Could be a so “important question” a “silly question”? Cioè a questa domanda si può semplicemente rispondere con un sì o con un no ?

Perché la domanda non sia una “silly question” è importante valutare: Cose abbastanza ovvie ad es. : il periodo del quale un certo trattamento è stato approvato per l’uso clinico L’effettiva diffusione che quel trattamento ha avuto nella pratica clinica Ma anche cose un poco meno ovvie: Le pazienti con malattia metastatica sincrona (perché?) popolazioni particolari (es. afro-americani) (perché?) I singoli sottogruppi biologici di pazienti (perché?)

Il quadro sembra essere il seguente… “grosso modo” Il quadro sembra essere il seguente…

Ma………

Cohort 4: 2006-plus A disturbing trend was that the aggressiveness of the disease when it appeared increased between cohort 1 and 4: the percentage of patients with visceral disease (metastatic disease appearing in organs such as the lung and liver) when first diagnosed with metastases increased from 33% to 45% between cohort 1 and 4.

Una mortalità invariata a fronte di un decorso più aggressivo Oggi, stiamo trattando le “stesse” malate di una volta?

Conclusions: Although survival in MBC remains unchanged over time, patients developing metastatic disease have a more aggressive disease that is presumably compensated by more effective treatment. This alteration of tumor biology in MBC may be explained by a negative selection of patients with adverse risk profiles due to the advantages of the adjuvant therapy. Migliore terapia adiuvante seleziona recidive più aggressive Se la sopravvivenza non cambia Allora vuol dire che c’è un miglioramento nelle terapie

Andiamo nel dettaglio

Cominciamo con delle curve in apparenza “sorprendenti”: la sopravvivenza del Ca mammario metastatico calcolata dal momento della diagnosi peggiora negli ultimi anni

Ma questa curva può essere suddivisa in 2 distinte parti, infatti abbiamo: OS in patients with MBC can be divided into A) the time interval between primary diagnosis and diagnosis of distant metastasis (MFS) (quello che chiamiamo “intervallo libero” ) B) the interval between diagnosis of metastasis and death (metOS). ( il periodo del “trattamento attivo della malattia metastatica” )

Anche questa prima parte della curva (intervallo libero) ha un andamento peggiorativo negli ultimi anni

Ma la seconda parte della curva (la parte del trattamento attivo) presenta un andamento sovrapponibile nel corso degli anni

In our hypothesis, the advantages in adjuvant therapy in the last decades lead to a negative selection of those patients who evidently experience distant recurrence. Hence, although we could not demonstrate an improvement in OS in MBC, we do not agree with the conclusion that there is no improvement in the management of MBC, as the present patients with distant disease are different than those presenting in the past.

Cerchiamo ora di vedere Come si comportano le pazienti con metastasi sincrone alla diagnosi che rappresentano invece un gruppo omogeneo dal punto di vista prognostico (nel senso che non sono state selezionate da una terapia adiuvante più o meno efficiente)

Patient Selection This study includes 724 consecutive breast cancer patients with metastases at diagnosis (stage IV). These patients have been treated in three French cancer centers (Institut Gustave Roussy,Villejuif; Centre Leon Berard, Lyon; and Centre Antoine Lacassagne, Nice) between 1987 and 2000.

(Paclitaxel, docetaxel, capecitabine, gemcitabine, oxaliplatin, trastuzumab)

Soprattutto in quali sottogruppi?

In conclusion, our study suggests that new treatments have allowed a survival improvement in breast cancer patients who present with metastasis at diagnosis. This survival improvement is dramatic in patients with HR-positive tumors, for whom median survival reaches 45 months.

The sample group for the present study was recruited from 6315 patients with breast cancer who were registered at the prospective tumour data bank of the two centres. A diagnosis of metastatic disease within 4 weeks after the initial diagnosis and before the start of any systemic treatment The date of diagnosis was used to define 2 specifically chosen 5-year time periods: 1998-2002 (first period, N = 90, first diagnosis during the period 1998-2002) 2003-2007 (second period, N = 126, first diagnosis in the period 2003-2007).

The time period of the first diagnosis was detected as a risk factor for overall survival. Those patients diagnosed in the more recent time frame had a significantly improved survival rate. The establishment of new therapy options may explain this finding.

This study includes 856 women who were diagnosed with de novo metastatic breast cancer between 1996 and 2010, in University Malaya Medical Centre (UMMC; 445 patients), Malaysia, National University Hospital (NUH; 185 patients), Singapore, or Tan Tock Seng Hospital (TTSH; 226 patients), Singapore. All three hospitals are tertiary referral centres, with prospective breast cancer registries since 1995 in UMMC and NUH, and 2001 in TTSH8,13

Substantial improvements in survival were observed in patients with de novo metastatic breast cancer in this Asian setting over the last two decades. This survival gain was largely attributed to improvement in treatment administrations

Popolazioni particolari (afro- americani) Perché studiarle ci fa capire alcune cose?

Among non-Hispanic white patients, overall survival and breast cancer–specific survival significantly increased (P .0001) over the three time periods. The absolute increases in overall survival and breast cancer–specific survival at 1 year from time periods 1 to 3 were 4.3% and 4.4%, respectively. However, no significant changes over time in overall and breast cancer–specific survival rates were observed among black women.

Accessibilità ai trattamenti In conclusion, our data support the results of other studies showing that over the past two decades, overall and breast cancer–specific survival of patients with stage IV breast cancer has improved. Although site of metastases may have had an impact on survival, we could not assess for this because SEER registry does not record this vital piece of information. In addition, our results indicate an increasing disparity in overall and breast cancer–specific survival over time between non-Hispanic white and black women with stage IV breast cancer. Accessibilità ai trattamenti

Accessibilità ai trattamenti Poor access to health care, less utilization of screening programs, comorbid conditions, and treatment differences have also been cited as causal factors for shorter survival in black women. If these factors have changed over time, they could potentially explain the widening disparity in survival between black and non-Hispanic white women.

I singoli sottogruppi di pazienti ?

Because the cohort consisted of a fully insured population with long-term membership sustainment, it is unlikely that survival rates by biologic subtype were highly dependent on treatment of recurrences. Because the cohort was assembled before the availability of Trastuzumab and AI these results more closely reflect the natural history of the disease in the absence of these targeted therapies, but they may not be generalizable to current practices. ma cosa succede proprio a quel gruppo di pazienti con la disponibilità dei nuovi trattamenti? Proprio quelli che andavano peggio…..

In summary, longer survival is strongly restricted to hormone receptor- and Her2- positive tumors most likely due to targeted therapies directed against the estrogen-receptor and Her2

In relazione ai trattamenti erogati Ritorniamo a considerare le popolazioni con neoplasia metastatica non-de novo In relazione ai trattamenti erogati

Cancer 2007;110:973–9. 2007 American Cancer Society.

In the early part of the 1990s, 25% of patients in BC did not receive any palliative systemic therapy, compared with only 10% in the later part of the decade. Thus, the current study appears to serve as a surrogate to suggest that systemic therapy for MBC is associated with improved survival. However, we believe there has never been a randomized controlled trial comparing a systemic agent with best supportive care to prove that survival can be improved by the treatment of MBC In the current era of multiple, active agents available forthe treatment of MBC, it is Iimprobable and likely unethical that this type of study ever will be performed.

Da poco per tutti A tanto per pochi….

Verso una possibile conclusione Le pazienti con malattia metastatica che osserviamo (recidive dopo le terapie adiuvanti oggi a disposizione) configurano un gruppo a peggiore prognosi Le pazienti con malattia metastatica de novo alle quali venga offerto un trattamento adeguato hanno avuto, nel corso degli anni un aumento di sopravvivenza Le pazienti che per motivi socio-economici non possono accedere ai trattamenti moderni, non hanno avuto, nel corso degli anni, un significativo aumento della sopravvivenza L’aumento di sopravvivenza osservabile è probabilmente ristretto a quei sottogruppi per i quali il maggior progresso è stato realizzato in termini di terapia target (RO+ / HER-2+) anche se non possiamo escludere che anche le migliori CT (Taxani) non possano avere influito positivamente Esistono comunque sottogruppi di pazienti per le quali, negli ultimi tempi, non si sono raggiunti significativi progressi in termini di OS (es. TNBC)

We should avoid false promises (which have occurred all too frequently in our field), but we should also avoid nihilism. The journey is worth taking, even if the goal currently seems elusive.

Ironically, only uncertainty is a sure thing. reminding ourselves of Osler’s maxim that “medicine is a science of uncertainty and an art of probability.” Ironically, only uncertainty is a sure thing. Certainty is an illusion.