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First let me express my admiration for the amazing work you are offering to the members/visitors of this site. You have brought so much benefit to so many. A Big Bravo!!!!! Please allow me to introduce myself.....I'm jwl, husband of Astrid, who was diagnosed with BC bone mets in the Spring of 2009. Rads helped a bit. Faslodex failed and so did 9 months of Xeloda to stop the cancer from spreading. Astrid took Zometa for 11 months. Until a month ago, the mets spread only in her bones but now she has skin nodules on her scalp. Astrid has suffered through chemo 3 times in 12 years and says that it's the last time: "No more chemo." She has refused to follow her oncologist's advice to take either Gemcitabine or Navelbine. He told her there was only a 25% chance that it would work....not very encouraging. Two and a half weeks ago she took a Quadramet injection to ease the bone pain but so far that has not kicked in....so she's still on very heavy pain killers. She is terribly weak and dizzy from cancer induced anemia. That is the main reason I am writing you to find out what treatments or CAM regime might help to re-energize her. Her oncologist says EPO is too dangerous to give her. But he offers no alternatives. At the moment RBC's are 2740000/mm3 and her Hemoglobine is 8.5 g/100ml. Plaquettes: 89,000/mm3. Any advice/info would be most appreciated. All the best, jwl First diagnosed in August 1998 (IDC, Stage IIB, N1, ER+PR+); treatment: 6 cycles of Taxol & Epirubicine, radiotherapy and tamoxifen for 5 years. Oophorectomy in 2002. In 2006, regional recurrence in armpit lymph nodes, excised; treatment: radiotherapy, 3 cycles of FEC 100 & 9 weekly cycles of Paclitaxel, then Femara. May 2009 diagnosed with advanced breast cancer with metastasis to bones; treatment: radio-therapy, followed by Faslodex without success and then Xeloda for 9 months which failed as well. Zometa for 11 cycles. Tested positive twice as carrier of BRCA-2 mutation. Recently the cancer has metastasized to her scalp. Only treatment at present: a Quadramet injection for severe bone pain on September 16. Astrid is being treated at the Centre Antoine Lacassagne in Nice, France.
Chief of Research
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Jwl and Astrid:
Thanks for the kind words of appreciation. Apologies for not having seen your postings before now, and given some few professional obligations I am just completing, I can say fairly confidently that I will have feedback for you within 24 hours, hopefully by tomorrow's eve - and although there are some complex issues to negotiate here, I think I perceive some light.
Thanks for your patience.
Breast Cancer Watch
Chief of Research
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Current Clinical Status
Asrid has been exposed to anthracycline and taxanes regimens, standard radiotherapy (RT), and tamoxifen, all in the pre-advanced disease setting. She then received FEC-100/T and then endocrine therapy with letrozole (Femara) after locoregional recurrence. Upon presentation with bone metastasis, she received sequentially RT, fulvestrant (Faslodex), capecitabine (Xeloda) and zoledronic acid (Zometa), with progression and new development of scalp cutaneous metastases, and has recently been treated with Quadramet radiopharmaceutical therapy for bone met-related pain.
General Treatment Issues
A couple of points and clarifications.
First, you have indicated that fulvestrant (Faslodex) failed, and I will assume that was on the traditional 250 mg monthly dose (after possibly a single 500 mg loading dose); at least here in the US the FDA has recently approved a double-strength schedule of 500 mg monthly, known to be more effective (and I and others are pressing for approval of a 750 mg dosing, which would allow fulvestrant (Faslodex) to be used effectively even in premenopausal women (without the need of surgical (oophorectomy) or medical ovarian suppression (via LHRH/GnRH analogs like goserelin (Zoladex) or leuprolide (Lupron)), so fulvestrant (Faslodex) therapy may have been suboptimal.
Second, I am unclear what therapy, endocrine and/or chemotherapy she remains on now; again I will assume no chemotherapy as you indicate she has rejected its deployment, but is she still on any
endocrine therapy (like letrozole (Femara, or any other endocrine agent)? And in any event, one option is a switching strategy: she has been exposed to a non-steroidal AI, namely letrozole (Femara), so one option is to try the only steroidal AI available, namely exemestane (Aromasin). Beyond this, there are two other endocrine options: (1) enable dual endocrine therapy, namely an AI plus another endocrine agent, and toremifene (Fareston), a tamoxifen-like relative, would be an option; (2) estrogen therapy, in the form of either megesterol (Megace) or estradiol (a rescue regimen, akin to fighting fire with fire).
This leads first to the issue of endocrine therapy or chemotherapy, or chemoendocrine therapy together, and I appreciate that Astrid is electing no
further traditional chemotherapy, her call doubtless. One alternative I will raise here is metronomic chemotherapy, which is mild and highly tolerable, and deploys continuous or near-continuous low-dose chemotherapy, which has been shown to have clinical efficacy along with powerful antiangiogenic activity. Something like Metronomic-C or metronomic-CM, where the "C" and the "M" are the same two components of the well-known and established CMF regimen (cyclophosphamide and methotrexate, respectively) is an option to take two examples, and reflects a compromise between tradition CT (chemotherapy) and its associated toxicity and no CT, retaining in the middle space some appreciable efficacy but largely avoiding major toxicity.
this in turns leads to the issue of biological therapy, which she apparently has not received to date, such as bevacizumab (Avastin), both for its ability to synergize co-administered oncotherapy, as well as for its antiangiogenic benefit, all with minimal toxicity, something that - barring insurance rejection of coverage, or lack of approved use - you may want to explore with her oncologist.
Cutaneous Scalp Metastasis
The field is somewhat split on treatment of
cutaneous (skin) metastases to the scalp from breast cancer, some favoring direct cutaneous mets treatment concurrent with other systemic therapy, others favoring a passive approach based on the rationale that standard systemic therapy itself should work on the cutaneous mets along with other involvement, and there hasn't to date emerged a clear consensus on this issue (I stand modestly in favor of direct treatment). But as I noted elsewhere in these forums in addressing skin metastasis from breast cancer, as to direct therapy, there are four progressive options: (1) local therapy with a 6% solution of miltefosine (Miltex, Impavido), (2) photodynamic therapy (PDT), (3) pulsed irradiation / brachytherapy, and (4) electrochemotherapy (ECT) with cisplatin typically used in skin mets from breast cancer, but the common starting point is topical Miltex therapy (not available in the US but should be accessible in Europe). The indirect approach, on the other hand, is via systemic therapy in general (endocrine and/or chemotherapy), and some case studies have shown that both tamoxifen (and by extrapolation, toremifene (Fareston) also) and AIs have been used successfully for scalp metastases (Madhup and collegaues, Breast 2006). If however the mets are a special form called carcinoma erysipeloides on the other hand, a cisplatin + 5-FU (called CDDP-F) regimen is used based on some early successes [Hinrichs and colleagues, Br J Dermatol 1999]. Acknowledging as I do the integrity of Astrid ultimately making her own choice as to further chemotherapy, in that connection it need be noted that, given the adverse prognosis and aggressive course of untreated cutaneous scalp mets, lack of therapy can rapidly compromise QoL and survival, an issue to weigh in any calculus of decision.
The Thorny ESA Issue in Chemotherapy-Induced Anemia (CIA) Therapy
am concerned over your oncologist absolute refusal to entertain ESA (erythropoiesis-stimulating agents) therapy for the treatment of CIA (chemotherapy-induced anemia) regardless of weighing harm:benefit ratio, and of failing to suggest alternatives: there are transfusions, and in addition, a report from the Society for the Advancement of Blood Management (SABM) 2008 Annual Meeting examined the issue of whether intravenous iron therapy can meet the unmet needs created by the new restrictions on ESAs, finding potential positive value, and possible therefore worth exploring.
Now as to the central question, a devil's dilemma it would appear, of the risk: benefit ratio for ESA therapy, it is important to recognize that none of the 8 trials considered by the March 2008 FDA ODAC entity who evaluated ESAs were within their licensed indications; specifically, excessively high Hb concentrations were targeted and/or ESAs were used in patients not receiving chemotherapy, hence not speaking to the most
critical issue, namely ESA therapy when used within currently approved indications. The recent safety data that reported a negative effect on survival, was when ESAs were used to treat anaemia that was either not chemotherapy related, or when used to maintain high levels of haemoglobin and prevent anaemia. All of these studies were not in accordance with existing guidelines, while safety data from clinical trials using ESAs according to the guidelines remain reassuring. [review of Isabelle Wauters and Johan Vansteenkiste in Belgium, Expert Opin Biol Ther 2009]. Then based on this questionable evidence base, the current guidelines (ASCO/ASH, ESMO, EORTC, and NCCN) therefore have suggested transfusion as the first-line treatment for CIA (chemotherapy-induced anemia). But note that red blood cell (RBC) transfusions are usually given when Hb levels decrease to near 8 g/dl and thus mainly to highly symptomatic patients, and transfusions result in immediate but often only transient relief of anemia-associated symptoms and they also carry risks such as hemolysis, immune suppression, iron overload, transmission of infectious agents and transfusion errors.
So where the guidelines have left us is that, as per ASCO/ASH, ESAs are indicated for the treatment of chemotherapy-induced anemia when the Hb levels approaches or falls below 10 g/dl with the aim to increase Hb levels and to avoid transfusions, while the updated EORTC guidelines recommend the initiation of ESA treatment at Hb levels of 9 – 11 g/dl based on anemia-related symptoms, and according to the European Medicines Agency (EMEA) guidelines, the target Hb level should be 10 – 12 g/dl and should not exceed 12 g/dl. And it note be noted ESAs are not indicated for the treatment of anemia in patients not receiving chemotherapy or the prevention of anemia in non-anemic patients undergoing chemotherapy. But it must be asked what convincing clinical judgment can follow from a meta-analysis, as we noted above, was of studies assessed that in fact did not proceed along the recommended guidelines? Neither the 2002 version nor the 2007 update of the guidelines produced by the American Society of Clinical Oncology and the American Society of Hematology had been followed. Similarly, in none of the trials were ESA agents given for the exact indications recommended by the US FDA.
And we have robust data to the contrary. The meta-analysis conducted by Maati Aapro and colleagues in Belgium of all 12 randomized, controlled studies of epoetin- b evaluated the impact of therapy at different Hb-initiation levels and to different target Hb levels on overall survival, tumour progression and thromboembolic events (TEE) found that epoetin- b and epoetin alfa therapy has no detrimental impact on survival or tumour progression when initiated at Hb levels up to 11 g dl-1, and that ther fore there was no evidence to suggest that high Hb values achieved during epoetin- b therapy are associated with an increased mortality, disease progression or TEE rate[Br J Cancer 2009], and the same investigators evaluated the balance between studies that show higher ESA-associated mortality and those that don't show ESA-associated mortality is examined in this review, finding that there are no convincing data to support ESA-induced tumor stimulation in patients. Thus this and other evidence we review briefly below suggest in the aggregate that ESAs decrease RBC transfusion needs and sustain targeted hemoglobin levels, and this ESA response does not significantly impact overall survival or mortality when ESAs are used within guidelines and labeling, and an overview of the ESA meta-analyses and their effects on survival showed the hazard ratio (HR) found that the HR decreased to 1.04 and 0.97, respectively, in analyses with long-term follow-up [Pere Gascón at the University of Barcelona, Oncologist 2008] (an HR of 1.00 shows no negative impact of the ESA on survival and an HR < 1.00 favors the ESA) [Oncologist 2009]. Note also that to date, all Cochrane meta-analyses that raised safety issues included studies none of which used ESAs according to current label guidance (i.e., using the lowest ESA dose needed to avoid RBC transfusion, and using ESAs only for treatment of anemia resulting from concomitant myelosuppressive chemotherapy, etc.).
So we can conclude that ESAs have a favorable risk–benefit ratio when used for labeled indications and this is further powerfully supported by the meta-analysis from Luciano Paladini and colleagues in Brazil (17 studies, n = 3,788 patients [Blood 2008]) which assessed the safety of ESAs when used according to label indications, in patients with CIA (instead of cancer-induced anemia) with an Hb level <11g/dl; this meta-analysis finding no difference in the mortality rate associated with the use of ESAs (relative risk, 0.95; 95% CI, 0.88–1.03; p = .22), and the authors concluded that, when ESAs are used as indicated on the label, they are not associated with a higher mortality risk, and the authors concluded that "When used as indicated on label, that is, for patients with chemotherapy induced anemia with Hb<11g/dl ESAs are
NOT associated with higher mortality rates and remain a safe option for these patient".
In addition, Heinz Ludwig in Austria and colleagues [J Clin Oncol 2009] conducted a sophisticated pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials of darbepoetin alfa (DA) in the treatment of patients with chemotherapy-induced anemia (CIA), and it as concluded that there seemed to be no association between DA and risk of death or disease progression in this meta-analysis of individual patient data from DA studies conducted in CIA, the approved indication for ESAs in oncology, and in addition in their analysis, DA increased the absolute risk for thromboembolic events modestly from 5% to 8% [J Clin Oncol 2009].
However, to reduce the risk for thromboembolic events, health care providers should use the lowest dose of ESAs that will gradually increase hemoglobin to a level that will avoid the need for transfusions, as stated in the prescribing information.
Finally, and more recently, John Glaspy at UCLA and colleagues conducted a recent meta-analysis of 60 studies (n = 15323 patients) which found that although there was a modest increase in risk for VTE (odds ratio (OR) = 1.48), there was no significant effect of ESAs on mortality / survival or disease progression [Br J Cancer 2010], and this was in agreement with the EPO-INT-47 Study Group
European multicenter RCT conducted by Paolo Pranzato in Italy and colleagues [Oncologist 2010]
Venous Thromboembolism (VTE) and Thromboembolic Events (TEE) Risk
On a different front, independent of survival and tumor promotion concerns that we reviewed above, there is a possibility of a higher incidence of
thromboembolic events / TEE (which includes transient ischemic attacks, stroke, myocardial infarction, pulmonary emboli, deep vein thrombosis) with ESAs, and the overall benefit–risk ratio must be considered on an individual patient basis, while also weighing the impact on the patient's QoL. As a caution, given that recombinant EPO can induce inflammatory cytokine production and can contract the plasma volume, with high doses of recombinant EPO being more likely to produce these effects, this suggests that three times weekly injections may be more physiologic than a single large weekly injection.
As to VTEs, the review of Joachim Fandreya and Mario Dicatoin in Germany and Luxembourg found
that in the ESA treatment–related trials, the HR is around 1.09; however, this includes off-label use, which can result in a higher incidence of VTEs, particularly in trials that target Hb levels higher than those recommended by current ESA labeling and trials that enroll patients who are non-anemic at baseline. And VTEs are independently common in cancer patients, with the relative risk for VTEs being in the range of 1.02–4.34 in cancer patients, depending on the type of cancer. So in studies with a higher risk for VTEs in comparison with the control group, the cancer-inherent VTE risk is the same in both groups, and from meta-analyses of ESA studies, the relative risk for a VTE falls within the ranges normally observed in the cancer patient population (and the incidence of VTEs appears not to be influenced by the ESA dose). It appears that the elevated risk for a VTE associated with ESAs is a class effect because TEEs were seen in studies done with the three types of ESAs (epoetin alfa, epoetin beta, and darbepoetin) but no head-on comparisons among the three ESAs have been conducted to address the issue of VTEs, and this and other reviews suggest that a higher incidence of VTEs should rarely be a problem if ESAs are used within labeling indications and where necessary with the use of anticoagulants.
However, caution does need to be exercised with the use of ESAs, taking into account the patient's comorbidities and carefully balancing the benefits against any possible risk for higher mortality, and proactive surveillance must be exercised - and based on the data, I believe along with other researchers that thrombocytosis should be considered as a marker of an inflammatory state and a predisposition to thrombosis when an ESA is being given - and clinicians should consider the potential benefit of combining the use of ESA with prophylactic anticoagulation.
Where We Stand
Therefore, there are a number of potentially promising options to explore:
(switching endocrine therapy to a steroidal AI, or to a tamoxifen-like analog like toremifene (Fareston); metronomic therapy; biological therapy in the form of bevacizumab (Avastin) to exploit synergy and antiangiogenic activity; systemic and/or direct interventions for cutaneous scalp mets, the potential of intravenous iron therapy for some remediation of chemotherapy-induced anemia; weighing the harm:benefit ratio of deploying ESAs for remediation of chemotherapy-induced anemia, where new evidence conspires to suggest that survival / outcome compromise is neither sufficiently established by any methodologically compelling data, nor likely given more robust evidence to the contrary when the evidence-based guidance strictures are observed for indication, and Hb range; weighing the harm:benefit ratio of ESA re VTE/TEE risk in the light of contrary evidence to suggest that risk is not appreciably in excess, or minimal, in patients without contra-indicative factors and morbidities; in the event of deploying ESA should this be elected, the precautions of strict surveillance along with adding concurrent anticoagulant therapy as prophylaxis to further mute any harms and risks of ESA deployment. Given the significant adverse impact of chemotherapy-induced anemia on QoL, it can as we demonstrated above, no longer be maintained that ESA therapy is contraindicated in select populations when observing the regulatory strictures and the precautions we have suggested, neither due to survival / outcome compromise, nor to risk of VTE / TEE, and in consultation with the patient, the latter must ultimately weigh benefit versus harm to decide, or not, to elect remediation via ESA therapy for the shortest duration and most constrained deployment consistent with regulatory guidance to achieve a sufficient benefit. any relevant clinical trials, especially for bone metastasis and/or for BRCA-mutated tumors; and finally CAM intervention: here as I have noted elsewhere to other users in these forums, I have developed something of a radical transformation of the original Edge-CAM regimen, namely Edge-CAM+, which of its 12 components, four are completely new, and the curcuminoid intervention has been radically revised and introduces a dual approach with a new ultra-high-availability formulation in addition to the piperine-based component, but for complex reasons this regimen at this time will remain unpublished, and so if interested, you'll have to send me a request by email, and given the complex and sensitive pharmacokinetics of the Edge-CAM+ regimen, it must be agreed in our communication exchange that the Edge-CAM+ regimen will be used as is, in toto, and not be supplemented or combined with any other natural agents.
What distance, and which direction, of all of these you and Astrid are willing to traverse is of course your determination alone, but these may serve as a framework of potential options to consider and explore, along with input from other oncologists as second or even third opinions should this not have been done as yet.
Breast Cancer Watch
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I am blown away by the effort you have put into analyzing the possible therapy choices for Astrid. This is a lot of information to digest right now. But I will bring up all the points you have raised with her oncologist and see where we might go from here. If he remains negative, I guess we will have to seek the advice of other oncologists. I am sorry that I did not make it clear that apart from the Quadramet injection Astrid is presently under no other treatment. Pain has been our major pre-occupation for the past 3 months. And the scare of the scalp mets. I have had the help of a pain specialist at the Centre Lacassagne in Nice and have been trying to find the right mix of pain killers to deal with her bone pain. Astrid has been in such pain that her Durogesic 75 patch (plus morphine for breakthrough pain) was increased to 100 just 6 days ago. But last night Astrid reacted so badly to the increase of Durogesic that I ripped off the extra 25 patch to bring the dose back to 75. She felt a bit better today, although had to suffer some withdrawal which I tried to treat with morphine. The pain is a real morale killer. We have to get that under control before she can move forward. As for the clinical trials, I am in contact with Astra-Zeneca and their Olaparib medical director and there is a possibility that Astrid might meet the criteria for a trial in Barcelona at the end of the year. I know it's a long shot but I feel (unlike our oncologist) that Olaparib could be a very positive (non-chemo) treatment for Astrid given her BRCA2 mutation status. So, you have given me lots of ideas to digest. And in so doing opened up the horizon a bit. For that I am very grateful. I will keep you as best informed as I can about the response to all your suggestions. Many, many thanks for all the time you have devoted to helping me help Astrid. Best regards, jwl
Registered: 1285793208 Posts: 9
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I am still trying to digest all the info/advice you sent me. One clarification: I hope I did not mislead you concerning Astrid's anemia. As far as I know it started because of the 9 months of Xeloda but is now exacerbated by the continuing spread of her bone mets. Don't know if that's a big deal regarding the case you've made for her oncologist to prescribed ESA treatment under very tight controls. A few points regarding Astrid's scalp mets: my reading indicates that Miltex is a bit rough with quite a bit of pain & potential scaring. Do you have other info that contradicts that? Also our oncologist claims that PDT is not used for scalp mets treatment. Do you have some info I can show him to prove he is wrong? I have been reading a lot about metronomic chemotherapy because of the low toxicity you mentioned and the oral route. These are essential for Astrid to even consider another chemo treatment. I would like to give her a really good article but so far cannot find one that directly relates to the treatment of her bone mets. Is Metronomic Chemo suitable for wide spread bone mets? Re the increase dosing for Faslodex. Is there any clinical evidence that shows that disease progression after 3 months on Faslodex 250 is reversed by taking Faslodex 500? RE AVASTIN. I thought it was designed to treat triple neg BC. Assuming the French still approve Avastin (after the FDA's recent decision) is this a treatment for Astrid's ER+/ PR+ cancer? Finally, I would appreciate a clarification about the following sentence: " (1) enable dual endocrine therapy, namely an AI plus another endocrine agent, and toremifene (Fareston), a tamoxifen-like relative, would be an option;" Does this mean taking 3 endocrine therapies at one time? I know you are one busy man answering so many questions, so hope you have a bit of time to respond to the above. And have some time to enjoy the upcoming weekend. All the best, jwl
Chief of Research
Registered: 1193612140 Posts: 1,129
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As I have already offered to you in private communication, apologies for the protracted delay. Here is my feedback, which for convenience I fold inline (in red) with your original posting (in which I have highlighted and numbered specific queries):
I am still trying to digest all the info/advice you sent me. One clarification: I hope I did not mislead you concerning Astrid's anemia. As far as I know it started because of the 9 months of Xeloda but is now exacerbated by the continuing spread of her bone mets. Don't know if that's a big deal regarding the case you've made for her oncologist to prescribed ESA treatment under very tight controls.
A few points regarding Astrid's scalp mets: my reading indicates that
 Miltex is a bit rough with quite a bit of pain & potential scaring. Do you have other info that contradicts that? Also our  oncologist claims that PDT is not used for scalp mets treatment. Do you have some info I can show him to prove he is wrong? Miltefosine Tolerability and Efficacy in Breast Cancer Cutaneous (Skin) Metastases Carolien Smorenburg and colleagues [Smorenburg CH, Seynaeve C, Bontenbal M, et al. Phase II study of miltefosine 6% solution as topical treatment of skin metastases in breast cancer patients . Anticancer Drugs 2000 Nov; 11(10):825-8] at the Rotterdam Cancer Institute used a 6% solution of miltefosine (MLT, Miltex) (topically once daily during first week, twice daily thereafter) in 20 breast cancer patients with progression of skin metastases (16 with additional non-skin metastasis). Activity was modest and without serious systemic toxicity even this was a relatively heavily pretreated patient population: in 18 evaluable patients there were four PR for a response rate of 22%, with seven patients showing stable disease, and three partial responses in patients with < 1.5 cm2 skin lesions. As to outcomes, median response duration was 2.5 months and median time to progression 1.9 months. The regimen was well tolerated, with no grade 3 and 4 toxicity, while 11 patients experienced only grade 1/2 adverse skin reactions and 2 experienced nausea and vomiting, and therapy discontinuation occurred in two patients due to nausea and in one patient due to skin toxicity. In this small study, there were no reports of pain nor scaring. In addition, JM Meerum Terwogt and colleagues [Terwogt JM, Mandjes IA, Sindermann H, et al. Phase II trial of topically applied miltefosine solution in patients with skin-metastasized breast cancer . Br J Cancer 1999 Mar; 79(7-8):1158-61 (PDF)] at the Netherlands Cancer Institute conducted a phase II study of MLT (once daily in the first week and twice daily thereafter, with a planned minimum treatment duration was 8 weeks) in 33 patients with cutaneous metastases from breast cancer in the following weeks, finding an overall response rate of 43% for the 30 evaluable patients, impressively with 23% complete response and 20% partial response, and a median response duration was 18 weeks, although I must point that the upper outlier reflecting prolonged response was 68 weeks; toxicity was primarily localized skin reactions controllable by a paraffin-based skin cream and, if required, by dose modification, with no systemic toxicities observed. These results are comparable to those obtained by the other investigators reviewed here and by Clive and Leonard [Clive S, Leonard RCF. Miltefosine in recurrent cutaneous breast cancer . Lancet 1999; 349:621-622] among numerous other cross-confirmative studies.
We also have strong RCT supporting data from the randomized double-blind, placebo-controlled, multicenter phase III study conducted by Robbert Leonard at the Wales Cancer Institute and colleagues [Leonard R, Hardy J, van Tienhoven G, et al. Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer . J Clin Oncol 2001 Nov 1; 19(21):4150-9] using MLT (2 drops/10 cm2, once daily during the first week and twice daily thereafter until treatment failure) in a very challenging cohort of 52 patients with inoperable progressive breast cancer skin lesions (superficial or flat skin lesions, depth of invasion ≤ 1 cm)) that were not otherwise manageable by either radiotherapy or by systemic (endocrine or chemotherapy) treatment, or both, finding a rate of response based on intention to treat patients of 33.3% for miltefosine solution (compared with 3.7% for placebo), and 29% of patients in the MLT group attaining stabilization at least for a limited period (compared to only 11% in the placebo group), and with cutaneous reactions well tolerated and only occasionally requiring cessation of treatment, demonstrating again that although MLT causes local toxicity, it is nonetheless well tolerated, and with zero systemic side effects.
Finally, Herbert Sindermann and colleagues [Sindermann H, Junge K, Burk K. Miltefosine Solution: Prognostic Factors for the Outcome of Topical Treatment of Skin Meta-static Breast Cancer . Onkologie 1994;17:21-26] conducted an overview analysis of data from multiple clinical phase II trials (n = 287) of miltefosine for skin metastases from breast cancer to identify prognostic factors for efficacy and tolerability, finding that infiltration depth was the most relevant prognostic factor for response of skin lesions (regardless of location), with a 39% response rate (complete, partial and minor responses) in patients having small nodular lesions (<= 1 cm) and/or lymphangitic infiltration without deep subcutaneous tumor mass., and a rate of objective regressions of 13% in patients with lesions outside these limits. However I should note that in cases MLT + ET (miltefosine + endocrine therapy concurrently) when MLT was in fact added in cases in which systemic endocrine therapy had failed to control the skin lesions, the response rate was an impressive 38% on the MLT + ET combination was observed (median TTP for skin lesions = 27 weeks). Here in this large overview analysis, pruritus was the most frequently reported local skin reaction (31%), followed by erythema (18%), but pain and burning were low at 10% each, and there was a virtual absence of systemic side effects; in addition, local reactions were found to be generally tolerable, and there was an observable decrease in the hazard rate for local reactions as the duration of treatment increased, implying that there was no significant risk for a sensitization. The authors concluded that the evidence supported the efficacy and tolerability of MLT in breast cancer cutaneous metastases, especially in patients with cutaneous lesions with limited depth of infiltration. So although there was some incidence of MLT associated pain, it was small (10%) and transient, and in none of the reviewed studies nor in the Smorenburg study was there any scaring observed.
Therefore as demonstrated above, from a review of the available literature, we can conclude both the efficacy, safety and tolerability of miltefosine for the treatment of cutaneous metastases from breast cancer.
I have been reading a lot about
metronomic chemotherapy because of the low toxicity you mentioned and the oral route. These are essential for Astrid to even consider another chemo treatment. I would like to give her a really  good article but so far cannot find one that directly relates to the treatment of her bone mets. Is Metronomic Chemo suitable for wide spread bone mets? Metronomic Therapy
Metronomic chemotherapy (MCT) is non-specific in benefit and efficacy as to site of metastasis, as is true also for all oncotherapy whether endocrine, chemotherapy or biological therapy, so bone metastasis is simply another context of application and no specific trials dis, or would, test specifically for single-site efficacy. To date, dozens of studies have demonstrated the clinical benefit of metronomic chemotherapy (MCT) across numerous malignancies including breast cancer, and across, more particularly, all types of breast cancer tumors, for both non-metastatic and especially metastatic disease, whether endocrine or non-endocrine, but the largest clinical trials investigating the efficacy and tolerability of metronomic chemotherapy have been conducted in patients with advanced breast cancer. In eight of these metronomic chemotherapy clinical trials, comprising almost 500 patients in total, metronomic chemotherapy alone (Sarmiento et al., Colleoni et al. (2002) and (2006), Wong et al., and Gonzalez-Billalabeitia) or in combination with endocrine therapy (Bottini et al.),
trastuzumab (Orlando et al.), or bevacizumab (Dellapasqua et al., Garcia-Saenz et al.) was shown to be breast cancer therapy, associated with minimal toxic effects for either primary systemic or palliative treatment of advanced, metastatic and/or resistant breast cancer patients, and with the average overall response rates (complete response (CR) plus partial response (PR)) of 39% (range = 12–88%) and overall clinical benefit rate / CBR (CR + PR + stable disease [SD] >6 months) of 57% (range 24–93%), comparing favorably to other standard modalities of treatment for breast cancer. [References: Sarmiento, R. & Gasparini, G. Antiangiogenic metronomic chemotherapy . Onkologie 31, 161–162 (2008); Colleoni, M. et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels . Ann. Oncol 13, 73–80 (2002); Colleoni, M. et al. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects . Ann. Oncol 17, 232–238 (2006); Wong, N. S. et al. Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of response . J Clin Oncol 28, 723–730 (2010); Gonzalez-Billalabeitia, E. et al. Long-term follow-up of an anthracycline-containing metronomic chemotherapy schedule in advanced breast cancer . Breast J 15, 551–553 (2009) [no abstract]; Bottini, A. et al. Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients. J Clin Oncol 24, 3623–3628 (2006); Orlando, L. et al. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer . BMC Cancer 6, 225 (2006); Dellapasqua, S. et al. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol 26, 4899–4905 (2008); Garcia-Saenz, J. A. et al. Bevacizumab in combination with metronomic chemotherapy in patients with anthracycline- and taxane-refractory breast cancer . J Chemother 20, 632–639 (2008).
Note also that metronomic chemotherapy is something of a misnomer, as it is not in fact restricted to chemotherapy, but as shown above includes endocrine therapy (e.g., letrozole (Femara), and biological therapy (bevacizumab (Avastin)), and even includes adjunct agents such as zoledronic acid (Zometa): so Xi-Chun's team [Xi-Chun H, Zhao X, Xu X, et al. Effect of metronomic use of zoledronic acid (ZOL) on antitumor and antiosteoclastic effects in breast cancer patients with bone metastasis . ASCO 2009 Annual Meeting. J Clin Oncol 27, 2009 (suppl; abstr e14603)] in China found that compared to the standard of a single-dose administration of zoledronic acid (Zometa), aka ZOL, an alternative ZOL regimen of weekly low (1 mg) single-dose administration resulted in a greater reduction in serum VEGF and NTx levels, with a significant trend over time during one month observation and with statistically equivalent levels of circulating CEA and CA15–3 levels, yet outcome-wise, patients who received metronomic-ZOL had a longer median time to disease progression (TTP) than those who had a single dose ZOL, suggesting that the metronomic use of low-dose ZOL appears to be more effective in terms of antitumor activity than the conventional regimen, providing long-lasting reduction of VEGF and NTx, and in prolonging TTP and stabilizing CA 15-3, confirmed more recently bt Zhao and colleagues [Zhao X, Xu X, Guo L, et al. Biomarker alterations with metronomic use of low-dose zoledronic acid for breast cancer patients with bone metastases and potential clinical significance . Breast Cancer Res Treat 2010 Sep 30].
Now, let me clarify my rationale for suggesting metronomic therapy is four-fold: (1) as clearly established in the metronomic therapy evidence base, it provides strong anti-angiogenic activity, relevant for both the fact
the bone metastases appear to be significantly angiogenic, and for the fact that anti-angiogenic therapy appears of benefit in a broad spectrum of breast cancer contexts and when given concurrent with other oncotherapies, appears to synergize them; (2) as such it can as I often say, stand as a poor-(wo)man's bevacizumab (Avastin) when the latter proves infeasible for whatever reason (insurance coverage, cost or potential regulatory restriction; (3) I offer it as a compromise option in Astrid's specific case, between standard chemotherapy and its discontinuation, respecting the integrity of any individual's decision in this complex arena; I am starting from the jumping point of a strong desire to avoid the toxicities associated with chemotherapy, and based on that assumption, both endocrine therapy as I suggested and metronomic therapy serve that purpose; and (4) I would be professionally remiss to not point out that some components and contributive factors to persistent and increasing bone pain in the bone-metastatic setting is the pathogenic and degenerative changes consequent to continued tumor growth, so both suggestions - endocrine therapy and metronomic therapy - are put forth as potential modalities to address further degeneration with its pathogenic promotion of further bone pain, but with a recognition of and attempt to honor Astrid's own perspective.
As to reading on this subject, although bone-met-specific coverage is not available, I would suggest a compelling case is made for metronomic therapy in the recent and elegant review by Graciela Scharovsky and colleagues [Scharovsky, OG, Mainetti, LE, Rozados, VR. Metronomic chemotherapy: Changing the paradigm that more is better . Curr Oncol 2009. 16:7-15 [PDF]], and the piece is reasonably accessible to informed non-professionals (naturally, this article can't possibly provide my inimitable je ne sais quoi , but might still prove a suitable resource).
increase dosing for Faslodex.  Is there any clinical evidence that shows that disease progression after 3 months on Faslodex 250 is reversed by taking Faslodex 500? Fulvestrant (Faslodex)
I was not making that argument, but rather suggesting that (1) fulvestrant-500 is clinical superior in outcome to standard fulvestrant-250 (precisely why the FDA has just approved the former); (2) that a 3 month trial of fulvestrant (at whatever dose) may be insufficient to declare benefit and efficacy, something I demonstrated in my
own review of this issue [Kaniklidis C. Fulvestrant loading, tumor markers, and ongoing trials. Commun Oncol 2007; 4:649-650 [PDF]] where I found that the median TTR (time-to-response) for fulvestrant can be around 3.1 months, so that we are right at the borderline, and it may be prudent if disease is not excessively rapidly progressing, to allow, given some small additional reasonable cushion or margin, perhaps a 14 week point before making judgment, as late responses are not uncommon; (3) and that fulvestrant resistance can not infrequently be overcome by the addition of another endocrine agent (aka, dual endocrine therapy), and in fact, vice versa.
AVASTIN. I thought it was designed to treat triple neg BC. Assuming the French still approve Avastin (after the FDA's recent decision) [ 5] is this a treatment for Astrid's ER+/ PR+ cancer?
Like metronomic therapy, the anti-angiogenic, anti-VEGF, and synergizing effects of bevacizumab (Avastin) are across the breast cancer spectrum, and it is not TNBC (or MBC, IBC, EBC) specific nor specific to any breast cancer subtype (luminal A, B, basal, etc.).
Finally, I would appreciate a clarification about the following sentence: " (1) enable
dual endocrine therapy, namely an AI plus another endocrine agent, and toremifene (Fareston), a tamoxifen-like relative, would be an option;"  Does this mean taking 3 endocrine therapies at one time?
Dual endocrine is a minimal requirement condition, that at least one endocrine agent is added to another: fulvestrant + AI, or either of these or tamoxifen plus ovarian suppression (whether
surgical (oophorectomy) or medical (as for instance, via goserelin (Zoladex) or leuprolide (Lupron). Not only may there be added benefit, but there may also be the potential to overcome any acquired endocrine resistance.
I know you are one busy man answering so many questions, so hope you have a bit of time to respond to the above.
I am always
glad to help, and please note that there are many other modalities not discussed, and I have restricted my discussion primarily to the issue of active oncotherapy, but of course there are other adjuvant interventions, especially for bone pain (among them the intranasal calcitonin which not only retards bone loss but also demonstrates clinically significant analgesia / pain relief, bisphosphonates (if Astrid in not already on such therapy), HD-D3 (high-dose vitamin D3), and several forms of interventional radiotherapy such as external beam radiotherapy (EBRT) and RFA (radiofrequency ablation), stereotactic radiosurgery (SRS, such as Cyberknife and gamma knife), as well as minimally invasive procedures like vertebroplasty and kyphoplasty, all evaluable by interventional radiation, surgical and pain management specialists, and there is of course a benefit to the potential inclusion of some form of mood support via antidepressants especially, as pain is itself known to be intimately involved in the cascade to mood disturbances in a complex vicious cycle.
And have some time to enjoy the upcoming weekend.
All the best,
Constantine Kaniklidis Breast Cancer Watch email@example.com
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Only bad news from the south of France. Astrid's last CT scan revealed further spreading of the bone mets and about 10 micro-nodules in her lungs. You probably won't be surprised to hear that Astrid's oncologist reacted negatively to all your treatment suggestions. Otherwise, he would have proposed them first, right? I read myself dizzy about metronomic chemotherapy, Astrid was willing to give it a try and I thought our oncologist would embrace her decision. Very Wrong. He said that it is not a protocol here in France or anywhere else. He said there's no evidence that it is any better than standard treatments for bc mets; said there had only been Stage II trials and so it had never been compared to existing approved IV chemos. But while he would not prescribe the CTX/MTX combo, he was willing to prescribe oral CTX 50mg per day. I have not been able to find anything on this as a mono therapy. Is it at all effective? We would certainly appreciate anything you can tell us about the side effects of CTX at this dosage. Alopecia, nausea & neuropathy being major concerns. As for trying Faslodex again at a double dose, the onco claimed the study which you referenced only increased OS by one month. He said he believed it was a waste of time to try it because Astrid's cancer clearly did not respond to Faslodex nor any of the other endocrine therapies. He thought Aromasin was so similar to the others(Femara) that Astrid had tried that as single therapy or dual therapy, none were going to work. We never got around to talking about treating her anemia. And the onco insists that only systemic treatment can deal with the scalp mets. After so much negativity, it is clear that I need to get a 2nd opinion or find a new oncologist. Tomorrow, Astrid goes back on Zometa. But we still have to wait for her blood count to bounce back a bit from the Quadramet injection before starting Metronomic-C. All suggestions always most appreciated. Best regards, jwl
Moon Goddess of Love & Hope
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Sending love to Astrid and to you, jwl.
I'm sorry you are having to deal, on top of everything else, with the closed-mindedness of Astrid's doctor. Constantine can explain it better, but it is very common for doctors to over-emphasize the OS, this can be very misleading--PFS and QoL issues all have to be considered, not to mention that doctors are most often talking about median survival, rather than a range--don't forget the outliers! Some people do extremely well with any given treatment and this often does not end up getting expressed in the studies very well, or mentioned when studies are referenced. I am the queen of getting second opinions and it has served me very well. Don't let the opinion of this one doctor stop you from exploring treatments that really could be beneficial to Astrid. I am thinking of you both so much, and sending healing light to the South of France, all the way from canada. I would also like to mention that I found the link to Astrid's Ikebana on your profile page and I have been absolutely blown away by the extreme beauty of her work. She is truly a master. How lucky I feel that you have shared that with us. I have several times gone through the slides--it really is pure Zen. Thank you. xoxox love janet
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I assure you that I will never, ever stop my search to help Astrid. But finding treatments here in France that are not part of "THE PROTOCOL" is not so easy. I think that most of the oncologists in the French National Health System would probably react the same way. On an upbeat note, though, I want to thank you for taking the time to look at Astrid's art. It is her life-line. It sustains her through the most difficult of times. She is very gifted but quite insecure about her work so she will be so pleased to hear your comments. I don't know where you find the strength to face your daunting situation. Optimism seems to be your middle name. Best wishes, jwl
Moon Goddess of Love & Hope
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Dear jwl, I completely empathize with you and the struggle you are having with protocols, it is not so dissimilar here in canada. There is a lot I have to be grateful for with the canadian medical system, but at the same time have found we are often a step behind the americans with many protocols. I have had many failures getting the combination of drugs I have been looking for, for myself, as well as for some dear dear friends...
I know your dedication to Astrid has and will continue to be of enormous benefit to her. Your love for her sings through all of your posts. I admire you both so much for your courage and perseverance. Thanks for your kind words. Hope and optimism I have found here at No Surrender! Along with lots of help and inspiration from my beautiful family and friends. Continuing to send the , love please keep us posted, and I'm sure Constantine will have some further guidance...I don't know where I would be in this journey without him... xoxox janet p.s. I can't believe Astrid would have even the slightest insecurity about her work! It is stunning, creative, meditative and breathtakingly beautiful.
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Metronomic Chemotherapy (MCT): Missing the Point, and the Data
Your oncologist's remarks re metronomic versus standard chemotherapy completely miss the point: I was after a compassionate and effective rescue therapy in the light of the patient's express desire to avoid or substantially mitigate the potential toxicity of standard schedules, and as such this was a fallback option not one of primary
choice independent of the patient's wishes.
And although irrelevant given this clarification I just proffered, your oncologist
is also wholly in error and against the evidence in claiming that metronomic therapy has not been directly evaluated against standard chemotherapy and that all we have is Phase II (non-comparative) trials. In fact we have Phase III randomized data supporting the higher efficacy of metronomic therapy, and while we don't have head-to-head comparisons in the metastatic setting itself (to be reported out shortly), nonetheless in the neoadjuvant setting (where in fact most of out data for TNBC therapies is based on) metronomic-AC was superior to standard AC chemotherapy (both arms were followed by paclitaxel (Taxol)) on the primary endpoint of pCR as shown in the landmark SWOG 0012 clinical trial in a population of 265 patients with IBC or LABC. In the overall undifferentiated population, pCR for metronomic-AC was 31% compared to 19% on standard AC, but in IBC it was 32% on metronomic, 12% on standard, while in ER-negative patients who benefited most from metronomic scheduling, the pCR was 43% on metronomic therapy - one of the highest pCR rates ever achieved in such challenging populations - compared to just 26% on standard chemotherapy.
And in any even casual review metronomic therapy has sustained response rates and outcome that compare favorably to standard chemotherapy: Colleoni's overall response rate of
19% and clinical benefit rate of 32% using metronomic-CM in very challenging advanced heavily pretreated metastatic breast cancer patients with primarily at least two or more sites of metastases, and with 26% of patients achieving durable long-term response (still responding after 12 months of metronomic therapy), all in the absence of any serious toxicity, or adverse events); or Dellapasqua's European Institute of Oncology trial overall response rate of 48% and a clinical benefit rate of 68% using metronomic XC-BEV (capecitabine (Xeloda) + cyclophosphamide (Cytoxan) + bevacizumab (Avastin)) in a population of metastatic and locally advanced (inoperable) breast cancer patients, all achieved without significant acute or delayed toxicity (only 4% grade > 2 leukopenia or neutropenia, and only 4% of the patients had any hair loss). Similarly in extensively pretreated metastatic breast cancer patients Munzone obtained 18% overall response rate and a clinical benefit rate (CBR) of 45% using metronomic PLD (Doxil), with excellent tolerability (neither grade 3 nor grade 4 hematological or clinical side effects were observed and only 2 patients experienced grade 3 hand-foot syndrome, with no recorded cardiac toxicity.
These and numerous other metronomic therapy studies collectively demonstrate that metronomic scheduling achieves response rate and outcomes in the same rage as observed for standard chemotherapy, while balancing clinical efficacy with a good quality of life in terms of reduced side effects, and as pharmaco-economic studies have shown, with typically low personal costs for the patient.
As therefore a respectful accommodation to the patient's, Astrid's, preferences while maintaining more than satisfactory efficacy concurrent with preservation of good QoL,
it is difficult for me - or any of the many experts in metronomic therapy with whom I have discussed this (including Robert Livingston, the "father" of metronomic therapy who was honored for his breakthrough therapeutic advance in a special ASCO merit award - along with, fittingly, a metronome) - to discern metronomic therapy as other than a viable alternative to standard chemotherapy, across all breast cancer settings, and subtypes.
Finally, I find it puzzling and more than a little inconsistent that while your oncologist inveighs against metronomic therapy, he is nonetheless differentially willing to deploy metronomic CTX - for which we lack compelling clinical supporting data as monotherapy - but not metronomic-CM, that is metronomic CTX
+ MTX, despite supporting clinical data from for example Colleoni (2002), Orlando (2006), Colleoni (2006); it is difficult to construe this as a rational motivation rather than a resistant and methodologically contrary act of arbitrary response to patient input, that does not speak well either to the maturity or dedication and objective commitment one expects from an oncology professional.
Fulvestrant (Faslodex): The Point, The Data
Here too your oncologist is being too
resistant and to boot misinformed: (1) again I was not directly advocating fulvestrant (Faslodex) but rather reflecting on a lost opportunity in using the lower 250 mg monthly dosing rather than the now approved 500 mg monthly dosing - and I should HD-fulvestrant (high dose fulvestrant: 500mg/mo) has been also approved in Europe since March of this year; clearly despite your oncologist's reservations, the European authorities (including France) saw things differently and far more positively than he does (and which includes the eminent Martine Piccart among numerous other European experts); (2) your oncologist is again in error in claiming that HD-fulvestrant offers only 1 month survival gain: in the latest published findings of the double-blind, parallel-group, multicenter, phase III CONFIRM trial (and reported at both SABCS and ASCO, and as landmark findings, published jointly in both JCO and in Cancer Research), the overall survival (OS) benefit of HD-fulvestrant versus standard-dosed fulvestrant was in fact 2.3 months, not one month; he seems to have confused the PFS with the OS findings: median PFS times was 6.5 and 5.5 month in the HD- and standard fulvestrant groups, respectively representing a 20% reduction in the risk of disease progression (assessed as time to disease progression (TTP)), but note that 34% of HD-FULV patients compared to just 25% of standard-FULV patients remained alive and progression free at 12 months (16% and 11%, respectively, at 24 months).
But as to overall survival, median times to death were 25.1 and 22.8 months for HD-FULV and standard dosing, respectively, a statistically significant benefit, and given no increased toxicity, this represents a clinically meaningful improvement in benefit versus standard-dose fulvestrant.
Indeed, on the basis of CONFIRM data (along with the previous positive findings from the FIRST and NEWEST trials), the independent data monitoring committee has authorize the trial investigators to offer crossover to 500 mg for ongoing 250-mg patients, considering that it would be unethical to deny the demonstrably more effective dose and consequent survival benefit as well as reduced risk of disease progression - all statistically and clinically significant - to trial patients. (And even if we were talking about just PFS - which we are not - and not OS also, let your oncologist try telling a patient that even a one month gain is not worthwhile; that is not the perspective of any patient I have ever encountered, and I, as opposed to others, would ethically also tell the patient that the one month was a median PFS, with some outcome many fold greater; ditto for the real 2.3 month gain in true overall survival, which has been enough to garner FDA approval for dozens of agents and regimens).
The Claim of AI Switching Futility
It must be appreciated, as Kent Osborne at Baylor, an expert
in endocrine resistance, has pointed it is not only endocrine resistance to all endocrine therapies via an acquired new driver escape pathway, but there is more frequently particularized resistance to a specific endocrine agent or regimen ( class-level versus drug-level endocrine resistance), and because of this and the well-known interchangeability of AIs that virtually all endocrine experts have acknowledged the viability of switching among AIs since any one particular patient may exhibit drug-level acquired resistance to one AI and not to another.
In addition, it is sophistry to suggest that these agents
are too similar to each other to expect differential response from switching: not only is this against all field experience - each AI has its own fingerprint and clinical signature - but missing two further points: (1) exemestane (Aromasin) and letrozole (Femara) are in fact not that similar - Aromasin is a steroidal type AI while Femara is a non-steroidal AI; (2) numerous studies have shown that there is at least partial non-cross resistance between steroidal and non-steroidal anti-aromatase agents independent of the sequence employed, as found by Gianfilippo Bertelli at South West Wales Cancer Institute, among others, suggesting that patients can receive Aromasin as their first anti-aromatase agent and still benefit from Femara or Arimidex after progression, and vice versa.
Cutaneous Metastases: Opening the Net Wider
Your oncologist with again unsurprising resistance claims that systemic therapy alone can influence cutaneous metastases: again this is against the evidence, and all the interventions I noted in my latest posting on this issue (to Anne/fierce1:
http://www.nosurrenderbreastcancersurvivorforum.org/post?id=4939526&goto=lastpost) have supporting data of therapeutic benefit (I will leave it to your oncologist to exercise himself with a PUBMED search right out of Medical Research 101 to discover the studies which are not in hiding). Still, it is doubtless the case that systemic therapy, although not by any means the sole modality, forms the critical backbone of any multi-modal management of cutaneous metastases.
Final Thoughts on the Vanishing Proactive Oncologist
Through these exchanges it has become clear that your oncologist for whatever reason or reasons is resistant to the sincere cooperation that is needed to explore and then present the multiple set of potential options that will both exhibit non-trivial efficacy and benefit to the patient while also at the same time respecting and working within the parameters of the benefits
own express preferences. I am an expert medical researcher and I would not have suggested therapeutic options based on scant or insufficient evidence - working within the confines of Astrid's understandable preferences - nor do I get the evidence wrong, as it were: I hug the evidence but don't smother it in a small and mean interpretation (by which I do not suggest emotional meanness, just "mean" in the sense of narrow and uncharitable reading of the data).
There are errors of judgment and errors
of fact - even, as I have shown above re metronomic therapy, errors of (in)consistency - that have been displayed here as you have reported your oncologist's dissenting views, and I am less troubled with those than I am the cramped and resistant therapeutic posture this all suggests. I am in service of saving, and prolonging, lives within the boundaries of patient preference and QoL considerations, and I believe that requires a more expansive and mutually cooperative clinical stance than I witness here, so a second opinion is massively mandated and consequently possibly a much needed change of venue vis a vis oncologist, although of course these decisions are ultimately and properly yours and Astrid's. I say this all in the spirit of respectful concern for Astrid's and you own wishes, and when there is a divergence between oncologist and patients on this matter, the oncologist is of lesser significance to me as I serve patients and only secondarily oncologists. Constantine Kaniklidis Breast Cancer Watch firstname.lastname@example.org