Download silly question

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?)
“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.
a) Migliore terapia adiuvante
seleziona recidive più aggressive
b) Se la sopravvivenza non cambia
c) 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.
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
Her2positive tumors most likely due to
targeted therapies directed against the
estrogen-receptor and Her2
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.
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.