Christian M. Kurbacher

Intense Dose-Dense Sequential Chemotherapy With Epirubicin, Paclitaxel, and Cyclophosphamide Compared With Conventionally Scheduled Chemotherapy in High-Risk Primary Breast Cancer: Mature Results of an AGO Phase III Study

PURPOSE Patients with primary breast cancer who have extensive axillary lymph node involvement have a poor prognosis after conventional adjuvant therapy. We compared intense dose-dense (IDD) adjuvant chemotherapy with conventionally scheduled adjuvant chemotherapy in patients with high-risk primary breast cancer. PATIENTS AND METHODS In this randomized, phase III trial, a total of 1,284 eligible patients with four or more involved axillary lymph nodes were randomly assigned to receive IDD sequential epirubicin, paclitaxel, and cyclophosphamide (IDD-ETC) every 2 weeks or conventionally scheduled epirubicin/cyclophosphamide followed by paclitaxel every three weeks. The primary end point was event-free survival (EFS). RESULTS At a median follow-up of 62 months, 5-year event-free survival rates were 62% in the conventional arm and 70% in the IDD-ETC arm, representing a 28% reduction of the relative risk of relapse (P < .001). This benefit was independent of menopausal, hormone receptor, or human epidermal growth factor receptor 2 status. The 5-year overall survival rates were 77% versus 82%, representing a 24% reduction of the relative risk of death (P = .0285). IDD therapy was associated with significantly more nonhematologic and hematologic toxicities, but no treatment-related death occurred. Four occurrences of acute myeloid leukemia or myelodysplastic syndrome (MDS) were observed in the IDD-ETC arm. No severe congestive heart failure was reported. CONCLUSION IDD-ETC was less well tolerated compared with conventional chemotherapy but significantly improved event-free and overall survivals in patients with high-risk primary breast cancer who had four or more positive axillary lymph nodes.

Use of an ex vivo ATP luminescence assay to direct chemotherapy for recurrent ovarian cancer.

Chemotherapy for recurrent ovarian carcinoma (ROC) produces response rates of 10-80% depending on the prevalence of platinum resistance. Most patients relapse within 1 year and median progression-free survival (PFS) is generally no more than 6 months. Previous pretherapeutic chemosensitlvity assays mostly failed to improve the outcome of patients with ROC. Newly developed ATP assays show promising retrospective correlation with clinical outcome. We report here the first results of ATP assay-directed chemotherapy in patients with ROC. Therapy was selected by the ATP tumor chemosensitivity assay (ATP-TCA) in a prospective open-label pilot trial for ROC. Objective response rate (ORR), PFS and overall survival (OAS) of the first 25 evaluable patients were retrospectively compared with those of 30 others having similar characteristics who were treated empirically within the same period. The actuarial median observation times were 80 weeks for the ATP-TCA group and 83.5 weeks for the control group, respectively. In the control group, a 37% ORR [two complete responses (CR) and nine partial responses (PR)] was followed by a median PFS of 20 weeks and a median OAS of 69 weeks, mainly related to the use of single-agent chemotherapy. The ORR in the ATP-TCA group was 64% (eight CR and eight PR) (p=0.04) with the majority of responses (11 of 16) achieved with novel combinations. The median PFS in this group was 50 weeks (p=0.003) and the median OAS was 97 weeks (p=0.145). Survival of responding patients was similar in both groups. Chemotherapy guided by the ATP-TCA produced a greater benefit with regard to both ORR and PFS in platinum-refractory patients. ATP-TCA-directed chemotherapy for ROC compares favorably with chemotherapy chosen by a clinician and often leads to the choice of novel drug combinations. These promising results now warrant confirmation by prospective randomized trials.

A prospective randomized controlled trial of tumour chemosensitivity assay directed chemotherapy versus physician's choice in patients with recurrent platinum-resistant ovarian cancer.

The primary aim of this randomized trial was to determine response rate and progression-free survival following chemotherapy in patients with platinum-resistant recurrent ovarian cancer, who had been treated according to an ATP-based tumour chemosensitivity assay in comparison with physicians choice. A total of 180 patients were randomized to assay-directed therapy (n=94) or physicians-choice chemotherapy (n=86). Median follow-up at analysis was 18 months. Response was assessable in 147 patients: 31.5% achieved a partial or complete response in the physicians-choice group compared with 40.5% in the assay-directed group (26 versus 31% by intention-to-treat analysis respectively). Intention-to-treat analysis showed a median progression-free survival of 93 days in the physicians-choice group and 104 days in the assay-directed group (hazard ratio 0.8, 95% confidence interval 0.59–1.10, not significant). No difference was seen in overall survival between the groups, although 12/39 (41%) of patients who crossed over from the physicians-choice arm obtained a response. Increased use of combination therapy was seen in the physicians-choice arm during the study as a result of the observed effects of assay-directed therapy in patients. Patients entering the physicians-choice arm of the study during the first year did significantly worse than those who entered in the subsequent years (hazard ratio 0.44, 95% confidence interval 0.2–0.9, P<0.03). This small randomized clinical trial has documented a trend towards improved response and progression-free survival for assay-directed treatment. Chemosensitivity testing might provide useful information in some patients with ovarian cancer, although a larger trial is required to confirm this. The ATP-based tumour chemosensitivity assay remains an investigational method in this condition.

Liposomal doxorubicin and weekly paclitaxel in the treatment of metastatic breast cancer.

The combination of paclitaxel and doxorubicin or epirubicin is highly active against metastatic breast cancer, yet may produce congestive heart failure. Liposome-encapsulated doxorubicin is a new formulation of doxorubicin with no dose-limiting cardiac toxicity. Twenty-one patients with metastatic breast cancer were treated with pegylated liposomal doxorubicin (20 mg/m2, day 1) and paclitaxel (100 mg/m2, days 1 and 8) for six cycles every 2 weeks. All patients had had relapse or progression on one to five previous chemotherapies. We observed two patients with complete and eight patients with partial remissions (48% response rate). Eight of the 10 responders had had previous therapy with epirubicin, doxorubicin or mitoxantrone. The mean remission duration was 5 months. Disease progression due to brain metastasis occurred in five cases. Severe side effects (grade 3 WHO) were alopecia (100%), skin toxicity in 29%, neuropathy in 24% and mucositis in 13%. Leukopenia (grade 4 WHO) was observed in 48%, but there was no cardiac toxicity, no death and no hospitalization. The combination of weekly paclitaxel and liposomal doxorubicin every 2 weeks is highly effective in previously treated patients. Based on the doses we administered, we recommend 15 mg/m2 liposomal doxorubicin every 2 weeks and 80 mg/m2 paclitaxel weekly.

INDIVIDUALIZING CHEMOTHERAPY FOR SOLID TUMORS : IS THERE ANY ALTERNATIVE?

The burgeoning understanding of the molecular basis of carcinogenesis and tumor drug resistance is matched by an appreciation of the complexity of individual tumors. This complexity underlies the heterogeneity of response to treatment and is a major barrier to improving the outcome of solid tumor chemotherapy. While individualization of chemotherapy is theoretically attractive, past attempts to provide such information have produced many papers and little progress. However, the disparate molecular make-up of tumors of the same clinicopathologic type suggests that there may be no alternative and recent progress suggests that individualization of cancer therapy could have considerable benefits. In this review, we consider the alternative methods which might be employed and the requirements which need to be met before they are introduced. It will be some time before molecular analysis can predict chemosensitivity, although this may prove feasible for more specific agents than those currently in use. However, newly developed cellular chemosensitivity assays such as the ATP-tumor chemosensitivity assay allied to selected molecular measurement may already have the potential to select optimal therapy for patients. We need to develop a diverse series of acceptable and biologically logical regimens for each of the common tumor types, all of which can be tested in vitro.

The role of chemotherapy in invasive cancer of the cervix uteri: current standards and future prospects

For many decades, invasive cervical cancer has been considered more or less chemoresistant and chemotherapy has been limited to patients presenting with overt metastatic disease or those suffering from pelvic recurrences which could not be advised to secondary local treatments. However, more than 20 different single agents are considered active in cervical cancer. Recent cooperative clinical trials have demonstrated the superiority of multi-modality strategies for patients with high-risk cervical cancer. These studies integrating chemotherapy as part of the primary therapeutic concept have provided the most significant improvement of locally advanced disease in more than three decades. This review summarizes current standards of chemotherapy for invasive cervical cancer and shows new developments which may improve systemic treatment of the disease.

ATP-based tumor chemosensitivity testing: assisting new agent development

Chemotherapy of cancer based on cytotoxic agents has proved successful in the treatment of many cancers. The number of agents available to the oncologist has grown steadily and drug combinations are in widespread use. The perceived success of these combinations makes the introduction of new agents difficult. For any new agent, multiple phase II and III trials are likely to be needed. Since phase II/III trials usually only address single issues, the cost of introducing a new agent is substantial. Multiple studies are required with different tumor types to define the activity profile of a new drug, followed by adjusted combinations to define the role of the new drug in conjunction with older ones. Recent advances in the understanding of cancer at a molecular level are already leading to new agent design. The next problem is how to introduce and use these agents. One possible approach is to trial the drugs with tumor cells ex vivo, using a chemosensitivity assay such as the ATP-based chemosensitivity assay which is designed to mimic the situation within the tumor accurately enough to examine issues of dose response, sequence and timing in many different tumors. The avoidance of cell lines ensures relevance and the sensitivity of some of these methods allows large numbers of mechanistically logical permutations to be tested with material from small numbers of patients. The results may be used to choose the most effective combinations for clinical testing in a limited number of subsequent phase II/III trials, saving money and time, while permitting new agents to be introduced faster.

Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay

Previous data suggest that lipophilic statins such as fluvastatin and N-bisphosphonates such as zoledronic acid, both inhibitors of the mevalonate metabolic pathway, have anti-cancer effects in vitro and in patients. We have examined the effect of fluvastatin alone and in combination with zoledronic acid in the ATP-based tumour chemosensitivity assay (ATP-TCA) for effects on breast and ovarian cancer tumour-derived cells. Both zoledronic acid and fluvastatin showed activity in the ATP-TCA against breast and ovarian cancer, though fluvastatin alone was less active, particularly against breast cancer. The combination of zoledronic acid and fluvastatin was more active than either single agent in the ATP-TCA with some synergy against breast and ovarian cancer tumour-derived cells. Sequential drug experiments showed that pre-treatment of ovarian tumour cells with fluvastatin resulted in decreased sensitivity to zoledronic acid. Addition of mevalonate pathway components with zoledronic acid with or without fluvastatin showed little effect, while mevalonate did reduced inhibition due to fluvastatin. These data suggest that the combination of zoledronic acid and fluvastatin may have activity against breast and ovarian cancer based on direct anti-cancer cell effects. A clinical trial to test this is in preparation.

Influence of Human Luteinizing Hormone on Cell Growth and CA125 Secretion of Primary Epithelial Ovarian Carcinomas in vitro

In the present study, the influence of human luteinizing hormone(hLH) on the growth and the CA 125 secretion of primary ovarian carcinoma cell cultures derived from 11 previously untreated patients was investigated. Two different patterns of in vitro growth of unstimulated ovarian carcinoma cells could be detected: 5 cell cultures in which no changes of cell number were observed during an incubation period of 6 days (group A) and 6 cell cultures which grew without any hormonal support (group B). All tumors of group A showed enhanced cell proliferation when hLH was added to the culture medium, reaching a maximum at dosages of 100 mIU/ml on day 2 after incubation, while such an effect was not observed in group B. In most cases, no positive correlation was found between hLH-induced cell growth and CA 125 release. Our findings demonstrated a dose-dependent hLH-induced stimulation of epithelial ovarian tumors in vitro.

Heterogeneity ofin vitro chemosensitivity in perioperative breast cancer cells to mitoxantroneversus doxorubicin evaluated by a microplate ATP bioluminescence assay

SummaryApart from clinical trials, mitoxantrone (MX) is rarely used in breast cancer (BC) due to the anticipated anthracycline cross-resistance. We have examined this drug versus doxorubicin (DOX) using data obtained fromin vitro microplate ATP tumor chemosensitivity assays (ATP-TCA) of BC cells which were derived from 55 chemotherapy-naive patients at time of primary surgery. Both drugs were tested at 6 different concentrations ranging from 6.25% to 200% peak plasma concentrationin vivo (PPC). Differences between DOX and MX observed for mean IC50, IC90, and a sensitivity index (SI) were not statistically significant.In vitro response rates were 44% for DOX and 52% for MX. 34 of 52 eligible assays (65%) showed comparable activity of both drugs whereas a lack of cross-resistance was observed in the remaining 18 (35%) tumors as indicated by differences for SI. Cumulative concentration-response plots of tumors respondingin vitro with a ≥ 50 percent or ≥ 90 percent tumor cell inhibition showed a strong dose-dependence for both DOX and MX at concentrations which normally can be achieved within clinical tumors (i.e. 6.25%-50% PPC). At higher concentrations, however, cytotoxicity of DOX and MX could not be improved by furtherin vitro dose escalation. Moreover, a substantial proportion of BC specimens (DOX: 48.1%; MX: 40.4%) did not experience a ≥ 90 tumor cell inhibition at 200% PPC. In conclusion,in vitro results obtained by ATP-TCA indicate that there is no cross-resistance between MX and DOX in a substantial proportion of BC patients. This may be clinically useful and suggests that combinations including MX should be tested in patients clinically resistant to DOX containing regimens. Since both drugs produced sigmoidal concentration-response curves, dose escalation beyond a certain point may not produce increased sensitivity.