- Email: [email protected]
Autotransplantation in solid tumors
AutotransPlantation A
in Solid Tumors
G. Spitzer SUMMA R Y. Studies are described of highdose therapy in metastatic breast cancer, early stage breast cancer, stage IV neuroblastoma, recurrent or bulky disease testicular cancer and Ewing’s sarcoma. The outcome in these subgroups with conventional therapy is described for comparison. The results of these studies suggest that high-dose therapy with autologous marrow support increases the proportion of patients with long-term survival without evidence of disease. Newer supportive care and recurrent high-dose therapy cycles of non-cross resistant regimens may improve outcome further in these diseases and increase the application to more resistant tumors.
Introduction
Metastatic Breast Cancer
This review cannot and will not cover all the clinical studies of autotransplantation in solid tumors. Several extensive reviews are published and should be referred to for a simple list of many publications in these areas.’ Instead, we will attempt to provide an overview of the most obvious impact of high-dose therapy with autologous bone marrow support in the therapy of solid tumors and some future major studies. The interpretation of studies in this area is difficult. Within any single diagnosis the patients have a heterogenous distribution of prognostic factors and are probably a heavily selected subset of the whole patient population. Such factors make it difficult to estimate accurately improvements in outcome over conventional therapy or, to compare differences, if they exist between different approaches to high-dose therapy in supposedly different patient groups. Despite these considerations, in this manuscript we will attempt to outline most areas where the results suggest an increment in long-term disease-free-survival (DFS) with high-dose therapy above that achieved with conventional therapy.
The application of particular recent interest and most debate is the intensification of therapy in patients with hormone refractory metastatic breast cancer. Depending on clinical stage, from 20-90% of patients with primary breast carcinoma will develop metastatic disease after primary therapy with curative intent. Standard combination chemotherapy yields a response rate of 50-70%. Of these, 1520% achieve a complete remission (CR), with a median response duration of 8- 15 months. Survival durations range from 12-27 months from the time of disease recurrence, with only about lo-15% of patients surviving beyond 5 years.2-4 Stage IV estrogen receptor-negative (ER-) or estrogen receptor-positive (ER+) patients who have become refractory to hormonal manipulation, behave in a more aggressive manner with a shorter survival and very few protracted disease-free survivors. The median survival of patients with ER-tumors approximates at best 15- 18 months, with at the most a 10% three-year progression-free and overall survival.’ Once patients who are ER + no longer respond to hormone manipulation, overall survival is similar to that of patients with the absence of estrogen receptor.6 A recent review of the experience at the M.D. Anderson Hospital with standard,
Gary Spitzer MD, St Louis University, Division of Medical Oncology, 3635 Vista, P.O. Box 15250, St. Louis, MO 63110-0250, USA. Bhd Rewews (1991) 5, LOS-I11 CB 1991 Longman Group UK Ltd
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AUTOTRANSPLANTATION
IN SOLID TUMORS
doxorubicin-containing combination chemotherapy programs in a group of 1424 patients with metastatic breast cancer was conducted. The median age of this group was 53 years (range 23-82). The median disease-free interval was 19 (range O-360 months). Most patients had a performance status of O-2 and only 16% of them had performance status 3 or 4. The median number of metastatic sites was 2. Two hundred and twenty-two of these patients achieved a complete remission with the combination FAC, fluorouracil, doxorubicin and cyclophosphamide (16%)’ The median duration of complete remission was 24 months (8% disease free at 2 years), but 5 years after initiation of therapy only 12% of the complete remission (CR) patients, 2% of all patients remained in remission. Even among those patients who achieve a complete remission, very few are longterm disease-free survivors. These are the results obtained from what is considered today the best combination chemotherapy for metastatic breast cancer. There have been a number of attempts to combine sequentially, or in an alternating fashion, two, or three combinations which were partially noncross-resistant. None of these studies have shown that alternating or sequential combinations improve the results produced by a FAC-type combination.8*g Initial clinical trials with high-dose, single agent chemotherapy have demonstrated that in a patient with metastatic breast cancer refractory to standard chemotherapy, higher objective response rates can be achieved (30-70%) than with any cytotoxic agent used at ‘standard doses’.” However, complete remissions with single agent high-dose chemotherapy were uncommon (< 10%) remission durations short (3-4 months), and no detectable impact on survival could be observed. High-dose combination chemotherapy (usually with combinations of alkylating agents) has been more successful in increasing the overall response rate in patients with refractory metastatic breast cancer (60-80%), and achieving a substantial percentge of complete remissions (20-50%). However, in contrast to the outcome in relapsed lymphoma remission durations were still short (2-7 months) and, with the exception of a very occasional long-term survivor, no impact on overall survival was observed. This lack of impact in relapse disease suggests that the dose-response of metastatic breast cancer is more shallow than that of lymphoma and timing of high-dose strategies will have to be earlier than in lymphoma. Since tumor burden is inversely correlated with response rate and, length of survival and, drug resistant clones of cells would surely limit the effectiveness of therapy, the maximum benefit of chemotherapy (including high-dose chemotherapy programs) would be expected in patients with minimal residual disease and showing response to therapy. The most recent generation of clinical studies with high-dose chemotherapy have included a ‘standard dose’ combination chemotherapy induction regi-
men to point of maximal response followed by the administration of high-dose chemotherapy as ‘consolidation’ treatment. Standard dose therapy has included anthracycline combined with either antimetabolites or alkylating agents and intensification has incorporated combinations of alkylating agents combined with cisplatin or carboplatin or the CVP (see later) combination used by us. Experience with this strategy is maturing, several studies now having significant median follow-up. The complete response rates achieved with this strategy (47-70%) are higher than those achieved with any other treatment approach to metastatic breast cancer. Almost 50% of patients with residual measurable disease following induction therapy are converted to CR, and an approximate 20-30% of patients in several trials remain in complete remission for periods exceeding 24 months.“-20 The price of these encouraging preliminary results obtained with high-dose consolidation programs is severe myelosuppression and extramedullary toxicity which results in early mortality for 5520% of patients depending on the high-dose therapy approach. Tandem High-dose Cyclophosphamide, Etoposide and Cisplatin (CVP)
To provide some greater details of these types of studies we enlarge on our strategy to high-dose intensification in metastatic breast cancer. Our approach to dose escalations in this and in our other successful high-dose therapy programs21-23 has probably been more cautious and conservative than that of other investigators in this field. We attempt to use a drug dose below the critical level where the increase in toxic effects on the tissues begins to exceed the tumor cell kill such that the therapeutic ratio is lost. We term that point the ‘ceiling dose’. The ceiling dose is regularly associated with a clinically worrisome frequency of extramedullary toxic effects such as cardiovascular, pulmonary, hepatic, neurological and vasculitis. These effects may be deemed by some as unacceptable, in the treatment of early disease like stage II breast cancer, where the patient’s median survival is lengthened significantly by even conservative therapy. Because of the concerns that the therapeutic effect within a single cycle may also be limited particularly, in solid tumors, we initiated programs based on the principle of what we now call tandem high-dose, below-ceiling-dose, low-toxicity chemotherapy. Some expanded discussion on the background of this approach is in an other recent publication.‘3 We have evaluated CVP, in more than 150 patients at four dose levels with tumors of various types (Table 1). Chemotherapy intensification using CVP has elicited complete remission in patients whose tumors had responded partially to prior chemotherapy, and there exists a proportion of long-term survivors (no tumor progression for >2 years after
BLOOD Table I Tumor
Patients type
Breast Lung Gastric Unknown primary Miscellaneous
treated
with CVP Patient
number
117 26 4 5 8
therapy) with miscellaneous diagnoses.‘-I3 Sixtyeight of these 150 patients are evaluable first-relapse estrogen-receptor-negative (ER - ) or primary hormone-unresponsive cancer and whose tumors remained stable or responded to induction therapy. These patients received their second cycle of CVP within 4 or 5 weeks of their initial therapy, and 97% of the patients received their second cycle within 3 or 8 weeks of that time, maintaining the principle of dose intensity. Tables 2a and 2b provide demographic information for these patients. The median disease-free interval of just over 1 year, the majority of patients having tumor involvement of two or more sites and predominantly visceral disease suggests that a favorable selection of patients with less volume of tumor and more indolent disease has not occurred. Thus, this program was tested on aggressive tumors in patients who had a high probability of an unfavorable outcome to conventional therapy. The induction therapy patients received in most instances was a combination of adriamycin and cyclophosphamide or, fluorouracil, adriamycin and cyclophosphamide. At the point of maximal response, which was a median of four cycles, patients then entered the intensification phase of therapy, which was meant to include two cycles of the CVP regime. The patient’s response to induction therapy is Table 2a Pretreatment characteristics cancer receiving tandem CVP
of patients
Total patients
68
Median age ER status ERER+ Unknown DFI
43 (27-62) % pts 60 26 16
Y I-2 y >2 Y
Soft tissue Lung Liver Lymph nodes Bone Mediastinum
of patients
N patients 22 (32) 31 (46) 14 (21) 7 (10) 22 (32) 13 (19)
(%)
with breast
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shown in Table 3a. The complete remission rate was 32% and the partial remission rate 50%; the remaining patients had stable disease. Forty-one of the 68 patients still had measurable disease when they entered the intensification phase. Of these 41 patients with measurable disease at the time of intensification, 46% achieved complete response through CVP therapy (Table 3b). This ‘conversion rate’ is an important indicator of the potential activity of this regimen. At the completion of intensification therapy and counting early deaths as failure, approximately 60% of the 66 evaluable patients achieved complete remission (Table 3~). The Figure is a graph of the progression-free survival curve; almost 20% of patients have been free of disease for more than 2 years. Only one relapse has occurred more than 2 years after therapy. Some insight into those patients who survived long-term without tumor progression is provided in Table 4. A sizable proportion have visceral metastatic disease, particularly in the lung, and a number of these patients have exceeded their disease free interval, probably eliminating the concept that these patients have not relapsed because of the indolent nature of disease. All of these patients have only modest bulk of tumor. The mortality rate associated with the use of tandem CVP (7%) is modest given the age of the patients and the fact that they were not germ-free isolated during treatment. The majority of patients experienced febrile episodes, and 50% of patients had a documented infection, predominantly gram-positive sepsis or pneumonia. Serious hepatic, vascular, cardiac, and pulmonary toxic effects did not occur. Table 3a Response to CVP in patients Induction therapy response 66 evaluable patients: 2 NED Response Complete Partial Stable
Patients 21 33 12
with breast cancer.
(%) 32 50 18
Table 3b Response to CVP in patients with breast cancer. Intensification response 41 evaluable patients--ZNED, 20 CCR, 5 ED
34 41 25
Table 2b Pretreatment characteristics cancer receiving tandem CVP Sites of metastatic disease (68 patients) Sites
with breast
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Response rate Complete Partial Stable Progression PR+progression
N patients 19 13 5 2 2
Table 3c Response to CVP in patients Overall response 66 evaluable patients-2 NED Response Complete Partial Stable Progression Early death
N patients 39 15 5 2 5
% 46 32 12 5 5
with breast cancer.
(%) 59 23 8 3 8
108 AUTOTRANSPLANTATION
IN SOLID TUMORS Metastatic
breast cancer progression free survival
80
100
50
150
200
Weeks
Figure Progression-free survival for 68 patients with metastatic breast cancer treated by ABMT. An approximate 20% long-term disease-free survival is suggested.
Table 4 Individuals with breast cancer treated by tandem CVP with progression-free survival greater than 2 years Disease sites
DFI*
PFS**
Nodes Lung Nodes Bone Lung, mediastinum Lung Lung Nodes Lung, mediastinum Lung
6 70 70 77 76 84 113 128 145 245
139+ 165f 109f 145+ 205 + 129 157+ 104f 159f 265 +
*Disease free interval prior to CVP **Progression free survival following CVP
Studies in Stage III and Stage II Breast Cancer The studies in stage IV breast cancer would seem to suggest that high-dose intensification has improved by some 10-l 5% the proportion of long-term disease free survivors. This effect is however, only in patients with lesser volume of disease. Obviously, the introduction of these approaches into still earlier stages of breast cancer in subgroups associated with poor long-term outlook may show more dramatic results. To comprehend the potential impact of high-dose therapy in these patients the natural history of these patients with the use of conventional therapy must be understood. The groups proposed and in whom studies have already been initiated are stage II and III disease with greater than 10 positive lymph nodes and stage IIIb.
Only a small percentage of the stage II patients (approximately 10%) and even less of the premenopausal patients have such extensive nodal involvement. Eight to 10 year follow-up reports with adjuvant combination chemotherapy suggest a superior outcome to that previously expected. There is an approximately 30-45% DFS. At shorter periods of follow up DFS ranges from 50% to almost 80% at 2 years and is 3565% at 3 years.24-27 Peterszszg in 53 patients (43 stage II > 10 nodes and 10 stage III) used 4 cycles of the equivalent to FAC followed by a single cycle of high dose chemotherapy consolidation with cyclophosphamide 5600 mg/m’, cisplatin 165 mg/m2 and BCNU 600 mg/ m2 and subsequent autologous bone marrow infusion. With a median follow-up of 14 months and a lead time of 40 months there have been 6 relapses, 3 local relapses in 6 patients who did not receive local irradiation. The estimated 3 year DFS is 80%. Studies from Japan in a small group of women with greater than 10 nodes show an impressive estimate of 80% DFS at 5 years.30 Neuroblastoma Stage IV neuroblastoma in children greater than l-year-old has a dismal long-term outcome. Approximately 25% of patients survive longer than 2 years and at best lo-15% are DFS beyond 2 years. Initial studies incorporated only high-dose Melphalan alone and unpurged marrow with some interesting im-
BLOOD
proved response rates and a small number of longterm DFS’S.~~*~’Several more recent studies incorporating total body irradiation and high-dose therapy with Melphalan and or other alkylating agents, some with double autografts and virtually all with ex vivo treatment of the graft with monoclonal antibodies or drugs to remove tumor cells have been published and reported. Therapy intensity of the high-dose intensification in these pediatric patients is more aggressive than that used in breast cancer. In overview, the DFS survival at 2 years of 30-40% (including patients transplanted and not transplanted) appears superior to conventional therapy. 33-36 Bone marrow was the most common site of relapse. There is some controversy as to whether a DFS plateau exists beyond 2 years of follow-up. Philip35 reviewing the European experience reported a continuing 30-40% relapse rate after this time period whereas Graham-Pole33 describes no such relapses after this period of followup. Patient subgroups with excellent tumor reduction to induction therapy (no residual measurable disease or positive tumor markers) have a potential 100% disease-free survival. The results in this disease certainly argue for a dose-response of modest nature. This is translated into increased disease-free survival and a question of a possible increased cure fraction. The role of ex vivo marrow manipulation cannot be evaluated. Marrow relapses could be secondary to either reinfusion of tumor cells or inability of the cytoreductive therapy to eliminate residual in-vivo tumor cells.
Germ Cell Tumors Combinations of etoposide (total dose 1200-2400 gm/ m’) and carboplatin (total dose 1350-1800 mg/m2) have been recently used with or without ifosfamide and, in a significant proportion with a double transplant approach to treat relapsed testicular tumors. Complete remission is induced in an approximate 30%. Approximately 50% are durable despite stated resistance to conventional dose cisplatin-based regimens. 37.38 Pico3’ used a combination of cisplatin 40 mg/m2 x 5, etoposide 350 mg/m2 x 5, and cyclophosphamide 1.6 g/m2 x 4 in 43 patients. This combination was ineffective for long-term disease control in patients not responding to alternative therapy prior to high-dose therapy challenge (resistant relapse), impressively effective in patients with residual sensitivity to conventional therapy (4/6 disease-free at 3 years) and promising in patients with extensive disease and consolidated following acceptable conventional therapy (17 still in continuous complete remission). Biron4’ using ifosfamide at doses of 3 g/ m2 for 4 doses and similar doses of cisplatin and etoposide achieved similar results. Combinations of high-dose etoposide, cisplatin or carboplatin with or without an alkylating agent may enhance long-term
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outcome in occasional patients with untreated testicular cancer and associated bad prognostic factors.
Ewing’s Sarcoma A small number of studies in the past showed encouraging response rates with high-dose therapy for relapsed Ewing’s Sarcoma. 41 Patient’s with Ewing’s Sarcoma with a primary tumor >8 centimeter or metastatic disease at diagnosis have a high probability of relapse from conventional therapy, approximately 80%. A recent analysis of 25 such patients treated with intensive induction therapy followed by myeloablative intensification has a projected 66% DFS at 3 years.42
Conclusion This has not been an exhaustive review of all studies of high-dose therapy in solid tumors. Instead there has been emphasis on areas where this author is of the opinion that the data not only suggests impressive response rates, an inevitable result with high-dose therapy but, also an increase in the proportion of patients with long-term disease-free survival. These results have generally been achieved in younger, high performance status patients and in tumor types with some inherent chemosensitivity, but with unfortunately dismal long-term survival, There exists the potential for an improvement in outcome in older patients and patients with underlying medical conditions with recent developments in supportive care (recombinant growth factors, peripheral blood stem cells). Such measures may allow the regular administration of recurrent cycles of high-dose therapy of similar or different nature of the intensity which may needed for disease of larger bulk, lesser sensitivity to induction therapy and for the resistant varieties of solid tumors such as melanoma, glioma and other common adult solid tumors.
References 1. Cheson B D, Lacerna L, Leyland-Jones B, Sarosy G, Wittes R E 1989 Autologous Marrow Transplant. Annals of Internal Medicine 110: 51-65 2. Carter K S 1974 The chemical therapy of breast cancer. Semin Oncol 1 (2): 131-144 G N, 3. Legha S S, Buzdar A U, Smith T L, Hortobagyi Swenerton K D, Blumenschein G R, Gehan E A, Bodey G P, Freireich E J 1979 Complete remissions in metastatic breast cancer treated with combination drug therapy. Ann Intern Med 91: 847-852 4. Aisner J, Weinberg V, Perloff M, Weiss R, Perry M, Korzun A, Ginsberg S, Holland J F 1987 Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each+ MER) for metastatic carcinoma of the breast: A CALGB study. J Clin Oncol 15: 152331533 5. Livingston R, Schulman S I987 Combination chemotherapy and systemic irradiation consolidation for poor prognosis breast cancer. Cancer 59: 1249-1254 6. Legha S S, Buzdar A U, Smith T, Swenerton K D, Hortobagyi G N, Blumenschein G R 1981 Response to hormonal therapy as a prognostic factor for metastatic
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autologous bone marrow transplantation for relapsed Hodgkin’s disease. Ann Intern Med 104: 163-168 Jagannath S, Armitage J 0, Dicke K A, Hagemeister F B, Smith K, Horwitz L J, Velasquez W S, Vaughn W P, Kessinger A, Cabanillas F, Spitzer G 1987 Updated results of CBV and autologous bone marrow transplantation for Hodgkin’s disease. In: Dicke K A, Spitzer G, Jagannath S, eds. Proceedings of the Third International Symposium on Autologous Bone Marrow Transplantation. Houston: The University of Texas Press, 217-221 Soitzer G. Dicke K A. Litam J. Verma D S. Zander A R. Lanzotti V, Valdiviesd M, Mcdredie K B, Samuels M 1980 High-dose combination chemotherapy with autologous bone marrow transplantation in adult solid tumors. Cancer 45: 3075-3085 Abeloff M D, Beveridge R A, Donehower R C, Fetting J H, Davidson N E, Gordon G G, Waterfield W C, Damron D J 1990 Sixteen-week dose-intense chemotherapy in the adjuvant treatment of breast cancer. J Nat1 Cancer Inst 82: 570-574 Bonadonna G, Gianna A M 1990 High-dose chemotherapy and Autologous Bone Marrow transplant for Adjuvant Treatment of poor-risk breast cancer. Oncology Journal Club, 2: 3-6 Kau S W, Buzdar A, Fraschini G, Hug V, Holmes F, Hortobagyi G 1989 Impact of adjuvant chemotherapy with FAC in patients with ten or more positive nodes in operable breast cancer. Proceedings of the American Society Clinical Oncology 8: 30 Rivkin S, Green S, Osborne C K, Metch B, Glucksburg H, McDivitt R Gad-El-Mawla N, Stephens R, Costanzi J 1989 Adjuvant combination chemotherapy (CMFVP) vs L-Phenyalinine mustard (L-Pam) for operable breast cancer with positive axillary lymph nodes: 10 year results. Proc Am Sot Clin Oncol. 8: 24 Peters W P, Ross M, Vredenburgh J, Jones R, Shpall E: High dose chemotherapy and autologous bone marrow support in the adjuvant treatment of primary breast cancer. Proceedings of the 5th International Symposium on Autolonous Bone Marrow Transplantation. Abstract 40, 1990 Peters W P, Davis R, Shpall E J, Jones R, Ross M, Marks L. Norton L. Hurd D. Durham N C 1990 Adiuvant chemotherapy involving high-dose combination cyclophosphamide, cisplatin and carmustine and autologous bone marrow support for stage II/III breast cancer involving ten or more lymph nodes (CALGB 8782): A Preliminary report Proc ASCO 9: Tajima T, Tokuda Y, Ohta M, Kubota M, Yokoyama S, Mitoma T, Murakami M, Shinozuka T, Nakamura U, Watanabe K, Tsuji K 1989 Role of autologous bone marrow transplantation in cancer chemotherapy. Low Temperature Medicine 15: 4450 Pritchard J, McElwain T J, Graham-Pole J 1982 High-dose melphalan with autologous marrow for treatment of advanced neuroblastoma. Br J Cancer 45: 86-94 Pritchard J, Germond S, Jones D, de Kraker J, Love S 1986 Is high-dose melphalan of value in treatment of advanced neuroblastoma? Preliminary results of a randomized trial by the European Neuroblastoma Study Group. Proc Am Sot Clin Oncol 5: 205 Graham-Pole J 1990 Autologous marrow transplantation (AMT) for metastatic neuroblastoma (NBL). Transplantation 5: suppl2 Proceedings of Sixteenth Annual Meeting of European Cooperative group for Bone Marrow Transplantation pp 58 Hartmann 0. Benhamou E. Beaujean F, Kalita C, Leiars 0, Patte C, Ben&d C, Flamant F, Thyss A, Deville A, Vannier J P, Pautard-Muchemble B, Lemerle J 1987 Repeated highdose chemotheraov followed by purged autologous bone marrow transplantation as consolidation therapy in metastatic neuroblastoma. J Clin Oncol 5: 1205-I 1 Philip T, Zucker J M, Bernard J L, Gentre J C, Michon J, Bouffnne E 1990 High-dose therapy with bmt as consolidation treatment in neuroblastoma-the LMCEl unselected group of patients revisited with a median follow UDof 55 months after BMT Transplantation 5: supnl2 Pioceedings of Sixteenth Annual Meeting of Euro&an Cooperative group for Bone Marrow Transplantation pp 22 Philip T, Bernard J L, Zucker J M, Pinkerton R, Lutz P,
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Bordigoni E, Ploouvier A, Robert A, Carton R, Philippe N, Philip I, Chauvin F, Favrot M 1987 Hieh-dose theranv with bone marrow transplantation for consoidation treatt&t in neuroblastoma: An unselected group of stage IV patients over 1 year of age. J Clin Oncol 5: 266-271 Nichols C R, Tricot G, Williams S D, van Besien K, Loehrer P J, Roth B J, Akard L, Hoffman R, Goulet R, Wolff S N. Giannone L. Greer J. Einhorn L H. Jansen J 1989 Dose intensive chemotherapy in refractory germ cell cancer-A phase I/II trial of high dose carboplatin and etoposide with autologous bone marrow transplantation. J Clin Oncol 7: 932-939 Rosti G. Salvioni R, Pizzocaro G, Valzania F, Marangolo M 1990 High-Dose Chemotherapy (HDC) with Carboplatin (CBP) and VP16 in germ cell tumors. Abstract 89 Pica J-L, Droz J-P, Ostronoff M, Baume D, Gouyette A, Beaujean F, Hayat M 1989 High dose chemotherapy with autologous bone marrow transplantation for poor diagnosis non-seminomatous germ cell tumors, in Dicke K A, Spitzer G, Jagannath S (eds): Autologous Bone Marrow Transplantation: Proceedings of the Fourth International Symposium. Houston, University of Texas M.D. Anderson
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Hospital and Tumor Institute, Scientific Publications, pp 469-476 40. Biron P, Philip T, Maraninchi D, Pica J L, Cahn J Y, Fumoleau P. Le Mevel A. Gastaut J A, Carcassonne M. Kamioner D, Herve P, Brunat-Mentigny M, Hayat M 1985 Massive chemotherapy and autologous bone marrow transplantation in progressive disease of nonseminomatous testicular cancer: a phase II study on 15 patients. In: Dicke K A, Spitzer G, Zander A R eds. Autologous Bone Marrow Transplantation: Proceeding of the First International Symposium Houston: University Texas, M.D. Anderson Hospital and Tumor Institute 203-10 41 Combleet M A, Corringham R E T, Prentice H G. Boesen E M, McElwain T J 1981 Treatment of Ewing’s sarcoma with high-dose melphalan and autologous bone marrow transplantation. Cancer Treat Rep. 65: 241-4 42 Graham-Pole J, Marcus R 1990 Autologous Marrow Transplants (ABMT) for patients (pts) with Ewing’s sarcoma (ES) at high risk for relapse (rel). Transplantation 5: suppl2 Proceedings of Sixteenth Annual Meeting of European Cooperative group for Bone Marrow Transplantation pp 22
in Solid Tumors
G. Spitzer SUMMA R Y. Studies are described of highdose therapy in metastatic breast cancer, early stage breast cancer, stage IV neuroblastoma, recurrent or bulky disease testicular cancer and Ewing’s sarcoma. The outcome in these subgroups with conventional therapy is described for comparison. The results of these studies suggest that high-dose therapy with autologous marrow support increases the proportion of patients with long-term survival without evidence of disease. Newer supportive care and recurrent high-dose therapy cycles of non-cross resistant regimens may improve outcome further in these diseases and increase the application to more resistant tumors.
Introduction
Metastatic Breast Cancer
This review cannot and will not cover all the clinical studies of autotransplantation in solid tumors. Several extensive reviews are published and should be referred to for a simple list of many publications in these areas.’ Instead, we will attempt to provide an overview of the most obvious impact of high-dose therapy with autologous bone marrow support in the therapy of solid tumors and some future major studies. The interpretation of studies in this area is difficult. Within any single diagnosis the patients have a heterogenous distribution of prognostic factors and are probably a heavily selected subset of the whole patient population. Such factors make it difficult to estimate accurately improvements in outcome over conventional therapy or, to compare differences, if they exist between different approaches to high-dose therapy in supposedly different patient groups. Despite these considerations, in this manuscript we will attempt to outline most areas where the results suggest an increment in long-term disease-free-survival (DFS) with high-dose therapy above that achieved with conventional therapy.
The application of particular recent interest and most debate is the intensification of therapy in patients with hormone refractory metastatic breast cancer. Depending on clinical stage, from 20-90% of patients with primary breast carcinoma will develop metastatic disease after primary therapy with curative intent. Standard combination chemotherapy yields a response rate of 50-70%. Of these, 1520% achieve a complete remission (CR), with a median response duration of 8- 15 months. Survival durations range from 12-27 months from the time of disease recurrence, with only about lo-15% of patients surviving beyond 5 years.2-4 Stage IV estrogen receptor-negative (ER-) or estrogen receptor-positive (ER+) patients who have become refractory to hormonal manipulation, behave in a more aggressive manner with a shorter survival and very few protracted disease-free survivors. The median survival of patients with ER-tumors approximates at best 15- 18 months, with at the most a 10% three-year progression-free and overall survival.’ Once patients who are ER + no longer respond to hormone manipulation, overall survival is similar to that of patients with the absence of estrogen receptor.6 A recent review of the experience at the M.D. Anderson Hospital with standard,
Gary Spitzer MD, St Louis University, Division of Medical Oncology, 3635 Vista, P.O. Box 15250, St. Louis, MO 63110-0250, USA. Bhd Rewews (1991) 5, LOS-I11 CB 1991 Longman Group UK Ltd
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AUTOTRANSPLANTATION
IN SOLID TUMORS
doxorubicin-containing combination chemotherapy programs in a group of 1424 patients with metastatic breast cancer was conducted. The median age of this group was 53 years (range 23-82). The median disease-free interval was 19 (range O-360 months). Most patients had a performance status of O-2 and only 16% of them had performance status 3 or 4. The median number of metastatic sites was 2. Two hundred and twenty-two of these patients achieved a complete remission with the combination FAC, fluorouracil, doxorubicin and cyclophosphamide (16%)’ The median duration of complete remission was 24 months (8% disease free at 2 years), but 5 years after initiation of therapy only 12% of the complete remission (CR) patients, 2% of all patients remained in remission. Even among those patients who achieve a complete remission, very few are longterm disease-free survivors. These are the results obtained from what is considered today the best combination chemotherapy for metastatic breast cancer. There have been a number of attempts to combine sequentially, or in an alternating fashion, two, or three combinations which were partially noncross-resistant. None of these studies have shown that alternating or sequential combinations improve the results produced by a FAC-type combination.8*g Initial clinical trials with high-dose, single agent chemotherapy have demonstrated that in a patient with metastatic breast cancer refractory to standard chemotherapy, higher objective response rates can be achieved (30-70%) than with any cytotoxic agent used at ‘standard doses’.” However, complete remissions with single agent high-dose chemotherapy were uncommon (< 10%) remission durations short (3-4 months), and no detectable impact on survival could be observed. High-dose combination chemotherapy (usually with combinations of alkylating agents) has been more successful in increasing the overall response rate in patients with refractory metastatic breast cancer (60-80%), and achieving a substantial percentge of complete remissions (20-50%). However, in contrast to the outcome in relapsed lymphoma remission durations were still short (2-7 months) and, with the exception of a very occasional long-term survivor, no impact on overall survival was observed. This lack of impact in relapse disease suggests that the dose-response of metastatic breast cancer is more shallow than that of lymphoma and timing of high-dose strategies will have to be earlier than in lymphoma. Since tumor burden is inversely correlated with response rate and, length of survival and, drug resistant clones of cells would surely limit the effectiveness of therapy, the maximum benefit of chemotherapy (including high-dose chemotherapy programs) would be expected in patients with minimal residual disease and showing response to therapy. The most recent generation of clinical studies with high-dose chemotherapy have included a ‘standard dose’ combination chemotherapy induction regi-
men to point of maximal response followed by the administration of high-dose chemotherapy as ‘consolidation’ treatment. Standard dose therapy has included anthracycline combined with either antimetabolites or alkylating agents and intensification has incorporated combinations of alkylating agents combined with cisplatin or carboplatin or the CVP (see later) combination used by us. Experience with this strategy is maturing, several studies now having significant median follow-up. The complete response rates achieved with this strategy (47-70%) are higher than those achieved with any other treatment approach to metastatic breast cancer. Almost 50% of patients with residual measurable disease following induction therapy are converted to CR, and an approximate 20-30% of patients in several trials remain in complete remission for periods exceeding 24 months.“-20 The price of these encouraging preliminary results obtained with high-dose consolidation programs is severe myelosuppression and extramedullary toxicity which results in early mortality for 5520% of patients depending on the high-dose therapy approach. Tandem High-dose Cyclophosphamide, Etoposide and Cisplatin (CVP)
To provide some greater details of these types of studies we enlarge on our strategy to high-dose intensification in metastatic breast cancer. Our approach to dose escalations in this and in our other successful high-dose therapy programs21-23 has probably been more cautious and conservative than that of other investigators in this field. We attempt to use a drug dose below the critical level where the increase in toxic effects on the tissues begins to exceed the tumor cell kill such that the therapeutic ratio is lost. We term that point the ‘ceiling dose’. The ceiling dose is regularly associated with a clinically worrisome frequency of extramedullary toxic effects such as cardiovascular, pulmonary, hepatic, neurological and vasculitis. These effects may be deemed by some as unacceptable, in the treatment of early disease like stage II breast cancer, where the patient’s median survival is lengthened significantly by even conservative therapy. Because of the concerns that the therapeutic effect within a single cycle may also be limited particularly, in solid tumors, we initiated programs based on the principle of what we now call tandem high-dose, below-ceiling-dose, low-toxicity chemotherapy. Some expanded discussion on the background of this approach is in an other recent publication.‘3 We have evaluated CVP, in more than 150 patients at four dose levels with tumors of various types (Table 1). Chemotherapy intensification using CVP has elicited complete remission in patients whose tumors had responded partially to prior chemotherapy, and there exists a proportion of long-term survivors (no tumor progression for >2 years after
BLOOD Table I Tumor
Patients type
Breast Lung Gastric Unknown primary Miscellaneous
treated
with CVP Patient
number
117 26 4 5 8
therapy) with miscellaneous diagnoses.‘-I3 Sixtyeight of these 150 patients are evaluable first-relapse estrogen-receptor-negative (ER - ) or primary hormone-unresponsive cancer and whose tumors remained stable or responded to induction therapy. These patients received their second cycle of CVP within 4 or 5 weeks of their initial therapy, and 97% of the patients received their second cycle within 3 or 8 weeks of that time, maintaining the principle of dose intensity. Tables 2a and 2b provide demographic information for these patients. The median disease-free interval of just over 1 year, the majority of patients having tumor involvement of two or more sites and predominantly visceral disease suggests that a favorable selection of patients with less volume of tumor and more indolent disease has not occurred. Thus, this program was tested on aggressive tumors in patients who had a high probability of an unfavorable outcome to conventional therapy. The induction therapy patients received in most instances was a combination of adriamycin and cyclophosphamide or, fluorouracil, adriamycin and cyclophosphamide. At the point of maximal response, which was a median of four cycles, patients then entered the intensification phase of therapy, which was meant to include two cycles of the CVP regime. The patient’s response to induction therapy is Table 2a Pretreatment characteristics cancer receiving tandem CVP
of patients
Total patients
68
Median age ER status ERER+ Unknown DFI
43 (27-62) % pts 60 26 16
Y I-2 y >2 Y
Soft tissue Lung Liver Lymph nodes Bone Mediastinum
of patients
N patients 22 (32) 31 (46) 14 (21) 7 (10) 22 (32) 13 (19)
(%)
with breast
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shown in Table 3a. The complete remission rate was 32% and the partial remission rate 50%; the remaining patients had stable disease. Forty-one of the 68 patients still had measurable disease when they entered the intensification phase. Of these 41 patients with measurable disease at the time of intensification, 46% achieved complete response through CVP therapy (Table 3b). This ‘conversion rate’ is an important indicator of the potential activity of this regimen. At the completion of intensification therapy and counting early deaths as failure, approximately 60% of the 66 evaluable patients achieved complete remission (Table 3~). The Figure is a graph of the progression-free survival curve; almost 20% of patients have been free of disease for more than 2 years. Only one relapse has occurred more than 2 years after therapy. Some insight into those patients who survived long-term without tumor progression is provided in Table 4. A sizable proportion have visceral metastatic disease, particularly in the lung, and a number of these patients have exceeded their disease free interval, probably eliminating the concept that these patients have not relapsed because of the indolent nature of disease. All of these patients have only modest bulk of tumor. The mortality rate associated with the use of tandem CVP (7%) is modest given the age of the patients and the fact that they were not germ-free isolated during treatment. The majority of patients experienced febrile episodes, and 50% of patients had a documented infection, predominantly gram-positive sepsis or pneumonia. Serious hepatic, vascular, cardiac, and pulmonary toxic effects did not occur. Table 3a Response to CVP in patients Induction therapy response 66 evaluable patients: 2 NED Response Complete Partial Stable
Patients 21 33 12
with breast cancer.
(%) 32 50 18
Table 3b Response to CVP in patients with breast cancer. Intensification response 41 evaluable patients--ZNED, 20 CCR, 5 ED
34 41 25
Table 2b Pretreatment characteristics cancer receiving tandem CVP Sites of metastatic disease (68 patients) Sites
with breast
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Response rate Complete Partial Stable Progression PR+progression
N patients 19 13 5 2 2
Table 3c Response to CVP in patients Overall response 66 evaluable patients-2 NED Response Complete Partial Stable Progression Early death
N patients 39 15 5 2 5
% 46 32 12 5 5
with breast cancer.
(%) 59 23 8 3 8
108 AUTOTRANSPLANTATION
IN SOLID TUMORS Metastatic
breast cancer progression free survival
80
100
50
150
200
Weeks
Figure Progression-free survival for 68 patients with metastatic breast cancer treated by ABMT. An approximate 20% long-term disease-free survival is suggested.
Table 4 Individuals with breast cancer treated by tandem CVP with progression-free survival greater than 2 years Disease sites
DFI*
PFS**
Nodes Lung Nodes Bone Lung, mediastinum Lung Lung Nodes Lung, mediastinum Lung
6 70 70 77 76 84 113 128 145 245
139+ 165f 109f 145+ 205 + 129 157+ 104f 159f 265 +
*Disease free interval prior to CVP **Progression free survival following CVP
Studies in Stage III and Stage II Breast Cancer The studies in stage IV breast cancer would seem to suggest that high-dose intensification has improved by some 10-l 5% the proportion of long-term disease free survivors. This effect is however, only in patients with lesser volume of disease. Obviously, the introduction of these approaches into still earlier stages of breast cancer in subgroups associated with poor long-term outlook may show more dramatic results. To comprehend the potential impact of high-dose therapy in these patients the natural history of these patients with the use of conventional therapy must be understood. The groups proposed and in whom studies have already been initiated are stage II and III disease with greater than 10 positive lymph nodes and stage IIIb.
Only a small percentage of the stage II patients (approximately 10%) and even less of the premenopausal patients have such extensive nodal involvement. Eight to 10 year follow-up reports with adjuvant combination chemotherapy suggest a superior outcome to that previously expected. There is an approximately 30-45% DFS. At shorter periods of follow up DFS ranges from 50% to almost 80% at 2 years and is 3565% at 3 years.24-27 Peterszszg in 53 patients (43 stage II > 10 nodes and 10 stage III) used 4 cycles of the equivalent to FAC followed by a single cycle of high dose chemotherapy consolidation with cyclophosphamide 5600 mg/m’, cisplatin 165 mg/m2 and BCNU 600 mg/ m2 and subsequent autologous bone marrow infusion. With a median follow-up of 14 months and a lead time of 40 months there have been 6 relapses, 3 local relapses in 6 patients who did not receive local irradiation. The estimated 3 year DFS is 80%. Studies from Japan in a small group of women with greater than 10 nodes show an impressive estimate of 80% DFS at 5 years.30 Neuroblastoma Stage IV neuroblastoma in children greater than l-year-old has a dismal long-term outcome. Approximately 25% of patients survive longer than 2 years and at best lo-15% are DFS beyond 2 years. Initial studies incorporated only high-dose Melphalan alone and unpurged marrow with some interesting im-
BLOOD
proved response rates and a small number of longterm DFS’S.~~*~’Several more recent studies incorporating total body irradiation and high-dose therapy with Melphalan and or other alkylating agents, some with double autografts and virtually all with ex vivo treatment of the graft with monoclonal antibodies or drugs to remove tumor cells have been published and reported. Therapy intensity of the high-dose intensification in these pediatric patients is more aggressive than that used in breast cancer. In overview, the DFS survival at 2 years of 30-40% (including patients transplanted and not transplanted) appears superior to conventional therapy. 33-36 Bone marrow was the most common site of relapse. There is some controversy as to whether a DFS plateau exists beyond 2 years of follow-up. Philip35 reviewing the European experience reported a continuing 30-40% relapse rate after this time period whereas Graham-Pole33 describes no such relapses after this period of followup. Patient subgroups with excellent tumor reduction to induction therapy (no residual measurable disease or positive tumor markers) have a potential 100% disease-free survival. The results in this disease certainly argue for a dose-response of modest nature. This is translated into increased disease-free survival and a question of a possible increased cure fraction. The role of ex vivo marrow manipulation cannot be evaluated. Marrow relapses could be secondary to either reinfusion of tumor cells or inability of the cytoreductive therapy to eliminate residual in-vivo tumor cells.
Germ Cell Tumors Combinations of etoposide (total dose 1200-2400 gm/ m’) and carboplatin (total dose 1350-1800 mg/m2) have been recently used with or without ifosfamide and, in a significant proportion with a double transplant approach to treat relapsed testicular tumors. Complete remission is induced in an approximate 30%. Approximately 50% are durable despite stated resistance to conventional dose cisplatin-based regimens. 37.38 Pico3’ used a combination of cisplatin 40 mg/m2 x 5, etoposide 350 mg/m2 x 5, and cyclophosphamide 1.6 g/m2 x 4 in 43 patients. This combination was ineffective for long-term disease control in patients not responding to alternative therapy prior to high-dose therapy challenge (resistant relapse), impressively effective in patients with residual sensitivity to conventional therapy (4/6 disease-free at 3 years) and promising in patients with extensive disease and consolidated following acceptable conventional therapy (17 still in continuous complete remission). Biron4’ using ifosfamide at doses of 3 g/ m2 for 4 doses and similar doses of cisplatin and etoposide achieved similar results. Combinations of high-dose etoposide, cisplatin or carboplatin with or without an alkylating agent may enhance long-term
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109
outcome in occasional patients with untreated testicular cancer and associated bad prognostic factors.
Ewing’s Sarcoma A small number of studies in the past showed encouraging response rates with high-dose therapy for relapsed Ewing’s Sarcoma. 41 Patient’s with Ewing’s Sarcoma with a primary tumor >8 centimeter or metastatic disease at diagnosis have a high probability of relapse from conventional therapy, approximately 80%. A recent analysis of 25 such patients treated with intensive induction therapy followed by myeloablative intensification has a projected 66% DFS at 3 years.42
Conclusion This has not been an exhaustive review of all studies of high-dose therapy in solid tumors. Instead there has been emphasis on areas where this author is of the opinion that the data not only suggests impressive response rates, an inevitable result with high-dose therapy but, also an increase in the proportion of patients with long-term disease-free survival. These results have generally been achieved in younger, high performance status patients and in tumor types with some inherent chemosensitivity, but with unfortunately dismal long-term survival, There exists the potential for an improvement in outcome in older patients and patients with underlying medical conditions with recent developments in supportive care (recombinant growth factors, peripheral blood stem cells). Such measures may allow the regular administration of recurrent cycles of high-dose therapy of similar or different nature of the intensity which may needed for disease of larger bulk, lesser sensitivity to induction therapy and for the resistant varieties of solid tumors such as melanoma, glioma and other common adult solid tumors.
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Bordigoni E, Ploouvier A, Robert A, Carton R, Philippe N, Philip I, Chauvin F, Favrot M 1987 Hieh-dose theranv with bone marrow transplantation for consoidation treatt&t in neuroblastoma: An unselected group of stage IV patients over 1 year of age. J Clin Oncol 5: 266-271 Nichols C R, Tricot G, Williams S D, van Besien K, Loehrer P J, Roth B J, Akard L, Hoffman R, Goulet R, Wolff S N. Giannone L. Greer J. Einhorn L H. Jansen J 1989 Dose intensive chemotherapy in refractory germ cell cancer-A phase I/II trial of high dose carboplatin and etoposide with autologous bone marrow transplantation. J Clin Oncol 7: 932-939 Rosti G. Salvioni R, Pizzocaro G, Valzania F, Marangolo M 1990 High-Dose Chemotherapy (HDC) with Carboplatin (CBP) and VP16 in germ cell tumors. Abstract 89 Pica J-L, Droz J-P, Ostronoff M, Baume D, Gouyette A, Beaujean F, Hayat M 1989 High dose chemotherapy with autologous bone marrow transplantation for poor diagnosis non-seminomatous germ cell tumors, in Dicke K A, Spitzer G, Jagannath S (eds): Autologous Bone Marrow Transplantation: Proceedings of the Fourth International Symposium. Houston, University of Texas M.D. Anderson
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Hospital and Tumor Institute, Scientific Publications, pp 469-476 40. Biron P, Philip T, Maraninchi D, Pica J L, Cahn J Y, Fumoleau P. Le Mevel A. Gastaut J A, Carcassonne M. Kamioner D, Herve P, Brunat-Mentigny M, Hayat M 1985 Massive chemotherapy and autologous bone marrow transplantation in progressive disease of nonseminomatous testicular cancer: a phase II study on 15 patients. In: Dicke K A, Spitzer G, Zander A R eds. Autologous Bone Marrow Transplantation: Proceeding of the First International Symposium Houston: University Texas, M.D. Anderson Hospital and Tumor Institute 203-10 41 Combleet M A, Corringham R E T, Prentice H G. Boesen E M, McElwain T J 1981 Treatment of Ewing’s sarcoma with high-dose melphalan and autologous bone marrow transplantation. Cancer Treat Rep. 65: 241-4 42 Graham-Pole J, Marcus R 1990 Autologous Marrow Transplants (ABMT) for patients (pts) with Ewing’s sarcoma (ES) at high risk for relapse (rel). Transplantation 5: suppl2 Proceedings of Sixteenth Annual Meeting of European Cooperative group for Bone Marrow Transplantation pp 22