventional therapy over the years. Several trials underway address the value of high-dose therapy in early stage, high-risk breast cancer patients (the group most likely to benefit from this type of therapy, based on the knowledge gleaned from the studies of transplants in patients with hematologic tumors), and these results are anxiously awaited by patients and health care professionals alike. In ovarian cancer, where high-dose chemotherapy and transplantation is becoming increasingly more common, many small phase H trials have shown high response rates but short response durations, and the data currently available make it difficult to maintain enthusiasm for this approach in patients with drug-resistant or large-volume disease. Several trials underway randomize patients with demonstrated drug sensitivity and a low volume of tumors (achieved either surgically or with conventional chemotherapy) to receive either high-dose therapy or more conventional consolidation approaches. Until these trials are complete, the value of high-dose therapy will remain unknown. There are little data regarding transplantation in patients with limited-stage small-cell lung cancer. A single randomized trial demonstrated an outcome advantage for high-dose therapy, but the patient numbers were too small to allow any definitive conclusions to be made. Large randomized trials in this population are needed to address the value of high-dose approaches. The preferred population in which to perform these trials would be patients with limited disease who respond to initial conventional chemotherapy and are subsequently randomized to receive conventional consolidation with chest and cranial radiation or high-dose therapy with the same radiation. Survival would be the only pertinent endpoint. No trials of this sort are currently underway. i40

Curr Probl Cancer, May/June i998

For patients with testis cancer, data suggest a clear survival benefit from high-dose chemotherapy and transplantation. Two groups of patients still have very poor outcomes---those with mediastinal primary disease and those who progress or relapse within 4 weeks of completion of standard, cisplatin-based therapy. It is unclear if high-dose approaches can salvage these patients. However, in patients whose disease recurs at a point more distant from conventional therapy, there is a potential for a long-term, diseasefree survival rate that may be as much as or more than 50% better than that of patients who have been treated with conventional salvage approaches. Finally, it is now possible to identify patients who are at a high risk of a poor outcome and who are candidates for high-dose approaches as part of initial therapy. These patients are currently being studied in an intergroup, randomized trial.

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here is a plethora of data documenting the value of high-dose chemotherapy followed by the rescue of lethally damaged hematopoietic stem cells with either autologous mononuclear cells harvested from the patient's marrow or mononuclear cells derived from the patient's blood, with the most success being apparent in cases of acute leukemias, chronic myelogenous leukemia, Hodgkin's and nonHodgkin's lymphoma, or multiple myelomas. When transplantation occurs in patients with these hematologic malignant tumors, there is a variable but real---cure rate that is achieved over and above that which would occur in these patients if they did not receive transplants. In cases of chronic myelogenous leukemia, transplantation is the only known curative form of therapy. Similarly, in cases of acute leukemias and lymphomas for which initial primary therapy has failed, transplantation offers the only real chance of long-term disease-free survival. Early data regarding myeloma are suggestive of a cure potential with transplantation. These topics have been recently reviewed. 1 Some of these studies used allogeneic marrow when autologous donation was not acceptable because of tumor involvement. Such transplants have typically shown a better outcome than autologous donations, although there have been no comparative trials. This better outcome is postulated to be caused by a graft-versus-tumor effect, in which the engrafted cells Curr Probl Cancer, May/June 1998

141

recognize the host tumor cells as foreign and attempt to destroy them, and that can be demonstrated in vitro in mixing experiments. It has been demonstrated in patients with malignant hematologic disease that the patients with drug-sensitive disease and low tumor burden will enjoy the best outcome following either kind of transplantation. Patients who received transplants at the time of clinical remission but had a high risk of relapse or patients treated into a clinical complete remission with standard drug doses before undertaking transplantations have better outcomes than patients treated at the time of relapse, when there is clinically evident disease, or both. Thus the basic tenets of transplantation that were learned as a result of working with patients with malignant hematologic disease were to select patients for transplantation whose disease was drug-sensitive and in complete clinical remission. This difficult lesson was learned after unsuccessful outcomes of the treatment regimen, high complication rates in those patients with extant disease, or both. Unfortunately, it does not appear that these basic rules were followed when transplantation began to be used for the treatment of solid tumors. Breast cancer is the solid tumor most commonly treated with transplantation. A recent study of breast cancer patients concluded that patients in whom the disease had metastisized and who also received transplants had 3-year probabilities of disease-free survival of 7%, 13%, and 32% if the transplant was carried out in patients with progressive disease, partially responding disease, or completely responding disease, respectively, after pre-transplant chemotherapyfl The cases reported to the Autologous Blood and Marrow Transplant Registry (ABMTR) from 1989 to 1995 indicate that breast cancer became the most frequent indication for autologous transplantation, and the use of transplantation in breast cancer cases increased sixfold during that time interval. Annually, from 1992 on, more breast cancer patients have received transplants than have patients with all types of lymphoma. Cases of transplantation reported to the ABMTR probably represent about 50% of the actual transplantations performed. 3 In 1994, 1,513 transplants were reported to the ABMTR, suggesting that as many as 3,000 procedures were performed that year. Even with the conservative estimate of the cost of an individual transplant at $50,000, the annual total cost of all of the transplants performed is now in excess of $150,000,000. Many third-party payers have refused to pay for this procedure, based on their assessment that there is inconclusive evidence of any benefit to the patient. Multiple legal battles have ensued that are frequently decided in favor of the patient. Many physi142

Curr Probl Cancer, May/June 1998

cians believe that this procedure is of value and are willing to testify on behalf of the patients. Henderson surveyed physicians in the United States and found that 80% felt bone marrow transplantation should be offered to women with metastatic breast cancer, despite the indefinite proof of benefit. Canellos felt that clinical trials have not yet answered the question of the value of transplantation in breast cancer, and he pointed out that only large randomized trials would be sufficient to do so. 4 Antman said in her survey that there has been a trend toward performing transplants in breast cancer patients with earlier stage, drug-sensitive disease, and in small uncontrolled studies. Only 11% of patients with advanced local disease and < 1% of patients with metastatic disease, all who had received transplants, were entered into a randomized controlled trial. Although this shift to performing transplants on patients whose disease has a better prognosis is a welcome change, it has the confounding problem of making early data analysis overly optimistic when contemporary, high-dose nonrandomized studies are compared with standard-dose chemotherapy studies in a less highly selected and often worse prognosis group. Although breast cancer has been the most extensively studied, there have also been studies of high-dose therapy in other solid tumors that typically display some degree of sensitivity to conventional doses of drugs. Thus this article will review the trials of high-dose chemotherapy and autologous transplantation in breast cancer, ovarian cancer, small-cell lung cancer, and germ cell testis cancer. Transplants performed in other tumors, such as soft tissue sarcoma, will not be reviewed here, since there is a limited amount of data available on those subjects. Data about pediatric solid tumors will not be included either, as this review will be limited to the discussion of the adult patient.

Breast Cancer In order to fairly and critically evaluate the role of transplantation in breast cancer, one can look only at prospective, randomized, controlled trials-the gold standard for decision-making in oncology--or one may also include phase II trials, in which there is an adequate and comparable control group with similar parameters of biologic behavior and in which standard therapy was administered. These trials can be looked at whether one is assessing response rate, progression-free survival, or overall survival, since in both metastatic and adjuvant settings known factors influence these outcome measures. Some factors may not be known, and randomized trials are less likely to inadvertently include an excess of either lower or higher risk patients in any arm of the study, thus skewing the results. Curr Probl Cancer, May/June 1998

143

A recent report by Rahman 5 makes this point in patients with metastatic breast cancer. In that retrospective analysis, which spanned nine years, 1,581 patients were enrolled in 18 studies in which doxorubicin-containing chemotherapy was administered in standard doses. Applying common eligibility criteria for entry into contemporary transplantation studies (age < 60, performance status < 2, response to recent chemotherapy, and normal end organ function), the authors of the study found 645 patients who were eligible and 936 who were ineligible for one or more reasons. The following results were found for the eligible and ineligible groups, respectively: complete response, 27% and 7%; median progression-free survival, 16 months and 8 months (p < 0.001); median overall survival, 30 months and 17 months (p < 0.001); 5-year survival, 21% and 6%; and 10-year survival, 7% and 2%. The authors concluded that "encouraging results of single-ann trials of high-dose chemotherapy could partially be due to selection of patients with better prognosis and further stresses the importance of completing ongoing randomized trials." In a similar adjuvant study6 of patients with high-risk disease (> 10 positive nodes), 265 patients were identified from a single institution over a 20-year period. Of these 265, 171 received standard adjuvant chemotherapy. These patients were grouped into those eligible for transplantation (n = 128) or those ineligible (n = 43), using criteria similar to those in Rahman's study of metastatic disease. Additionally, a contemporary cohort of patients (n = 39) that met transplantation eligibility was selected, and that group was treated with high-dose therapy. Outcome results for the two cohorts of eligible and ineligible historical patients, respectively, were: 5-year disease-free survival, 37% and 16% (p < 0.05); and 5-year overall survival, 55% and 23% (p < 0.01). When eligible historical patients were compared with contemporary treated patients, no differences were observed in either disease-free survival or overall survival. The authors concluded that "meeting high-dose chemotherapy inclusion criteria is an independent indicator of favorable prognosis in high-risk breast cancer patients and the selection of patients by these criteria may explain, at least in part, the promising short-term results of nonrandomized adjuvant high-dose chemotherapy trials in high-risk breast cancer." With this introduction and this caveat in place, the next sections will review high-dose trials in metastatic and high-risk breast cancer.

Metastatic Disease Trials that used high-dose chemotherapy and bone marrow or stem cell transplantation were derived from a search of the Medline files at the National Library of Medicine. Phase II studies from the past 10 years that 144

Curr Probl Cancer, May/June 3.998

included at least 15 treated patients were reviewed. Only the trials that reported progression-free survival (or median response duration), overall median survival (or 2-year survival), or both, were included, since response rate alone gives little indication of the value to the patient. The Food and Drug Administration requires demonstration of survival advantage or, in rare cases, improvement of quality of life before a new pharmaceutical is approved for use. It seems appropriate to use similar standards when reviewing the high-dose studies. Of 41 trials evaluated, 16 met the above criteria for inclusion into Table 1, which depicts trials of high-dose chemotherapy for metastatic disease. In some of the trials, high-risk adjuvant and metastatic patients were reported together and outcomes were not described for each group individually. In those situations, outcome measures may have been estimates, or the groups may have been reported separately. All but a single trial were performed in the United States, where the major growth in transplantation technology has occurred. Save for one study, 16 the trials were performed in single institutions. Although these studies were frequently performed on patients who may not have responded to pre-transplant chemotherapy, the patients are not separated, since this practice represents the reality of overall treatment of breast cancer. In Table 1, the last two columns show the percentage of patients who survived for 2 years following the transplant and the transplant-related mortality rate (typically, death within 100 days of the transplant). In many of the studies these numbers are similar, suggesting that the therapeutic index of the transplant procedures was not good. Since the decade in which these studies were performed, however, there has been an improvement in the supportive care of patients, which may reduce the transplant mortality rate. Nevertheless, these statistics speak for themselves, and any patient contemplating transplantation for metastatic breast cancer should be aware of the chance of early and treatment-related death. In the 16 trials listed, a total of 602 patients received transplants (an average of 38 patients per trial), and response rates varied from 41% to 90%. These response rates were calculated in several ways. Some trials, which included standard induction chemotherapy followed by autologous bone and marrow transplant (ABMT), only reported patients who underwent ABMT in the denominator; others used an intent-to-treat analysis that included all patients, regardless of their progression to ABMT. There was no discernible difference in the response rates of the studies of cases in which transplantation took place after induction chemotherapy versus those in which transplantation occurred initially. Curr Probl Cancer, May/June 1998

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In the largest study which used only stage IV, chemotherapy-naive patients, the response rate was mid-range (69%) and the median survival was the longest reported (31 months). Only 23 patients in that study (20%) had received adjuvant chemotherapy, so most represented a population without the negative prognostic factor of recurrence following adjuvant therapy. Among patients with measurable disease, there was a response rate of 58% to induction with doxorubicin, methotrexate and fluorouracil, but this was not statistically significantly different from the 50% response rate in patients in which adjuvant therapy failed. Ninetythree patients (82%) received ABMT, while 21 did not, for reasons including treatment-related death, inadequate marrow collection, interval progression of disease, patient refusal, and major protocol violation. The final response rate of 69% after ABMT generated an additional response rate of only 11%, suggesting that the high-dose therapy was marginally effective in the induction of further antitumor activity. Only 6 patients were converted to a better response category by high-dose chemotherapy, and long-term disease control was rare, with only 18% of the patients remaining progression-free at this time. To place ABMT into perspective, it is necessary to evaluate the outcomes of the many patients treated with standard-dose therapy. It is also important to reiterate the fact that end results in most of the trials of ABMT were based on denominators that included only patients who eventually received transplants rather than on the entire cohort. Only the studies from Hopkins 8 and Response Technology 16reported end results as intent-to-treat, which is the more conventional way to report results and has been used in standard-dose studies over the years. Table 2 summarizes the outcomes of standard-dose chemotherapy in metastatic breast cancer studies that have been published in the last 10 years and before the era of taxanes, which have only recently been incorporated into ABMT preparative regimens. Again, 16 trials were identified in which response and survival rates were reported, allowing for comparison, in a nonrandomized way, with those trials that employed high-dose therapy. One study 34 evaluated two different doses of epirubicin, neither requiring stem cell support. The overall response rates in the studies of standard-dose therapy are lower than those of the high-dose studies, but the median survival rates are quite similar. Even in the standard-dose studies performed in single institutions, the response rates and median survivals are marginally better than in the large, cooperative group, multiinstitutional trials. With the exception of the Response Technology study, all high-dose studies were performed in single institutions where there was a potential for greater selection bias. To further emphasize the effect Curr Probl Cancer, May/June 1998

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that selection bias may have, one need only examine the results of a large Eastern Cooperative Onocology Group study in which 10-year follow-up is available. In that trial, 37 the overall response rate was 68%, the complete response rate was 28%, and the median survival was 17 months for the entire cohort of patients. In the group of estrogen receptor-positive patients treated with cyclophosphamide/doxorubicin/fluorouracil (CAF) and receiving oophorectomies, however, the response rate (73%) and the complete response rate (20%) were similar, but the median survival was 59 months. If one eliminated those patients with bony or hepatic metastatic disease (the former difficult to assess for response and the latter usually a negative outcome prognosticator), the response rate rose to 91% and the complete response rate to 51%. Thus patient selection may significantly affect outcomes, in both the response rate and the median survival time. In the often quoted high-dose study from Duke University,7 all the patients were premenopausal (age < 50 years) and few had bone or liver involvements. As a result, there was an impressive 77% response rate and a complete response rate of 54%, but the median survival was a disappointing 10 months. One can attempt to compare nonrandomized studies with randomized ones by weighting the response rates and the median survivals according to the number of patient entries so that larger studies have a greater impact on outcome measures. When this approach is used regarding the studies outlined in Tables 1 and 2, there is a weighted response rate of 68% and a median survival of 18.5 months in the high-dose studies, while in the standard-dose trials the response rate is 53% (significantly lower statistically), but the median survival is 18.2 months. Thus it is difficult to conclude from this semi-mathematical approach that high-dose therapy with transplantation offers much except an improved response rate. Although important, only if this can improve median survival or cure rates will it have any appeal to health care practitioners or economists. In a recently reported randomized trial, 38 patients with hormone-insensitive and chemotherapy-naive metastatic breast cancer were initially induced into a complete remission with doxorubicin-based chemotherapy. Ninety-six of the 423 patients entered a complete remission and were then randomly put into groups for transplantation that would occur either immediately or at the time of relapse. Although the disease-free survival was superior in the group that received transplantation immediately (0.9 months versus 0.3 months), the overall survival was superior when transplantation was delayed until relapse (1.9 years versus 3.2 years). Of course, this randomized trial begs the question of whether high-dose chemotherapy initially or at relapse is superior to more standard doses of Curr Probl Cancer, May/June 1998

149

therapy at relapse, but the details of this study are not yet published. One must wonder if the initial high-dose therapy group which relapsed had such poor survival because of recurrence with a highly drug-resistant clone of ceils or because of fatal long-term complications from the transplant. The message that this study should send to physicians conducting trials is that early analysis of the indicators of efficacy--response rate and progression-free survival--may not translate into improvement in either quantity or quality of life, which are the ultimate requirements for any new therapy to be considered as a standard of care. There has been a single randomized trial of standard versus high-dose therapy in metastatic breast cancer. 39 In that trial, 90 patients were randomly assigned to either 6 to 8 cycles of standard doses of mitoxantrone, vincristine, and cyclophosphamide, or two courses of high-dose mitoxantrone (40 mg/m2), cyclophosphamide (2400 mg/m2), and etoposide (2500 mg/m 2) x 2 with stem cell support. Responses rates (53% vs 96%), complete response rates (4% vs 51%), and median survival (45 weeks vs 90 weeks) were superior for the high-dose arm. This study, however, failed to resolve the debate regarding high-dose therapy in breast cancer. First, the trial was small and statistically underpowered. Small changes in the recurrence rate--in this case, if the disease recurred in as few as 1 or 2 patients--could have rendered the results statistically insignificant. Second, the follow-up in this study was relatively short and long-term survival has not been assessed. Third, the response rate of 53% and the complete response rate of 4% in the conventional ann were lower than would be expected. The studies shown in Table 2 had apparently similar patient populations, but outcomes this poor were not reported. Fourth, the patients were generally younger than an unselected population and may have had other prognostic factors that make comparison with the larger unselected group of patients in Table 2 untenable. Finally, there is not a significant difference between median progression-free survival and median overall survival in the patients who received transplants. One must consider that the transplantation may have changed some of the already drug-resistant cellular clones to a biologically more aggressive state. These results must be cautiously interpreted and the outcomes of larger randomized trials must be reported before the adoption of this high-dose approach. Ongoing studies that may help answer this question include the study mentioned above, 38 which is asking when it is best to transplant rather than if it is wise to transplant at all. A second study from Philadelphia, which recently closed, gave patients with measurable metastatic disease standard doses of CAF followed by standard cyclophosphamide/methotrexate/fluorouracil (CMF) or high-dose 3.50

Curr Probl Cancer, May/June 3.998

therapy with carboplatin, cyclophosphamide, and thiotepa. Results of this study are anxiously awaited. The National Cancer Institute of Canada is also mounting a trial in which patients are initially treated with an epirubicin-based combination and then those patients with responsive disease are randomized to receive or to not receive high-dose therapy with cyclophosphamide, carboplatin, and mitoxantrone.

High-RiskAdjuvant Disease The rationale for the use of high-dose chemotherapy in early stage, highrisk breast cancer is based on the assumption that high doses will be more effective when the tumor burden is smallest and the tumor clones do not have either intrinsic or acquired drug resistance. As discussed previously, clinical studies in both leukemia and lymphoma have shown high-dose therapy to be most effective for patients with small tumor burdens and drug-sensitive tumors. Retrospective studies by Hryniuk have shown there to be a dose-outcome relationship in the early stages of breast cancer,4° as dose intensity is increased. The data collected describe the effects of doses of cyclophosphamide, methotrexate, and fluorouracil, but not doxorubicin, which is the most common agent used in adjuvant therapy of breast cancer. A subsequent report suggested a similar dose-outcome relationship with CAF regimens. 41 The Medline files were searched for information about high-risk breast cancer trials, as they were in the previous section for information about metastatic breast cancer trials, and trials were included that had more than 10 patients and that showed disease-free or overall survival, or both. To date, there are no completed randomized trials of high-dose therapy in high-risk breast cancer, thus all the data are coming from phase II trials. Table 3 summarizes these trials. When the largest series of patients is examined, it is seen that 84 patients, all with more than 10 positive nodes, had an actuarial event-free survival of 72% with a median follow-up of 3.3 years. Peters compared these results with pooled data from three Cancer and Leukemia Group B (CALGB) trials which included 245 patients with > 10 positive nodes who received conventional adjuvant chemotherapy. The event-free survival in that group was 50% during a similar time period. However, the short follow-up in the high-dose study makes it impossible, at this point, to know if long-term survival and cure will be affected. In view of the high morbidity associated with the procedure, Peters suggested that a prospective randomized trial was warranted to verify these encouraging early results. Peters has also recently presented data pooled from multiple institutions on 662 women who were treated with ABMT for highrisk breast cancer and who had received multiple preparative regimens, Curr Probl Cancer, May/June 1998

151

and he reported a 50% event-free survival at 5 years. 42 It is nearly impossible to compare these data with either Peters' large series or with a large series using conventional therapy, since the patients in this pooled database encompass a highly selected population with variable prognostic factors and various high-dose regimens. Another interesting paper documents the potential problems with comparing unselected series of patients for conventional therapy with the more highly selected patients that are evaluated for high-dose therapy and transplantation. A more extensive investigation of 30 patients referred for ABMT discovered unsuspected metastatic disease in 23% of the patients undergoing evaluation. Subsequently, these patients did not receive transplants, further emphasizing the fact that a cohort undergoing transplant is likely to have lower risk for recurrence because patients with cryptic advanced disease have often been removed from the group. 43 Had any of these patients been referred for conventional therapy, the bone marrow would not have been obtained and the prognostically negative marrow involvement detected. The need for randomized trials to address this issue is emphasized by two reports from randomized trials in high-risk breast cancer that compare standard doses of chemotherapy with higher-than-standard doses in cases that do not require marrow support. Those two trials reached conflicting conclusions. In a large National Surgical Adjuvant Breast Project study (n = 2305) comparing variable dose intensity with variable total dose of cyclophosphamide and doxorubicin, no difference could be discemed in the patients' 5-year disease-free or overall survival, whether their doses of cyclophosphamide had been doubled from 600 to 1200 or they had received 2 instead of 4 cycles of adjuvant therapy.44 In all three arms of this study the dose of doxorubicin was 60 mg/m 2. A second trial by the CALGB 45 came to a different conclusion, which can best be summarized by saying that using low-dose doxorubicin as an adjuvant yielded a poor outcome. In that study, CAF was administered in a low dose (300/30/300 x 4), intermediate dose (400/40/400 x 6), or high dose (600/60/600 x 4) to patients with node-positive breast cancer. Only the group receiving the low dose had inferior outcomes, suggesting that when therapy falls below a certain threshold poorer results accrue, and also suggesting, once again, that there is probably a plateau to the doseresponse curve above which little additional clinical benefit is obtained. Multiple reports of standard-dose adjuvant trials can be contrasted with the few high-dose phase II studies. Table 4 summarizes those trials that meet the criteria of adequate size and of having 5-year outcome data of some type available. It is obviously not possible to compare these data, 152

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since they are nonrandomized. Nevertheless, it seems appropriate to contrast the trials that produced 5-year disease-free survival, since this is the best indicator of the real efficacy of a treatment regimen. There appears to be a higher rate of disease-free survival in those patients treated with high-dose adjuvant therapy, with the average being 70% for patients on high-dose therapy and 40% for those treated in a conventional manner. Nevertheless, as has been mentioned before, the only parameter that would recommend high-dose therapy as a standard of care would be an improved long-term survival rate and a higher proportion of cured patients. Several ongoing or planned randomized trials will hopefully answer the question of whether high-dose chemotherapy and transplantation improve these outcomes in breast cancer. A list of these trials appears in Table 5. The unfortunate part is that, though these trials will likely yield similar results, none will produce any definitive conclusions because the small number of patients participating in the studies make them statistically underpowered. It would seem far better to select a reasonable transplant regimen and then accrue an adequate number of patients to participate in a national trial that would ultimately answer the question. Gradishar 57 has recently outlined the problems associated with developing such a national trial, based on both physician and patient bias, and he has concluded that the question of the value of high-dose therapy remains unanswered and awaits the results of randomized trials.

Summary The general concept proposed by those most in favor of high-dose therapy is, basically, more is better. However, when one critically examines the data, there appears to be a dose below that typically used clinically and which leads to inferior outcome, as was demonstrated in the CALGB study. 45 The National Surgical Adjuvant Breast Project trial was unable to demonstrate any difference between two regimens (both in clinically relevant ranges) where one was higher in both total dose and dose intensity. 44 It may not be necessary to use doses so high that they require stem cell support. Norton 58 popularized the concept of dose density, which shortens the interval between treatment cycles and uses doses of single agents requiring only cytokine support rather than stem cell support, in an attempt to achieve high total dose and dose intensity simultaneously. In fact, typical total doses used in a transplant regimen are less than the total doses in several cycles of most standard treatment regimens. This concept of dose density is currently being evaluated, in randomized trials, against more conventional therapy. 154

Curr Probl Cancer, May/June 1998

TABLE 5. Ongoing or Planned Randomized Trials in Breast Cancer Metastatic Disease Group Philadelphia NClC Pegase 03 Belgium

Induction CAF or CMF FEC/FAC FEC Taxane

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CMF x 2 yrs --T x l -~ ECx4

CTCb CMitoxCb CT T x l ---) Mitox/LP

CAF, Cyclophosphamide/doxorubicin/fluorouracil; CMF, cyclophosphamide/methotrexate/fluorouracil; CR, complete clinical response; PR, partial clinical response; CTCb, cyclophosphamide/thiotepa/carboplatin;. FEC, fluorouracil/epirubicin/cyclophospharnide; FAC, CAF; CmitoxCb, cyclophosphamide/mitoxantrone hydrochloride/carboplatin; CT, cyclophosphamide/thiotepa; Taxane; paclitaxel or docetaxel; T, peclitaxel; EC, epirubicin/cyclophosphamide; Mitox/LP, mitoxantrone hydrochloride/phenylalanine mustard. Table Courtesy of Dr. E.A. Eisenhauer, NCIC Clinical Trials Office.

Adjuvant Disease Nodes _> 4

_>6 _> 8 _> 10

Group Milan Scandanavia Italian Netherlands Manchester SFGM/FNCCC ECOG German CALGB/SWOG/NClC

Standard Rx E x 3 --) CMFx 6 CEF x 8 CEF x 6 CEF x 5 CE x 8 CEF x 4 CAF x 4 CE x 4 --~ CMF x 3 CAF x 4 --) cbp

High Dose Rx High Dose Sequential CEF x 4 -~ CTCb CEF x 4 -~ CEL CEF x 4 --~ CTCb CE x 4 --) CTCb CEF x 4 --~ Cmitox CAF x 4 -~ CT CE x 4 -~ CTMitox CAF x 4 --~ CBP

E, Epirubicin; CMF, cyclophosphamide/methotrexate/fluorouracil; CEF, cyclophosphamide/epirubicin/ fluorouracil; CTCb, cyclophosphamide/thiotepa/carboplatin; CEL, cyclophoshamide/epirubicin/Lphenylalanine mustard; CE, cyclophosphamide/epirubicin; SFGM, Societ6 Francaise de Greffe de Moelle; CEF, cyclophosphamide/epirubicin/fluorouracil; Cmitox, cyclophosphamide/mitoxantrone; ECOG,Eastern Cooperative Oncology Group; CAF, cyclophosphamide/doxorubicin/fluorouracil; CT, cyclophosphamide/ thiotepa; CMF, cyclophosphamide/methotrexate/fluorouracil; CTMitox, cyclophosphamide/thiotepa/ mitoxantrone; CALGB/SWOG/NClC, Cancer and Leukemia Group B/Southwest Oncology Group/National Cancer Institute of Canada; cbp, cyclophosphamide/carmustine/cisplatin, small dose; CBP, cyclophosphamide/carmustine/cisplatin, high dose. Table Courtesy of Dr. E.A. Eisenhauer, NClC Clinical Trials Office.

Even with current approaches to circumvent hematologic toxicity with bone marrow mononuclear cells or selected stem cells from the peripheral blood, two facts have not been and cannot be addressed. First, even though the dosages used in high-dose therapy for some drugs may be 2times (doxorubicin), 4-times (cyclophosphamide, paclitaxel), 5-times (carboplatin), or even 10-times (mitoxantrone, melphalan) higher than doses used in conventional therapy, eventually non-hematologic toxicity supervenes and prevents further dose escalation. In the studies from Duke University using triple alkylating therapy, the incidence of interstitial pneumonitis was 31% and there was a 12% treatment-related mortality rate. Thus, pushing drugs past their limits in terms of hematologic effects may lead to fatal and life-threatening complications in more patients than Curr Probl Cancer, May/June 1998

155

the technology may save, even if it is effective. Second, most studies of drug resistance in vitro have shown the level of resistance to be in the range of 1 to 3 logarithms, which is not an attainable level in clinical practice today. Finally, the economic cost of this technology is considerable, as it averages $50,000 per transplant. With an anticipated 3,000 such transplants this year, the annual cost would be $150,000,000, which is more than 15% of the entire budget of .the National Cancer Institute. Thus, a national clinical trial appears to be mandatory. Several are underway, and clinicians and patients need only to support them in order to answer this important question of whether highdose therapy and transplantation can improve outcome in early high-risk breast cancer or even metastatic breast cancer. The stakes are high, but the potential payoff is well worth it if more women with breast cancer can be saved from death.

Ovarian Cancer Although fewer transplants are performed each year on patients with ovarian cancer and so less data available about these transplants, the prevalence of ovarian cancer is increasing. In a report from the National Bone Marrow Transplant Registry last year on 341 patients who received transplants between 1992 and 199759 a median survival was reported that was not significantly better than that of patients who received single agent paclitaxel as salvage therapy. In that retrospective review, 72% of patients had responded to pre-transplant chemotherapy. There was a 7% incidence of transplant-related mortality and a 2-year probability of survival of 37%, with the best response and survival seen in those patients who had achieved a complete response to pre-transplant chemotherapy. These same patients also responded well to standard-dose therapy, particularly if the interval between initial chemotherapy and recurrence was greater than 6 months. The topic of dose intensity without transplantation in ovarian cancer has been recently reviewed. 6°'61 There have been at least 11 randomized trials that have compared standard doses of carboplatin or cisplatin-based chemotherapy with double doses of the same, either as single agents or in combination. The majority of these trials have not shown an advantage in most outcome parameters. The retrospective meta-analysis performed by Levin and Hryniuk provides a rationale for many of these studies; the results of their study of many trials suggested an improvement in both response rate and survival resulting from a greater dose intensity (administered amount of chemotherapy in mg/m2/unit of time). 62'63 A second meta-analysis suggested that platinum dose intensity was unimportant 156

Curr Probl Cancer, May/June 1998

whereas total dose intensity (intensity of all administered drugs) was, and also important was the percentage of patients with low tumor volume at the initiation of therapy. 64 While these minimal data from randomized studies suggest that there is little effect on outcomes for patients receiving clinically relevant doses, proponents of intense therapy have suggested that there may be a second shoulder to the dose-response curve that, when reached, will improve outcomes. It is on this belief that studies of patients who have received ovarian cancer transplants have been based. A review of experimental chemotherapy in ovarian cancer patients summarizes various approaches to increasing dose intensity, abrogating doselimiting toxicities to allow further dose escalation, or both. 65 That review notes that regimens employing high-dose chemotherapy typically increase doses 3 to 10 times before non-hematologic toxicities intervene (ototoxicity for carboplatin, mucositis for mitoxantrone and etoposide, cardiac toxicity for cyclophosphamide, and gastrointestinal toxicity for melphalan). The only therapy that allows dose escalation to levels greater than 10-fold is intraperitoneal instillation of drugs, a topic that is beyond the scope of this review. However, there is one published, randomized trial suggesting an 8-month survival advantage and less toxicity for cisplatin given intraperitoneally as opposed to intravenously. 66 What is clear from studies of ovarian tumor cells in vitro is that levels of resistance are typically greater than a logarithm: cisplatin and carboplatin, 13 to 40 times greater67,68; paclitaxel, 20 to 50 times greater69; and anthracyclines, 100 to 400 times greater. If such levels of resistance apply in the clinical setting, the potential levels of dose escalation that are possible with highdose systemic therapy and transplantation will not allow this degree of resistance to be overcome. Only intraperitoneal approaches allow the escalation to doses greater than one logarithm, but there is always the possibility that drug delivery by passive diffusion will be inadequate and that disease outside the regional area of adequate perfusion (the peritoneal cavity free of adhesive peritonitis) may receive little drug exposure, since systemic drug levels are typically low with this approach. There are aspects of ovarian cancer that make it more attractive than breast cancer as a possible target for high-dose therapy. First, advanced ovarian cancer is just as sensitive to cytotoxic therapy as advanced breast cancer, and the levels of many of the agents involved in the therapy can be increased several times before non-hematologic toxicity supervenes. Second, ovarian cancer rarely metastasizes to bone marrow, making it easier and less risky to transplant autologous marrow and reducing the need to purge the marrow prior to transplantation. Finally, ovarian cancer Curr Probl Cancer, May/June 1998

157

remains confined to the peritoneal cavity for most of its natural history, making it unlikely that the tumor will recur in other sites, such as the central nervous system. Unfortunately, as in the case of breast cancer, the trials of high-dose therapy and transplantation in ovarian cancer have been performed in single institutions with small sample sizes, were mostly nonrandomized, used various preparative regimens, treated patients with variable prognostic factors, and were generally performed at the time of recurrence rather than as part of primary therapy or as part of consolidation in drug-sensitive, low-volume settings. The same parameters were used to search for studies of transplantation in ovarian cancer as were used to search for breast cancer studies. Table 6 summarizes the studies available, which are all phase II in nature. Only those studies specifically designed for ovarian cancer or broader phase II studies where ovarian cancer patients could be separated were cited. Several phase I/II studies in multiple solid tumors contain some patients with ovarian cancer, but if these patients were not described separately, the studies are not included. Only studies with at least 10 patients were listed and only when some endpoint was available; for example, response rate, disease-free survival, or overall survival. Most transplant regimens for ovarian cancer are based on escalated doses of cyclophosphamide and carboplatin, and include mitoxantrone, melphalan, ifosfamide, etoposide, and most recently, paclitaxel. The response rates from these 6 trials that were reported were good. In the cases where response rates were not reported, the patients had entered the study with non-measurable (often reflecting low-volume) disease, and, as might be anticipated, median survival and long-term survivals are best in studies where the response rate is not reported. In multiple multivariate analyses in ovarian cancer patients, tumor volume at the initiation of either primary or salvage therapy has been prognostic of outcome. Patients who initially have smallvolume and non-measurable disease have median survivals that are usually double those of patients with high-volume disease. The two largest and most recently published trials 72,73 both concluded that the data were interesting but that prospective, randomized, controlled trials were necessary. Stiff73 suggested that patients with low-volume disease--achieved by either surgical or more standard chemotherapeutic means--were the preferred patients for prospective trials. His trial was the only one large enough to allow multivariate analysis of the factors that are prognostic for outcome after transplantation. That study concluded, not surprisingly, that patients with low-volume, drug-sensitive tumors had the best outcome. This lesson the should have been learned from the 30 years of previous transplant experience with malignant hematologic disease. 158

Curr Probl Cancer, May/June 1998

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It is important that practitioners do not reach the same conundrum with ovarian cancer as the one which exists involving breast cancer and transplantation. The trials done on patients with ovarian cancer give insight only about outcomes in small single institution studies where there is the distinct possibility of patient selection bias. Also, the studies run the gamut from patients refractory to chemotherapy to patients who are basically chemotherapy-naive. Those with drug-resistant disease may have high response rates to high-dose chemotherapy, but the response durations are typically less than 9 months and there is little likelihood that this approach will have any impact on long-term disease control. Further phase II studies of new combinations of preparative regimens in this population will not provide sound data, since again there may be high response rates, short response durations, and an inability to determine whether the new high-dose regimen is efficacious without performing a phase III randomized trial against standard therapy. It is important to remember from more than two decades of investigation that patients with large-volume disease and whose tumor volume is less-than-optimally reduced by therapeutic means typically survive, on average, only half as long as their counterparts who have small-volume disease at the initiation of chemotherapy. How much of this differential is based on the actual salutary effect of surgery versus the intrinsic tumor biology is not nor is it likely to be known. Nevertheless, it would seem that patients with large-volume disease who have received high-dose therapy would not be an optimal population in which to test this concept as an initial therapy, since some 20% to 30% of these patients have intrinsic drug resistance and would be certain to fail attempts at disease control with high-dose therapy. The best population in which to test the concept of high-dose therapy with transplantation is made up of patients who have had some standard chemotherapy and who have been shown to have drugsensitive, low-volume disease following primary chemotherapy and who are at the outset of the high-dose therapy. Table 7 outlines the ongoing or planned randomized trials of ovarian cancer patients which will hopefully address the relative value of transplantation in ovarian cancer, either applied as part of initial therapy or in the previously treated patient as part of consolidation of a response to standard therapy. In all of these protocols, the high-dose therapy will be compared with a standard-dose therapy consisting of a platinum compound in routine doses and either cyclophosphamide or paclitaxel. It is hoped that these trials, when complete, will allow definitive statements to be made about the value of high-dose therapy in ovarian cancer. There remains a bias on the part of physicians to offer transplantation to 160

Curr Probt Cancer, May/June 1998

TABLE 7, Randomized Trials of High-Dose Chemotherapy in Ovarian Cancer Group GINECO GOG NWAST CRC AGO FI NOVA ROME

F or C C C C F F F F

PACL

CARB

CYTX

LPAM

X X X X

X X X X X X X

X X X X X X IFOS

X

MITX

THIO

ETOP

X

F, First line; C, consolidation; PACL, paclitaxel; CARB, carboplatin; CYTX, cyciophosphamide; LPAM, melphalan; MITX, mitoxantrone; THIO, thiotepa; ETOP, etoposide; GINECO, Groupe des Investigateurs Nationaux pour I'Etude des Cancers Ovariens; GOG, Gynecological Oncology Group; NWAST, Netherlands Working Party on Autoiogous Transplantation in Solid Tumors; CRC, Cancer Research Campaign; AGO, Arbeitsgemeinschaft Gynakologische Onkologie; FINOVA, Finnish Ovarian Cancer Trials Group; ROME, Rome; IFOS, ifosfamide. Courtesy Dr. E. A. Eisenhauer, NClC Clinical Trials Office.

patients whenever possible, even without definitive proof of its value. This was demonstrated by the poor early accrual of patients for the intergroup study in the United States, which in part appears to be due to that bias. Eligibility criteria for that trial was recently broadened to facilitate achievement of the accrual goals, but this may make the patient population much more heterogeneous with respect to both well-defined drug sensitivity and low tumor volume. On the other hand, the results will be more generalizable. Appropriately, third-party payers have recognized the economic utility of supporting these trials in ovarian cancer to discover the value of high-dose therapy and transplantation, which is significantly more expensive than standard therapy.

Summary There appears to be minimal, if any, dose effect for systemic cisplatin given in doses of 20 to 50 mg/m2/week or for carboplatin between the area under the curve of 4 to 12 for patients with ovarian cancer. The existence of a second threshold of drug effectiveness is postulated as a rationale for high-dose studies, but this has so far been unproved. Several phase II studies with high-dose therapy in low-volume, chemotherapysensitive patients appear promising in terms of response rates, but there has been no significant durability of the higher responses. However, the numbers in these trials are too small to allow definitive conclusions regarding efficacy. While high-dose chemotherapy cannot yet be considered as a standard of care for any subset of patients with ovarian cancer, it is clear that further high-dose approaches seem unwarranted for patients with either high-volume disease or with resistance to platinums or taxanes in standard doses. Ongoing randomized trials will be important to Curr Probl Cancer, May/June 1998

161

determine the overall value of this approach. If a second trial evaluating the efficacy of intraperitoneal therapy as compared with intravenous therapy shows positive results, this may offer a less toxic alternative for highdose therapy that should be considered in future studies.

Small-Cell Lung Cancer Small-cell bronchogenic carcinoma accounts for about 25% of the 180,000 new cases of lung cancer in the United States annually. As noted above, small-cell lung cancer--even in patients with limited disease presentations-is often associated with the early onset of metastatic disease, apparently from previously established micrometastases which theoretically should lend themselves most readily to high-dose therapy and transplantation. An additional problem with the natural history of small-cell lung cancer with regard to high-dose chemotherapy is the propensity of this tumor to metastasize to the central nervous system. Even with highdose systemic therapy, few drugs can traverse the blood-brain barrier in sufficient quantities to eliminate established and subclinical micrometastases in that site. Although there were some attempts at high-dose therapy for other types of lung cancer in the 1970s, contemporary studies have been primarily focused on small-cell disease, as it is felt to be a systemic disease at the outset and it is the only histogenetic type of cancer that is exquisitely sensitive to chemotherapy. In addition, small-cell lung cancer is responsive to several drugs that can be effectively dose-escalated with primary doselimiting hematopoietic toxicity, including cyclophosphamide, ifosfamide, etoposide, carboplatin, and carmustine. These latter two drugs are only borderline active, however, as single agents in standard doses in smallcell disease. In 50% of patients with limited disease and 20% of patients with extensive disease, complete response rates are common with regimens made up of cyclophosphamide, etoposide, and doxorubicin. Another problem unique to small-cell lung cancer is the frequent contamination of the marrow with tumor cells, in which cases transplantation may reinfuse a significant burden of tumor cells unexposed to cytotoxic chemotherapy.76 Even with the more recent use of peripheral blood stem cell reconstitution, there is evidence that tumor cells may contaminate the infusion. 77 Data regarding correlation between dose intensity and outcome are minimal and somewhat confusing. Klasa et al. 78 retrospectively reviewed 60 studies involving therapy of extensive and limited small-cell lung cancer. The endpoints that were examined included response rate and median survival. There was no correlation between outcome and dose intensity of 162

Curr Probl Cancer, May/June 1998

TABLE 8, Randomized Trials Using Interval Reduction to Increase Dose Intensity

Number of Patients

Stage

Regimen

% Resp

Median Survival (rues)

Furuse r9

228

Ext

L CAV/EP H CODE+G

77 85

10.6 11.9

Murray 8°

219

Ext

L CAV/EP H CODE

52 66

10.6 11.8

Sculier 81

223

Lim, Ext

L CAE H 7-drug

61 69

9.9 11.3

Steward82

301

Lim, Ext

L VICE q 28 H VICE q 21

76 87

---

65

Lim, Ext

Author

Wol183

L VICE 94 16.3 H VICE+G 94 17.3 E_xt, Extensive; L, low dose; CAV,cyclophosphamide/doxorubicin/vincristine; EP, etoposide/cisplatin; H, high dose; CODE, cisplatin/vincristine/doxorubicin/etoposide; Lira, limited; CAE, cyclophosphamide/ doxorubicin/etoposide; 7-Drug, vincristine/vindesine/cyclophosphamide/doxorubicin/etoposide/ methotrexate/cisplatin; VICE, vincristine/ifosfamide/carbopiatin/etoposide; q, every; G, filgrastim.

the cyclophosphamide/doxorubicin/vincristine sulfate (CAV) regimen. However, there was a positive correl~ttion between the relative dose intensity of cyclophosphamide and outcome in limited disease only. With the cyclophosphamide/doxorubicin/etoposide (CAE) and cyclophosphamide/doxorubicin/vincristine/etoposide (CAVE) regimens, dose intensity correlated positively with median survival, and in extensive disease there was a positive correlation between cyclophosphamide intensity and survival. With the etoposide/cisplatin (EP) regimen, there were no correlations seen with the entire regimen or with the individual drugs. The authors of the study concluded that the analysis could not clearly demonstrate any correlation between dose intensity and outcome in small-cell lung cancer. Most of the studies of high-dose therapy without stem cell support in small-cell cancer have been phase III in nature, and they can be divided into those that increased dosages to achieve a greater intensity and those that decreased intervals between courses to affect intensity. Table 8 shows the studies in which interval reduction was used to increase dose intensity. In many of these studies, the response rates were higher with the more dose-intensive arm. In no case was median survival statistically better with the intense therapy 'except for in Steward's 82 study, which was published recently and in which the median follow-up had only reached 8 months. In the study by Woll, 83 the median survivals were not different, in large part due to more treatment-related deaths in the intense group (6 vs 1), but the 2-year survival was superior for the intense group (32% vs Curr Probl Cancer, May/June 1998

163

TABLE 9. Randomized Trials Using Increased Dose to Increase Dose Intensity Author Cohen84

Number of Patients Stage

Median Survival (mos)

Regimen

Doses L 50/10/500 H 100/15/1000 L 1000/40/1 H 1500/60/1 L 1200/40/225/100 H 1800/60/330/120

5.0 10.5 --

32

Um, Ext

CcMC

Figueredo 85

103

Lim, Ext

CAV

Pujo186

125

Ext

CEEP

Johnson87

298

Ext

CAV

L 1000/40/1 H 1200/70/1

8.0 6.8

Arriagada88

105

Lim

CAPE

L 900/40/80/225 H 1200/40/100/225

26% 2-yr 43% 2-yr

90

Ext

EP

L 240/80 H 400/135

10.7 11.4

Ihde89

10.8 8.9

Lim, Limited; E~t, extensive; CcMC, Iomustine/methotrexate/cyclophosphamide;L, low dose; H, high dose; CAV, cyclophosphamide/doxorobicin/vincristine;CEEP, cyclophosphamide/epidoxorubicin/etoposide/cisplatin; CAPE,cyclophosphamide/doxorubicin/cisplatin/etoposide;EP, etoposide/cispiatin.

15%). The authors did not state if the 2-year survivors were disease-free or not. In most of the studies, the intervals between courses were lengthened more than those for dose-intense therapy that had been originally lengthened due to toxicity or the need for cytokine support to allow administration of the therapy on schedule. The overall impression that can be derived from these studies is that dose intensity in the range allowed here does not make a significant difference in outcome for patients with small-cell lung cancer, particularly for those patients with extensive-stage disease. Table 9 lists studies in which dosages were increased to improve intensity while maintaining the same cycle time as the less intense therapy. The planned increase in dose intensity was always less than twofold, and most of the studies failed to report actual rather than planned dose intensity. In the study by Arriagada, 88 which reports the greatest outcome benefit, only the doses of cyclophosphamide and cisplatin were escalated by 30% and only in the first cycle of therapy, so the overall increase in dose intensity over the 6 courses of therapy was minimal. The study by Cohen 84 was prior to the modem era of therapy for small-cell disease, and it reported a survival advantage for the high-dose therapy, but the survival for the standard-dose therapy is poor by modem standards. In the study by Pujo186 it was not possible to increase doses of therapy by 50% even with cytokine support; toxicity was greater with the intense therapy and survival was better with standard therapy. Thus, it was only the recent study by Arriagada that reported a survival advantage at 2 years. 164

Curr Probl Cancer, May/June 1998

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There are few trials of high-dose therapy and transplantation in smallcell lung cancer. Table 10 lists four trials that all together account for only 69 patients. The largest trial treated only 32 patients, so conclusions must be interpreted with caution since such a small number of patients was involved and because all of the studies were performed in single institutions with the potential for selection bias. Nevertheless, even this small amount of data indicates quite clearly that patients with extensivestage small-cell lung cancer are poor candidates for high-dose chemotherapy. In the two studies with significant percentages of extensivestage patients, there was significant treatment-related mortality, and there were no long-term survivors. These patients should not be candidates for high-dose therapy. Patients with limited-stage disease, on the other hand, have a reasonable 2-year survival. Such patients, who have already received standard therapy, usually as multi-agent chemotherapy with thoracic and cranial radiation therapy, would be ideal candidates to be randomized into two groups for a study that would compare patients who would then receive high-dose therapy with those who would receive no further therapy. There is a single published trial of a randomized study in small-cell lung cancer.94 In that study, 101 patients with both limited and extensive smallcell lung cancer were given standard therapy consisting of methotrexate, vincristine, cyclophosphamide, doxorubicin, cisplatin, and etoposide, as well as prophylactic cranial irradiation. Patients who responded to this regimen (n = 45) were subsequently randomized to receive conventional doses of cyclophosphamide, carmustine, and etoposide or one cycle of high-doses of these same agents, followed by autologous marrow reinfusion. In this small trial there was a statistically significant (p = 0.002) relapse-free survival advantage for the high-dose therapy (28 weeks vs 10 weeks). However, no overall survival advantage was noted, and there were more treatment-related deaths (4 vs 0) for the high-dose group.

Summary The data currently available clearly suggest that patients with extensivestage disease are poor candidates for high-dose approaches. Patients with limited-stage disease and who respond well to standard doses of chemotherapy may derive benefit from consolidation with high-dose therapy in combination with radiation therapy to the chest and the central nervous system. Nevertheless, the small numbers of patients treated in phase II trials and the statistically underpowered single phase II! study do not allow any definitive conclusions regarding this approach to be made at this time. No randomized trials available evaluate high-dose consolida166

Curr Probl Cancer, May/June 1998

tion therapy in small-cell lung cancer, and they are urgently needed if the value of this approach is to be addressed.

Testis Cancer Approximately 25% of patients with advanced germ cell tumors of the testis fail to achieve lasting complete responses with conventional cisplatin-based combination chemotherapy. Several prognostic factors have been identified that can predict adverse outcomes, including the primary tumor site (extragonadal), the histology (yolk sac elements or trophoblastic elements), the stage of the disease's progression, and the presence of massively elevated markers (AFP, LDH, and ~-HCG) or long half-life of these markers. In contradistinction to the solid tumors reviewed above, ample data show a curative potential with high-dose approaches in testis cancer. As was the case in early studies of bone marrow transplantation in leukemia and lymphoma, initial trials in testis cancer focused on patients who had sustained two or more recurrences after conventional therapy and in whom cure with further standard-dose approaches was not associated with long-term survival. Early studies often used etoposide and carboplatin in high doses, and the numbers of patients treated were small. Nevertheless, as experience has been gained, high-dose chemotherapy and transplantation has been used more and more for patients in earlier stages of this disease and most recently as part of primary therapy for patients with risk factors for recurrence following standard therapy.

Salvage Therapy Table 11 details the outcomes of patients treated with high-dose therapy at the time of recurrence. In all of these studies, there are patients who experience long-term survival and are probably cured with high-dose therapy. Though not clear from the table, patients with mediastinal primaries (extragonadal) and those with cisplatin-refractory disease had the poorest outcomes. Also, there is a certain price to be paid with this approach, as there were treatment-related deaths in nearly every study, and these deaths cannot be predicted before the decision to transplant has been made. However, it appears less likely that a therapeutic advantage can be gained by using this approach for patients with extragonadal primary tumors, multiple prior regimens, drug-resistant disease, and premorbid organ-function abnormalities from prior standard chemotherapy. With the obvious mixed success of employing high-dose therapy at relapse, transplantation has more recently been used in earlier stages of disease as consolidation therapy following the initial response to standard Curr Probl Cancer, May/June 1998

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chemotherapy in those patients with adverse prognostic factors for longterm disease control. Table 12 depicts three studies which have used this approach. The two studies by Motzer 1°2,1°3deserve special note. Although they were not randomized trials comparing high-dose therapy to conventional therapy, there were ample data from the same institution in a similar cohort of patients who had been treated with conventional therapy. In contrasting these four studies, which all have similar overall patient numbers and similar prognostic factors, it was found that 25 % of patients who received conventional therapy were alive and disease-free, while 50% who had received high-dose therapy were. Similarly, median survival with conventional therapy was 13 months, and in the two high-dose therapy studies, the median had not been reached in one and was 40 months in the other. From a statistical point of view, these differences were highly significant and led the investigators to initiate a randomized trial in intermediate and high-risk patients comparing four courses of conventional bleomycin, etoposide, and cisplatin versus two cycles of the same followed immediately by two courses of high-dose therapy with cyclophosphamide (150 mg/kg), carboplatin (1800 mg/m2), and etoposide (1800 mg/m 2) with autologous stem cell rescue. This trial is now ongoing as a collaborative trial with participation by two national cooperative groups and three large cancer centers. The outcome of this trial will be instrumental in making definitive conclusions about whether or not high-dose therapy should be part of the standard regimen of treatment for high-risk patients. If the results of this trial are positive, it is likely that this approach will be used in other patients at earlier points in the natural history of their testis germ cell tumors.

Summary The data clearly show that high-dose therapy with transplantation can lead to cures for patients with recurrent tumors. Data suggest that the ongoing randomized trials of conventional-dose versus high-dose therapy will give results in favor of the high-dose therapy. Of the tumors discussed in this article, testis cancer is the most drug-sensitive, and conventional chemotherapy has had the greatest impact on long-term survival of patients with this disease. If the randomized trial in testis cancer yields negative results, it seems unlikely that current high-dose approaches in breast cancer, ovarian cancer, and small-cell lung cancer will prove to be beneficial.

Conclusion It is clear from the studies of high-dose chemotherapy in patients with solid tumors that technology allows the administration of high doses (3 to Curr Probl Cancer, May/June 1998

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5 times the normal dose) of multiple cytotoxic agents with acceptable toxicity, particularly in institutions with more experience and that employ the increasingly common procedure of using peripheral blood progenitor cells to reconstitute the marrow. Although there is a rationale for the use of high-dose therapy based on the success of this therapy in lymphoma and leukemia, solid tumors are rarely so drug-sensitive and are often more heterogeneous at diagnosis. Further rationale is based on the premise that a linear dose-response relationship exists. Unfortunately, clinical practice suggests that this is not the case in solid tumors, and multiple clinical trials comparing standard therapy with therapy that is twice as intense as the standard have generally been unable to show a survival advantage, and the more intensive therapies have been more toxic. The hope is for a second shoulder to this dose-response curve, with improved tumor cell kill resulting from greater dose intensity of primarily myelosuppressive agents when coupled with stem cell rescue. No clinical data support this second shoulder, and in vitro studies have typically required 1 to 3 log increases in drug concentration to cause cytotoxicity after resistance has been generated in cell lines passaged in low drug concentrations. Such dose increases are not currently technically possible. Solid tumor transplant enthusiasts continue to offer the technology to patients with the implied or even stated hope for a cure, even though the available data do little to support such contentions, except in the case of testis cancer. A decade of high-dose chemotherapy and autologous transplantation has at least demonstrated that patients with large tumor burdens and drug refractory disease are not appropriate candidates for this approach. Phase FII studies that continue to take place under the guise of defining better preparative regimens for patients with metastatic breast cancer, palpable or imageable ovarian cancer, or extensive stage small-cell lung cancer need to cease. However, there remains a rationale for exploring further high-dose approaches in localized and high-risk breast cancer, microscopic ovarian cancer or ovarian cancer that has responded to standard therapy but is likely to recur, and limited-stage small-cell lung cancer. In all of these patient cohorts, however, the transplant strategy should be prospectively and randomly compared with standard therapeutic approaches, with attention paid not only to response and survival rates but also to toxicity, pharmacoeconomic, therapeutic index, and quality of life issues. Only with this rigorous and time-tested scientific approach to inquiry will the findings regarding the clinical efficacy of and need for high-dose therapy and transplantation be accepted by the medical community. It is the responsibility of all clinicians, academically-based or not, to support these important trials so that accrual targets are met and these major issues resolved. 170

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References 1. Appelbaum FR. The use of bone marrow and peripheral blood stem cell transplantation in the treatment of cancer. CA Cancer J Clin 1996;46:146-64. 2. Antman KH, Rowlings PA, Vaughan WP, et al. High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America. J Clin Oncol 1997;15:1870-9. 3. Graves EJ. Detailed diagnoses and procedures. National Hospital Discharge Survey, 1989. Vital and Health Statistics--Series 13: Data From the National Health Survey, 1991;108:1-236. 4. Canellos GP. Selection bias in trials of transplantation for metastatic breast cancer: have we picked the apple before it was ripe? J Clin Oncol 1997;15:3169-70. 5. Rahman ZU, Frye DK, Buzdar AU, et al. Impact of selection process on response rate and long-term survival of potential high-dose chemotherapy candidates treated with standard-dose doxorubicin-containingchemotherapy in patients with metastatic breast cancer. J Clin Oncol 1997;15:3171-7. 6. Garcia-Carbonero R, Hidalgo M, Paz-Ares L, et al. Patient selection in high-dose chemotherapy trials: relevance in high-risk breast cancer. J Clin Onco11997;15:3178-84. 7. Peters WP, Shpall EJ, Jones RB, et al. High-dose combination alkylating agents with bone marrow support as initial treatment of metastatic breast cancer. J Clin Oncol 1988;6:1368-76. 8. Kennedy MJ, Beveridge RA, Rowley SD, et al. High-dose chemotherapy with reinfusion of purged autologous bone marrow following dose-intense induction as initial therapy for metastatic breast cancer. J Natl Cancer Inst 1991;83:920-6. 9. Crown J, Kritz A, Vahdat L, et al. Rapid administration of multiple cycles of highdose myelosuppressive chemotherapy in patients with metastatic breast cancer. J Clin Oncol 1993;11:1144-9. 10. Antman K, Ayash L, Elias A, et al. A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy. J Clin Oncol 1992;10:102-10. 11. Ayash LJ, Elias A, Wheeler C, et al. Double dose-intensive chemotherapy with autologous marrow and peripheral-blood progenitor-cell support for metastatic breast cancer: a feasibility study. J Clin Oncol 1993;12:37-44. 12. Williams SF, Gilewski T, Mick R, et al. High-dose consolidation therapy with autologous stem-cell rescue in stage IV breast cancer: follow-up report. J Clin Oncol 1992; 10:1743-7. 13. Ghalie R, Williams SF, Valentino LA, et al. Tandem peripheral blood progenitor cell transplants as initial therapy for metastatic breast cancer. Biol Blood Marrow Transplant 1995; 1:40-6. 14. Holland HK, Dix SP, Geller RB, et al. Minimal toxicity and mortality in high-risk breast cancer patients receiving high-dose cyclophosphamide, thiotepa, and carboplatin plus autologous marrow/stem-cell transplantation and comprehensive supportive care. J Clin Oncol 1996; 14:1156-64. 15. Klumpp TR, Goldberg SL, Magdalinski AJ, et al. Phase II study of high-dose cyclophosphamide, etoposide, and carboplatin (CEC) followed by autologous hematopoietic stem cell rescue in women with metastatic or high risk non-metastatic breast cancer: multivariate analysis of factors affecting survival and engraftment. Bone Marrow Transplant 1997;20:273-81. Curr Probl Cancer, May/June 1998

171

16. Weaver CH, West WH, Schwatrzberg LS, et al. Induction, mobilization of peripheral blood stem cells (PBSC), high-dose chemotherapy and PBSC infusion in patients with untreated stage IV breast cancer: outcomes by intent to treat analysis. Bone Marrow Transplant 1997;19:661-70. 17. Bensinger WI, Schiffman KS, Holmberg L, et al. High-dose busulfan, melphalan, thiotepa and peripheral blood stem cell infusion for the treatment of metastatic breast cancer. Bone Marrow Transplant 1997;19:1183-9. 18. Myers SE, Mick R, Williams SE High-dose chemotherapy with autologous stem cell rescue in women with metastatic breast cancer with involved bone marrow: a role for peripheral blood progenitor transplant. Bone Marrow Transplant 1994;13: 449-54. 19. Vaughan WP, Reed EC, Edwards B, et al. High-dose cyclophosphamide, thiotepa and hydroxyurea with autologous hematopoietic stem cell rescue: an effective consolidation chemotherapy regimen for early metastatic breast cancer. Bone Marrow Transplant 1994; 13:619-24. 20. Dunphy FR, Spitzer G, Fomoff JE, et al. Factors predicting long-term survival for metastatic breast cancer patients treated with high-dose chemotherapy and bone marrow support. Cancer 1994;73:2157-67. 21. Vincent MD, Powles TJ, Coombes RC, et al. Late intensification with high-dose melphalan and autologous bone marrow support in breast cancer patients responding to conventional chemotherapy. Cancer Chemother Pharmacol 1988;21:255-60. 22. Hortobagyi GN, Frye D, Buzdar AU, et al. Complete remission in metastatic breast cancer: a thirteen year follow-up report. Proc Annu Meet Am Soc Clin Oncol 1988;7:37. 23. Roth B J, Sledge GW, Williams SD, et al. Methotrexate, vinblastin, doxorubicin, and cisplatin in metastatic breast cancer: a phase II trial of the Hoosier Oncology Group. Cancer 1991 ;68:248-52. 24. Jodrell DI, Smith IE, Mansi JL, et al. A randomised comparison of mitoxantrone, methotrexate and mitomycin C and cyclophosphamide, methotrexate and 5-FU as first line chemotherapy for advanced breast cancer. Br J Cancer 1991;63(5):794-8. 25. Henderson IC. Window of opportunity. J Natl Cancer Inst 1991;83:894-6. 26. Falkson G, Tormey DC, Carey P, et al. Long-term survival of patients treated with combination chemotherapy for metastatic breast cancer. Eur J Cancer 1991 ;27:973-7. 27. Ingle JN, Foley JF, Mailliard JA, et al. Randomized trial of cyclophosphamide, methotrexate, and 5-fluorouracil with or without estrogenic recruitment in women with metastatic breast cancer. Cancer 1994;73:2337-43. 28. Skeel RT, Andersen JW, Tormey DC, et al. Combination chemotherapy of advanced breast cancer. Comparison of dibromodulcitol, doxorubicin, vincristine, and fluoxymesterone to thiotepa, doxorubicin, vinblastin, and fluoxymesterone: an Eastern Cooperative Oncology Group study. Cancer 1989;64:1393-9. 29. Marschke RF, Ingle JN, Schaid DJ, et al. Randomized clinical trial of CFP versus CMFP in women with metastatic breast cancer. Cancer 1989;63:1931-7. 30. Stewart DJ, Evans WK, Shepherd FA, et al. Cyclophosphamide and fluorouracil combined with mitoxantrone versus doxorubicin for breast cancer: superiority of doxorubicin. J Clin Oncol 1997; 15:1897-905. 31. Bishop JF, Dewar J, Toner GC, et al. Paclitaxel as first-line treatment for metastatic breast cancer: the Taxol Investigational Trials Groups, Australia and New Zealand. Oncology 1997;11(4 suppl 3):19-23. 32. Aisner J, Cirrincione C, Perloff M, et al. Combination chemotherapy for metastat172

Curr Probl Cancer, May/June 1998

33.

34.

35.

36.

37.

38.

39.

40. 41. 42.

43.

44.

45.

46.

47.

ic or recurrent carcinoma of the breast--a randomized phase III trial comparing CAF versus VATH versus VATH alternating with CMFVP: Cancer and Leukemia Group B study 8281. J Clin Oncol 1995;13:1443-52. Bennett JM, Muss HB, Doroshow JH. A randomized multicenter trial comparing mitoxantrone, cyclophosphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast carcinoma. J Clin Oncol 1988;6:1611-20. Focan C, Andrien JM, Closon MT, et al. Dose-response relationship of epirubicinbased first-line chemotherapy for advanced breast cancer: a prospective randomized trial. J Clin Oncol 1993; 11:1253-63. French Epirubicin Study Group. A prospective randomized phase II trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 1988;6:679-88. Blomqvist C, Elomaa I, Rissanen P, et al. Influence of treatment schedule on toxicity and efficacy of cyclophosphamide, epirubicin, and fluorouracil in metastatic breast cancer: a randomized trial comparing weekly and every-4-week administration. J Clin Oncol 1993;11:467-73. Falkson G, Gelman RS, Tormey DC, et al. Treatment of metastatic breast cancer in premenopausal women using CAF with or without oophorectomy: an Eastern Cooperative Oncology Group study. J Clin Oncol 1987;5:881-9. Peters WP, Jones RB, Vredenburgh J, et al. A large, prospective, randomized trial of high-dose combination alkylating agents (CPB) with autologous cellular support (ABMS) as consolidation for patients with metastatic breast cancer achieving complete remission after intensive doxorubicin-based induction therapy (AFM). Breast Cancer Res Treat 1997;37:35. Bezwoda WR, Seymour L, Dansey RD. High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: a randomized trial. J Clin Oncol 1995;13:2483-9. Hryniuk W, Levine MN. Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 1986;4:1162-70. Hryniuk WM, Levine MN, Levin L. Analysis of dose intensity for chemotherapy in early (stage II) and advanced breast cancer. NCI Monogr 1986; 1:87-94. Peters W. Event-free survival in 662 high-risk, stage II/IIIA breast cancer patients undergoing high-dose chemotherapy with stem cell rescue. Proceedings of the Keystone Bone Marrow Transplant Meetings; January 20, 1994; Keystone, Colo. Crump M, Goss PE, Prince M, et al. Outcome of extensive evaluation before adjuvant therapy in women with breast cancer and 10 or more positive axillary lymph nodes. J Clin Oncol 1996;14:66-9. Dimitrov N, Anderson S, Fisher B, et al. Dose intensification and increased total dose of adjuvant chemotherapy for breast cancer: findings from NSABP B-220 Proc Annu Meet Am Soc Clin Oncol 1994;13:A58. Wood WC, Budman DR, Korzun AH, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 1994;330:1253-9. Peters WP, Ross M, Vredenburgh JJ, et al. High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 1993;11:l 132-43. De Graaf H, Willemse PH, de Vries EG, et al. Intensive chemotherapy with autol-

Curr Probl Cancer, May/June 1998

173

48.

49.

50.

51.

52.

53. 54. 55.

56.

57. 58. 59. 60. 61. 62. 63. 64. 65.

174

ogous bone marrow transfusion as primary treatment in women with breast cancer and more than five involved axillary lymph nodes. Eur J Cancer 1994;30:150-3. Haas R, Schmid H, Hahn U, et al. Tandem high-dose therapy with ifosfamide, epirubicin, carboplatin and peripheral blood stem cell support is an effective adjuvant treatment for high-risk primary breast cancer. Eur J Cancer 1997;33:372-8. Son-do G, Doroshow JH, Forman SJ, et al. High-dose chemotherapy and stem-cell rescue in the treatment of high-risk breast cancer: prognostic indicators of progression-flee and overall survival. J Clin Oncol 1997;15:2882-93. Buzzoni R, Bonadonna G, Valagussa E et al. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectahle breast cancer with more than three positive axillary nodes. J Clin Oncol 1991;9:2134-40. Jones SE, Moon TE, Bonadonna G, et al. Comparison of different trials of adjuvant chemotherapy in stage II breast cancer using a natural history data base. Am J Clin Oncol 1987;10:387-95. Abeloff MD, Davidson NE, Donehower RC, et al. Sixteen-week dose-intense chemotherapy in the adjuvant treatment of breast cancer. J Natl Cancer Inst 1990; 82:570-4. Davidson NE, Abeloff MD. Adjuvant therapy of breast cancer. World J Surg 1994;18:112-6. Rivkin SE, Green S, Metch B, et al. Adjuvant CMFVP versus melphalan for operable breast cancer with positive axillary nodes. J Clin Oncol 1989;7:1229-38. Misset JL, di Palma M, Delgado M, et al. Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16year median follow-up duration. J Clin Oncol 1996;14:1136-45. Senn HJ, Maibach R, Castiglione M, et al. Adjuvant chemotherapy in operable breast cancer: cyclophosphamide, methotrexate, and fluorouracil versus chlorambucil, methotrexate, and fluorouracil--11-year results of Swiss Group for Clinical Cancer Research trial SAKK. J Clin Oncol 1997;15:2502-9. Gradishar WJ, Tallman MS, Abrams JS. High-dose chemotherapy for breast cancer. Ann Intern Med 1996; 125 ;599-604. Norton L. Evolving concepts in the systemic drug therapy of breast cancer. Semin Oncol 1997;24(4 Snppl 10):3-10. Horowitz M, Stiff PJ, Veum-Stone J, et al. Outcome of autotransplants for advanced ovarian cancer. Proc Annu Meet Am Soc Clin Oucol 1997;33:A1262. Thigpen JT. Dose-intensity in ovarian cancer: hold, enough? J Clin Oncol 1997;15: 1291-3. McGuire WE How many more nails to seal the coffin of dose intensity? Ann Oncol 1997;8:311-3. Levin L, Hryniuk WM. Dose intensity analysis of chemotherapy regimens in ovarian cancer. J Clin Oncol 1987;5:756-67. Levin L, Simon R, Hryniuk W. Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis. J Nat1 Cancer Inst 1993;85:1732-42. Ben-David Y, Rosen B, Franssen E, et al. Meta-analysis comparing cisplatin total dose intensity and survival. Gynecol Oncol 1995;59:93-101. McGuire WE Ovarian cancer: experimental chemotherapy. Hematol Oncol Clin North Am 1992;6:927-40. Curr Probl Cancer, May/June 1998

66. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335:1950-5. 67. Godwin AK, Meister A, O'Dwyer PJ, et al. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione syntheses. Proc Natl Acad Sci U S A 1992;89:3070-4. 68. Parker RJ, Eastman A, Bostwick-Bruton F, et al. Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulations. J Clin Invest 1991;87:772-7. 69. Giannakakou P, Sackett D, Mickley L, et al. Characterization of non-PGP paclitaxel resistance in the human ovarian cancer cell line A2780. Proc Annu Meet Am Assoc Cancer Res t995;36:A2721. 70. Lotz JP, Boulenc C, Andre T, et al. Tandem high-dose chemotherapy with ifosfamide, carboplafin and teniposide with autologous bone marrow transplantation for the treatment of poor prognosis common epithelial ovarian carcinoma. Cancer 1996;77:2550-9. 71. Viens P, Gravis G, Blaise D, et al. High-dose chemotherapy with bone marrow rescue for patients with FIGO stage III or IV common epithelial ovarian carcinoma responding to first line treatment. Proc Annu Meet Am Soc Clin Oncol 1995;14: A811. 72. Legros M, Dauplat J, Fleury J, et al. High-dose chemotherapy with hematopoietic rescue in patients with stage III to IV ovarian cancer: long-term results. J Clin Oncol t997;15:1302-8. 73. Stiff PJ, Bayer R, Kerger C, et al. High-dose chemotherapy with autologous transplantation for persistent/relapsed ovarian cancer: a multivariate analysis of survival for 100 consecutively treated patients. J Clin Oncol 1997; 15:1309-17. 74. Dauplat J, Legros M, Condat P, et al. High-dose melphalan mad autologous bone marrow support for treatment of ovarian carcinoma with positive second-look laparotomy. Gynecol Oncol 1989;34:294-8. 75. Mulder PO, Willemse PH, Aalders JG, et al. High-dose chemotherapy with autologous bone-marrow transplantation in patients with refractory ovarian cancer. Eur J Clin Oncol 1989;25:645-9. 76. Stahel RA, Mabry M, Skarin AT, et al. Detection of bone marrow metastases in small-cell lung cancer by monoclonai antibody. J Clin Oncol 1985;3:455-61. 77. Brugger W, Bross KJ, Glatt M, et al. Mobilization of tumor cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumors. Blood 1994;83:636-40. 78. Klasa RJ, Murray N, Coldman AJ. Dose-intensity meta-anaiysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin Oncol 1991;9:499-508. 79. Furuse K, Kubota K, Nishiwaki Y, et al. Phase III study of dose intensive weekly chemotherapy with recombinant human granulocyte-colony stimulating factor (GCSF) versus standard chemotherapy in extensive stage small-cell lung cancer. Proc Annu Meet Am Soc Clin Oncol 1996;15:A1117. 80. Murray N, Livingston R, Shepherd F, et al. A randomized study of CODE plus thoracic irradiation vs alternating CAV/EP for extensive stage small-cell lung cancer. Proc Annu Meet Am Soc Clin Oncol 1997;16:A1638. 81. Sculler JP, Paesmans M, Bureau G, et al. Multiple-drug weekly chemotherapy versus standard combination regimen in small-cell lung cancer: a phase I/I randomized study conducted by the European Lung Cancer Working Party. J Clin Oncol 1993;11:1858-65. Curr Probl Cancer, May/June 1998

175

82. Steward WP, von Pawel J, Gatzemeier U, et al. Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in smallcell lung cancer: a prospective randomized study of 300 patients. J Clin Oncol 1998;16:642-50. 83. Woll PJ, Hodgetts J, Lomax L, et al. Can cytotoxic dose-intensity be increased by using granulocyte colony-stimulating factor? a randomized controlled trial of lenograstim in small-cell lung cancer. J Clin Oncol 1995;13:652-9. 84. Cohen MH, Creaven PJ, Fossieck BE, et al. Intensive chemotherapy of small-cell bronchogenic carcinoma. Cancer Treat Rep 1977;61:349-54. 85. Figueredo AT, Hryniuk WM, Strautmanis I, et al. Co-trimoxazole prophylaxis during high-dose chemotherapy of small-cell lung cancer. J Clin Oncol 1985;3:54-64. 86. Pujol JL, Douillard JY, Riviere A, et al. Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colonystimulating factor in extensive-stage small-cell lung cancer: a multicenter randomized phase III study. J Clin Oncol 1997;15:2082-9. 87. Johnson DH, Einhom LH, Birch R, et al. A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1987;5:1731-8. 88. Arriagada R, Le Chevalier T, Pignon JP, et al. Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 1993;329: 1848-52. 89. Ihde DC, Mulshine JL, Kramer BS, et al. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive stage small-cell lung cancer. J Clin Oncol 1994;12:2022-34. 90. Stewart P, Buckner CD, Thomas ED, et al. Intensive chemoradiotherapy with autologous marrow transplantation for small cell carcinoma of the lung. Cancer Treat Rep 1983;67:1055-9. 91. Spitzer G, Farha P, Valdivieso M, et al. High-dose intensification therapy with autologous bone marrow support for limited small-cell bronchogenic carcinoma. J Clin Oncol 1986;4:4-13. 92. Ihde DC, Deisseroth AB, Lichter AS, et al. Late intensive combined modality therapy followed by autologous bone marrow infusion in extensive-stage small-cell lung cancer. J Clin Oncol 1986;4:1443-54. 93. Elias AD, Ayash L, Skarin AT, et al. High-dose combined alkylating agent therapy with autologous stem cell support and chest radiotherapy for limited small-cell lung cancer. Chest 1993;103:433-5S. 94. Humblet Y, Symann M, Bosly A, et al. Late intensification chemotherapy with autologous bone marrow transplantation in selected small-ceU carcinoma of the lung: a randomized study. J Clin Oncol 1987;5:1866-73. 95. Nichols CR, Tricot G, Williams SD, et al. Dose-intensive chemotherapy in refractory germ cell cancer--a phase VII trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation. J Clin Oncol 1989;7:932-9. 96. Mulder PO, de Vries EG, Koops HS, et al. Chemotherapy with maximally tolerable doses of VP 16-213 and cyclophosphamide followed by autologous bone marrow transplantation for the treatment of relapsed or refractory germ cell tumors. Eur J Clin Oncol 1988;24:675-9. 97. Broun ER, Nichols CR, Kneebone P, et al. Long-term outcome of patients with 176

Curr Probl Cancer, May/June 1998

98.

99.

100.

101.

102.

103.

relapsed and refractory germ cell tumors treated with high-dose chemotherapy and autologous bone marrow rescue. Ann Intern Med 1992; 117:124-8. Barnett M J, Coppin CML, Murray N, et al. High-dose chemotherapy and autologous bone marrow transplantation for patients with poor prognosis non-seminomatous germ cell tumours. Br J Cancer 1993;68:594-8. Lotz JP, Andre T, Donsimoni R, et al. High dose chemotherapy with ifosfamide, carboplatin, and etoposide combined with autologous bone marrow transplantation for the treatment of poor-prognosis germ cell tumors and metastatic trophoblastic disease in adults. Cancer 1995;75:874-85. Broun ER, Nichol CR, Gize G, et al. Tandem high dose chemotherapy with autologous bone marrow transplantation for initial relapse of testicular germ cell cancer. Cancer 1997 ;79:1605 - 10. Droz JE Pico JL, Ghosn M, et al. A phase H trial of early intensive chemotherapy with autologous bone marrow transplantation in the treatment of poor prognosis non-seminomatous germ cell tumors. Bull Cancer 1992;79:497-507. Motzer RJ, Mazumdar M, Gulati SC, et al. Phase H trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Natl Cancer Inst 1993;85:1828-35. Motzer RJ, Mazumdar M, Bajorin DF et al. High-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Clin Oncol 1997; 15:2546-52.

Curr Probl Cancer, May/June 1998

177