Autografting

High-dose melphalan and autologous stem cell transplantation as consolidation treatment in patients with chemosensitive ovarian cancer: results of a single-institution randomized trial

Article metrics

Abstract

The role of high-dose chemotherapy (HDCT) in epithelial ovarian cancer (EOC) remains controversial. This study was initiated to compare the efficacy and tolerability of HDCT as a consolidation approach in women with chemosensitive advanced EOC (FIGO stages IIC–IV). Patients who had achieved their first clinical complete remission after six cycles of conventional paclitaxel and carboplatin combination chemotherapy were randomly assigned to receive or not high-dose melphalan. The primary objective was to compare time to disease progression (TTP). A total of 80 patients were enrolled onto the trial. Patients who were randomized to receive HDCT were initially treated with cyclophosphamide 4 g/m2 for PBPC mobilization. HDCT consisted of melphalan 200 mg/m2. Of the 37 patients who were allocated to HDCT, 11 (29.7%) did not receive melphalan either due to patient refusal (n=5) or due to failure of PBPC mobilization (n=6). In an intent-to-treat analysis, there were no significant differences between the two arms in TTP (P=0.059) as well as in overall survival (OS) (P=0.38).

Introduction

The current management of advanced epithelial ovarian cancer (EOC) includes cytoreductive surgery followed by combination chemotherapy.1, 2, 3, 4 The combination of paclitaxel with a platinum analogue is the preferred chemotherapy regimen in the treatment of newly diagnosed patients with advanced EOC.5, 6, 7, 8, 9, 10, 11, 12 Despite the progress that has been achieved by incorporating paclitaxel into first-line regimens, the majority of these women will develop recurrences and will die of their disease as chemotherapy drug resistance leads to uncontrolled cancer growth.

High-dose chemotherapy (HDCT) with stem-cell transplantation, allowing great increases in drug delivery, has been proposed as a way to overcome drug resistance.13, 14 Limited data are available on HDCT and hematopoietic support as first-line treatment in advanced EOC and the ideal patient population as well as the best treatment regimen still remain to be established. Multiple courses of HDCT rescued with PBPC transplantation has been proposed in patients with previously untreated advanced disease. Unfortunately, this aggressive approach failed to improve the outcome of patients.15, 16, 17 Other groups treated patients with a course of single HDCT as a consolidation therapy following standard-dose induction.18 However, the first randomized trial comparing HDCT with conventional-dose maintenance therapy in consolidation of advanced ovarian cancer did not show significant advantages in terms of disease-free survival and overall survival (OS) for the HDCT arm.19

This phase III study was initiated to compare the efficacy and tolerability of HDCT as a consolidation approach in patients with advanced EOC who were in first complete clinical remission after six cycles of paclitaxel and carboplatin at standard doses.

Patients and methods

Study population

Initial selection included newly diagnosed patients with pathologically confirmed EOC FIGO stages IIC–IV who had undergone cytoreductive surgery. Other eligibility criteria included age of 70 years or less; Eastern Cooperative Oncology Group performance status of 0, 1 or 2; a granulocyte count of at least 1.5 × 103 per mm3, a hemoglobin level of at least 10 g/dl, a platelet count of at least 100 × 103 per mm3, a serum creatinine level of 1.7 mg/dl or less, a serum bilirubin of 2.0 mg/dl or less and alanine aminotransferase and aspartate aminotransferase values of no more than twice the upper normal level. Patients with a history of angina, myocardial infarction or congestive heart failure and patients with symptoms, signs or electrocardiogram findings suggestive of heart disease were excluded. All patients provided informed consent in accordance with institutional review board guidelines.

Treatment plan

Before randomization, all patients received six cycles of combination chemotherapy (Figure 1). Chemotherapy was given on an outpatient basis and consisted of paclitaxel, 175 mg/m2, administered as an intravenous infusion in 500 ml of 0.9% saline over 3 h. Carboplatin was targeted at AUC 6. Complete physical and gynecological examination, urinalysis, creatinine and liver function tests, serum CA 125, performance status and toxicity evaluations were conducted before each cycle. Chemotherapy was discontinued in cases of progressive disease (PD) or unacceptable toxicity and patients had to be withdrawn from the study. Assessments of tumor response were performed every other course. Cases considered to have partial response (PR) or disease stabilization (SD) after six cycles also went off study while patients with clinical complete response (cCR) were randomly assigned to observation only or HDCT. Pathological response was confirmed by a second look laparotomy (SLL) performed within 2 months after the final cycle of induction chemotherapy.

Figure 1
figure1

Study flowsheet: Enrollment of patients. AUC, area under the curve; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; SLL, second look laparotomy; PBPC, peripheral-blood progenitor cells.

HDCT and hematopoietic rescue

In the high-dose arm, cyclophosphamide 4 g/m2 was administered intravenously over 1 h for mobilization of PBPC. Lenograstim was given at a fixed dose of 263 μg/day, subcutaneously, 24 h afterwards and daily thereafter until PBPC collection was completed. The collection of PBPC was performed when the post-cyclophosphamide induced leucopenia nadir first exceeded 5 × 103 per mm3. A minimum of 2 × 106 CD34+ cells per kilogram of body weight were collected by leukapheresis using a COBE Spectra Blood Cell Separator (COBE Laboratories, Lakewood, CO, USA) programmed for mononuclear cell collection. HDCT was administered immediately after completion of PBPC collection. Melphalan 200 mg/m2, diluted in 1000 ml of 0.9% saline, was administered intravenously over 2 h. PBPC were rapidly reinfused through the central venous catheter 24 h after completion of chemotherapy. All patients received lenograstim 526 μg daily, subcutaneously, starting the day after PBPC reinfusion. Patients were discharged from the hospital when their neutrophil and unsupported platelet counts reached 1 × 103 per mm3 and 25 × 103 per mm3, respectively, in the absence of suspected or documented complications.

Evaluations

WHO criteria for response and toxicity were used during the induction phase.20 Patients who had normalization of serum CA 125 levels and complete resolution of all measurable or evaluable disease for at least 4 weeks after initial chemotherapy were considered to have a cCR and were enrolled in the study.

After treatment, follow-up of patients included a physical examination and serum CA 125 measurement every 3 months, while appropriate imaging procedures (CT or MRI) were routinely performed every 6 months. Imaging studies were performed earlier when clinically indicated. Progression-free and OS were measured from the date of initial diagnosis until disease progression or death for any reason, respectively.

Statistical analyses

All analyses were primarily based on an intention-to-treat principle, including all randomized patients. The main end point of the study was to evaluate any difference in TTP curves between the two randomization groups, assuming that HDCT would result in a two-fold increase in the median TTP of 1.5 years for patients not receiving high-dose melphalan. Therefore, in order to achieve 80% power for a two-sided test at a 5% statistical significance level, 33 women per group were required.

Randomization was performed with a non-stratified simple randomization algorithm, using sealed envelopes in order to allocate patients into two arms, HDCT or observation. The randomization scheme did not include balancing parameters since in such relatively small trials stratification may result in imbalances in the sample size between groups. The estimated study duration was 10 years, under the hypotheses of a median TTP of 1.5 years for the group of women not receiving HDCT and an overall annual accrual rate of 10 women.21

Patient characteristics were compared with the χ2 or Fisher's exact test,22 for nominal variables, and the Kruskall–Wallis test for ordinal variables. TTP and OS were estimated with the Kaplan–Meier method,23 while univariate comparisons were performed with the log-rank test.24 Cox proportional hazard analysis25 was used to examine, in a multivariate setting, the association of TTP and OS with the following variables: randomization group, age above or below the median (<54 years vs 54 years), tumor grade (1+2 vs 3), disease FIGO stage (II+III vs IV), histology, initial debulking (optimal vs suboptimal) and size of initial tumor residuum (<1 cm vs 1–5 cm vs >5 cm). The backward stepwise variable selection method with removal criterion P>0.10 was used. First order interactions of randomization group with all the variables were checked in the final model while time-dependent analysis, as performed in order to verify Cox model's assumption. A P-value less than 0.05 was considered statistically significant. All analyses were performed using SAS Release 8.02 (SAS Institute Inc., Cary, NC, USA).

Results

Between September 1996 and April 2001, a total of 80 patients were randomly assigned to receive (n=37) or not (n=43) HDCT. The median follow-up was 6.3 and 5.8 years for the HDCT arm and the control arm, respectively, a difference which was not statistically significant. Patient characteristics were well balanced between the two arms (Table 1). The differences observed in the number of stage IV patients and patients with residual disease>5 cm between the two arms were not statistically significant (P=0.49 and P=0.32, respectively) 11 patients (29.7%) in the HDCT arm did not receive the planned treatment for the following reasons: five patients refused to undergo chemotherapy with melphalan 200 mg/m2, and 6 patients had to be withdrawn due to inadequate PBPC collection. In the subgroup of 11 patients, who did not receive a transplant, 1(9%) had stage IV disease and 9 (82%) suboptimal debulking.

Table 1 Baseline patient characteristics

Toxicity and hematopoietic recovery after HDCT and PBPC transplantation

The median number of PBPC infused was 5.4 × 106 CD34+ cells/kg (range, 2.0–13.9) (Table 2). All patients engrafted following HDCT. A total of 13 patients (50%) developed neutropenic fever that required empiric antimicrobial therapy. The median number of platelet transfusions was two (range, 0–4), and that of RBC transfusions was one (range, 0–4). A neutrophil count of 0.5 × 103 per mm3 was reached at a median of 10 days (range, 7–11) after reinfusion of the PBPC graft, and a platelet count of 25 × 103 per mm3 after 11 days (range, 9–13), respectively. The most frequent grade 3/4 non-hematological toxicities after HDCT were nausea and vomiting (41%), diarrhea (57%) and oropharyngeal mucositis/esophagitis (81%).

Table 2 Hematopoietic recovery after high-dose melphalan and PBPC rescue

There were no treatment-related deaths and the median hospital stay was 17 days (range, 14–25).

Remission duration and survival

A total of 52 women relapsed, 21 (56.8%) in the HDCT arm and 31 (72.1%) in the control arm, while 34 (42.5%) women died during the study period, 14 (37.8%) in the HDCT arm and 20 (46.5%) in the control arm. Median TTP was 7.1 years (range, 0.2–8.1+ years) in HDCT arm and 1.5 years (range, 0.2–7.8+ years) in the control arm (P=0.059) (Figure 2a). Median OS has not been reached yet for patients randomized to receive high-dose melphalan (range, 0.5–8.1+ years) while it was 6.1 years (range, 0.5–8+ years) in the control arm (P=0.38) (Figure 2b).

Figure 2
figure2

Time to disease progression (TTP) (a) and overall survival (b) for patients randomized to HDCT (solid line) or not (dotted line).

Univariate analysis did not reveal any statistically significant variables for TTP. Trends for statistical significance were observed for randomization arm (P=0.059), initial debulking (P=0.052) and the size of residual tumor (P=0.092). With regard to OS, statistically significant variables were tumor grade (P=0.022) and debulking (P=0.039). Stage was among those variables which did not significantly influence neither TTP nor OS. Multivariate analysis for variables associated with TTP showed that treatment arm was a significant predictor only in relation to grade. More specifically, within grade three patients, women who were randomized to the control arm had an increased risk of disease progression (hazard ratio 3.005, P=0.017), while for patients with well or moderately differentiated tumors no significant differences were found (P=0.49). Furthermore, among patients randomized to receive HDCT, women with grade 3 tumors had a better outcome (hazard ratio 0.242, P=0.003), a result that was not found for patients in the control arm (P=0.89). Finally, suboptimal debulking was an adverse prognostic factor (hazard ratio 1.980, P=0.032) for disease progression. With regard to OS, multivariate analysis showed that grade 3 and suboptimal debulking were the only significant prognostic factors (P=0.005 and P=0.0075, respectively). Overall, it should be noted that when testing the proportional hazards assumption for treatment group, the assumption was verified for OS but not for TTP.

In order to further clarify the effect of HDCT on patient outcome, additional multivariate analyses were performed with patients grouped according to actual treatment received (HDCT, n=26 vs no HDCT, n=54). The results were similar to those of the intent-to-treat analysis.

More specifically, treatment status was a significant predictor of TTP only in relation to grade. Within grade 3 patients, women who were not treated had an increased risk of disease progression (hazard ratio: 3.40, P=0.017), while for patients with well or moderately differentiated tumors no significant differences were found (P=0.87). Furthermore, among patients who were treated with HDCT, women with grade 3 tumors had a better outcome (hazard ratio 0.25, P=0.17) a result that was not found for patients not treated (P=0.48). Suboptimal debulking remained an adverse prognostic factor (hazard ratio 1.97, P=0.035) for disease progression. With regard to OS, as in the intent-to-treat analysis, grade 3 and suboptimal debulking were the only significant prognostic factors (P=0.010 and P=0.023, respectively).

Second look laparotomy was performed in 32 (40%) patients. The remaining patients withdrew their consent to the procedure. Among 17 women who were autotransplanted, SLL was positive in 2 (11.8%) and negative in 15 (88.2%) patients, respectively. SLL was positive in 6/15 (40%) patients treated with conventional chemotherapy only (P=0.11). The pattern of TTP difference between treatment groups did not change within each SLL subgroup.

Discussion

The first pilot studies of HDCT with stem cell support in ovarian cancer were performed in relapsed/refractory patients and have found relatively high response rates compared with conventional-dose regimens. However, the responses were brief in duration and no survival advantage could be demonstrated. Subsequent trials with one or multiple cycles of HDCT have found similar results.13, 14, 26, 27, 28, 29 Because HDCT does not appear effective in advanced refractory patients, investigators focused their attention on patients with earlier, less resistant and less bulky disease. In this context, HDCT has been given either after debulking surgery and standard conventional-dose platinum containing chemotherapy or as a part of the initial treatment plan. Rapidly sequenced HDCT with PBPC transplantation in the front-line has been proposed in previously untreated patients. However, results of these trials showed the failure of this strategy to improve the outcome.15, 16, 17

An interesting approach is the use of HDCT as consolidation in chemosensitive patients, in an effort to kill residual clones and avoid the chemoresistant relapse. There have been several relatively small studies evaluating the potential of HDCT consolidation in the treatment of advanced EOC.18, 19, 28, 30, 31, 32, 33, 34 The heterogeneity of these reports, may prohibit solid conclusions to be drawn on the real value of this approach; nevertheless, some interesting observations included the inferiority of the outcome of HDCT-treated patients who had not achieved a complete pathological remission after induction treatment18, 30 and the non-superiority of high-dose carboplatin-based consolidation over conventional-dose consolidation chemotherapy with the same agent.19

We conducted a single institution randomized trial of high-dose melphalan with PBPC support as consolidation treatment after induction with standard paclitaxel-carboplatin, in patients with chemosensitive advanced EOC. The median OS was increased for the HDCT arm, but this difference was not statistically significant. The median TTP was 7.1 years for the HDCT arm and 1.5 years for the control arm, a difference that was marginally significant (P=0.059) but may also be attributed to the relatively lower frequency of patients with stage IV disease and residual disease <5 cm that was observed in the HDCT arm. Moreover, there was an imbalance of positive SLL rates between patients who underwent HDCT and those who did not. However, the pattern of TTP difference between treatment groups was similar within each SLL subgroup. TTP in the control arm was relatively comparable to that in much larger studies which utilized the paclitaxel and carboplatin regimen as first-line treatment for advanced EOC. On the other hand, the median OS of the same arm was clearly superior to those of the aforementioned studies.6, 8, 10, 11 We also obtained a significantly longer median TTP in the HDCT arm when compared to the corresponding survivals of earlier non-randomized studies that used HDCT as consolidation treatment for EOC. In these studies, TTP ranged from 29 to 35 months, and OS from 54 to 75 months, respectively,18, 19, 30, 31 whereas with a median follow-up of 5.8 years the median OS of our HDCT arm has not been reached yet. It should be mentioned here, that median TTP and OS were 21.2 and 44.4 months, respectively, in a retrospective, multicenter EBMT study which included 91 patients in first complete remission treated with HDCT,32 while, in the recently published randomized study of the Finnish Ovarian Cancer group,34 TTP and OS reached 16.6 months and 64.3 months, respectively.

The fact that almost one third of our patients (29.7%) who were allocated to the HDCT arm did not ultimately receive melphalan does not distort our conclusions since multivariate analysis with the patients stratified according to treatment status showed almost identical results. The percentage of patients who failed to mobilize (6 out of the 32 who received mobilization treatment, 19%) is relatively high. This could be attributed to the suppressive effect on bone marrow function of the induction chemotherapy which implemented full six cycles of paclitaxel and carboplatin. In the study of Grénman et al.34 which utilized only three cycles of the same combination in the induction phase of treatment, adequate stem cell collection was achieved in all patients who received mobilization treatment.

The paclitaxel and carboplatin combination that was used in the induction phase is currently the standard of care in first-line treatment of advanced EOC with proven superiority in terms of response rate, TTP, and OS when compared to non-paclitaxel containing regimens in most randomized trials.3, 5, 7 An effective induction regimen may be of significant importance for ovarian cancer patients for which HDCT is considered. In previous studies with HDCT consolidation in EOC patients who had received cisplatin-based induction regimens,18, 19, 31 complete pathological responses had been observed in 33–62% of patients. Legros et al.18 observed that patients who had achieved a pCR (36%) after induction with conventional dose chemotherapy had superior 5-year OS after HDCT in relation to patients who had not, suggesting that pCR prior to HDCT may be an important predictor of improved outcome in this setting.

In our trial, we enrolled patients with chemosensitive disease, all of whom were in complete clinical remission. Pathological CR was observed in 75% of those who were subjected to SLL (n=24/32) and if this reflects the overall rate of pCR among randomized patients, it might account for the improved outcomes observed, especially in the HDCT arm. In respect to the interesting observation of improved progression-free survival in patients with grade 3 disease who received HDCT as shown in our analyses, one should note the limitation that subgroup analyses were not incorporated in the original design of the study.

All patients of our HDCT arm received the same conditioning regimen with melphalan 200 mg/m2. This alkylating agent has been used in HDCT regimens for patients with EOC because it is active in this tumor entity at a standard dose which can be safely escalated when associated with hematopoietic rescue.35 Dose–response relationships have been well documented in ovarian cancer cell lines, animal models and in clinical settings.36, 37, 38 Melphalan at a dose of 140 mg/m2 has resulted in a broad spectrum of antitumor activity in different neoplasms, including ovarian cancer.36, 39 We administered a higher dose of this alkylating agent that has different mechanisms of action avoiding cross-resistance with the agents used in induction.40 In the previously mentioned studies, the patients received various HDCT regimens which incorporated or not melphalan in doses ranging from 100 to 140 mg/m2.

Toxicity in the HDCT group was acceptable with no treatment-related deaths. Most patients experienced moderate nausea, vomiting, diarrhea, stomatitis and esophagitis. Nausea and vomiting occurred early after melphalan administration, was most severe on the first day of therapy, and usually responded to HT3 antagonists and dexamethasone. Half of our autotransplanted patients developed neutropenic fever that was successfully treated with empiric antimicrobial therapy.

Overall, in the present trial, HDCT failed to yield a statistically significant improvement of outcome in EOC patients on cCR after induction with paclitaxel and carboplatin. Our data shall be interpreted with caution given the small size of the study population and the fact that patients in the control arm were not treated with conventional-dose consolidation chemotherapy.

References

  1. 1

    Landis SH, Murray T, Bolden S, Wingo PA . Cancer statistics, 1999. CA Cancer J Clin 1999; 49: 8–31.

  2. 2

    Ozols EF, Rubin SC, Thomas G, Robboy S . Epithelial ovarian cancer. In: Hoskins WJ, Perez CA, Young RC (eds). Principles and Practice of Gynecologic Oncology. Lippincott Williams & Wilkins: Philadelphia, 2000, pp 981–1057.

  3. 3

    Cannistra SA, Bast Jr RC, Berek JS, Bookman MA, Crum CP, DePriest PD et al. Progress in the management of gynecologic cancer: consensus summary statement. J Clin Oncol 2003; 21 (Suppl 10): 129–132.

  4. 4

    Cannistra SA . Cancer of the ovary. N Engl J Med 2004; 351: 2519–2529.

  5. 5

    Mc Guire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334: 1–6.

  6. 6

    Neijt JP, Engelholm SA, Tuxen MK, Sorensen PG, Hansen M, Sessa C et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 2000; 18: 3084–3092.

  7. 7

    Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000; 92: 699–708.

  8. 8

    Du Bois A, Lück HJ, Meier W, Adams HP, Möbus V, Costa S et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003; 95: 1320–1329.

  9. 9

    ICON1, EORTC-ACTION. International Collaborative Ovarian Neoplasm Trial 1 and Adjuvant Chemotherapy In Ovarian Neoplasm Trial. Two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 2003; 95: 105–112.

  10. 10

    Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 2004; 96: 1682–1691.

  11. 11

    Aravantinos G, Fountzilas G, Kosmidis P, Dimopoulos MA, Stathopoulos GP, Pavlidis N et al. Paclitaxel plus carboplatin versus paclitaxel plus alternating carboplatin and cisplatin for initial treatment of advanced ovarian cancer: long-term efficacy results. A Hellenic Cooperative Oncology Group (HeCOG) study. Ann Oncol 2005; 16: 1116–1122.

  12. 12

    Du Bois A, Weber B, Rochon J, Meier W, Goupil A, Olbricht S et al. Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d'Investigateurs Nationaux pur l'Etude des Cancer Ovariens. J Clin Oncol 2006; 24: 1127–1135.

  13. 13

    Mc Guire III WP . High-dose chemotherapeutic approaches to ovarian cancer management. Semin Oncol 2000; 27 (Suppl 7): 41–46.

  14. 14

    Perillo A, Bonanno G, Pierelli L, Rutella S, Scambia G . Mancuso S: stem cells in gynecology and obstetrics. Panminerva Medica 2004; 46: 49–59.

  15. 15

    Aghajanian C, Fennelly D, Shapiro F, Waltzman R, Almadrones L, O'Flaherty C et al. Phase II study of ‘dose-dense’ high-dose chemotherapy treatment with peripheral-blood progenitor-cell support as primary treatment for patients with advanced ovarian cancer. J Clin Oncol 1998; 16: 1852–1860.

  16. 16

    Schilder RJ, Brady MF, Spriggs D, Shea T . Pilot evaluation of high-dose carboplatin and paclitaxel followed by high-dose melphalan supported by peripheral blood stem cells in previously untreated advanced ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2003; 88: 3–8.

  17. 17

    Ledermann JA, Frickhofen N, Wandt H, Bengala C, Champion K, Hinke A et al. A phase III randomised trial of sequential high dose chemotherapy (HDC) with peripheral blood stem cell support or standard dose chemotherapy (SDC) for first-line treatment of ovarian cancer. J Clin Oncol 2005; 23 (Suppl 16): 456s; abstract 5006.

  18. 18

    Legros M, Dauplat J, Flenny J, Cure H, Suzanne F, Chassagne J et al. High-dose chemotherapy with hematopoietic rescue in patients with stage III to IV ovarian cancer: long-term results. J Clin Oncol 1997; 15: 1302–1308.

  19. 19

    Curé H, Battista C, Biron P, Bay JO, Lotz J, Lioures B et al. Phase III randomized trial of high-dose chemotherapy and peripheral blood stem cell support as consolidation in patients with advanced ovarian cancer: 5-year follow-up of a GINECO/FNCLCC/SFGMTC study. Bone Marrow Transplant 2005; 35 (Suppl 2): 552; abstract 0270.

  20. 20

    Miller AB, Hoogerstraten B, Staquet M, Winkler A . Reporting results of cancer treatment. Cancer 1981; 47: 207–214.

  21. 21

    Machin D, Campbell MJ, Fayers PM, Pinol A . Statistical Tables for the Design of Clinical Studies, 2nd edn. Blackwell Scientific Publications: Oxford, 1998.

  22. 22

    Agresti A . Categorical Data Analysis. John Wiley & Sons: New York, 1990.

  23. 23

    Kaplan E, Meier F . Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

  24. 24

    Peto R, Peto J . Asymptotically efficient rank invariant test procedures. J Stat Soc (Series A) 1972; 135: 185–198.

  25. 25

    Cox DR . Regression models in life tables (with discussion). J R Stat Soc B 1972; 34: 187–220.

  26. 26

    Shpall EJ, Clarke-Pearson D, Soper JT, Berchuck A, Jones RB, Bast RC et al. High-dose alkylating agent chemotherapy with autologous bone marrow support in patients with stage III/IV epithelial ovarian cancer. Gynecol Oncol 1990; 38: 386–391.

  27. 27

    Brown ER, Belinson JL, Berek JS, McIntosh D, Hurd D, Ball H et al. Salvage therapy for recurrent and refractory ovarian cancer with high-dose chemotherapy and autologous bone marrow support: a Gynecologic Oncology Group pilot study. Gynecol Oncol 1994; 54: 142–146.

  28. 28

    Stiff PJ, Bayer R, Kerger C, Potkul RK, Malhotra D, Peace DJ et al. High-dose chemotherapy with autologous transplantation for persistant/relapsed ovarian cancer: a multivariate analysis of survival for 100 consecutively treated patients. J Clin Oncol 1997; 15: 1309–1317.

  29. 29

    Pujade-Lauraine E, Cure H, Battista C, Guastalla JP, Chiurazzi B, Fabbro M et al. High dose chemotherapy in ovarian cancer. Int J Gynecol Cancer 2001; 11 (Suppl 1): 64–67.

  30. 30

    Bertucci F, Viens P, Delpero JR, Bardou VJ, Faucher C, Houvenaeghel G et al. High-dose melphalan-based chemotherapy and autologous stem cell transplantation after second look laparotomy in patients with chemosensitive advanced ovarian carcinoma: long-term results. Bone Marrow Transplant 2000; 26: 61–67.

  31. 31

    Salerno MG, Ferrandina G, Greggi S, Pierelli L, Menichella G, Leone G et al. High-dose chemotherapy as a consolidation approach in advanced ovarian cancer: long-term results. Bone Marrow Transplant 2001; 27: 1017–1025.

  32. 32

    Bengala C, Guarneri V, Ledermann J, Rosti G, Wandt H, Lotz JP et al. High-dose chemotherapy with autologous hematopoietic support for advanced ovarian cancer in first complete remission: retrospective analysis from the Solid Tumor Registry of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 2005; 36: 25–31.

  33. 33

    Lotz J-P, Bouleuc C, André T, Touboul E, Macovei C, Hannoun L et al. Tandem high-dose chemotherapy with ifosfamide, carboplatin, and teniposide with autologous bone marrow transplantation for the treatment of poor prognosis common epithelial ovarian carcinoma. Cancer 1996; 77: 2550–2559.

  34. 34

    Grénman S, Wiklund T, Jalkanen J, Kuoppala T, Mäenpää J, Kuronen A et al. A randomized phase III study comparing high-dose chemotherapy to conventionally dosed chemotherapy for stage III ovarian cancer: The Finnish Ovarian Cancer (FINOVA) study. Eur J Cancer 2006; 42 (14): 2196–2199.

  35. 35

    Piver MS . Ovarian carcinoma. A decade of progress. Cancer 1984; 54 (Suppl 11): 2706–2715.

  36. 36

    Maraninchi D, Abecasis M, Gastant JA, Herve P, Sebahoun G, Flesch M et al. High-dose melphalan with autologous bone marrow rescue for the treatment of adult solid tumors. Cancer Treat Rep 1984; 68: 471–474.

  37. 37

    Von Hoff DD, Clark GM, Weiss CR, Marshall MH, Buchok JB, Knight WA et al. Use of in vitro dose response effects to select antineoplastics for high-dose or regional administration regimens. J Clin Oncol 1986; 4: 1827–1834.

  38. 38

    Frei III E, Teicher BA, Holden SA, Cathcart KN, Wang YY . Effect of alkylating agent dose: preclinical studies and possible clinical correlation. Cancer Res 1988; 48: 6417–6423.

  39. 39

    Lazarus HM, Herzig RH, Graham-Pole J, Wolff SN, Phillips GL, Strandjord S et al. Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer. J Clin Oncol 1983; 1: 359–367.

  40. 40

    Schabel Jr FM, Trader MW, Laster Jr WR, Wheeler GP, Witt MH . Patterns of resistance and therapeutic synergism among alkylating agents. Antibiot Chemother 1978; 23: 200–215.

Download references

Author information

Correspondence to C Papadimitriou.

Rights and permissions

Reprints and Permissions

About this article

Keywords

  • ovarian cancer
  • high-dose melphalan
  • consolidation
  • autotransplantation

Further reading