Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

42nd Annual Meeting of the American Society of Clinical Oncology

Atlanta, Georgia / June 2-6, 2006

The taxanes including paclitaxel and docetaxel have long proven to be active in both the adjuvant and metastatic setting for a variety of malignancies, among them breast cancer. Despite their activity, failure does occur, at which point further options for patients who have become refractory to them remain limited. The epothilone B analog ixabepilone is similar in its mechanism of action to the taxanes, in that it is a microtubule-stabilizing agent but it appears to remain effective in tumours that have become refractory to standard taxane therapy.

In one study of 126 such patients, response to treatment with single-agent ixabepilone, given intravenously at a dose of 40 mg/m2 as a three-hour infusion every three weeks, was encouraging. All patients were “highly resistant” to the anthracyclines, the taxanes and capecitabine, reported Dr. Eva Thomas, Assistant Professor of Medicine, Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston. Resistance in this study was defined as progression within eight weeks of receiving the last dose of an agent or the development of metastatic disease within six months of receiving the last agent. Patients were treated until disease progression or toxicity developed (median of three cycles). Of 113 evaluable patients, the objective response rate (ORR) as rated by an independent radiology facility (IRF) was 11.5% while the ORR as rated by investigators was 18.6%.

The median duration of response was 5.7 months, according to IRF assessments, and eight patients who responded had over a 50% decrease in target disease. The same number of responders were progression-free for six months. Median progression-free survival for evaluable patients was 3.1 months, while median survival in evaluable patients was 8.6 months. “Interestingly, several of the responders had received not only all three previous agents but many additional regimens as well, and some had even undergone bone marrow transplantation and still had some response to ixabepilone,” Dr. Thomas said.

Most patients tolerated the compound well, she added, the main toxicity being peripheral neuropathy, seen with all microtubule-stabilizing agents. In this study, 17 patients developed grade 3 / 4 neuropathy after a median of four cycles. However, “in virtually all patients, the neuropathy was reversible when treatment ended, so that is very important,” Dr. Thomas observed. Grade 3 and 4 neutropenia occurred in approximately half of patients but the incidence of febrile neutropenia was low, occurring in only three patients.

There was, however, one treatment-related death due to septic shock seen in association with grade 4 neutropenia and 11% of patients discontinued treatment due to treatment-related adverse events. “With disease progression, quality of life for these patients is substantially decreased, as is their lifespan,” Dr. Thomas noted, “so for patients who respond and who tolerate the drug well, a median [progression-free] survival of 3.1 months is absolutely meaningful.”

She commented, “Unlike many other cancers, we’re fortunate because in breast cancer, many of our patients have been treated with many agents and they still have an excellent performance status—they are still working, they travel and they are nowhere near ready for palliative care. So we need additional options to be able to maintain control of their disease and their quality of life for whatever time they have left. [Breast cancer] patients do respond to more agents and they are ready for continued lines of therapy.”

Another study of patients who had not received prior taxane therapy confirmed the activity of ixabepilone in metastatic breast cancer. As presented by study chair Dr. Neelima Denduluri, Fellow, National Cancer Institute, Bethesda, Maryland, 23 patients, seven of whom had received one prior metastatic course of chemotherapy, were treated with ixabepilone 6 mg/m2/day on days 1 through 5, every three weeks, until disease progressed or unacceptable toxicity developed. Twenty-three patients received a median of eight cycles. “We had a great response rate at 57%,” Dr. Denduluri noted, “and the median time to progression (TTP) was 5.5 months.”

The principal toxicity again was neuropathy, which occurred in approximately half of patients but no patient developed grade 3 to 4 sensory neuropathy and hematological toxicity was mild. Grade 3 to 4 neutropenia, for example, occurred in only five out of 23 patients across 210 cycles of chemotherapy and there were no episodes of febrile neutropenia.

Investigators also noted that acetylated a-tubulin levels increased from baseline to cycle 2 in 6 patients, “meaning that the target was reached and that ixabepilone did stabilize the microtubules which helps slow disease progression,” Dr. Denduluri observed.

She explained how she and co-investigators sought to evaluate the epothilone B analog’s effect on neuropathy. “In this schedule, where we treat patients on days 1 through 5 every three weeks, the neuropathy we observed is not as pronounced as it is with the taxanes, particularly paclitaxel. So we simply wanted to see how patients do on ixabepilone who had never received a taxane, as far as both neuropathy and bone marrow suppression were concerned.”

She further commented on the novel agent, “Right now, ixabepilone seems to be able to overcome resistance in taxane-pretreated patients who are resistant to the taxanes, so it could be used as a second- and third-line agent in patients who fail prior regimens.”

Results were presented from the Trastuzumab and Vinorelbine or Taxane (TRAVIOTA) study. HER-2-positive patients with metastatic breast cancer also demonstrated that trastuzumab, given with either vinorelbine or a weekly taxane, produced meaningful clinical responses. As reported by lead author Dr. Harold Burstein, Breast Oncology Center, Dana-Farber Cancer Institute, and Assistant Professor of Medicine, Harvard Medical School, Boston, Massachusetts, 81 patients with HER-2-positive, stage IV breast cancer were randomized to one of the two arms: trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly thereafter and weekly vinorelbine 25 mg/m2; or the same trastuzumab weekly paclitaxel 80 mg/m2 or weekly docetaxel 35 mg/m2. The primary end point was the ORR.

Response rates based on less strict criteria than those required by the Response Evaluation Criteria in Solid Tumors (RECIST) showed that 17% of patients in the trastuzumab/vinorelbine arm achieved a complete response (CR) while 49% achieved a partial response (PR). Some 20% in the trastuzumab plus weekly taxane arm similarly achieved a CR, while 50% achieved a PR. Median TTP in the trastuzumab/vinorelbine arm was 8.5 months vs. six months in the trastuzumab/taxane arm. “Vinorelbine was associated with more frequent grade 3 or 4 hematological toxicity and dose delay because of myelosuppression,” investigators indicated, “but the side-effect profile was consistent with previous experience with these regimens.”

Side effects and more specifically the effect of adding trastuzumab to a chemotherapy regimen, as well as a weekly vs. every-three-week administration of paclitaxel, was the focus of a quality-of-life study presented by lead author Dr. Michelle Naughton, Wake Forest University School of Medicine, Winston-Salem, North Carolina.

Out of 585 patients randomized to the Cancer and Leukemia Group B (CALGB) 9840 study, quality-of-life data were available for 394 participants. HER-2-normal patients were randomized to either a standard regimen of paclitaxel; weekly paclitaxel; standard paclitaxel/trastuzumab; or weekly paclitaxel/trastuzumab. Patients with HER-2-positive tumours also received trastuzumab and either standard or weekly paclitaxel. Results showed that HER-2-negative patients had better global quality-of-life scores and fewer cancer symptoms when receiving weekly paclitaxel either with or without trastuzumab than those receiving every-three- week taxane therapy.

In an unforeseen development, the use of trastuzumab in the same HER-2-negative patients led to improved role and emotional functioning and fewer arm and breast symptoms than in those who did not receive trastuzumab. In contrast, no quality-of-life differences were seen among HER-2-positive patients receiving either weekly or every three-week paclitaxel. “The higher quality-of-life scores in HER-2-negative patients receiving trastuzumab was unexpected but may be related to fewer reported breast and arm symptoms experienced by these patients,” Dr. Naughton suggested.

Quality of life was similarly compared in patients with metastatic breast cancer randomized to either gemcitabine/docetaxel or capecitabine/docetaxel in an unrelated phase III trial.

“Overall, there were no differences in quality of life and response rates or PFS between the two arms,” noted Dr. Pierre Fumoleau, Centre Georges-François-Leclerc, Dijon, France. However, patients receiving gemcitabine did report more fatigue and lack of energy by the third cycle than the capecitabine group. Capecitabine patients in turn reported more tingling in the hands and feet and burning or sore eyes than did gemcitabine patients.

“With everything else—including response rate, TTP, PFS and quality of life—all being equivalent, there were some differences in side effects with these two regimens,” Dr. Fumoleau observed, “and further analysis incorporating clinical outcomes may better explain quality-of-life outcomes.”

Cardiac Toxicity

Cardiac toxicity has been one of the most concerning side effects associated with trastuzumab use, particularly in patients pre-treated with anthracycline-based chemotherapy. Nevertheless, when it occurs, it appears to remain largely asymptomatic and when symptomatic, it appears to be relatively easily managed, according to a study presented by Dr. Valentina Guarneri, Assistant Professor of Medical Oncology, Modena University Hospital, Italy. In a review of long-term cardiac toxicity in patients with HER-2-positive metastatic breast cancer treated at the M.D. Anderson Cancer Center, she and colleagues identified 173 patients who had received trastuzumab-based therapy for at least one year.

“The median cumulative time on trastuzumab was 21.3 months,” investigators observed, “and median follow-up was 32.2 months.” Twenty-eight per cent of patients experienced a cardiac event—defined as either an asymptomatic drop in left ventricular ejection fraction (LVEF) below 50%; a drop of 20 percentage points in LVEF relative to baseline; or signs and symptoms of congestive heart failure.

Only three patients experienced an asymptomatic drop in LVEF of 20 points. Another 27 patients experienced grade 2 cardiac toxicity while 18 patients experienced grade 3 cardiac toxicity and there was one cardiac-related death.

“At one year, the cardiac event-free survival rate was 87.3%,” investigators noted, “and all but four patients had improved LVEF or symptoms of congestive heart failure after stopping trastuzumab or with appropriate therapy.” Indeed, cardiac toxicity in this group of patients proved to be manageable and largely reversible without having to discontinue trastuzumab therapy in some patients, Dr. Guarneri indicated. Once toxicity resolved, 26 patients received further treatment with trastuzumab, 16 of whom experienced no further events.

Interestingly, 85% of patients in the study had received prior anthracycline therapy, yet prior treatment with a taxane—not prior anthracycline exposure—was the only factor that was significantly associated with a cardiac event, investigators stressed.

Epiphora and Canalicular Stenosis

Exposure to the taxane docetaxel and its association with symptoms of epiphora along with its anatomical correlate, canalicular stenosis, was the object of another study presented by Dr. Bita Esmaeli, Associate Professor of Medicine and Chief, Section of Ophthalmology, University of Texas M.D. Anderson Cancer Center.

“In this prospective trial, each patient underwent an ophthalmologic examination, as well as probing and irrigation of the lacrimal drainage apparatus at baseline and at every four to six weeks after initiation of docetaxel,” investigators reported. Twenty-eight patients with metastatic breast cancer received docetaxel on a weekly schedule and another 28 patients received docetaxel given every three weeks. As Dr. Esmaeli observed, almost two-thirds of patients treated with weekly docetaxel developed symptoms of epiphora, which were graded as mild in seven patients; moderate in five others and severe in six patients.

Moderate to severe canalicular stenosis was also observed in approximately one-third of patients in the weekly group. Thirty-nine per cent of patients in the every-three-week regimen also developed epiphora and in this group, symptoms were graded as mild in nine patients, moderate in one patient and severe in another. No patient in the every-three-week group developed moderate to severe canalicular stenosis. “Both the symptom and its anatomic correlate are more severe in patients who receive weekly docetaxel,” Dr. Esmaeli observed, “and the best way to manage it would be to monitor these patients as they receive their docetaxel, ideally either at baseline or soon after they become symptomatic. Patients should also see an ophthalmologist who is familiar with this side effect every four to six weeks and undergo probing and irrigation as necessary.”

The use of topical steroids also effectively treats symptoms, she added, with most resolving in this particular cohort with either conservative or surgical management.

Economic Results from a Single Centre

As important a contribution as trastuzumab has made to the treatment of HER-2 over-expressing breast tumours, investigators are asking how long countries such as France, which offers equal universal health care, to all, can afford to provide trastuzumab to appropriately selected candidates.

In an analysis of the cost delivered by a single institute, health economist Marian Doz, Institut Curie, Paris, reviewed 137 medical reports of patients who received trastuzumab either in combination with chemotherapy or as a single agent in maintenance therapy.

Results of her analysis revealed that it cost over €43,000 on average to treat each HER-2-positive patient with metastatic breast cancer with trastuzumab for the first year. In the second and third year, it cost over €36,000 per patient to receive trastuzumab. Ms. Doz stated, “Trastuzumab is by far the largest agent cost for the institute, accounting for 78% of the hospital stay cost per patient and 4.2% of the hospital’s entire budget, so this analysis shows how exorbitantly expensive it is to treat patients with trastuzumab in France.”

Given the move towards using the agent in the adjuvant setting, “expenses can be expected to increase exponentially,” the French group added.

Diagnostic Strategies

A variety of studies presented on breast cancer here suggested that the diagnosis of metastatic breast cancer and management of associated complications may be made easier through several new strategies. As presented by Dr. Massimo Cristofanilli, Associate Professor of Medicine, Department of Breast Medical Oncology, University of Texas, M.D. Anderson Cancer Center, investigators sought to confirm the prognostic significance of circulating tumour cells in 123 patients with metastatic breast cancer.

Each patient provided a 7.5 mL sample of blood which was analyzed for circulating tumour cells with the CellSearch System. The Swenerton score was also calculated for each patient, reflecting the total burden of metastatic disease. A cancer antigen (CA) 27-29 assay was also performed and overall survival (OS) rates for those with normal CA 27-29 scores were compared to those with high scores. OS was also compared between those with hormone receptor (HR)-positive vs. HR-negative tumours. In patients who tested negative for circulating tumour cells, the median OS was 24.3 months, compared with 13.2 months for those who tested positive for circulating tumour cells. Positivity was defined as the presence of five or more circulating tumour cells.

For those with normal CA 27-29 scores, median OS was 24.2 months vs. 12.8 months for those with high scores. There was a trend towards a shorter OS in those with a high Swenerton score compared with those with lower scores, while OS was 28.3 months for those with HR-positive tumours vs. 15.2 months for those with HR-negative tumours. On multivariate analysis, however, the detection of five or more circulating tumour cells emerged as the strongest prognostic factor out of all factors examined, carrying with it a 2.7-fold greater risk of death compared with patients who tested negative for circulating tumour cells.

“The detection of circulating tumour cells before initiation of therapy in women with metastatic breast cancer is a significant predictor of survival,” investigators concluded, “and the detection and monitoring of circulating tumour cells represents an ideal surrogate marker for prospective clinical trials in this disease.”

Korean investigators in turn demonstrated the feasibility of identifying metastatic and non-metastatic tumours by microarray assay using formalin-fixed paraffin-embedded breast cancer tissue, although preliminary results require validation in a larger cohort of patients.

Reductions in urinary N-telopeptide (NTX) levels in response to zoledronic acid therapy may also be used to predict treatment response for patients with bone metastases. As noted by George Dranitsaris, PharmD, Toronto Sunnybrook Regional Cancer Centre, Toronto, patients with bone metastases are usually treated with pamidronate first but a substantial proportion of them either fail to respond to first-line bisphosphonate therapy or their response wanes with time. Zoledronic acid is a more potent bisphosphonate to which patients are more likely to respond but it is also more expensive. Consequently, being able to identify which patients will derive palliative benefit from second-line zoledronic acid is potentially very useful.

In a test involving 30 patients with either a documented skeletal-related event or bone progression while taking either clodronate or pamidronate, Toronto investigators found that any reduction in urinary NTX levels at week 1 following introduction of zoledronic acid predicted a palliative response to treatment eight weeks later, defined as a reduction of at least two units in the worst pain score, which was achieved in over 40% of patients receiving zoledronic acid. There were also statistically significant reductions in scores for worse pain, average pain and the number of pain sites.

“This is the first study to demonstrate that second-line therapy with the more potent bisphosphonate, zoledronic acid, is able to provide substantial palliative benefit and that a week 1 drop in urinary NTX may be a useful marker for identifying which patients will derive palliative benefits from second-line treatment,” investigators concluded.

Localization of topoisomerase I (topo I) may also help predict response to topo I inhibitors such as irinotecan in metastatic breast cancer as well. As presented by Dr. Stacy Moulder, University of Texas, M.D. Anderson Cancer Center, topo I poisons need enzyme interaction with DNA to control disease.

A total of 51 patients with metastatic breast cancer received treatment with gemcitabine plus irinotecan and tumour biopsies were obtained in nine patients prior to treatment in order to assess where topo I ended up—either in the cytoplasm or in the nucleus, where it should, as Dr. Moulder noted. In this limited data set, the two lowest nuclear-to-cytoplasmic ratios were associated with lack of response to irinotecan, Dr. Moulder reported. Early findings thus suggest that the new assay may predict patients who are unlikely to respond to treatment with a topo I inhibitor.

Preliminary findings presented by Dr. Steven Limentani, Associate Medical Director, Blumenthal Cancer Center, Charlotte, North Carolina, also suggest that the toxicity associated with a new recombinant HER-2 vaccine is acceptable and that the vaccine is able to elicit specific antibody responses that bind to the HER-2 receptor.

“The vaccine also induced specific T-cell immunity,” Dr. Limentani noted, “and with the addition of a T-cell response, you are potentially able to prevent disease recurrence.”

Lastly, an analysis of factors that predict outcome for metastatic breast cancer patients receiving third-line chemotherapy suggests that prior treatment response is the best predictor of how well patients will do with third-line therapy. The study involved 149 patients treated at the Royal Marsden Hospital for metastatic breast cancer.

“The chemotherapy regimens and best response to treatment for all three lines of chemotherapy were recorded,” investigators explained, “and TTP and survival after third-line chemotherapy were studied as well.”

As reported by Dr. Aleksandra Kuciejewska, Clinical Fellow, Royal Marsden Hospital, London, UK, patients who did not respond to previous treatment—defined in this study as those in whom disease stabilized or progressed in response to treatment—had a much poorer response to third-line chemotherapy than those who achieved either a CR or PR.

In this group, response rates were only 20%, TTP was three months and median OS was six months. The median time to death after patients in this group progressed was also only two months. In contrast, there was a 45% response rate, TTP was four months and median OS was 12 months among those who achieved either a CR or a PR to first- and second-line regimens. Importantly, these findings were independent of the chemotherapy regimen used either in first-, second- or third-line treatment, Dr. Kuciejewska added.

“We’re not saying you shouldn’t give third-line chemotherapy; what we are saying is that you should think twice about it in patients who did not achieve a treatment response to prior therapy. You have to ask yourself: Is it worth putting patients through the toxicities for a poor outcome? For these patients, physicians should consider best supportive care or, for the patient is fit enough, entry into a phase I trial,” Dr. Kuciejewska concluded.

Summary

Unlike many other cancers, patients with metastatic breast cancer often still have an excellent performance status and continue to respond to multiple lines of chemotherapy. Because of this, it is important to have available new treatment options such as ixabepilone that has proven to be active in taxane-refractory metastatic breast cancer, and which will allow for continued disease control for many more months to come. Neuropathy does occur but ixabepilone appears to be associated with less neuropathy than taxanes and its use is associated with a good quality of life in the majority of patients.

Other findings indicate that the use of trastuzumab, given together with either vinorelbine or a weekly taxane, is clinically active in metastatic breast cancer as well and provides meaningful clinical responses. Quality of life and acceptable toxicity levels were the focus of a number of studies this year, and for the most part, findings suggest that predictable toxicities associated with the use of a variety of chemotoxic regimens is acceptable and manageable. New diagnostic strategies and novel therapies including an anti-HER-2 vaccine promise to refine the management of metastatic breast cancer in the future and potentially improve outcomes.