Tumori, 95: 828-831, 2009
Paclitaxel-dependent prolonged and persistent complete remission four years from first recurrence of secondary breast angiosarcoma Donatella Gambini1, Roberto Visintin1, Elisa Locatelli1, Barbara Galassi1, Claudia Bareggi1, Letterio Runza2, Francesco Onida3, and Maurizio Tomirotti1 1
Medical Oncology Unit, and 2Pathology Unit, IRCCS Foundation “Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena”, Milan; 3Department of Medical Sciences, University of Milan, Milan, Italy
ABSTRACT
Among angiosarcomas, radiation-induced breast sarcomas (RIBS) represent a wellknown entity generally characterized by a poor outcome, especially in patients with advanced disease. Despite the unfavorable prognosis, some chemotherapeutic agents have been used to treat these malignancies, occasionally with success. Treatments with demonstrated activity against sarcomas include ifosfamide-based regimens and, more recently, taxane derivatives. We report a case of a patient having a secondary breast angiosarcoma recurring early after surgery, who achieved complete remission following treatment with weekly paclitaxel. After 4 years of maintenance therapy, with an interval between consecutive administrations of no longer than 3 weeks, the patient is still in complete remission. A locoregional recurrence was documented twice during this period, the first as a consequence of a brief treatment interruption and the second because of a treatment delay. Nonetheless, in both instances a new complete remission was rapidly achieved with the resumption of the same treatment, without evidence of any significant adverse effects. We discuss the highly unusual behavior of this malignancy and the possible role of the two different mechanisms of action of paclitaxel-antiangiogenic versus cytotoxic-depending on the schedule of administration, with evidence of “false” drug-resistance.
Introduction Radiation-induced breast sarcoma (RIBS) is a well-known entity, representing 2.53.3% of all sarcomas1,2. Angiosarcomas, which account for 15% of all RIBS, are generally associated with poor outcome, leading to a dismal prognosis in patients with advanced disease3. In this setting, toxicity should never overcome the potential benefits resulting from chemotherapy. In particular, in patients with locally advanced disease who are not eligible for local treatment, systemic chemotherapy offers an important chance of cure due to possible tumor shrinkage and increased likelihood of a favorable surgical outcome. In these cases, chemotherapy regimens associated with the highest response rates should always be used4. In recent years, in addition to classical ifosfamide-based regimens, new agents have been developed for the treatment of soft tissue sarcomas, including a few quite effective ones, at least in selected histological subtypes5-7. In angiosarcomas, where no standard of treatment has yet been established, taxane derivatives (paclitaxel and docetaxel), used alone or in combination with doxorubicin and/or ifosfamide and/or platinum derivatives, displayed good activity8-17. In 1997, paclitaxel was approved by the US Food and Drug Administration (FDA) for the treatment of AIDS-related Kaposi sarcoma. Due to further evidence of efficacy in subsequent studies, in June 2007 the agent was registered in Italy for the treatment of soft tissue sarcomas. Here we report the case of an elderly patient with locally advanced breast angiosar-
Key words: secondary breast angiosarcoma, paclitaxel, metronomic therapy, antiangiogenic therapy. Correspondence to: Donatella Gambini, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Unità di Oncologia Medica, Padiglione Bergamasco, Via Commenda 19, 20122 Milan, Italy. Tel +39-02-55032673; fax +39-02-55032659; e-mail
[email protected] Received October 13, 2008; accepted February 17, 2009.
PACLITAXEL-DEPENDENT ANGIOSARCOMA REMISSION
coma who developed recurrences after 2 surgical resections and was treated successfully with weekly paclitaxel, exhibiting paclitaxel dependence to maintain complete remission (CR).
Case report In 1999, a 79-year-old woman diagnosed with breast cancer (ductal invasive adenocarcinoma, T1 N0 M0 – G3) underwent a left quadrantectomy with axillary dissection, followed by radiotherapy (56 Gy) and hormone therapy (tamoxifen, 20 mg/day for 5 years). Her past medical history included lung tuberculosis with therapeutic pneumothorax; bilateral hysterosalpingooophorectomy for adenomyosis and lipoleiomyoma; and arterial hypertension treated with diuretics and a calcium channel blocker. In January 2004, a mammography revealed a 3.5-cm lesion in the left breast. Fine-needle aspiration cytology was suggestive of sarcoma and a total mastectomy was performed, leading to a definitive diagnosis of highgrade angiosarcoma, possibly radiation induced. Because of the patient’s age, no further treatments were administered and the woman was enrolled in a follow-up program. Four months later, she underwent surgical resection of a newly appeared cutaneous lesion. Histological examination documented angiosarcoma recurrence with infiltration of the pectoralis muscle. Two months later (June 2004), a new local recurrence was noted, and the patient was finally referred to our oncology unit. At that time the patient had a sole soft, 1-cm cutaneous lesion with a marked vascular component. She had no clinical or radiological evidence of any further localization of the disease and had a very good performance status (ECOG = 0). Because radiotherapy was not feasible due to previous irradiation of the same field, paclitaxel 80 mg/m2 weekly was chosen as the first-line treatment on the basis of the evidence of its efficacy in the literature and the patient’s advanced age and comorbidities, the latter advising against the use of ifosfamide and adriamycin. The treatment was started in July 2004, after the implantation of a bicameral pacemaker for the presence of a junctional rhythm, with left and right bundle branch block alternance. Complete disappearance of the neoplastic lesion was observed after 1 one month of treatment (i.e., 4 administrations), although weekly paclitaxel was continued for a further 2 months, for a total of 12 administrations. At this stage the treatment was stopped and the patient was kept under clinical observation. Two months later, a new rapidly progressing cutaneous recurrence was noted, comprising a 2.0-cm soft lesion and two 1.5-cm prominent nodules, surrounded by an ecchymotic area; one of these nodules was in the
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contralateral breast. Further radiological investigations ruled out the presence of other distant metastases. Because of the previous prompt and excellent response, in March 2005 treatment with paclitaxel was resumed, using the same dose and schedule of weekly administration. A new CR was achieved after less than 2 months of such therapy, which was continued up to the eighth administration. At that point, because it was reasonable to plan long-term maintenance treatment, we started a “tailored” schedule, planning a progressive delay between the following consecutive administrations. Paclitaxel, at the same dose (80 mg/m2), was first administered every 2 weeks ,then every 3 weeks up to December 2005, when the CR status was confirmed by a new complete staging procedure. Thereafter, also because the patient was in excellent general condition, the treatment schedule was further modified by the progressive extension of the delay between consecutive administrations, i.e., every 4 weeks until December 2006 and then every 5 to 6 weeks. In March 2007, when we were almost considering to stop the ongoing every-6-weeks treatment schedule, a new local recurrence was noted. In particular, a slightly raised cutaneous lesion in the same right breast area of a previous recurrence appeared, including a wide hemorrhagic component (Figure 1A). Nonetheless, resumption of the weekly schedule of paclitaxel administration was once more able to elicit a rapid response (Figure 1B) followed by a new CR (Figure 1C). We therefore decided to maintain the every-3-weeks administration schedule, which, on the base of our patient’s clinical course, we thought represented the best treatment strategy to prevent further recurrences. In this patient the very prolonged therapy with paclitaxel was well tolerated. She experienced only grade 1-2 fatigue, grade 1-2 neutropenia, and moderate iron deficiency anemia; significant alopecia was not observed with the every 3 to 4 weeks schedule of administration. Quality of life was also very good and the therapy did not affect the patient’s daily or social activities; in addition, we observed no morbidity due to paclitaxel administration, nor did the chemotherapy hamper the patient’s recovery from occasional chemotherapy-independent problems (in particular a traumatic fracture of the right humerus, which healed normally).
Discussion The unusually long survival after a diagnosis of advanced disease (4 years) and the subsequent long-lasting CR with the same agent make this case worth reporting. Angiosarcoma accounts for 15% of all radiation-induced breast sarcomas. The latency period was reported to be shorter in radiation-induced breast angiosarcomas than in angiosarcomas occurring in other sites3.
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D GAMBINI, R VISINTIN, E LOCATELLI ET AL
Among breast sarcomas, angiosarcomas have the worst prognosis: Zelek et al. reported 0% disease-free survival versus 49% for other types of breast sarcoma at 10 years18, and in a recently published series of breast sarcomas, angiosarcoma was the histological type with the worst outcome3. Nevertheless, in a minority of patients very good responses to chemotherapy-based treatments have been observed. Abraham et al. reported on a patient with a multifocal scalp angiosarcoma along with lymph node and brain metastases, who was treated with surgery, radiotherapy and chemotherapy [mesna, doxorubicin, ifosfamide, and dacarbazine (MAID), for 6 courses] and showed no evidence of disease 10 years after diagnosis19; Mathew et al. reported a long-lasting remission (2 years) in a patient with metastatic epithelioid angiosarcoma of a seminal vesicle treated with weekly infusion of doxorubicin, paclitaxel and cisplatin13. Recently, paclitaxel has been used for the treatment of angiosarcoma, alone or in combination with other agents, demonstrating efficacy and safety, with only 1 case of death from bleeding of skin lesions a few days after paclitaxel administration20. Paclitaxel is a microtubule-targeting agent (MTA) with antiangiogenic properties. Several studies showed that both microtubule-stabilizating agents, such as paclitaxel, and microtubule-depolymerizing agents, such as vinblastine, inhibit endothelial cell function and play a crucial role in slowing the angiogenesis-mediated progression of cancer. It is worth emphasizing that these peculiar antiangiogenic properties can be achieved more effectively, both in vitro and in vivo, by administering MTAs at low doses as so-called metronomic therapy21,22 than with standard schedules. In a review of their experience with paclitaxel in angiosarcoma, Fata et al.8 reported only 1 case of a patient with angiosarcoma of the scalp who was switched to the weekly schedule when progression occurred with the standard 3-hour infusion of paclitaxel 175 mg/m2 every 3 weeks. The patient achieved a CR with both schedules lasting 4 months and 10 months, respectively. Similar cases were reported in patients with metastatic breast
A
B
and ovarian cancer, and these results strongly suggest that switching from one schedule to another could overcome drug resistance. However, our case appears to be different. As a matter of fact, a metronomic schedule could give only a partial explanation of the tumor behavior: whereas CR was repeatedly induced by the weekly schedule, disease-free status was maintained by schedules of every 3 to 4 weeks’ administration of 80 mg/m2 of paclitaxel. Moreover, in vitro data indicate the need for a very short interval between doses: indeed, it has been shown that endothelial growth arrest lasts for only 3 days after paclitaxel withdrawal, suggesting incomplete inhibition of angiogenesis for longer intervals23. In our patient, the delay between consecutive drug administrations seems to be the only factor implicated in recurrence, without there being evidence of real drug resistance. This case raises questions as to whether different genetic metabolic patterns might explain different responses to different time schedules, and as to whether age- and/or tumor-dependent or other mechanisms (other than the antiangiogenic activity) might be involved in this setting. The case of our patient provides further evidence of the efficacy and safety of paclitaxel in angiosarcoma, especially considering the protracted therapy duration and the patient’s advanced age; in particular, while we underline the possible important role of a “tailored” administration schedule, notably when histological type, age, and comorbidity significantly narrow the therapeutic options, we also emphasize the possibility of a persistent and dramatic response to chemotherapy in advanced angiosarcoma. Furthermore, we point to the very good tolerance to paclitaxel. Our patient has always been very well, and only heart arrhythmias could have been underestimated because of previous pacemaker implantation. We obviously realize that this case represents an anecdotal experience, and that its analysis cannot be generalized. Because complementary radiotherapy has become a standard of care in the setting of breast-conserving surgical treatment, and the outcome of patients has signifi-
C
Figure 1 - A) Local recurrence of cutaneous angiosarcoma: a slightly raised cutaneous lesion is evident, including a wide hemorrhagic component. B) Partial response after 1 administration of paclitaxel (1 week). C) Complete remission.
PACLITAXEL-DEPENDENT ANGIOSARCOMA REMISSION
cantly improved over the past decade, it is possible to speculate that radio-induced breast angiosarcomas will increase in the near future, even if new radiation techniques, which allow normal tissue sparing, are promising and may limit secondary malignancies3. Therefore, new contributions to the knowledge of rare malignancies like breast angiosarcomas appear to be clinically urgent.
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