Dear Aamir

There must be a large number i am thinking. i am personally aware of at least 2 dozen and these patients remained alive 8 plus years with excellent quality of life with minimal therapy (bisphosphpnates, hormonal therapy when appropriate or oral chemo with Xeloda, Herceptin when appropriate). these mets were in the vertebral bodies, skull base, ribs, femur. i am hoping this discussion might help clarify the matter.

and of course it would be nice to go back and get proteomics and GEP and whole genome sequencing done on their primary cancer if available.

Both HER2 positive as well as HER2-NEG, ER/PR+

This seems like an interesting question one could explore through text mining of electronic medical records. Assuming those specific records are available and are not too sparse of course.

First, incidence: Bone is the most common site of breast cancer recurrence, and in general the prevalence of skeletal disease is greatest in breast and prostate carcinoma but still high in thyroid malignancy and others.

As to survival, the median survival after the first recurrence of breast cancer to the bone is 20 to 24+ months (Coleman et al., Br J Cancer 1987, among numerous others). But note that the probability of survival for patients with bone metastases from advanced breast cancer (ABC) is dependent on the subsequent development of metastases at extraosseus sites, so that BC patients with bone metastases plus additional non-bone organ involvement had a median survival of 1.6 years.

Bone Metastasis Predictors

At this point, an intensive amount of research is focusing on prediction of bone metastatic disease. Potentially predictive non-molecular factors for the confinement of disease to the skeleton are older age, postmenopausal women with lobular carcinoma, and absence of poorly differentiated, ductal, high-grade (grade 3) tumors, and these patients typically present initially with no or minimal axillary lymph node involvement (especially node-negative patients).

At the pathological / immunohistochemical (IHC), leading bone experts Alan Lipton at Penn State demonstrated suggestively in the landmark NCIC CTG MA.14 trial that higher pretreatment serum B-CTx, which is a powerful marker of bone resorption, is a significant predictor of shorter RFS (recurrence-free survival) for bone-only metastasis.

Breast Cancer Subtype Dependencies

As with most phenomena of malignant transformation, the characteristics and natural history of bone metastasis in breast cancer show distinct differences according to the molecularly identified breast cancer subtypes. Thus, in a study of the distribution of organ site-specific relapse within the intrinsic breast cancer molecular subtypes, an association was seen between the ER-positive luminal subtypes and bone as a site of relapse (Muller et al., Nature 2001).

The BCCA (British Columbia Cancer Agency) study of the distribution of metastatic behavior across breast cancer subtypes (Kennecke et al., J Clin Oncol, 2010), bone was the predominant site of metastasis for the luminal A (66.6%), luminal B (71.4%), and luminal/HER2 (65%) groups and the least common site in the basal group (39%).

In addition, I should note that the profile of bone metastasis is radically different according to the BC subtypes, as if different diseases: so, when bone relapse occurred in the HER2 subtype, the genes upregulated did not overlap in the slightest with those in luminal (hormone-positive) tumors, entailing that bone metastases occur via different genetic / molecular processes in different intrinsic breast cancer subtypes. This strongly answers in the affirmative Fatih Uckun's shrew query, that bone metastasis from breast cancer is indeed a distinct and unique pathological, molecular, and genetic form of metastatic breast carcinoma.

Molecular Predictors

Therefore besides the highly dominant predictor of ER-positivity, at the molecular level potential predictors of bone metastasis including PTHrP and its receptor osteopontin, the interleukins especially IL-8, RANK and RANK ligand RANKL), bone sialoprotein, tumor cell surface integrins, and Fas/Fas-ligand, among others.

In this connection, recently several groups have published microarray multigene expression profiles that are predictive for bone metastases in breast cancer, but despite this expanding and increasingly intimate knowledge there is still no well-validated, reliable marker or assay to predict an elevated risk of future bone metastasis, although both the CTx marker and certain still to mature gene expression signatures hold the greatest hope of fruition into workable predictors.

The Dark Side

Despite the best of modern bone-targeting therapies including the exceptional highly active injectable bisphosphonate zoledronic acid (Zometa) and the newly approved monoclonal antibody RANKL-binder denosumab (Xgeva, Prolia), something like as much as two thirds of patients with bone metastasis subsequently develop an SRE, skeletal-related event that will necessitate surgical intervention, palliative radiotherapy to bone lesions, and these SREs include malignant hypercalcemia and highly painful and disruptive spinal cord compression with consequent loss of mobility, social functioning and interaction, and compromised quality of life (QoL), causing significant morbidity but also significantly and adversely affect survival.

Therefore despite relatively favorable comparative survival, bone metastasis for breast cancer nonetheless remains a challenging clinical entity for which we need far superior targeted therapeutic tools. We also need to refine our knowledge of which non-bisphosphonate non-MoAb chemotherapeutic agents might exerts bone-preferential cytotoxic activity, with some recent and emerging appreciations for both preclinical, molecular and translational research, and finally also we need to understand and differentiate between the more standard indolent bone metastatic progression compared to the less frequent but non-trivial cases of highly aggressive rapidly progressive bone mets with grim prognosis.

In regards to SRE, a very important factor is the involvement of a skilled interventional radiologist and preemptive use of vertebroplasty to stabilize the vertebral bodies that are involved.

If a PET scan was included in staging and no lesions were detected in lung, liver, or brain, I believe the progression of Stage IV breast with bone involvement to a Stage IV cancer with visceral involvement may not be that common while on treatment with aromatase inhibitor + Zometa or chemo (e.g. Xeloda, Vinorelbine) + Zometa combinations. If however such patients are treated only for "comfort", then it is quite likely that secondary seeding will occur.

In a young woman with bone metastases, brain is frequently involved as well - specially in HER2+ patients. But again, it appears that the course may be indolent even in such patients as long as liver and lungs are not involved. In other words, a patient with brain + liver mets has a very different course than a patient with brain + bone mets.

It is of course very important not to continue ineffective treatments. Especially for patients with visceral metastases. In this regard, fusion technology provides a powerful diagnostic tool for timely termination or modification of ineffective treatments. Empirical patient-tailored chemotherapy should also be offered to metastatic adenocarcinoma patients as an alternative to the clinical trial and hospice options.

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=40&abstractID=31071

In breast cancer, bone meastases are definetely correlated with a better prognosis, because they can be treated by bisphosphnates or rankl-ligands an even ,if they are estrogen and or progesterone positive, with a hormon-therapy.

In such cases this diseas appears as a chronic one.

Dear Wolfgang,

Any thoughts as to why they do not rapidly disseminate and progress ?

Fatih

A number of additional options have recently become available.

http://www.medpagetoday.com/HematologyOncology/BreastCancer/34204

http://cancergrace.org/breast-cancer/2012/07/25/new-targeted-therapy-approved-for-er-positive-her2-negative-breast-cancer-afinitor-with-aromasin/

http://cancergrace.org/breast-cancer/2012/07/25/new-targeted-therapy-approved-for-er-positive-her2-negative-breast-cancer-afinitor-with-aromasin/

The link to denosumab is attached

http://www.medpagetoday.com/HematologyOncology/BreastCancer/34204

The answer to the question is Yeah!, bone metastases are linked to better prognosis, as stated in Vincent T. de Vita, Principles and Practice of Oncology, 9th edition, page 1440, table 106.23 that summarizes the prognostic factors in advanced breast cancer. There is some very recent literature on the subject, that can be found conducting search in Entrez Pubmed. Regarding Denosumab, a drug with an overwhelming superiority in all endpoints of clinical trials, an Australian group suggested that it can be non cost-effective and proposed a cost per QALY gained with Denosumab of more than $500'000. Good luck! Salut +

Bruce R. Zetter: "The cellular basis of site-specific tumor metastasis" N Eng J Med, 1990, Vol 122 nº 9, 605-612. There are probably many papers that cited this and can be accessed thru the appropriate feature of MedLine. Salut +

The take home message is:

Stage 4 breast cancer # Stage 4 breast cancer

Unfortunately many patients are told they have stage 4 breast cancer and then pushed to participate in clinical trials.

Stage 4 breast cancer with liver metastases = bad news for the patient

Stage 4 breast cancer with bone metastases (even with lymph mets) alone without brain or liver mets is not the same kind of bad news for the patient

Hello Fatih,

some papers and informations about whole genome sequencing of breast cancer. Maybe there are some informations usefull for you:

http://www.ncbi.nlm.nih.gov/pubmed/22362584

http://www.biomedsearch.com/nih/Allele-specific-up-regulation-FGFR2/18462018.html

http://www.ihop-net.org/UniPub/iHOP/gismo/88209.html

http://jama.jamanetwork.com/article.aspx?articleid=897133

https://ir.lifetechnologies.com/releasedetail.cfm?releaseid=725296

A team from our department recently updated long-term follow-up of patients with bone marrow micrometastases at time of initial breast surgery. In this study the presence of bone marrow micrometastases (detected by immunohistochemistry) is independently associated with shorter overall and disease-free survival.

http://www.ncbi.nlm.nih.gov/pubmed/23104395

And according to Fatih it is not clear which news is worst – bone or bone marrow involvement?

Hello Alexander,

Very interesting. Bone marrow involvement would likely put a patient at immediate risk for visceral metastases due to direct access to blood. I assume that the same patients would also have a higher number of circulating breast cancer cells/cancer stem cells.

My question relates to bone (not bone marrow) metastases.

Kind regards

Fatih

I'm not sure if I've aprehended the goal of the comment of Fatih Uckun about "Stage 4 Breast ca patients being pushed to clinical trials". As of today, the state of the art in disseminated Breast cancer may be considered the sequential use of single agent therapies, that yield positive results with minimal risks, that are not reasonable in the setting of a non-curable (almost never) disease, where palliation should not produce unbearable side effects or put life in danger. In the frame of an advanced disease no longer responding to known therapies, offering to the patients the possibility of entering a Clinical Trial can give positive results, and they do give it in around 25% or more of cases, some evidence exists, and an article several years ago that cited the case of a patient suffering a Hairy Cell Leukemia, for which no standard treatment active enough existed at the time of the diagnosis, and having surpassed 10 years of survival in good general condition and performance status, just moving from a clinical trial with a new drug to another CT, all published in the Journal of Clinical Oncology. Regarding the true actual existence of the condition of voluntary participation in the trials, the good old Helsinki declaration and its amendments are more than clear about what should be done regarding experimentation involving human subjects, obviously, the existence of a rule is not equal to the rule being effectively fulfilled, think in the commandements about sexual behaviour, and the continued spread of sexually transmitted diseases in the millennia elapsed since the law was communicated. It's not structures or laws that make medical practice right from an ethical point of view, and bearable to patients and societies, but sole the involved phisicians' morality.

Dear Jose,

I agree with your definition of the state of the art. But the practical reality is that such patients are often put on clinical trials sponsored by pharmaceutical companies before being given any standard therapy. Example: I have witnessed patients with colorectal cancer enrolled on a natiowide gemcitabine trial and by a very large community oncology group (which is a multibillion dollar company) before Xeloda was ever used.

The physician's morality is influenced by the physician's knowledge of what constitutes an effective strategy and sound judgment. A physician who believes that every stage IV cancer patient should be sent to hospice (and such physicians do exist in very large numbers) may find it immoral to give Xeloda to a colon cancer patient or Aromasin to a breast cancer patient. In regards to voluntary participation, the informed consents are used but it is very rare to see the informed consent process followed. I wished this was not the case.

In summary, we have no disagreement about the fundementals. We are just looking at the issue from different positions of the reality. The reality maybe very different in your hometown or country.

Very best

Fatih

My work in the field of Clinical Trials at The Upjohn Co ended in Dec 1988, after 5 years of job, from then on, I just have some experience as advisor to the CRO CABYC, my comments are not purely especulative, but not too far from. Regarding the measures than can be implemented to reinforce fulfilling the rules about experimentation in humans, first rule came in the 19th century Prussia, after Dr. Neisser tested a Syphilis vaccine he invented, first CT is reported as the call of Louis "XVI" of France to B Franklin, Guillotin and others to test if the "Animal magnetism" of Mesmer was a true fact, but as in anything, the measures can be so tight that they anihilate freedom, and human actions in the absence of freedom lack any moral value. Some approaches to rule reinforcement will end in things too close to female genital mutilation to be acceptable, the cost of an inspection body eliminating any fault would be unaffordable, and the principles of presumption of innocence and beneficence must always prevail.

Please make the purpose of question clear. What kind of patient population are we talking about? Stage IV BC patient also having bone mets (at least two metastatically affected organ system!), or Stage IV BC patients having ONLY bone mets?

My question relates to Stage IV female breast cancer patients with bone metastases who do NOT have metastases in their liver, lungs, or brain. While most of these patients have bone only disease, many will have still their primary lesion in the breast and the associated axillary and/or mediastinal lymph nodes.

I will suggest here that this is a surprisingly complex issue and that many confounders and modulators may be at play to paint a more favorable picture of bone-only metastatic disease from breast cancer, than the robust data warrant, and that associations with:

- endocrine-positive status,

- oligometastatic disease,

- total bone tumor burden and indolent versus aggressive subtypes, and the

- differential role of bisphosphonate therapy on distinct risk-classes of bone-only MBC

need to be considered closely for a sufficiently fuller understanding of skeletal metastases that would more enable more refined and targeted therapeutic interventions.

MBC SURVIVAL RATES

First a brief précis: median survival of undifferentiated MBC populations is 22 months overall. Bone-only metastases are at a median OS of ~26 months compared to ~21 months in patients with both bone and visceral metastases (but see bellow on a broader range rather than single value), while patients with visceral-only metastasis have 18 - 19 months median OS [1].

And note that the more indolent disease course of bone-only MBC may be the result of hormone-responsive disease, since many patients with bone-only metastases have ER+/PR+ tumor biology treatable with endocrine (hormonal) therapy, and in addition, supportive care with bisphosphonates may itself also contribute to the apparently more indolent disease course [2]. So, pooling hazard ratio data across trials, survival from bone-only MBC was significantly reduced in HER2-positive and triple negative (TNBC) disease by about one third (based on the ~24 month median Coleman and others found, median OS was no more than ~16 months in these non-endocrine tumor biologies, the ratio being maintained independent of any specific initial median OS considered), suggesting a strong - but not exclusive - tumor-biology-driven model of bone-only MBC.

BONE-ONLY VERSUS SINGLE-VISCERA-ONLY MBC: SURVIVAL CONVERGES

But it is time to appreciate that the matter is not so clear-cut. First consider the authoritative GOCS Trial (Grupo Oncológico Cooperativo del Sur) [3] of bone-only versus visceral-only metastatic breast cancer disease. This GOCS Trial confirmed that the probability of survival for advanced BC patients with bone metastases is significantly influenced by subsequent development of extraosseus metastases. In a recent study from Ronald Coleman and colleagues of 367 patients with bone metastases, advanced BC patients with disease clinically confined to the skeleton had median 2.1 years survival, compared to 1.6 years for those with additional non-bone organ involvement. Clearly bone-only metastases that are skeletal-confined have a modest but significant survival edge over bone plus extraosseus metastases, and we note that the profile of such patients includes old age, postmenopausal status, with lobular carcinoma, and non-poorly differentiated, ductal Grade 3 tumors, and are more likely to present initially with little or no axillary lymph node involvement [4].

Here let me note that although the recent MD Anderson retrospective review [5] appears to show vastly longer median OS for bone-only MBC, of 51.9 months! - an aberrant value divergent from the balance of the evidence to date which ranged from ~24 to ~26 months [7] on the lower end, out to 28 months [8] or even 32 months [6] on the high end - the study exhibits a number of serious methodological limitations: no control was made for bone tumor burden / number of bone metastases, nor for ECOG performance status which varied widely and significantly between treatment groups, nor for whether there were metastatic new sites of bone metastases or subsequent non-bone distant disease sites, similar limitations, along with small size, affecting a recent Korean series [9]. With the longest plausible median OS from a robust series (the Turkish Institute of Oncology review [6] being 32 months, the weight of the evidence finds for a range of 24 - 32 months median OS for bone-only BC metastases, with the most robust data clustering within the 24 - 18 month range, in agreement with a large just reported review [16] from researchers at Kings College London School of Medicine who examined cumulative survival after diagnosis of bone metastasis in 1589 women with breast cancer differentiated into three groups: (Group 1) bone-only metastasis; (Group 2) bone-only metastasis followed by visceral metastases; (Group 3) visceral metastases followed by bone metastasis. Median survival after bone-only metastasis diagnosis was 2.3 years (27.6 months) in Group 1, and 0.96 years in Group 2, and 0.91 years in Group 3.

BONE V LIVER

Now a study in contrast: examining the case of liver-only versus liver and extra-liver metastases, the EORTC Breast Cancer and Early Clinical Studies Groups [10] conducted a retrospective analysis of two large prospective, randomized metastatic breast cancer trials (EORTC Trials 10923 and 10961) examining clinical outcomes for liver-only versus liver plus extra-hepatic metastatic disease. The median survival of patients with liver metastases alone was 22.7 months (1.9 years) compared to liver plus extra-hepatic metastasis of 14.2 months (1.2 years) [EORTC Trial 10923] and 27.1 months (2.3 years) and 16.8 months (1.4 years), respectively [EORTC Trial 10961] (and most patients with liver-only metastases have disease progression in their liver again). So finally, if we take the median across the two trials, then median survival for liver-confined metastasis is ~2.1 years, and ~1.3 years for extra-hepatic progression.

What's important to note therefore is that for skeletal-confined bone metastasis we have a median survival of 2.1 years, compared to 1.9 - 2.3 years, averaged to 2.1 years cross-trial, for liver-confined metastasis, clearly of no clinically relevant difference (albeit near statistical significance if the EORTC Trial 10961 is used (unfairly) solely as comparator). For extraosseus metastatic progression versus extra-hepatic metastatic progression, the numbers are 1.6 years versus 1.3 years, respectively, again of bare or minimal clinical relevance. (I should note that things are better in my own database of metastatic breast cancer (MBC) consults (all metastatic sites of involvement, bone and/or visceral and/or CNS) accumulated over ten years, over 300+ in the U.S. alone having elected to adhere to my integrative oncology regimen which includes high-dose docosahexaenoic acid (DHA), so I am able to confirm better median overall outcome among the HD-DHA group, in keeping with the Phase II INSERM clinical trial [11], pushing median OS out to near three years from a median OS of 22 months (undifferentiated MBC, but by subgroup analysis even for ER-negative disease), and that includes also a significantly longer survival for bone-only metastatic patients).

INDOLENT VERSUS AGGRESSIVE BONE-ONLY MBC PHENOTYPES

Furthermore, we need to control for distinct indolent versus aggressive phenotypes in bone metastases: we know from solid RCT data that serum N-telopeptide (NTX), a marker of bone resorption, correlates with clinical outcomes in patients with bone-only or bone plus soft tissue metastasis in breast cancer [12]. As with other BC subtype, there is also considerable heterogeneity in patients with bone-only metastasis. Thus, median survival in patients with elevated baseline serum NTX levels stands at ~22.1 months (1.8 years) compared with 31.3 months (2.6 years) for non-elevated baseline NTX, suggesting that studies that found for aberrantly long survival of bone-only metastasis were likely confounded by bone-tumor burden: high burden constitutes a subtype with poor outcome and as we've seen above, not appreciably better than single-viscera-only disease, and these findings have lead to our foremost bone experts like Alan Lipton at Penn State and Ronald Coleman at Sheffield to conclude from their reviews that "survival is highly variable in women with bone metastases from breast cancer" including with bone-only MBC, with lactate dehydrogenase (LDH) levels defining distinct subtypes (high LDH incurring 2 - 6-fold greater risk of death) [13].

Furthermore, most studies failed to differentiate solitary metastatic bone lesions from multiple metastatic bone lesions, yet solitary involvement was associated with longer survival times than multiple involvement [14] (a distinction that is captured in part by markers of bone tumor burden such as NTX and LDH), and given that solitary metastatic bone lesions account for approximately 41% of all initially diagnosed metastatic bone lesions, this can clearly help to weigh toward a more favorable outcome prognosis in undifferentiated populations.

The presence of such prognosis-divergent subtypes is I would suggest often blurred by the fact that until recently with the introduction of the RANKL inhibitor denosumab (Prolia, Xgeva), the vast preponderance of bone-metastatic BC patients were prescribed the bisphosphonate zoledronic acid (Zometa), and in a landmark just-published exploratory analysis of placebo-controlled trials (in press [15]) conducted by an international collaboration, zoledronic acid significantly improved OS in the subset of patients (n=423; 38%) with elevated baseline NTX but not - and this is important - in patients with non-elevated NTX at baseline, a survival effect moreover that was independent of skeletal-related event (SRE) prevention. In addition, zoledronic acid reduces the incidence of micrometastases in the bone marrow, as shown in the ABCSG-12 Trial and numerous other confirmative studies.

CONCLUSIONS, AND LESSONS TO LEARN

We can conclude therefore that although in undifferentiated populations of bone-only MBC, survival outcome can be construed as relatively favorable, the facts are more complex when we compare against limited disease or oligometastatic disease status such as bone-only versus single-viscera-only MBC where survival outcomes converge with only minimal clinically relevant distinction, and still more complex when we consider potential confounders such as solitary versus multiple bony lesions, and total tumor burden in general suggesting degrees of indolency and aggressiveness, as well as the highly selective and differential positive impact of bisphosphonate therapy on distinct risk-classes of bone-only MBC.

Thus we are left with some challenges of more accurately defining the extent of bone-only MBC to hone our therapeutic interventions more optimally, and to assure that patients with higher-risk disease receive more aggressive treatment and management than has often been recognized until now, while at the same time as my colleague Fatih Unkun has stressed, more favorably prognostic patients are spared overtreatment or encouragement into inappropriate experimental clinical trials simply on the - mistaken - basis of being advanced breast cancer (Stage IV) and hence by implication of poor prognosis, and we finally need to start using differential tumor burden metrics such as NTX and LDH to achieve such requisite selectivity. [I will have more to say on the issue of "clinical trial" channeling in my next posting, in agreement with Fatih's sentiment expressed above].

Finally we need to confront a controversy that has seduced many clinicians into favoring RANKL inhibition over bisphosphonate therapy: this stems from the - wholly correct - observation that the RANKL inhibitor denosumab (Prolia, Xgeva) is demonstrably superior to the bisphosphonate zoledronic acid (Zometa), but - and this is what is being missed - only as to the significant reduction of skeletal-related events (SREs). There is no credible evidence to date that denosumab favorably affects true overall survival, as does zoledronic acid, nor that it reduces the incidence of bone micrometastases, which again zoledronic acid does. In the total balance of benefits of (1) reduction of SRE, (2) maximization of overall survival, and (3) reduction of micrometastatic disease - and possibly also of survival benefit also to non-bone metastatic disease, as a pending review of mine will suggest - it is simply incautious to gravitate to denosumab over zoledronic acid, a trend we are perhaps regrettably beginning to witness (I with colleagues in the EU are beginning to experiment with a dual, interleaved schedule of denosumab and zoledronic acid).

References

1. Domchek SM, Younger J, Finkelstein DM, et al. Predictors of skeletal complications in patients with metastatic breast carcinoma. Cancer 2000;89:363-368.

2. Coleman RE, Smith P, Rubens RD. Clinical course and prognostic factors following bone recurrence from breast cancer. Br J Cancer 1998;77:336-340.

3. Perez JE, Machiavelli M, Leone BA, et al. Bone-only versus visceral-only metastatic pattern in breast cancer: analysis of 150 patients. A GOCS study. Grupo Oncológico Cooperativo del Sur. Am J Clin Oncol 1990; 13(4):294-8.

4. Coleman, R. E. (1997), Skeletal complications of malignancy. Cancer, 80: 1588–1594.

5. Niikura N, Liu J, Hayashi N, et al. Treatment outcome and prognostic factors for patients with bone-only metastases of breast cancer: a single-institution retrospective analysis. Oncologist 2011; 16(2):155-64.

6. Yavas O, Hayran M, Ozisik Y. Factors affecting survival in breast cancer patients following bone metastasis. Tumori 2007 Nov-Dec; 93(6):580-6.

7. Domchek SM, Younger J, Finkelstein DM, et al. Predictors of skeletal complications in patients with metastatic breast carcinoma. Cancer 2000;89:363-368.

8. Scheid V, Buzdar AU, Smith TL, Hortobagyi GN. Clinical course of breast cancer patients with osseous metastasis treated with combination chemotherapy. Cancer 1986 Dec 15; 58(12):2589-93.

9. Lee SJ, Park S, Ahn HK, et al. Implications of bone-only metastases in breast cancer: favorable preference with excellent outcomes of hormone receptor positive breast cancer. Cancer Res Treat 2011; 43(2):89-95.

10. Atalay G, Biganzoli L, Renard F, et al., EORTC Breast Cancer and Early Clinical Studies Groups. Clinical outcome of breast cancer patients with liver metastases alone in the anthracycline-taxane era: a retrospective analysis of two prospective, randomised metastatic breast cancer trials. Eur J Cancer 2003; 39(17):2439-49.

11. Bougnoux P, Hajjaji N, Ferrasson MN, Giraudeau B, Couet C, Le Floch O. Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial. Br J Cancer 2009 Dec 15; 101(12):1978-85.

12. Ali SM, Demers LM, Leitzel K, et al. Baseline serum NTx levels are prognostic in metastatic breast cancer patients with bone-only metastasis. Ann Oncol 2004; 15(3):455-9.

13. Brown JE, Cook RJ, Lipton, A, Coleman RE. Serum lactate dehydrogenase is prognostic for survival in patients with bone metastases from breast cancer: a retrospective analysis in bisphosphonate-treated patients. Clin Cancer Res 2012 Nov 15; 18(22):6348-55.

14. Koizumi M, Yoshimoto M, Kasumi F, Ogata E. Comparison between solitary and multiple skeletal metastatic lesions of breast cancer patients. Ann Oncol 2003; 14(8):1234-40.

15. Coleman RE, Lipton A, Costa L, et al. Possible survival benefits from zoledronic acid treatment in patients with bone metastases from solid tumours and poor prognostic features—An exploratory analysis of placebo-controlled trials. J Bone Oncol 2013.

16. Holmberg L, Harries M, Agbaje O, et al. Incidence Of Bone Metastases And Survival After A Diagnosis Of Bone Metastases (Bm) In Breast Cancer Patients. 37th ESMO Congress Vienna, Austria, 28 September – 2 October 2012. Ann Oncol (2012) 23 (suppl 9): ix116-ix143.

Constantine Kaniklidis

Director of Medical Research,

No Surrender Breast Cancer Foundation (NSBCF)

European Association for Cancer Research (EACR)

Dear dr Kaniklidis: your note is a throrough an up-to-date review on the subject. Considering your clinical and research experience, and not so much the early data, may I request from you an oppinion on the most adequate way for the assessment of presence and extent of bone disease, including bone tumor burden? Scintigraphy has the theoretical possibility of both false positives and false negatives, MRI may be more difficult to access or expensive, bone turnover markers can be influenced by other bone and endocrine conditions, and if you wait until you see a hole in a bone, or to have the patient entering the ER for a pathologic fracture or hypercalcemia for making the Bone Disease diagnosis, you may be missing some opportunities for improving patient's QoL and QALY Survival. Thanks, salut +

Jose, Good question.

There are four purposes involved in this issue:

(1) the detection and quantification of bone-metastatic disease;

(2) total bone-metastatic tumor burden,

(3) survival-prognosis, and

(4) tumor response to treatment.

I will first treat the detection and quantification of bone-metastatic disease at the lesion level, and return to the others in closing.

Although the standard of care has been - and still remains in the majority - the bone scan (BS) via traditional Technetium-99m (99m Tc) bone scintiscanning (ie, radionuclide bone scanning), as the most cost-effective and widely available whole-body screening test for the assessment of bone metastases, the most robust data aggregated to date despite some methodological limitations and variability in study-specific estimates, show nonetheless that in subjects who underwent both bone scan (BS) and PET imaging, the sensitivity of PET was non-inferior or slightly higher (median sensitivity = 84.0%) than that of bone scan (median sensitivity = 80.0%), while the specificity of PET was generally higher (median specificity = 92.0%), and significantly so, than the specificity of bone scan (BCS) (median specificity = 82.4%), thus, importantly, providing fewer false negatives from PET than from bone scan [Ohta et al., Nucl Med Commun 2001; Yang et al., J Cancer Res Clin Oncol 2002; Dose et al., Nucl Med Commun 2002; Gallowitsch et al., Invest Radiol 2003; Abe et al., Ann Nucl Med 2005; Nakai et al., Eur J Nucl Med Mol Imaging 2005; Mahner et al., Ann Oncol 2008; Hahn et al., Acta Radiol 2011; Houssami N, Costelloe CM. Ann Oncol 2012].

What of other imaging modalities? SPECT (single photon emission computed tomography), which is essentially a cross-sectional bone scan, has yet to demonstrate consistent advantage over either bone scan or PET, but only one small study weighed in on this issue that meet my inclusion criteria (Uematso et al., AJR Am J Roentgenol 2005) and it is methodologically questionable under my critical appraisal as the bone lesions estimates are atypically high (900 lesions in 15 subjects, with just four subjects accounting for 163 lesions in the majority of these), and these estimates are implausible from extensive field and clinical experience, leaving the need for more mature data to clarify the role, if any, of SPECT or SPECT/CT imaging.

Where does MRI fit in?

(1) First as to MRI versus bone scan, only two studies were includable (Altehoefer et al. Eur J Radiol 2001; Engelhard et al, Eur Radiol 2004) and although both suggest some 10% greater sensitivity of MRI over BS, their results on specificity are inconsistent.

(2) But the rising star on MRI-based imaging of bone metastasis, is actually DW-MRI, diffusion-weighted magnetic resonance imaging. DW-MRI has been evaluated against integrated PET/CT, and although a small study (n=20), PET/CT showed a clearly higher accuracy than DW-MRI, with 100% sensitivity/specificity for PET/CT compared to 86% / 8% for DW-MRI. Given this, and the limited scope of supporting evidence, DW-MRI remains an attractive and emerging modality whose greatest strength is in bone marrow assessment for diagnosis and for therapy response assessment, without radiation exposure, but it clearly on the evidence to date remains a work in progress requiring mature and robust head-to-head trial to support any advantage, in terms of accuracy, over either bone scan or PET (or PET/CT) imaging.

Conclusions on Detection and Quantification Modalities for Bone Metastasis

So although many clinicians and associated pathology / radiology staff may continue to deploy the affordable and reasonably, but not especially, accurate bone scintigraphy, the evidence now finally suggests, as I conclude, that this may be a disservice to the patient, given that PET is comparable sensitive but significantly more specific than bone scan, and the associated reduction of false negatives - erroneous declaration of metastasis-free status in the presence of actual metastatic bone disease - is clearly to the advantage of both clinician and patient. Then MRI, especially DW-MRI, can be used not in initial assessment, but as what I call a resolution technology, namely in the assessment of indeterminate findings on previous bone or PET (or PET/CT) scan, resolving the disputed lesion observation.

Conclusions on Prognostic / Predictive Modalities for Bone Metastasis

Bear in mind however that bone scans, PET and PET/CT, MRI and DW-MRI, are detection technologies - the detection and quantification of bone-metastatic disease generally at the lesions level - while a distinct set of technologies, with the possible exception of DW-MRI when it matures further, provide superior prognostic/predictive markers of (1) total bone-metastatic tumor burden, (2) survival-prognosis, and (3) tumor response to treatment, with some cross-category overlap, and at this time the best evidence supports both N-telopeptide (NTX) and lactate dehydrogenase (LDH) in these roles. High NTX or LDH levels at early baseline strongly suggest for high-risk disease and potentially compromised survival, while their reduction after therapeutic intervention(s) can quickly signal treatment benefit long before lesion or tumor burden reduction becomes measurable on scans, with the corollary that sequential and significantly rising levels suggest treatment reassessment, complimenting, but anticipating, the verification of response by imaging technologies taken at 3 to 6 month levels.

My Own Approach: A Brief Summary of Principles

Since for me a false negative on bone-metastatic disease is can be a tragic miscalculation for the patient, allowing disease progression to go undetected when early intervention is demanded, I favor based on systematic review and critical appraisal of the evidence to date, PET or PET/CT over bone scan because of superior specificity, in combination with aggressive monitoring (monthly) of NTX (or LDH although the data on NTX is appreciably more mature) in the intervals between imaging (preferably no later than three months), in conjunction also with traditional tumor markers (my preference is CA 15-3 for breast cancers and most epithelial malignancies). This is an aggressive highly proactive approach to assure early alert and to most effectively guide therapeutic intervention, which as I have argued above and elsewhere, should always include:

(1) zoledronic acid (Zometa) in the U.S. or the non-nitrogen bisphosphonate clodronate (Bonefos, Clasteon, Loron) in the EU and elsewhere, with scrupulous monitoring and defensive management of oral hygiene to minimize the risk of development of ONJ (osteonecrosis of the Jaw);

(2) chemoendocrine therapy over just endocrine therapy for hormone-positive disease;

(3) aggressive anti-HER2 biologic + chemotherapy in any ER-positive or ER-negative HER2-positive patients;

(4) HD-DHA (high-dose omega-3 fatty acid component Docosahexaenoic Acid (DHA), as I indicated and motivated above;

(5) assurance via sufficient supplementation of optimal Vitamin D3 levels (serum 25(OH)D), and close monitoring of calcium levels both to assurance optimality at no more than 1500 mg total (dietary + supplemental) daily, and internals levels for avoidance of hypercalcemia;

(6) close SRE management via evaluation by oncological radiology of the relative benefits of various radiotherapy modalities, and by interventional radiology of candidacy for radiopharmaceutical / radionuclide therapy, and/or for stereotactic interventions (SRS/GKS, SRS/CKS, SRS/LINAC, or SBRT), or RFA (radio-frequency ablation)-based technologies w/wo cementoplastic intervention;

as the most critical components of bone metastasis management.

Constantine Kaniklidis

Director of Medical Research,

No Surrender Breast Cancer Foundation (NSBCF)

European Association for Cancer Research (EACR)

Regarding the possible therapy choices for Bone metastasis, there's a bomb launched by an Australian group: "Cost effectiveness of Zoledronic Acid (ZOL) vs Denosumab (Dmab) in prevention of Skeletal Related Events (SRE)", J A Carter et al, 2011 ASCO Annual meeting proceedings, Abstract 9025, Support Therapy Section. They propose that the cost for QALY gained with Dmab may be above $400000, but another group based in the same continent published that some approaches to BHV screening in pts that are going to receive any therapy that may trigger a fulminant hepatits by reactivation or immune reconstitution, specially chemotherapy, is also for them not cost-effective, but a Serious Adverse Event that may cause death must be considered in a different way, and the account of costs they made in the assessment of cost-effectiveness of BHV screening in Cancer patients seems not being precise enough, and biaised. Everything counts in making an Rx decisión.

There is an article published in Oncogene, 2013/32, by N-O Ching et al, on the RUNX pathways, underscoring the involvement of RUNX2 on Bone Metastasis, and its interactions with Estrogen Receptors and Hormone Therapy for Breast cancer. It looks to me as a good way to start digging in databases. Salut +

ABSOLUTELY RIGHT. PLEASE READ THIS ARTICLE: Implications of Bone-Only Metastases in Breast Cancer: Favorable Preference with Excellent Outcomes of Hormone Receptor Positive Breast Cancer.Cancer Res Treat. 2011 June; 43(2): 89–95.

Published online 2011 June 30. doi: 10.4143/crt.2011.43.2.89

Thank you Mohamed. I had not seen this paper. I wonder if a patient with bone only metastases and primary breast tumor should have the breast tumor removed or only pailliatively treated. Have you seen any info about that matter.

Yeah! it seems, but I'm not aware of the issue specifically addressed in Bone-only metastasis. An abstract in an Annual SCO meeting showed improved results with Lymph Node Surgical removal of periclavicular tumor affected LNs in metastatic Breast Cancer limited to this region, there's also an article by JA Perez-Fidalgo et al: 'Removal of primary tumor improves survival in metastatic Breast cancer. Does timing of surgery influence outcomes? -Breast 2011, Dec 20(6):548-54; Blanchard DK et al. 'Association of surgery with improved survival in Stage IV Breast cancer patients' Ann Surg 2008, May; Baviera GV et al 'Effect of primary tumor extirpation in Breast cancer patient who present with Stage IV disease and an intact primary tumor', Ann Surg Oncol 2006 Jun; all these articles point to improved results with removal of the primary tumor, however, there's also a german article indicating no effect, but it involves less than 80 patients in total. Salut +

Hello Jose, thank you very much. I am putting in here the abstracts of those papers as others may also be interested to learn about this. Much appreciated !!!

Breast. 2011 Dec;20(6):548-54. doi: 10.1016/j.breast.2011.06.005. Epub 2011 Aug 3.

Removal of primary tumor improves survival in metastatic breast cancer. Does timing of surgery influence outcomes?

Pérez-Fidalgo JA, Pimentel P, Caballero A, Bermejo B, Barrera JA, Burgues O, Martinez-Ruiz F, Chirivella I, Bosch A, Martínez-Agulló A, Lluch A.

Source

Department of Medical Oncology, Hospital Clinico Universitario, Avda Blasco Ibanez s/n, 46018 INCLIVA, Valencia, Spain. [email protected]

Abstract

BACKGROUND:

Resection of intact primary tumor is controversial in metastatic breast cancer patients. The aim of this study is to review the impact of surgical resection of primary tumor on overall survival and to assess the role of timing of surgery on survival rates.

METHODS:

208 patients with metastatic breast cancer diagnosed between 1982 and 2005 in the Hospital Clinico of Valencia (Spain) were analysed. Exclusion criteria were age >80, PS 3-4, Charlson score 3 or follow-up < 90 days. 123 of these underwent surgery and 85 did not. In order to assess the role of timing, the "surgery" cohort was divided into two sub-groups: "before" (n = 78) or "after" (n = 45) diagnosis of disseminated disease.

RESULTS:

In the surgery group, patients underwent mastectomy with axillary dissection (82.9%), without axillary dissection (8.9%) and conservative surgery (8.1%). After a median follow-up of 29.68 months, median OS in the "surgery" and the "non-surgery" groups were, 40.4 and 24.3 months. Removal of the primary tumor therefore had a significant positive impact on survival rates (p < 0.001). Benefits of surgery were observed mainly in patients with visceral disease (p = 0.005); no statistical differences were found in those with bone disease (p = 0.79). Univariate analysis for overall survival (OS) identified surgery, performance status, clinical T stage, hormone receptors and number and type of metastases as variables that impacted on survival. In the multivariate test, only resection of primary tumor and estrogen receptors maintained statistical significance, surgery having a protective effect with an HR 0.52 (95% CI 0.35-0.77). No differences in survival were found between the two sub-groups according to the timing of surgery: "before" vs "after"(p = 0.996).

CONCLUSIONS:

Resection of primary tumor should be considered not only as a palliative or preventive strategy but also as an approach that possibly contributes to the control of the disease in selected patients.

Ann Surg. 2008 May;247(5):732-8. doi: 10.1097/SLA.0b013e3181656d32.

Association of surgery with improved survival in stage IV breast cancer patients.

Blanchard DK, Shetty PB, Hilsenbeck SG, Elledge RM.

Source

Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. [email protected]

Abstract

OBJECTIVE:

This study aims to examine the role of surgery in patients with stage IV breast cancer.

BACKGROUND:

Historically, women who present with metastatic breast cancer are not offered surgical treatment. However, recent reports indicate that surgery may improve outcome. Using a large database of women whom presented with stage IV breast cancer, we compared outcome of patients who had resection of their primary cancer to those who did not.

METHODS:

Of 16,401 patients, 807 had stage IV disease at presentation, and 395 survived >90 days and were included in this analysis. Clinical and tumor characteristics, surgical treatment, and survival were compared for the surgically versus nonsurgically treated patients.

RESULTS:

Two hundred and forty-two patients (61.3%) had definitive surgery for their primary tumor and 153 (38.7%) did not. Patients who underwent surgery were significantly older, were more likely to be white, more often had hormone receptor positive disease, had small primary tumors, and had fewer metastatic sites and less visceral involvement. The median survival of surgically treated patients was 27.1 months versus 16.8 months for patients without surgical resection (P < 0.0001). In multivariate analysis, which included surgical treatment, age, race, estrogen and progesterone receptor status, number of metastatic sites, and presence of visceral metastases, surgery remained an independent factor associated with improved survival (P = 0.006).

CONCLUSION:

Patients with stage IV breast cancer who had definitive surgical treatment of their primary tumors had more favorable disease characteristics. However, after adjustment for these characteristics, surgical treatment remained an independent factor associated with improved survival.

Hi!. Thank you for your cooperation, I'm a bit lazy. This is the German study that says no advantages were in surgery of primary tumor for advanaced -Stage IV Breast Cancer.

1. Onkologie. 2011;34(11):607-12. doi: 10.1159/000334061. Epub 2011 Oct 28.

Primary tumor excision in stage IV breast cancer at diagnosis without influence

on survival: a retrospective analysis and review of the literature.

Rosche M, Regierer AC, Schwarzlose-Schwarck S, Weigel A, Bangemann N, Schefe JH,

Scholz CW, Possinger K, Eucker J.

Klinik für Onkologie und Hämatologie, Charité - Universitätsmedizin Berlin,

Germany. [email protected]

Comment in

Onkologie. 2011;34(11):581-2.

BACKGROUND: Patients with synchronous metastastic breast cancer and intact

primary tumor traditionally undergo systemic treatment. Surgical intervention at

the primary site is typically reserved for palliation and often replaceable by

radiation. Nevertheless, local surgery in metastatic breast cancer has become an

issue of great controversy since retrospective studies published during the

recent years suggested a slight benefit from an operative procedure. We evaluated

the effect of surgery on long-term survival and progression-free survival in

synchronous stage IV breast cancer.

METHODS: We retrospectively reviewed the records of all breast cancer patients

treated at our institution between 1986 and 2007. Information recorded for each

patient included age, tumor characteristics, metastasis characteristics, therapy,

progression-free survival, and overall survival. Survival data were compared

between surgical and nonsurgical patients.

RESULTS: 61 patients with synchronous metastastic breast cancer and intact

primary tumor were analyzed. 26 patients (43%) received no primary site surgery

and 35 (57%) patients had surgery. Overall survival and progression-free survival

determined via the Kaplan-Meier method showed no significant difference between

the surgery and the non-surgery group.

CONCLUSION: In patients with metastatic breast cancer, the operation of the

primary tumor did not influence overall survival or progression-free survival.

Copyright © 2011 S. Karger AG, Basel.

This other is the one I cited about benefits of affected supraclavicular LN extirpation:

PMID: 22104157 [PubMed - indexed for MEDLINE]

49686-74

Survival benefit of neck dissection for patients with breast cancer with supraclavicular lymph node metastasis.

Subcategory:

Metastatic Breast Cancer

Session Type and Session Title:

General Poster Session, Breast Cancer - Metastatic

Abstract Number:

1069

Citation:

J Clin Oncol 28:15s, 2010 (suppl; abstr 1069)

Author(s):

S. Chen; Chang Gung Memorial Hospital, Taipei, Taiwan

Background: The incidence and outcome of supraclavicular lymph node metastasis (SLNM) were poorly defined for it had been combined with axillary relapse as regional nodal failure in the literatures, and further surgical treatment for the regional nodal relapse had never been evaluated. Methods: A total of 5,409 consecutive women with primary breast cancer who received surgical treatment in the single institute from 1990 to 2003 were included in the study. Isolated chest wall recurrence as first event was defined as local relapse. SLNM was defined as only isolated ipsilateral site neck nodal recurrence. All SLNM had tissue proof. Neck dissection defined as curative intent to remove all nodes and soft tissue in neck level IV and part of III and V, incisional or excisional biopsy of neck node were not included. Median follow up was 84 months. Results: There were 271 patients (5.0%) developed local relapse and 127 patients (2.3%) suffered from SLNM. Forty-nine in 127 SLNM patients had received neck dissection. There were no significant differences of age distribution, initial tumor size, axillary nodal involvement, estrogen and progesterone receptor, HER2/neu status, level II dissection, adjuvant chemotherapy, hormonal therapy, and radiotherapy between the two groups of neck dissection or not. The 5, 10 years overall survival (OS) for local relapse, SLNM and distant metastasis were, 38.7%, 26.1%; 21%, 9.2%, and 13.8%, 7.0%, respectively. The 5, 10 years OS for those received neck dissection or not were 30.6%, 16.1%, and 14.9% 4.7% (p=0.002); the 5, 10 years distant metastasis-free survival were 16.3%, 8.2%, and 8.5, 3.8%, respectively (p=0.004). In multivariate analysis, neck dissection, disease-free interval, and hormonal therapy were independent prognostic factor for survival, the hazard ratio, 95% confidence interval were 1.715 (1.165 ~ 2.524), 1.473 (1.016 ~ 2.137) and 1.490 (1.023 ~ 2.169), respectively. Conclusions: Isolated SLNM should not consider as distant metastasis, and aggressive surgery is benefit for patients.

Source URL: http://meetinglibrary.asco.org/content/49686-74

How often are this approaches used in everyday's practice, and in how many centers? Regards, salut +

I'd say the primary Tumor removal in ColoRectal Cancer that is diagnosed in a Stage IV or metatstatic condition may be also beneficial, although some of the recent papers on the subject don't support this conclusion. Time will tell us, but surgery of primary and of metatstasis in advanced or Stage IV tumors was considered 'anti-oncology' not many years ago, and the Paradigm is changing very fast.

Jose, Fatih:

Issue 1: Bone Metastasis Prognosis: Once More into the Breach

First, it's vital to recognized that like all tumor biologies of breast cancer (luminal, basal, claudin-low, HER2, etc.), bone metastases exhibit intrinsic heterogeneity as to risk, and once these relaizations are integrated, this paints a very different, but far more realistic, picture of prognosis and risk in bone-only metastatic BC disease:

(1) Thus, the large genetic analysis conducted at UNC [Harrell et al, Breast Cancer Res Treat, 2011] using a dataset of >1,000 human breast tumor gene expression microarrays representing data from clinical studies found that the hazard ratio (HR) for breast cancer metastasis-free survival in luminal cases was 1.7, and compared to liver metastasis cases which was also 1.7 (confirming my analysis from prospective trial data I cited above in my own contribution), but for basal classes was almost half that, standing at 0.9 and for claudin-low tumors, at 0.8. This strongly suggests, as do dozens of other studies that the prognostically favorably status of ER+ disease is the overwhelming contributor to the apparent favorable prognosis of bone-only metastases, and studies therefore need to distinguish prognostic favor conferred by ER+ disease versus bone-only disease. The study cited [by Mohamed Akl ] above [Cancer Res Treat 2011] was intrinsically limited from doing that, as it's population was restricted to hormone-positive disease, and given it's other methodological limitations (only 15% of patients with bone-only metastases, homogeneous cohort (Korean) from a single institution, plus all the constraints and limits of a retrospective study, adds little to the conversation.

(2) All of the above cited studies failed to recognize the fact of phenotypic differences in risk, with low and high risk subgroups in any bone-only metastasis population: both P1NP (Procollagen type I N-terminal propeptide) [Dean-Colomb et al., Breast Cancer Res Treat, 2013] and PAM50 [Gnant et al., 5th IMPAKT Breast Cancer Conference, Brussels 2013] stratify this group in distinct risk subgroups. Thus, a baseline P1NP level >= 75 ng/mL predicts both increased risk of bone metastasis (hazard ratio, 2.7) as well as poor overall survival (OS) rate. Similarly, at the 11 year median follow-up point, 98.7% of patients who were classified by PAM50 (over a validated set of 50 discriminator genes) as having low risk did not encounter a late metastasis between 5 - 10 years follow-up, compared to 91.5% of those with a high PAM50 score, and this was true also of patients with bone-only metastases (regardless of node-positive or node-negative status), indicating that within the class of ER+ patients, there are significant subgroups of bone-only metastases patients with dramatically compromised prognosis, recurrence and survival.

(3) In addition, another failure to discern high versus low-risk subgroups of bone-only metastatic disease can be seen in the risk subgrouping via SRE (skeletal related events): thus using both the massive Danish Cancer Registry [Yong et al, Breast Cancer Res Treat, 2011] and the SEER database [Sathiakumar et al, Breast Cancer Res Treat, 2012] mortality hazards ratios among women with bone metastasis with or without SRE can be estimated. In analyses restricted to women with bone metastasis, the adjusted HR was 1.5 (95% CI 1.4–1.6) for women with bone metastasis plus SRE, compared with women with bone metastasis but without SRE. The sobering numbers are that 5-year survival was 75.8% for breast cancer patients without bone metastases, only 8.3% for patients with bone metastases (note that this is nothing to write home about as they say), and a mere 2.5% for those with both bone metastases and SREs, a grim outcome that puts the lie to the casual but naive generalization that bone-only disease is prognostically favorable. And one can, and should ask, well but how many bone-only met patients have involved SREs either at breast cancer diagnosis or during follow-up? The answer is 46%, so almost half of bone-only metastasis BC ER+ patients have a grim prognosis and dramatically reduced survival (just 2.5% alive at 5 years).

So we know there is prognostic heterogeneity with the class of bone-only metastasis BC patients (and even within the narrow class of solely ER+ disease) and that studies that fail to identify and recognize the low and high risk subgroups (via P1NP, PAM50, and SRE status, among others) cannot generalize conclusions on prognostic favorability legitimately.

Issue 2: Outcome Benefit of Primary Tumor Resection

A second point somewhat unrelated line of discussion was introduced by Jose Gros above, and followed up my colleague Fatih Uckun, a very important controversy indeed, namely of whether primary tumor resection in MBC favors survival, and both Jose and Fatih's contributions are, unsurprisingly, both valuable and thought-stimulating in this debate.

However, a systematic review with individual study critical appraisal unambiguously shows that we are in a state of equipoise and have insufficient methodologically robust data to support any conclusion of a clinically relevant survival benefit accruing from primary tumor resection: along with the Rosche study cited above, the Japanese Shibasaki study (Breast 2011) no benefit was observed; in the Lynn Sage study [Hazard et al., Cancer 2008], chest wall control was associated with improved OS regardless of whether surgical resection of the tumor was performed; in the Shien study (Oncol Rep 2009) there was no benefit of surgery in older patients; and tellingly - to connect this second issue to our first - in the Blanchard study (cited above, Ann Surg 2008), there was no significant difference in overall survival (OS) between surgery and no surgery for patients with bone metastases only, a finding verified in the Spanish Pérez–Fidalgo study [Breast 2011].

Furthermore, the set of positive studies all exhibit significant confounding factors such as primary surgery timing (pre or post- radiologic staging detecting metastatic disease), tumor biology status, degree of metastatic burden, the nature of systemic therapy (type and timing/delivery, sites of metastases (visceral or bone only), and performance status, among many others, and in fact a careful and critical review shows that in most of the widely cited positive series surgical removal of the primary tumor was performed mainly in patients with oligometastatic disease, who also were systemic therapy-responsive and with good performance status with no visceral metastases (such as Babiera [Ann Surg Oncol 2006]; Rapiti [J Clin Oncol 2006]; Blanchard [Ann Surg 2008]; Hazard [Cancer 2008]; Shien (Oncol Rep 2009]; among many others.

Given these considerations and limitations, we have no methodological evidence-based warrant to declare the benefit, or the absence of same, of primary tumor resection in MBC, and must await, in equipoise on the question, the mature data of the in-progress Prospective Randomized Phase III E2108 Trial assessing the benefit of early local therapy on the primary tumor in MBC patients. We can speculate about seeding and self-seeding hypotheses and related theoretical underpinnings including the countervailing and negative potential for the promotion of tumor cell proliferation by suppression of cell-mediated immunity (argued eloquently by Mark Goldstein and Luca Mascitelli who formulate it as "Surgery and cancer promotion: are we trading beauty for cancer", QJM 2012), for which a highly plausible and seductively compelling case can be made from intense analysis of several lines of human clinical trial data, as well as molecular cogency. Such considerations should give us pause in too readily putting our faith in the positive benefit of primary resection in metastatic disease, of any malignancy, not just breast cancer. But these remain fascinating but still essential exercise in speculation, and speculation is not evidence. Roughly one year from now in 2014, as the E2108 trial completes and reports its finding (along with comparable trials in other malignancies), we will learn the answer. I believe, from my reviews and critical appraisals and deep-mining of the data, that I know the answer that E2108 may bring, but that too is speculation!

Regarding the controversy about Surgery or Not to Surgery of Primary Tumor in metastatic or Stage IV Breast and Colon Cancer, my feeling is that, although there are some studies giving neutral results, none suggested a detrimental effect in this kind of Surgical approach, and thus, even if it's not very correct from a methodology point of view, I'd consider the situation as pointing a beneficial value of Surgey of Primary Tumor in Stage IV Breast and CRC. The subject deserves being repeatedly addressed in some sufficiently large and stratified CTs. Salut +

A correction, and a dissension:

(1) The subject deserves being settled in some sufficiently powered selection-bias-controlled prospective, not another retrospective, Phase III RCT, of which there is precisely one and only one, the E2108 ECOG clinical trial currently in progress and reporting findings in 2014.

(2) Until then we have insufficient evidence of a survival benefit from primary tumor resection in the MBC context for the reasons I presented and every one - no exception - of the positive trials was subject to significantly compromising selection bias (among other methodological defects - and these are not studies that are not "correct" methodologically, they are methodologically defective ones whose uncontrolled selection bias undermines their conclusions) sufficient to undermine their conclusions, as the best of most robust of these studies' authors admit properly and candidly - for example, Sara Samiee's Canadian team in their retrospective review of 111 MBC patients who note that although improved overall survival and symptomatic local control appear to be found in the surgically treated patients, this group in fact had significantly less aggressive disease at presentation raising the likelihood that the improve outcome was secondary to the imbalance of the selection of a prognostically more favorable set of subjects in the surgical intervention group who may therefore have had improved outcome independent and regardless of any surgical intervention, true across all the positive studies. This demanded, as they commendably note, that they must conclude that the optimal local management of MBC patients "remains unknown", that primary tumor resection lacks any evidence-based consensus (and stands against ESMO and other guidelines), and that clinical practice cannot be informed nor changed until validation, or its absence, arrives through the specific prospective randomized trial E2108.

(3) The apparent absence of harm is manifestly neither evidenced nor assuring since none of the studies was designed to look for any (like the induction of angiogenesis in dormant distant micrometastatic foci, the removal of countervailing angiostatin, suppression of cell-mediated immunity, catecholamine surge from stress of surgery with consequent beta2-adrenergic signaling cascading into robust increased VEGF expression locally and systemically, increased risk and incidence of secondary cancer rates [witnessed in gynecological malignancies where increased secondary renal cancer has been observed post-surgically], and proliferation of distant dormant micrometastases, among many others) nor was any study powered to detect (and with insufficient follow-up time to allow for emergence) any harm even had they been designed to explore it. I am not reassured that trials failed to find something they were neither designed nor powered to detect, nor do I consider subjecting patients to potentially unnecessary surgery as other than collateral harm, once it is explained to them ethically that there is insufficient evidence of benefit and equally insufficient evidence of lack of harm, and that - to be professionally honest with the patient - the issue cannot be dispositively answered until the results of prospective RCT data from the E2108 clinical trial reports in 2014.

SURVIVAL BENEFIT OF ADJUVANT ZOLEDRONIC ACID

An important systematic review and meta-analysis of zoledronic acid in BC bone disease has just released its conclusions [Valachis et al., Oncologist 2013] and they are important enough to take especially note of here in this context, briefly summarized below:

The systematic review and meta-analysis from Antonis Valachis and colleagues of 15 eligible randomized clinical trials to estimate the impact on survival and fracture rates of the use of zoledronic acid versus no use (or delayed use) in the adjuvant treatment of patients with early-stage (stages I–III) breast cancer. use of zoledronic acid resulted in a statistically significant better overall survival outcome compared to no zoledronic acid treatment, or placebo. This adds to the previous positive findings [Mauri et al, J Natl Compr Canc Netw 2010] that a statistically significant lower risk for breast cancer recurrence was observed among patients receiving zoledronic acid.

Thus, zoledronic acid not only has a protective anti-fracture benefit (21% lower risk), but also reduces the risk of death by 19%, likely due to prevention of tumor cell adhesion to bone, induction of tumor cell apoptosis, angiogenesis inhibition, blockade of interactions with mesenchymal stem cells, and elimination of micrometastatic tumor cells from the bone marrow. Finally, I note in this connection that this is a decided advantage over the non-bisphosphonate RANKL inhibitor denosumab which although superior on the clinical endpoint of SRE reduction, has demonstrated no survival benefit.

dear dr Kaniklidis: you're right again! The adrenergic cascade from the surgical and other stressors may push tumor growth, this may be one of the reasons why Propranolol was suggested as having specific disease benefits in Cancer patients; the interactions between therapies for Co-morbidities and the Cancer disease outcomes are probably insufficiently addresed, and those who are in the condition of trying to obtain some data about this, as the Madrid's Health Service, SERMAS, where all Primary Care doctors have in their offices and use since early in the 2000s an Electronic History , data storage, and disease coding and outcome recording, with connections to central data repositories, don't seem working too much in this line, their main concern seems to be protecting their turf.

Jose:

Shrewd observation about beta blockers. And so true about the underutilization and misutilization of the otherwise innovative potential of centralized digital repositories like SERMAS. Narrow self-protection never serves the advance of science!

Constantine

Dear Constantine,

Did the meta-analysis include studies with the RANKL inhibitor. Why would you think, there would not be a similar survival advantage for those agents.

Kind regards

Fatih

It would be very good waiting for the results of ongoing CTs, but to adequately weight the results of the German and Chinese studies cited above, just counting gives an impression: No Satistically Significant benefit of Surg vs No-Surg, in the German Study: total 61 patients, Chinese Study about the benefits of Neck Dissection in pts with Supraclavicular LN mts from Breast cancer: 5409 patients. ¿Alguien da más? salut +

74387-102

Cost-effectiveness of zoledronic acid (ZOL) versus denosumab (Dmab) in prevention of skeletal-related events (SREs) in metastatic breast cancer (mBC).

Subcategory:

Supportive Care

Session Type and Session Title:

Poster Discussion Session, Patient and Survivor Care

Abstract Number:

9025

Citation:

J Clin Oncol 29: 2011 (suppl; abstr 9025)

Author(s):

J. A. Carter, S. J. Snedecor, S. Kaura, M. Botteman; Pharmerit North America, Bethesda, MD; Oncology, Health Economics, and Outcomes Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ

Background: Dmab has been approved in the United States for prevention of SREs in mBC on the basis of the results of a phase III trial comparing Dmab vs. ZOL in mBC. In this trial, overall survival, disease progression, and serious adverse events (SAEs) were similar across treatments. The cost of a Dmab injection ($1,650) is nearly 2x that of ZOL’s ($887). This analysis assessed the cost effectiveness of Dmab vs. ZOL in mBC from a U.S. managed care perspective. Methods: A literature-based Markov model was developed to estimate the survival, quality-adjusted life-years (QALYs), number and costs of SREs, and drug and administration (Dmab=$32.46; ZOL=$153.86) costs for patients (pts) receiving Dmab or ZOL. Inputs were selected to reproduce the phase III trial outcomes up to 28 months. QALYs were estimated by assigning utilities to health states (prior to SRE; SRE; post-SRE, and death). SRE-related costs and utilities were obtained from the literature. Per-event SRE costs ranged from $4,039 (vertebral fracture) to $20,734 (bone surgery). In sensitivity analysis, SAEs were included ($15,441/pt with a SAE). Future outcomes were discounted at 3%/year. Results: Dmab resulted in fewer SREs, more QALYs, and lower SRE-related costs, but higher drug-related and total costs vs. ZOL, resulting in an incremental cost of $6,884/pt (Table). The cost per QALY gained was $644,000 when excluding SAEs ($613,000/QALY when including SAEs). Conclusions: Dmab is predicted to result in an incremental cost/QALY gained >$600,000. This high cost/QALY is due to the higher drug acquisition cost of Dmab, combined with the limited prevention of SREs and lack of overall survival/disease progression benefits vs. ZOL. The cost/QALY of Dmab is far higher than what is considered to be good value for a medical intervention ($50,000 to $100,000/QALY), thus raising questions regarding Dmab’s value in mBC.

77475-102

Cost-effectiveness of universal hepatitis B virus screening in patients beginning chemotherapy for solid tumors.

Subcategory:

Supportive Care

Session Type and Session Title:

General Poster Session, Patient and Survivor Care

Abstract Number:

9054

Citation:

J Clin Oncol 29: 2011 (suppl; abstr 9054)

Author(s):

F. L. Day, J. Karnon, D. Rischin; Peter MacCallum Cancer Centre, Melbourne, Australia; Department of Public Health, University of Adelaide, Adelaide, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

Background: Universal screening for chronic hepatitis B virus (HBV) infection prior to chemotherapy has been recommended by the Centers for Disease Control. We evaluated the cost-effectiveness of HBV screening prior to chemotherapy given for non-hematopoietic solid tumors (ST). Methods: A decision-analytic model was used to compare the cost-effectiveness of a universal patient screening program conducted as per professional guidelines, versus no screening, in hypothetical patient cohorts beginning adjuvant chemotherapy for early breast cancer or palliative chemotherapy for advanced non-small cell lung cancer. Survival times were extrapolated using Markov models. Probabilities were derived from published studies and costs estimated from the perspective of the Australian health care system. One-way and probabilistic sensitivity analyses were performed, including with the application of an alternative HBV screening strategy. Results: Using an incremental cost-effectiveness ratio (ICER) threshold of $50,000 Australian dollars per life year (LY) saved, universal HBV screening was not cost-effective for adjuvant patients (ICER $88,173/LY, 13% probability of being cost-effective), palliative patients ($1,343,482/LY, 0%) or pooled (all) ST patients ($149,771/LY, 1%). Sensitivity analyses found screening approached cost-effectiveness among adjuvant patients with the highest reported rates of undiagnosed chronic HBV (65%; $51,979/LY) or HBV reactivation with chemotherapy (41%; $48,799/LY). Cost-effectiveness was also significantly influenced by HBV population prevalence, but insensitive to the relative risk reduction with prophylaxis or prophylactic antiviral drug used. An alternative screening strategy employing HBSAg testing only produced the most economically favorable results, with ICER $30,075/LY (80% probability) for adjuvant patients and $51,115/LY (43%) for the pooled cohort. Conclusions: Universal HBV screening conducted as per current guidelines is not cost-effective in patients with non-hematopoietic ST. Screening may be economically favorable in selected patient subpopulations and/or with simplification of the screening strategy.

This proposal about cost-effectiveness of VHB Screening in patients receiving Chemotherapy may deserve a thorough analysis and discussion, be it for the Paradigm that although the cost of saving a life can be assessed, a life is always priceless.

Fatih, Jose:

You both raise really excellent issues! So I will take these up in turn below and try to do justice to them based on the best critically appraised evidence to date:

Denosumab's Lack of Survival benefit in Breast Cancer

The Valachis systematic review and meta-analysis (SR//MA) only reviewed zoledronic acid (Zometa), but all other robust SR/MAs [2-4] have all concluded that to date denosumab in breast cancer failed to exhibit any significant benefit in overall survival. Indeed, in a pooled analysis [2] of seven different reports culled from three randomized controlled trials (RCTs) involving an aggregate population of 5723 patients, it was found that despite denosumab significantly delaying time to first on-study skeletal-related event TTF-SRE, time to multiple skeletal-related events (TTM-SRE), and pain worsening (but not pain) for patients with bone metastases compared with zoledronic acid, the two groups failed to diverge significantly with respect to overall survival, disease progression, and pain improvement, but remember that was of the time of review, which predates by a year the appearance of the Valachis SR/MA.

So what would the inclusion of the Valachis SR/MA in a new SR/MA of this issue do to the conclusions to date? I decided to answer that question in advance of any Cochrane Review, by using the RevMan review tool from the Cochrane Collaboration Group to generate an SR/MA conducted strictly within protocol boundaries the Cochrane Review Protocols, using both both fixed and random statistical models, in particular the de facto standard of random statistical models, namely the DerSimonian and Laird random-effects models, and in all cases the RevMan-generated Cochrane-compliant SR/MA concluded (1) that in breast cancer there was no evidentiary support for any survival benefit of denosumab, and (2) that use of zoledronic acid did in fact exhibit a significant benefit in overall survival (using in all cases only RCT data). And I also ran an accelerated approximation of a CRD/Dare-compliant SR/MA as well as a Joanna Briggs Institute-compliant SR/MA, with no difference in conclusions drawn.

Indeed, it is telling that before the Valachis SR//MA appeared, only three randomized studies [5-7] reported overall survival data on these two agents, with no differences between denosumab and zoledronic acid, confirmed in the MD Anderson SR/MA [3], but although there was no statistically significant difference in overall survival for denosumab compared with zoledronic acid for prostate cancer also (in addition to breast cancer), and although an ad hoc analysis of the trial [7] including various malignancies types revealed a trend toward more favorable survival in patients with non-small cell lung cancer (NSCLC) who received denosumab, nonetheless - and very sobering - the same analysis revealed that myeloma patients actually had DECREASED survival (HR 2.26, and so those with multiple myeloma demonstrated more favorable survival in recipients of zoledronic acid, compared to denosumab.

Therefore, with a survival benefit for denosumab observed only for patients with NSCLC, and with no benefit in either breast or prostate cancer, coupled with INCREASED mortality in denosumab-treated patients with myeloma, we begin to see that denosumab exhibits complex and dissonant activities and influences on overall survival, with some at least provisional evidence of negative survival impact, unlike, and in stark contrast to zoledronic acid as per the Valachis SR/MA.

Trouble in Paradise: A Bit of Dark Side to Denosumab

As to the WHY of it, we have no dispositive data but there is some molecular plausibility to the mixed survival effects of denosumab. Consider that both clinical and preclinical data suggest that zoledronic acid, besides multiple direct and indirect complex anticancer effects, may have also strong anti-angiogenic activity, in contrast to denosumab which in both in vitro and in vivo settings failed to exhibit any antiangiogenic activity. Given this, denosumab's mixed complex effects on survival may in part be modulated by how strongly, or weakly, we are contending with a highly pro-angiogenic / pro-VEGF malignancy (NSCLC for example is strongly so, as tends to be (with some differences by molecular type) breast cancer), and this would further suggest to me as a plausible hypotheses that a survival advantage for zoledronic acid, but not denosumab, may also emerge in colorectal cancer (CRC) for instance, given the strong correlation between VEGF expression and poor prognosis in CRC.

Another dimension of this may be that RANKL is known and decisively demonstrated to be expressed in cells of the immune system, including activated T lymphocytes, B cells, and dendritic cells; indeed, we already know that RANK activation by RANKL is essential for both the growth of T cells and the functioning of dendritic cells, also enhances the survival of dendritic cells and antigen presentation. What this implies is that inhibition of RANKL by denosumab might alter subtly and not always positively immune function, suggested by increased susceptibility to infections, something amply documented in preclinical evidence (in vitro, and in vivo rodents and monkeys), and it is again sobering that using best available evidence from a meta-analysis of RCTs (including the large FREEDOM registration trial) it has been observed that denosumab was associated with a borderline increased risk of serious infections (risk ratio 1.25) in women with postmenopausal osteoporosis when an intention-to-treat analysis was used [9]. It may be that with further more rigorous trials and especially with longer follow-up capable of detecting durable modulations in immune functioning, adverse immunomodulatory effects of denosumab may emerge.

We must also remember that unlike bisphosphonates, denosumab has a brief post-market period, so it would be prudent to remain vigilant regarding potential adverse events related to RANKL inhibition in tissues other than bone, as well as those related to bone turnover oversuppression, both as to suboptimal tissue specificity (compromised selectivity of effect on bone alone) and as to hyper-effects "(exaggerated” on bone tissue, namely oversuppression of bone remodeling, hypocalcemia, decreased or delayed fracture healing, and osteonecrosis of the jaw, all of which are begin to emerge (for example

denosumab exhibits compared to zoledronic acid a far higher incidence rate of hypocalcemia (OR = 2.05 [10]), and furthermore be sobered by the fact that preclinical data suggests an effect of denosumab on tumor growth and even on carcinogenesis, with a role for the RANKL–RANK pathway in non-bone-related mechanisms such as mammary gland development and tumorigenesis [11]. The typical max of five year follow-up is simply insufficient to measure the emergence of these long-term sequelae (we would need at least 10 - 15 data). And the role of anti RANKL in the prevention of bone cancers remains controversial, given its association with both pro and anti-tumor effects in preclinical models [12].

In this context it is also worthy to note the FDA ODAC decision to not approve denosumab in castrate-resistant prostate cancer for the prevention of bone metastasis. Although much has been made of the endpoints of bone-metastasis-free survival or time to first bone metastasis, in both BC and PC trials, the FDA completely and reasonably questions the clinical relevance of these since they were derived by post hoc analysis, and has stated it is underwhelmed by a 4+ month benefit when weighed against the negatives of increased hypercalcemia, far greater incidence of osteonecrosis of the jaw (ONJ), and lack of data for denosumab's long-term safety and efficacy, in stark contrast to zoledronic acid. Therefore, the weight of the systematically reviewed and critically appraised evidence to data finds for a survival benefit of zoledronic acid in the breast cancer context, and none for denosumab.

Cost-Efficacy Analysis

Jose:

The ASCO 2011 (Cater et al, J Clin Oncol 2011) report you cite on the cost-effectiveness of denosumab raises serious question regarding the value of denosumab in MBC. To be fair, there are contradictory conclusions here however, with several studies concluding for positive cost-efficay (Hilligmann & Regenstir, Bone 2010; Jönsson et al, Osteoporos Int. 2011; Chau et al., J Med Econ. 2012; and Stopeck et al, J Med Econ. 2012) but except for the Stopeck study, these evaluated benefit in the treatment of post-menopausal osteoporosis, not in the far more challenging and relevant context of SRE prevention in malignancies, so the data remains inconsistent, although I would largely agree with the recent JCO editorial conclusion of "Incremental Benefit, Debatable Value" [13], with near-twice cost of zoledronic acid translating to as the editorial notes an estimated increase in costs of hundreds of millions of dollars per year to the US health care system, and I would note in fact soon to be vastly higher given that the 2013 introduction of a generic version of zoledronic acid, leaving it an open question whether the modest incremental gains provided by denosumab therapy justify such a disproportionate increase in cost, and so demanding a highly cautious case-by-case determination.

Finally, I have noted to the FDA, to UK's NICE and other evidence-based authorities that we in fact do not know what real-world denosumab can do: in the vast number of patients in the trials, the groups were denosumab-naive versus zoledronic acid-naive populations, but I would argue that increasingly the real work of oncology practice presents a field with large numbers of patients being elected for denosumab therapy who have already been pre-treated with a bisphosphonate, almost invariably zoledronic acid, and no trial addressed this critical question, of whether denosumab is both safe and effective in zoledronic-pretreated populations, and given the very long in-dwelling residencies of bisphosphonates and their incorporation into the bone matrix, it is far from clear to this researcher that denosumab would exhibit the same benefits as it does now in the more artificial environment of zoledronic-naive patients.

References

1. Valachis A, Polyzos NP, Coleman RE, et al. Adjuvant therapy with zoledronic Acid in patients with breast cancer: a systematic review and meta-analysis. Oncologist 2013; 18(4):353-61.

2. Sun L, Yu S. Efficacy and Safety of Denosumab Versus Zoledronic Acid in Patients With Bone Metastases: A Systematic Review and Meta-analysis. Am J Clin Oncol 2012 Oct 8.

3. Peddi P, Lopez-Olivo MA, Pratt GF, Suarez-Almazor ME. Denosumab in patients with cancer and skeletal metastases: a systematic review and meta-analysis. Cancer Treat Rev 2013; 39(1):97-104.

4. Ford JA, Jones R, Elders A, et al. Denosumab for treatment of bone metastases secondary to solid tumours: systematic review and network meta-analysis. Eur J Cancer 2013; 49(2):416-30.

5. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin KdB, Lichinitser RH, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28:5132–5139.

6. Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813–822.

7. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29:1125–1132.

8. Misso G, Porru M, Stoppacciaro A, et al. Evaluation of the in vitro and in vivo antiangiogenic effects of denosumab and zoledronic acid. Cancer Biol Ther 2012 Dec 1; 13(14):1491-500.

9. Toulis KA, Anastasilakis AD. Increased risk of serious infections in women with osteopenia or osteoporosis treated with denosumab. Osteoporos Int. 2010;21(11):1963–1964.

10. Qiao G, Zheng S, Qi W, Min D, Shen Z, Yao Y. Comparison of efficacy and safety of denosumab versus zoledronic acid for treating skeletal-related events caused by bone metastasis in patients with malignant solid tumors and multiple myeloma: A Meta-analysis of randomized controlled trials. Tumor 2013; 33(1):48-57.

11. Drooger JC, van der Padt A, Sleijfer S, Jager A. Denosumab in breast cancer treatment. Eur J Pharmacol 2013 Mar 29.

12. Lamoureux F, Moriceau G, Picarda G, Rousseau J, Trichet V, Redini F. Regulation of osteoprotegerin pro- or anti-tumoral activity by bone tumor microenvironment. Biochim Biophys Acta. 2010;1805:17–24.

13. West H. Denosumab for prevention of skeletal-related events in patients with bone metastases from solid tumors: incremental benefit, debatable value. J Clin Oncol 2011 Mar 20; 29(9):1095-8.

i really appreciate this correspondence. Over the yyears i treated many VIP patients with this condition. Almost all 200 plus of them had a modified mastectomy to have the tumor removed, which was also used for biological studies. All patients received Zometa (or earlier Aredia) . Almost all patients were hormone receptor positive and received aromasin (some earlier pts received femara) All patients received low dose Xeloda 1 g BID 1 week on 1 week off which was much better tolerated than the 2 wk scchedules at twice the dose levels. Some of the younger patients with multiple bone mets involving their spine also received adria plus taxol or carbo plus taxol for 3 cycles after their surgery. some needed vertebroplasty when they presented with excruciating spine pain and the same patients also received palliative radiation to the site. With a 10 plus year follow up no one progressed. most importantly, we stopped treatments after 3 years except for Zometa.

Some one in my family now has this condition and she is reveiving her treatments at a University based breast center in Germany. She had no surgery. she had no chemotherapy. she received femara and zometa. After one year she was switched to Aromasin plus zometa. And she was most recently switched to affinitor plus denosumab plus aromasin. I am not involved in her care but will share this info with her so she can discuss it further with her treating doctors.

I'd like testing the Capecitabine or UFT or S-1 in a one week on, one week off schedule, but with a priming dose of IV 5-FU of around 400 mg/m2 on day one each week on, as in the de Gramont regime for CRC, it may help reaching faster the steady state concentrations in blood, and is an approach proven beneficial very early in the UFT studies, but Cape differs to other Oral FPs in that it's tumor activated. Sorry, I don't see patients now.

when using 5-FU the daily iv regimens in older CRC patients make people really sick in contrast to weekly 250-500 mg per m2 dose levels. This one week on and one week off approach also helped us back then using iv drugs every 2 weeks and combining them with Xeloda. example Irinotecan every two weeks and xeloda starting after first dose and continuing for a week. then no xeloda until the 2nd dose of Irinotecan. the dose levels for Xeloda were kept at 1-1.5 per dose BID. Or in MBC, weekly Herceptin plus Xeloda etc

back then I really liked Xeloda. I used to think I start at a low dose assuming the worst case scenario and best case scenario. in the worst scenario, patient metabolism would render Xeloda at higher doses very toxic ( hence the lower dose) and tumor cells might be quite sensitive in the best case scenario even to a little bit of TS inhibition (hence the low dose). So in patients 60 and older, or patients with IHD or MI, we were able to achieve excellent patient compliance with reduced dose levels. This was some 10 years ago.

The Xeloda technical file now includes the possibility of LV modulation, with Capecitabine doses of 850 mg/m2 bid, and the Manual of Oncology by D Casciato and M Territo points that when used for modulating FluoroPyrimidines, LV should be dosed at least 30 to 60 minutes before the FP, to allow sufficient time to metabolism taking place; missing this may be among the reasons for the very wide range of LV doses used to modulate FPs?, there are also old hints that in regimes like the Al-Sarraf and derivatives, a possibility exists of giving FU before CisPt and obtaining better results, and early data also pointed that FU before CDDP at equitoxic doses may give the same CBR with a reduced Drug use. Any comments on both things?

1. Cancer Chemother Pharmacol. 2008 Oct;62(5):745-52. Epub 2007 Dec 13.

Pretreatment with 5-FU enhances cisplatin cytotoxicity in head and neck squamous

cell carcinoma cells.

Ijichi K, Adachi M, Hasegawa Y, Ogawa T, Nakamura H, Kudoh A, Yasui Y, Murakami

S, Ishizaki K.

Central Laboratory and Radiation Biology, Aichi Cancer Center Research Institute,

1-1 Kanokoden, Chikusa-ku, Nagoya, Japan. [email protected]

Comment in

Cancer Chemother Pharmacol. 2009 May;63(6):1181-3.

PURPOSE: In the treatment of head and neck malignancy, cisplatin and 5-FU have

been used the most as chemotherapeutic agents. The difference in efficacies of

these is unclear and controversial. To investigate more effective schedule, we

analyzed the cytotoxicity in different treatment sequence with two agents in

vitro and the mechanism for different effectiveness.

METHODS: UM-SCC-23 and UM-SCC-81B, head and neck squamous cell carcinoma cell

lines, were analyzed for cellular killing in alternative sequence treatment with

cisplatin and 5-FU. The treatment schedule was designed based on the clinical

regimen. To determine the mechanism for the difference of cytotoxicity with each

schedule, cell cycle distributions of both cells after 5-FU treatment with

various durations were analyzed by flow-cytometry and immunostaining with

anti-PCNA and anti-BrdU.

RESULTS: 5-FU pretreatment followed by cisplatin treatment showed higher cell

killing in both types of cells than the reverse treatment schedule. In the cell

cycle analysis and immunostaining after the treatment of 5-FU, the rate of

PCNA-positive cells was increased from 24 to 144 h in both cells. The rate of

BrdU-positive cells of UM-SCC-81B in flow-cytometry was also increased, while

that of UM-SCC-23 was gradually decreased. These data suggested that the cells

treated with 5-FU for more than 144 h were still in the S-phase with or without

DNA synthesis.

CONCLUSIONS: In head and neck carcinoma cells, we showed 5-FU pretreatment

enhanced cisplatin cytotoxicity. The result of cell cycle analysis and

immunostaining showed S-phase arrest by treatment of prolonged 5-FU treatment.

The very long arrest in S-phase might be a mechanism to enhance cisplatin

cytotoxicity by 5-FU pretreatment. We thus suggest pretreatment with 5-FU to

enhance the effectiveness of cisplatin-based chemotherapy.

PMID: 18075740 [PubMed - indexed for MEDLINE]

Another one in the same line, will this bite the dust?

1. Anticancer Res. 2001 Jul-Aug;21(4A):2463-9.

Pretreatment with 5-fluorouracil enhances cytotoxicity and retention of DNA-bound

platinum in a cisplatin resistant human ovarian cancer cell line.

Tanaka T, Masuda H, Naito M, Tamai H.

Department of Surgery, Kyushu Dental College, Kitakyushu, Japan.

A combination of 5-fluorouracil (5-FU) and cisplatin

(cis-Diamminedichloroplatinum(II); CDDP) was administered to CDDP-sensitive

(A2780) and -resistant (2780CP) human ovarian cancer cell lines in vitro in order

to investigate the effects of 5-FU pretreatment on CDDP cytotoxicity, removal of

DNA-bound platinum (Pt-DNA) and cellular glutathione (GSH) level. The cells were

incubated with various doses of 5-FU for 24 hours, and then exposed to various

doses of CDDP after a drug-free interval of 24 hours. Pretreatment with 5-FU (0.5

- 2.0 microg/ml) augmented the cytotoxicity of CDDP in 2780CP cells, but did not

affect A2780 cells. 2780CP cells lost 23.0 to 41.9% of their total Pt-DNA

determined by flameless atomic absorption spectrophotometry at 6 to 24 hours

after exposure to 10.0 microg/ml CDDP alone; nevertheless, 1.0 microg/ml 5-FU

pretreatment caused a significant delay in removal of Pt-DNA (3.8, 1.5 and 7.2%

at 6, 12 and 24 hours after exposure to CDDP, respectively). At 24 hours after

15.0 microg/ml CDDP exposure, 2780CP cells pretreated with 5-FU lost only 15.7%

of their total Pt-DNA, although the platinum removal rate with CDDP alone was

28.4%. The GSH levels in 2780CP cells were similar in the presence or absence of

5-FU pretreatment. These data indicated that 5-FU pretreatment enhances the

cytotoxicity of CDDP and reverses CDDP resistance in 2780CP cells and that its

mechanism is related to the inhibitory effect of 5-FU on DNA repair, and not to

cellular GSH levels.

PMID: 11724308 [PubMed - indexed for MEDLINE]

i dont have much experience with cisplatin combination. I used Cisplatin plus taxol combination instead of the cisplatin 5 FU combination.

Dr Cesar Mendiola published in Clinical & Translational Oncology a case report of a woman with a metastatic NSCLC that had good and lasting responses with capecitabine, I guess he was pioneer in the posterior use of drugs such as S-1 in NSCLC, besides the Japan trials on adjuvant therapy for NSCLC with UFT. Early reports with LV+ UFT or LV + 5-FU in NSCLC were not very good, the OncoPaz group reported some trials on this many years ago, but perhaps the subject of LV modulation or not and of Fluoropirymidines for non-Squamous Cell, NSCLC may be worth considering again, now we can assay DPD and TS, that have prognostic value on the kind of CT agent an individual case of NSCLC will respond, but we always meet the Wall of tumor heterogeneity, both in space and in time, and wer'e not very sure of how good the tactics of rotating agents with different mechanisms of resistance is valuable, unfortunately very few patients with advanced cancer live long enough as to prove or dismiss the concept of rotation of Cancer therapy agents. Salut +

I wonder if it was perhaps a neuroendocrine tumor. Capecitabine has been shown to be active against such malignancies in a Phase II UK trial (PI: Dr. DC Talbot, Dr. Nick Reed, Dr David Famuia). I would typically use vinorelbine or Gemzar + Vinorelbine (no Gemzar if patients required radiation therapy) in such patients. But i did not see more than 20 patients alltogether. But vinorelbine + xeloda probably would also be an active combination.

dear dr Fatih: thanks for your attention. No it wasn't a Neuroendocrine Tumor, at least the article stated without no room for doubt that it was an Adenocarcinoma, full text of article can be accessed at Springer, but if I remember well, the text is in Spanish language, hope automatic web page translators may give an acceptable english version. Salut +

1. Clin Transl Oncol. 2009 Aug;11(8):554-7.

Is capecitabine a new choice of treatment for lung adenocarcinoma? A case report

involving partial response in second line of treatment and hypothesis of the

biological basis.

Mendiola C, Vaz MA.

Médicos Colaboradores en Oncología Médica, Hospital Ruber Internacional, Madrid,

Spain.

In lung cancer different histologies have different biologies. Active agents in

non-small-cell lung cancer (NSCLC) include platinums, paclitaxel, docetaxel,

gemcitabine, erlotinib, pemetrexed and vinorelbine. We report a case of a patient

with metastatic lung adenocarcinoma with high levels of LDH and CEA with clear

partial response to capecitabine after several lines of chemotherapy. The

increase in thymidine phosphorylase (TP) expression in NSCLC could provide a

rationale for the use of capecitabine in this tumour. More research is needed to

try to explain the striking activity of capecitabine in this patient with lung

adenocarcinoma and high levels of CEA and to find molecular targets to predict

the response to this agent.

PMID: 19661033 [PubMed - indexed for MEDLINE]

It might be interesting to use Xeloda in combination with Alimta as the activity of thymidylate synthase (target for Xeloda) has been shown to render NSCLC patients resistant to Alimta.

http://www.ncbi.nlm.nih.gov/pubmed/21487406

It is of course noteworthy that in a very nice study from Japan, an oral fluoropyrimidine derivative that is also currently under evaluation for the treatment of NSCLC as a thymidylate synthase–targeted agent has been shown to enhance activity of EGFR targeting agents

http://mct.aacrjournals.org/content/9/6/1647.long

Sequential MTX -5-Fu is also one of my fovorite CombinationChemotherapy schedules

Int J Cancer. 1991 Feb 1;47(3):401-7.

Schedule-dependent in vitro combination effects of methotrexate and

5-fluorouracil in human tumor cell lines.

Tsai CM, Gazdar AF, Perng RP, Kramer BS.

Chest Department, Veterans General Hospital-Taipei, Taiwan, Republic of China.

Because of conflicting reports of clinical synergy, we used the tetrazolium-based

colorimetric (MTT) assay to test in vitro combination effects of methotrexate

(MTX) plus 5-fluorouracil (FUra) in 4 schedules on 2 human non-small-cell lung

cancer cell lines (adenocarcinoma, NC1-H23; bronchio-alveolar-cell carcinoma,

NC1-H358), and 1 human colorectal adenocarcinoma cell line (SNU-C1). The complete

3 dimensional set of isoboles in the dose range under study was generated by a

microcomputer-based method. We found that the combination effects of 8-hr

sequential FUra-MTX, simultaneous administration of MTX-FUra, and 8-hr sequential

MTX-FUra were clearly antagonistic for all 3 cell lines. In contrast, the

combination cytotoxic effects of 24-hr sequential MTX-FUra were much more active.

Our in vitro model thus clearly shows that MTX-FUra interactions are highly

schedule-dependent. This provides a rational basis for testing sequential

MTX-FUra with a longer administration interval than usually employed clinically.

PMID: 1847123 [PubMed - indexed for MEDLINE]

Cancer Res. 1985 Jul;45(7):3354-8.

Sequential infusions of methotrexate and 5-fluorouracil in advanced cancer:

pharmacology, toxicity, and response.

Benz C, DeGregorio M, Saks S, Sambol N, Holleran W, Ignoffo R, Lewis B, Cadman E.

Preclinical studies have suggested that synergistic antitumor toxicity occurs

when methotrexate (MTX) is administered prior to 5-fluorouracil (FUra). A

protocol of sequenced, overlapping infusions of MTX and FUra was designed to

achieve 5 microM MTX serum levels lasting 36 h and 1 to 5 microM FUra levels

lasting 24 h, with leucovorin started at the end of the MTX infusion. Thirty-nine

patients with metastatic neoplasms received a total of 127 treatment courses;

two-thirds of the patients had received prior treatment with radiation therapy or

chemotherapy; most of the latter treatment regimens included MTX or FUra. In

three patients, the duration of FUra infusion was prolonged up to 72 h to

determine the toxic limits of therapy. Blood samples were collected during

treatment courses to estimate the half-lives and total-body clearances of MTX and

FUra. The initial serum half-lives and total-body clearances of both MTX and FUra

appeared within the range of reported normal values. The terminal half-life of

MTX appeared less than previously reported values, and there appeared to be a

substantial delay in achieving a FUra steady-state concentration; these two

differences may have resulted from either the prolonged intervals of drug

infusion or from metabolic interaction between the two drugs. During the 127

courses of treatment, nearly one-half of the patients experienced mild toxicity

occurring after at least one treatment, but this toxicity was predominantly Grade

I mucositis and/or diarrhea. Of the three patients who received extended

intervals of FUra infusion, none was able to tolerate more than 48 h of FUra

without developing mucositis. Thirty-four patients were evaluable for response;

no one experienced a complete response, but 11 (32%) patients had either a

partial or minimal response. Adenocarcinomas as a group, arising from the lung,

gut, breast, and unknown site, appeared to respond best. Sequenced MTX-FUra

infusion by this schedule is a generally well-tolerated regimen that deserves

further clinical assessment.

PMID: 4005858 [PubMed - indexed for MEDLINE]

Comput Biomed Res. 2000 Jun;33(3):211-26.

Optimizing drug regimens in cancer chemotherapy by an efficacy-toxicity

mathematical model.

Iliadis A, Barbolosi D.

Department of Pharmacokinetics, Faculty of Pharmacy, University of Marseilles,

27, boulevard Jean Moulin, Marseille Cedex 5, 13385, France.

In cancer chemotherapy, it is important to design treatment strategies that

ensure a desired rate of tumor cell kill without unacceptable toxicity. To

optimize treatment, we used a mathematical model describing the pharmacokinetics

of anticancer drugs, antitumor efficacy, and drug toxicity. This model was

associated with constraints on the allowed plasma concentrations, drug exposure,

and leukopenia. Given a schedule of drug administrations, the mathematical model

optimized the drug doses that can minimize the tumor burden while limiting

toxicity at the level of the white blood cells. The main result is that the

optimal drug administration is an initial high-dose chemotherapy up to saturation

of constraints associated with normal cell toxicity and a maintenance continuous

infusion at a moderate rate. Data related to etoposide investigations were used

in a feasibility study. Simulations with the optimized protocol showed better

performances than usual clinical protocols. Model-based optimal drug doses

provide for greater cytoreduction, while limiting the risk of unacceptable

toxicity.

Copyright 2000 Academic Press.

PMID: 10860586 [PubMed - indexed for MEDLINE]

Anticancer Res. 2012 Dec;32(12):5407-14.

Evaluation of 5-FU Plasma Concentration by 13C Breath Test in Patients Treated

with Oral 5-FU Analogs.

Higashida M, Matsumoto H, Kubota H, Murakami H, Kawabe Y, Nakashima H, Oka Y,

Okumura H, Nakamura M, Hirai T.

577 Matsushima, Kurashiki, Okayama 701-0192, Japan. [email protected].

Background/Aim: The objective of this study was to investigate the influence of

digestive gastrointestinal absorption function on the pharmacokinetics of the

orally-administered anticancer drug, Tegafur-gimestat-otastat potassium (TS-1),

by measuring the plasma 5-fluorouracil (5-FU) concentration using stable isotope

breath tests.PATIENTS AND METHODS: Twenty-nine patients with

progressive/recurrent digestive organ cancer were enrolled for this

pharmacokinetic study, and blood samples were obtained from each patient. The

area under-the-time-concentration curve between 0 and 480 min (AUC0-480 min),

time-of-drug concentration peak (T(max)), maximum drug concentration (C(max)) and

the half-life period (t(1/2)) of 5-FU were investigated. Simultaneously, a

continuous (13)C-acetate breath test was performed for each patient. The

parameters measured with the breath test were the area under the (13)CO(2)

excretion rate curve between 0-4 h (AUC(0-4h)), peak (13)CO(2) value and

elimination rate constant (K(el)) value.

RESULTS: The AUC(0-8h) and C(max) of 5-FU were significantly correlated with

K(el) (p=0.012 and p=0.024, respectively), and the 5-FU C(max) value was

significantly correlated with the peak value of (13)CO(2) (p=0.037). Multivariate

regression analysis also found the C(max) of 5-FU to be associated with K(el)

(p=0.0118). The C(max) and AUC(0-8h) of 5-FU were also significantly correlated

(p

I forgot saying, that soon after the original article by Gewirtz about sequential MTX - 5FU in advanced Breast cancer was published, and after in one of my patients, nursery forgot to adminsiter all of the doses of LV that Gewirtz advised as rescue, one every 4 hours, 6 10 mg LV doses in total, and nothig happened to this patient, but Gewirtz stated that LV was necessary, and it also stabilized TS. As not long after the start of Capecitabine use, a case of Capecitabine toxicity was published in a patient that had received before LV modulating 5-FU, the authors pointed that the organism was saturated with folates, and even in the absence of actual LV concomitant dosing with Capecitabine, the patient sufferd the toxicity that initially made advisable not to dose LV with Capecitabine; as discussed, the possibility of LV + Xeloda is today in the technical data file, of dosing LV and then Capecitabine in a reduced dosage of 850 mg / m2 bid, my doubt is about reducing the LV rescue after sequential MTX 5-FU to a single 10 mg dose, 10 mg LV is many, many times the daily amount of Folic acid an adult needs, and at least from a theoretical point of view, it can be proposed that if you give too much LV in the first CT courses, the next dosings of MTX may lack action, as the LV present in the body contrarrests the MTX antifolate action. Probably it can be tested, but today there are better drugs than this in advanced Breast ca, perhaps a patient having exhausted all known lines may be put on this as salvage therapy, but it's an ancient concept. Regards, salut +

Dear Jose,

Like you don't need to worry about bladder toxicity unless you use high doses of Cytoxan, you probably don't need to worry about neurotoxicity at low MTX doses. My assumption would be that LV in the Gewirtz study probably served to enhance 5FU activity rather than prevent MTX neurotoxicity. What was suggested to the nurse is not a high enough dose to prevent neurotoxicity from high dose MTX. Was a MTX level ever determined ?

But the use of LV in combination with Xeloda probably would be a little risky for some patients, especially for patients with ischemic heart disease. As you said, there are too many other options to choose from anyway.

Hello again Fatih!: No, the nurses' action of missing all 6 10 mg / m2 Oral LV doses, one every 4 hours, was their mistake, no indication from anybody was given about this. The MTX in the Gewirtz regime is 200 mg / m2, then at least one hour later 5-FU 600 mg / m2, both drugs in the same schedule and doses repeated one week later, then 2 weeks of rest (Gewirtz said that the longer the time between the MTX and the 5-FU dosing, up to 24 h, would increase efficacy, but feared toxicity and advised not to widen the gap without further data from testing on the schedule, however, some used later a 24 h lapse between the MTX and the following 5-FU IV dosing, and no relevant increase in toxicity was described) The chances of having Neurotoxicity from this range of doses [200 mg / m2 MTX] are low, and I guess the idea of Gewirtz in advising these 6 doses of 10 mg / m2 LV was preventing Hematologic toxicity; as the range of MTX doses in this protocol is much lower than in the usual high-dose MTX regimes, where the number of LV rescue doses is mandatorily guided by the blood MTX levels, the measuring of MTX levels with the Gewirtz sequential MTX / 5-FU doses of 200 mg / m2 MTX +1h, then 600 mg / m2 5-FU was not even envisaged. Thanks for your interest. Salut +

Hello Jose. Thanks for this clarification.

Regarding the complex issue of intermediate dose MTX and LV rescue, professor Garcia-Foncillas, head of the Medical Oncology dept in the Jimenez Diaz Foundation (FJD, Madrid, Spain) told me that if you add folates, the tumor becomes 'metabolically addict' to the pathways that include folates, and this may add in the Anti-folates having a greater effect, however, as it's long ago known, among others, from the papers of Goldie & Coldman and of Norton & Simon, any anticancer drug you may use, unless it obtains a log cell killing high enough to erradicate stem cells, in a shorter or longer lapse selects cells resistant to the drug, that would be the ones in the regrowth, relapse or progression of tumor, and not always tumors are homogeneous from primary to metastasis, or from one part of a lump to other region in the same lump, this is in the basis of the concept currently explored of switching drugs in maintenance therapy of NSCLC having reached at least Stable Disease after 4-6 CisPt containig doublet courses, no more are needed, and this rationale can be used also in advanced Stage IV Breast Cancer, where we know that Sequential Single Agent Therapy is the approach most adapted in terms of RFS, safety and tolerability, metastatic Cancer differs from the Adjuvant setting in that the goal is just palliation, and you can't apply a remedy that is worse than the disease it's intended for. Thanks for your attention. Salut +

On the general subject of metastasis, you can watch in www.e-esmo.net a lecture by Elizabeth Comen, held in April 11, 2013 and recorded, of free and open access, entitled: 'New paradigms to explain metastasis'. Salut +

Fatih, Jose:

An Update on Bone Metastasis from ASCO 2013

The results from the Italian retrospective observational multicenter study conducted by Nicola Silvestris and colleagues was just reported at ASCO 2013 (2 Jun), reviewing the natural history of gastric cancer (Non-CRC) patients with bone metastasis. Median survival (undifferentiated population) was 6 months after diagnosis of bone metastasis but only 3 months after first SRE (skeletal-related event), while for patients who did not experience SREs, median survival was 5 months. Most importantly was the benefit when zoledronic acid was received early, before the first SRE, with a median time to the first appearance of SRE being significantly prolonged (7 months) compared to control (4 months). P:0.0005). In all this to-date largest multicenter study of bone metastases from gastric cancer demonstrated, against conventional wisdom, that in fact bone metastases are not so rare, and are typically aggressive with relatively early onset of SREs in the majority of patients, although, positively, zoledronic acid significant extended the time to first SRE and in addition increased median survival after diagnosis of bone metastasis. In a similar review of NSCLC (Kuchuk et al, ASCO 2013), median overall survival for patients with bone metastases with SRE was 5.5 months (6.4 for those without), without largely comparable results from another retrospective survey (Aantine et al., ASCO 2013) where median survival after bone metastases diagnosis was 8 months but reduced to 6 months after first SRE. In addition, it's being demonstrated (Salem et al., ASCO 2013) for NSCLC that the development of new bone metastases may be predictive of subsequent development of brain metastases (shorter brain metastases-free interval), but anti-VEGF/antiangiogenic therapy (bevacizumab) decreased the likelihood of developing bone metastases within 2 years from 43% to 27%, suggesting that anti-VEGF therapy can positively influence the development of both bone and brain metastasis in NSCLC.

In a retrospective review (Yasuda et al., ASCO 2013) of patient with bone metastasis from renal cell carcinoma (RCC), the zoledronic-treated group demonstrated significantly longer OS (80.8% 1-year survival) compared to the non-zoledronic-treated group (59.1%), showing that zoledronic acid not only reduces SREs but can improved overall survival in RCC patients.

In the breast cancer context that I have already systematically and critically reviewed (see above), it has been demonstrated that the addition of zoledronic acid to neoadjuvant chemotherapy improves both response and survival - independently of any bone metastasis - in resectable invasive Stage IIA-IIIB breast cancer HER2-negative patients for both postmenopausal BC patients and in those with triple-negative breast cancer, with the pCR rate increased threefold or more in postmenopausal women (from 5.4% to 18.4%) and also in women with TNBC (from 11.8% to 35.3%), and even more dramatically, in postmenopausal women with TNBC, the pCR rate with zoledronic acid was an exceptional 50% compared to 0% in the same group on chemotherapy alone.

These just reported (May 31 - June 4th, 2013) results continue to confirm:

(1) the unsettlingly grim (even compared to visceral metastases) prognosis of most bone metastasis in several malignancies (gastric cancer, NSCLC, and RCC, and others reviewed by me previously), especially after development of first SRE which generally happened early unless zoledronic acid was instituted early;

(2) the positive benefit of zoledronic acid on overall survival (not to date consistently and robustly established with denosumab);

(3) that in certain contexts like breast cancer - and likely others, pending data to be released - the addition of zoledronic acid to chemotherapy even in the absence of frank bone metastasis may dramatically increase pCR and positively influence outcome, and

(4) that in certain contexts (NSCLC; other data pending) the addition of anti-VEGF/antiangiogenic therapy may significantly (by almost half) reduce the risk of the development of bone (and brain) metastasis. (In settings where bevacizumab access is problematic, I use metronomic therapies which are highly antiangiogenic (a "poor man's anti-VEGF/bevacizumab") such as ULD (ultra low-dose) continuous capecitabine or metronomic CM, among others).

Constantine Kaniklidis

Director of Medical Research,

No Surrender Breast Cancer Foundation (NSBCF)

European Association for Cancer Research (EACR)

Brand new, fresh report: 'identifying the metastatic seeds of Breast Cancer' . Angera H Kuo and Michael F Clarke, Nature Biotechnology 2013, 31, 504-505 . You'll tell us!

Jose:

It's an thoughtful, intelligent commentary by two Stanford researchers, Angera Kuo and Michael Clarke, on the issue of metastasis initiation via CTCs (circulating tumor cells), based on two just published studies, (1) the German study [Baccelli et al., Nature Biotechnology 2013] on the identification of CTC BC cells that are metastasis-initiating in a xenograft assay, and (2) the Baylor/MDA study [Zhang et al., Sci Transl Med 2013] on the identification of a protein signature for CTC metastatic competency to the brain in CNS metastases from breast cancer.

Although the studies are competent, both speculate on the potential characterization of some subset of the metastasis-initiating CTCs as cancer stem cells (CSCs), and here, as with so many investigators, they enter questionable ground. Why? Because the only FDA approved CTC assay is CellSearch which explicitly identifies any blood cell as a CTC if and only if it binds with a EpCAM-specific antibody. The Baccelli study uses a phenotype of EpCAM+ (along with CD44, putatively a CSC marker), while the Zhangg study - investigating precisely the same question - uses EpCAM- cells (with ALDH, another putative CSC marker), but both are introduced into a mice host to observe (a) metastasis-initiation in gneral, and (b) in the Zhang study, brain metastasis in particular, and both again positing a subpopulation of claimed CSC as integral to the metastatic cascade.

But problem is that the metastasis-initiating cells (MICs) identified in these two studies in fact represent two quite different populations: EpCAM+ (with CD44+) and EpCAM– (with ALDH+), and no plausible explanation can be easily derived as to how this inconsistency arises or is resolvable, especially difficult since the two studies used different breast cancer subtypes.

This underlines for me a concern I have oft stated and discussed, namely of whether tumor metastasis formation is restricted to or coextensive with cancer stem cells (CSCs), a question posited by Yuzuru Niibe in these forums on ResearchGate and in his own publications, apparently under the wide-spread assumption that the answer is in the affirmation. This is incorrect and against the evidence, as I have demonstrated in my lengthy evidence-based review and response to his query.

What the evidence supports as I concluded is:

(1) CSCs are neither necessary, nor sufficient (as to their insufficiency, this is a point my colleague Fatih Uckun has shrewdly made earlier), for metastasis formation, and going beyond this, that more broadly, neither are CSCs necessary or sufficient for cancer in general, neither for carcinogenesis nor tumorigenesis, and I am arguing for a more nuanced appreciation of the difference between metastasis-initiating cells (MICs), and tumor-initiating cells (TICs), on the one hand, and cancer stem cells (CSCs) on the other, and indeed as these two dueling inconsistent studies suggest, and as I have marshalled evidence to support, tumorigenic cells cannot be distinguished by common CSC markers at all, leading to a fundamental problem of lack of coherent identification.

It is clear therefore as I argued, on the evidence, that for both metastasis-formation and for carcinogenesis / tumorigenesis, cancer stem cells (CSCs) need not (always) apply. This brings us away from the miasma of the cancer stem cell (CSC) hypothesis as somehow an "Ur-process" of all cancer, to a more mature perspective that I have been advocating against the CSC "hyper"-media, that:

(1) not all that is significant that needs to be said about metastasis is said by the CSC hypothesis, and

(2) not all that is significant that needs to be said about cancer is said by the CSC hypothesis.

With, to date after decades (40+ years) of CSC research and hundreds and hundreds of published papers, the absence of any methodologically robust human clinical - not just preclinical animal-model level - evidence of the cancer stem cell (CSC) hypothesis as critical to carcinogenesis, tumorigenesis, malignant transformation and metastasis formation - indeed after four decades we even lack any evidence of dedifferentiation as occurring in primary tumors in vivo - the business of unraveling oncogenesis and the abiding mysteries of cancer and metastasis goes on, and remains wider, and significantly beyond, just the constrained scope and boundaries of the cancer stem cell (CSC) hypothesis.

So the sooner researchers, and their research funding, begin to cease to see CSCs everywhere, and realize the inherent limitations in the explanatory adequacy and sufficiency of the currently immature cancer stem cell (CSC) hypothesis, the more research initiatives can refocus energies in more productive directions until robust confirmatory human clinical data on CSCs arrives, if it shall. And until such time of proof of concept, it is unlikely that targeting putatively rare - I have in fact argued and shown that they are often not in the slightest bit rare - CSCs will have any clinically relevant effect on real patient outcomes, but rather will continue to stand as an ineffective and unfounded therapeutic strategy.

I had long time ago the idea that UPA and PAI1, proposed as markers of aggressiveness of Breast cancer, an issue now more centered for everyday practice in things such as Ki67, was, as it are an equivalent of Fybrin Degradation Products, a marker that some intravascular activation of coagulation cascade was taking place, and as vascular endothelium lesions are a trigger of intravascular coagulation, if UPA and PAI1 may be just a marker that cancers cells went through the vessels' walls in its way from epithelial to mesenchimal transition. Is this a sound rationale? Thanks, I always wonder the reason why you give such a good teaching as the one you're giving for free! Salut +

A pair of references: 'Implications of Bone Only metastasis in Breast cancer: Favorable Preference with Excelent Outcomes of Hormone Receptor Positive Breast cancer'; Ju Jin Lee et al, Cancer Res Treat 2011; 43(2): 89-95

and

1. World J Surg Oncol. 2013 Jun 4;11(1):127. [Epub ahead of print]

Eradication of breast cancer with bone metastasis by autologous formalin-fixed

tumor vaccine (AFTV) combined with palliative radiation therapy and adjuvant

chemotherapy: a case report.

Kuranishi F, Ohno T.

Skeletal metastasis of breast carcinoma is refractory to intensive

chemo-radiation therapy and therefore is assumed impossible to cure. Here, we

report an advanced case of breast cancer with vertebra-Th7 metastasis that showed

complete response to combined treatments with formalin-fixed autologous tumor

vaccine (AFTV), palliative radiation therapy with 36 Gy, and adjuvant

chemotherapy with standardized CEF (cyclophosphamide, epirubicin, and 5FU),

zoledronic acid, and aromatase inhibitors following mastectomy for the breast

tumor. The patient has been disease-free for more than 4 years after the mammary

surgery and remains well with no evidence of metastasis or local recurrence.

Thus, a combination of AFTV, palliative radiation therapy, and adjuvant

chemotherapy may be an effective treatment for this devastating disease.

PMID: 23734861 [PubMed - as supplied by publisher]

Enjoy it!

Salud †

A new general reference about mts

http://www.cancerworld.org/Articles/Issues/56/September-October-2013/e-Grand-Round/619/New-paradigms-to-explain-metastasis.html