Stable Disease in Advanced Colorectal Cancer: Therapeutic Implications
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ANTICANCER RESEARCH 26: 511-522 (2006)
Review
Stable Disease in Advanced Colorectal Cancer:
Therapeutic Implications
LARA MARIA PASETTO1, MARIO ROSARIO D’ANDREA2,
ANTONIO JIRILLO1, ELENA ROSSI1 and SILVIO MONFARDINI1
1Medical Oncology Division, Azienda Ospedale – Università, Via Gattamelata 64, 35128 Padova;
2Medical Oncology Department, Azienda ASL13, Largo San Giorgio 3, 30033 Noale (Venezia), Italy
Abstract. Colorectal cancer is one of the most common 10-20% of the patients. When radical surgery resection is
neoplasms in Western Countries and ranks second as a cause not possible, chemotherapy has to be considered as purely
of death due to cancer. The overall mortality at 5 years is about palliative (2). With the introduction of new drugs, overall
40%. Patients with resectable metastatic disease can be cured, survival (OS) and toxicity have improved, and the duration
but for those who cannot, treatment is purely palliative, and of treatment has become longer. A recent question is how
overall survival (OS) is from approximately 7 to 24 months. far can a therapy be continued if there is only a stabilization
Infusional regimen with modulated 5Fluorouracil (5FU) gives of disease (SD) in "non responders" or if there is a SD
an objective response rate (RR) of up to 30-40%. The addition (therefore, a response stabilization) in initial "responders"
of CPT11 or oxaliplatin to 5FU improves RR, time to (with partial remission - PR - or complete remission - CR)
progression (TTP) and OS with a stabilization of disease (SD) and how important is SD for these patients. In this last case,
in 40-70% of cases and 20-40%, respectively. The concurrent the definition of SD means "no new tumors appear and only
utilization of selective biological agents as growth factor little change in the size of the known tumors", but it does
receptors acting at a molecular level and influencing the not mean "no change". For this reason, a small amount of
processes of tumor formation and growth, increases tumor cell growth over baseline is still considered to be SD. This is
apoptosis and inhibits tumor growth; as a result, the tumor appropriate since there is some uncertainty in all
regresses or is inhibited, with consequently prolonged OS and measurements, but it also means that over a short period of
TTP. This paper examines the problem related to the treatment time, continued growth can still be called SD even if the
of metastatic colorectal cancer with SD. Current doubts treatment is not effective.
regarding the continuation of one treatment until disease
progression (PD) with a risk of toxicity, whether or not to use How is stable disease determined? "Genetic" and
a less toxic "maintenance" therapy after a fairly aggressive "immunological" systems as well as the "microenvironment"
"induction" therapy in "stabilized" responders, or whether to of the tumor and host can, "spontaneously" or "induced by
stop the treatment in the presence of a SD confirmed after at pharmacological agents", determine SD. Slow growing
least two consecutive evaluations, are present. cancers, for a natural distribution of disease growth rate,
can easily appear to be relatively stable over short periods
Liver and lung metastases are the major cause of morbidity or have natural periods of relative stability; so it is often
and mortality in patients with gastrointestinal carcinomas unclear if SD is "tumor-" or "treatment-related".
(1). A curative resection of these metastases is possible in
Genetic causes. Those factors which can cause "genetic"
variability in response to treatment act during the cascade
of events resulting in colorectal cancer (3-7). These events
Correspondence to: Lara Maria Pasetto, Divisione di Oncologia
involve a series of mutations, each of which confers a
Medica Direzione, Azienda Ospedale – Università, Via
Gattamelata 64, 35128 Padova, Italy. Tel: +39 049- 8215931, Fax: proliferative advantage on cells, culminating in clonal
+39-049-8215932, e-mail: laramary@libero.it expansion (8-10). Mutations leading to loss of function in
these genes (mismatch repair - MMR - genes) lead to
Key Words: Stable disease, metastatic, colorectal cancer, review. general genetic instability, one of the characteristics peculiar
0250-7005/2006 $2.00+.40 511ANTICANCER RESEARCH 26: 511-522 (2006)
to cancer cells (7) and to drug resistance (with consequent
response to the treatment and initial SD) (11, 12).
Immunological causes. At the beginning of the disease, the
cytotoxic reaction (T cytotoxic lymphocytes, TCL) against
tumoral cells or intratumoral mutations (loss of antigen
recognized by TCL) control the neoplastic mass increase
thereby stabilizing its growth, but when the number of
neoplastic cells increases, this control is lost and the tumor
grows (Figures 1 and 2). Actually, the dynamical basis of
tumoral growth is controversial. Many models have been
proposed to explain cancer development and immunologic
system intervention. The descriptions employ exponential,
potential, logistic or Gompertzian growth laws (13) (Figures
1 and 2). Some of these models are concerned with the
interaction between cancer and the immunological system.
Among other properties, these models are concerned with
the microscopic behavior of tumors and the emergence of
cancer. Gompertzian law correctly describes solid tumor Figure 1. Tumoral growth, diagnosis and treatment. The Gompertzian
growth. The model predicts that near zero, tumors always model predicts that near zero, tumors tend to grow, but the growth fraction
tend to grow, but the growth fraction is not constant, is not constant, therefore it decreases exponentially with time (the growth
therefore it decreases exponentially with time (the growth fraction peaks when the tumor is approximately 37% of its maximum
size). When a patient with advanced disease is treated, the tumor mass is
fraction peaks when the tumor is approximately 37% of its
larger, its growth fraction is low, and the fraction of cells killed is,
maximum size). When a patient with advanced disease is therefore, small.
treated, the tumor mass is larger, its growth fraction is low,
and the fraction of cells killed is, therefore, small. At that
point, immunological contraposition never suffices to induce
a complete regression of the tumor. Instead, a stable endothelial cells in tumor-associated blood vessels is simply
microscopic equilibrium between cancer and immunological too low for chemotherapy to have a significant therapeutic
activity can be attained, so the theory of immune impact. Alternatively, the endothelial cells might be
surveillance is plausible. Since immunity cannot induce a protected from chemotherapy-induced cell death by high
complete tumor regression, therapy is required, but final local concentration of endothelial cells survival factors, such
levels of immunocompetent cells and tumoral cells are as vascular endothelial growth factor (VEGF) or various
finite, thus post-treatment regrowth of the tumor is certain others. A third possible hypothesis is that the anti-
(13, 14). The response to therapy in drug-sensitive tumors angiogenic effect of chemotherapy is masked by the way
depends, to a large extent, on where the tumor is in its chemotherapy is usually administered (the long breaks
particular growth curve. between drug administration that are necessary to allow the
patient to recover from the side-effects of the MTD
Microenvironment causes. Dividing endothelial cells are chemotherapy reduce the anti-angiogenic effects of the
present in the growing blood vessels that are found in drugs) (16). A state of acquired drug-resistance (with
tumors and, like other normal dividing cells, seem to be consequent "tumor-related" SD or progression of disease
susceptible to chemotherapeutics (15) (Figure 3). [PD]) could apparently be reversed by shifting the focus of
Elimination of these dividing endothelial cells, or of their the treatment away from the drug-resistant cancer cell
division, would probably lead to an anti-angiogenic effect. population to the drug-sensitive tumor endothelium (i.e.,
Moreover, as host vascular endothelial cells are assumed to with anti-VEGF) (16).
be genetically stable and lack the diverse genetic defect
characteristics of cancer cells that lead to drug resistance, The rule of targeted therapy towards the "microenvironment"
the putative effects of chemotherapy might be more durable in the stabilization of colorectal cancer. A possible way to
in the face of continued therapy. Many tumors, however, are increase therapeutic activity, reduce the level of toxicity and
intrinsically drug-resistant or rapidly acquire resistance after generally to revert drug-resistance and stabilize cancer
showing initial responsiveness to chemotherapy regimens. disease could be to change the pharmacological agents’
So, it would seem that chemotherapy has minimal anti- target from the tumoral cells to the tumor’s proliferating
angiogenic effects. Perhaps the proportion of dividing microvasculature (with more genetically stable cells),
512Pasetto et al: Stable Disease In Colorectal Cancer
Figure 2. When a CR or PR are achieved, the growth fraction decreases exponentially with time but after a brief period, it tends to grow again.
513ANTICANCER RESEARCH 26: 511-522 (2006) Figure 3. Angiogenesis is necessary for tumor progression. modifying (with no prolonged drug-free breaks) their high endothelial apoptosis (18, 19). As a result, endothelial dose to a continuous and/or daily, lower dose (a tenth to a apoptosis would precede tumor cell apoptosis, and therefore third of the MTD) with the so called "metronomic" the tumor regresses or is inhibited (with consequent SD), administration (17). The anti-angiogenic properties of this whether or not the tumor cells are resistant to the drug, and form of administration (with consequent apoptosis of with little or no host toxicity. The absence or reduction of endothelial cells in the vascular bed of tumors and with intratumoral vascularization should reduce tumor nutrients minimization of total tumor burden, rather than complete and oxygenation, blocking disease proliferation but not eradication) could also be further increased by the causing extensive tumor regression (20). concurrent utilization of selective angiogenesis inhibitors Bevacizumab (Avastin), the new drug introduced for the acting at a molecular level and influencing the processes of treatment of metastatic disease, favorably neutralizes tumor formation and growth. Such inhibitors increase tumor VEGF, one of the best characterized pro-angiogenic growth cell apoptosis and inhibit tumor growth by inhibiting factors, by blocking its ability to activate its receptor on the endothelial proliferation and migration and/or by inducing endothelial cells (21). In colorectal cancer, an increased 514
Pasetto et al: Stable Disease In Colorectal Cancer expression of VEGF correlates with invasiveness, vascular associated with an improved "clinical benefit" (CB) (24). density, metastases, recurrence and prognosis. In patients Cetuximab (Erbitux), a chimerical monoclonal antibody with significant tumor burdens, anti-VEGF, a recombinant highly selective for the EGFR over-expressed by 25-80% of humanized monoclonal antibody to VEGF, decreases tumor colorectal cancer tumors with advanced disease, induces a blood perfusion and volume, interstitial fluid pressure, the broad range of cellular responses in most, but not all, number of circulating endothelial cells and tumors expressing EGFR (apoptosis promotion, cell fluorodeoxyglucose uptake, thereby prolonging TTP and OS proliferation, angiogenesis and metastases inhibition). It and stabilizing disease more than inducing tumor regression also enhances sensitivity to radio-chemotherapy to which (7). It is still unknown whether targeting one factor or a cancer cells have become resistant. In colon carcinoma, an limited profile of factors provides meaningful antitumor autocrine loop exists whereby ligands for the EGFR activate activity for most patients or for only an undefined subset. In the receptor. By inhibiting the autocrine or paracrine the advanced disease, tumors have already activated various activation of the EGFR, tumor cells that may typically pathways that allow them to easily override the angiogenic survive in their caustic microenvironment with low pH and restriction of one inhibitor (22). A more successful pO2 tension, may undergo spontaneous apoptosis. In this approach could involve combinatorial strategies to target case, this so-called "cytostatic"-targeted therapy may acquire cells themselves (i.e. anti-VEGF plus anti- epidermal growth a therapeutic potential, leading, not only to tumor factor receptor EGFR), along with the stroma (that is made stabilization, but also to tumor cell apoptosis and regression up of endothelial, perivascular and inflammatory cells) or because of the inhibition of critical signaling pathways (28). with conventional therapy (cytotoxic agents acting in a While the vast majority of preclinical data with cetuximab synergic way but with a different mechanism). In alone has primarily demonstrated cytostatic activity and combination with 5FU-based chemotherapy, which modest efficacy, data combining cetuximab with marginally amplifies the pro-apoptotic effects of the chemotherapeutics effective or ineffective cytotoxic chemotherapy have against activated endothelial cells, but presumably not demonstrated marked synergy with dramatic improvement against other types of normal dividing cells (23), the anti- in antitumor activity (29). Increased disease control (CR + VEGF bevacizumab, improves TTP (9.0 versus 5.2 months) PR + SD: 33.8% versus 56.3%, p=0.0032) and longer times and OS (21.5 versus 13.8 months) (24). The addition of to disease progression (1.5 versus 4 months, p
ANTICANCER RESEARCH 26: 511-522 (2006)
sustained inhibition of this enzyme could result in Table I. Trials which became the basis for the U.S. and European
downstream regulation of molecular markers associated with approval of CPT11 and Oxaliplatin as a first-line treatment for metastatic
colorectal cancer.
sensitivity and resistance to these agents. It has also been
found that thymidine phosphorylase (TP), the activating Authors Drugs No. PTS RR (%) MST
enzyme for 5FU, and the pyrimidine catabolism enzyme (months)
dihydropyrimidine dehydrogenase (DPD) are involved in
tumor response. Patients with low expression of all 3 of the Saltz IFL (with 5FU/LV 683 39 vs 21 vs 21 14.8 vs
(40) bolus) vs (p=0.001) 12.6 vs 12.0
genes have significantly longer survival than those with a
Mayo Clinic vs Duration (p=0.04)
high value of any one of the gene expressions; the CPT11 125 mg/m2/ of response
intratumoral gene expression level of DPD is associated with wk x 4 wks q 6 wks (after 4-6 wks):
tumor response to 5FU (37), while high gene expression of 39 vs 21 vs 18
TS (38) and TP (39) identifies non-responsive tumors to for 9 mo
5FU-based therapy. The use of more than one independent
Douillard AIO or "FOLFIRI" 387 49 vs 31 17.4 vs 14.1
determinant of response now permits the identification of a (41) (with infusional (pPasetto et al: Stable Disease In Colorectal Cancer
Table II. Optimox trial (49).
FOLFOX 4
until PD
vs
FOLFOX 7 LV5FU FOLFOX 7
x 6 cycles
➝ x 12 cycles
➝ x 6 cycles
Induction therapy Maintenance Therapy
RR 58% vs 64% (p=ns)
PFS 9.2 vs 9 (p=ns)
OS 20.7 vs 21.4 months (p=ns)
TDC=PFS post FOLFOX + PFS post FU/LV if PR or SD=9.9 vs 11.3 months (p=ns)
vs=versus; PD=progressive disease; RR=response rate; PFS=progression free survival; OS=overall survival; TDC=time of disease control;
PR=partial remission; SD=stable disease; 5FU=5Fluorouracil; LV=levamisol; ns=not significant.
The OPTIMOX "stop and go" strategy is a convenient alternative in terms of costs, toxicity, PFS and OS to FOLFOX 4 administered until
progressive disease.
p=0.23), thus these findings provided no clear evidence of a two arms. No difference was seen in the mean global health
benefit in continuing therapy indefinitely until PD. Even if status QoL score between both groups at 12 weeks after
"intermittent" therapy in some cases leads to earlier PD, random assignment. For most patients, the decision to
retreatment on PD, delaying the emergence of drug- continue on irinotecan was influenced by PD or treatment-
resistant clones and improving long-term cancer-control, related toxicity. However, for 17% of patients in whom this
prevents a substantial detriment to survival; moreover, decision was clinically relevant, there seemed to be little
improved QoL during periods without chemotherapy, benefit from continuing CPT11, though the drug was well
compensates for earlier PD. tolerated without any deterioration in QoL.
According to the authors, the actual problem in these A more recent and a slightly different approach is the so
patients could be related, first to the duration and called "stop and go". A phase III randomized study on 526
effectiveness of the induction therapy to ensure the best patients (49) (Table II) was presented by the OPTIMOX
response; a long induction therapy could lead to drug trial. The FOLFOX 4 regimen administered continuously
resistance, and subsequent rechallenging could be less until PD (arm A) was compared with FOLFOX 7 regimen,
effective. Patients should also achieve a good response to followed by 12 cycles of simplified 5FU/LV and later by
the rechallenged therapy. Furthermore, the time between FOLFOX 7 reintroduction (arm B). RR was similar (58.8%
termination of the induction therapy and PD should be in arm A and 59.5% in arm B); median PFS was 9.2 and 9.0
relatively long in order to obtain a better response. Lastly, months (p=0.47), and median OS was 20.7 and 21.4 months
patients out of treatment should be frequently followed (p=0.75), respectively. Due to similar results, the arm B
until PD, in order to restart therapy quickly at the first sign strategy appeared to be a convenient alternative in terms of
of progression. Although this trial was undertaken with a costs and toxicity to FOLFOX 4 administered continuously
monochemotherapy (5FU or raltitrexed), similar results until PD. This modality should be evaluated in future trials
have also been recently confirmed with the introduction of for those patients with prolonged SD in which toxicity and
new agents, such as oxaliplatin or CPT11 (47). Additional cost are too high to continue the treatment until PD with the
costs and toxicity related to these drugs, can be a future same regimen (46-50).
justification for an intermittent therapy with consequent A similar study conducted in 37 elderly patients (50)
delay of a second-line therapy until the rechallenged indicated that the use of a less toxic maintenance therapy
regimen fails. after a fairly aggressive induction therapy resulted in
In a multicenter phase III trial (48) on 333 patients with equivalent TTP and OS (65 weeks in arm A and 90 weeks
advanced colorectal cancer, the two policies of defined- in arm B) when compared with a more conventional
duration versus continuous CPT11 treatment were treatment given until patients could not continue or had
compared. After receiving 8 cycles of CPT11, 55 patients PD. The results of this trial are intriguing but will need to
with response or SD were randomly assigned to stop be confirmed in larger randomized trials before being
irinotecan (n=30) or continue until PD (n=25). From the accepted as the new standard of care.
time of random assignment, there were no differences in To further increase long-lasting SD in a pathology such
failure-free survival (p=0.999) or OS (p=0.11) between the as colorectal cancer, in which OS has recently improved
517ANTICANCER RESEARCH 26: 511-522 (2006) Table III. The Popov et al. study (53). PD=progressive disease; OS=overall survival; PR=partial remission; SD=stable disease; CR=complete remission; ns=not significant Patients with SD and CB could be a target group for policy "to treat until PD"; patients with SD but without symptom improvement have no benefit from further chemotherapy and in these patients treatment should be stopped sparing them from unnecessary toxicity. with the introduction of new drugs, a different way of PS (12 and 21 months, respectively) than in those with poor administration of the same drugs has been studied. The PS (8 and 10 months, respectively, p
Pasetto et al: Stable Disease In Colorectal Cancer
Table IV. Flow chart: "non responders" (only SD, from the onset of the treatment).
Table V. Flow chart: "responders" (CR or PR followed by SD).
treat SD as evidence that the therapy in question benefits up CB, as evidence that the treatment is promising, even
or holds promise for the treatment of advanced cancer. when the majority of cases of alleged benefit are SD.
Some authors combine the concepts of SD and objective In the Popov study (53) (Table III) on 97 evaluable
response, defining them as CB, and some press releases play patients whether SD with CB was associated with a benefit
519ANTICANCER RESEARCH 26: 511-522 (2006)
in survival or TTP was investigated, and no difference was achievement of a RR. A good compromise could be obtained
detected between responders and "SD-CB" patients by distinguishing between "responders" or "non responders"
(p=0.24), but there was a significant difference between achieving a SD those that are "symptomatic" at diagnosis from
responders and patients with SD without CB (p=0.0004). those which are "asymptomatic". Patients would then be
SD-CB patients also displayed significant difference evaluated for clinical improvement, and those with CB would
compared to those with PD (p=5.1x10–6). be treated until PD with the same therapy or with metronomic
The results of this study indicate that under the category or chronomodulated infusion, or by alternating an induction
"SD" there are two different subpopulations of patients with therapy with a continuative therapy to prolong the responses,
quite different symptom responses and improvements in thereby reducing the toxicity rate (Tables IV and V).
QoL as an effect of chemotherapy, different TTP and Currently, there is little clinical data supporting SD as an
perhaps even different survivals (60). endpoint or the utility of continuing treatment until PD, and
"Symptomatic patients" at diagnosis, with subsequent SD, useful guidelines are lacking. Common clinical practice
but who never achieve PR or CR, and CB, could be a target varies little from the clinical trial attitude. Sometimes,
group for the "treat until disease progression" policy. Patients therapy is stopped after two subsequently instrumental
with SD, who have not achieved PR or CR, but without checks for SD and is re-initiated after a new PD, with either
symptom improvement, have no benefit from further the original therapy (in the case of relapse of at least 3
chemotherapy, so the treatment should be stopped to spare months after the discontinuation of 4-6 months of successful
patients unnecessary toxicity. In reality, we have no data as treatment) (44, 66), or with another therapy, However, the
to whether a different number of chemotherapy cycles in the characteristics of this approach are still unclear. The recent
groups of patients with and without CB could lead to a bias introduction of biological therapy, which has a better effect
in survival estimation. "Asymptomatic patients" at diagnosis, on biological tumor cell cycles since the response duration
with SD, who are still asymptomatic after 4 chemotherapy rather than the response is influenced, may help to resolve
courses, make up a group for which it is hard to make a these problems. New drugs, such as bevacizumab or
decision to either continue or stop chemotherapy. cetuximab which have greater cytostatic than cytotoxic
SD in "responders". A current problem is understanding effects could therefore be useful in prolonging the positive
the duration of the responses of disease, or rather the "time results already obtained with the cytotoxic chemotherapeutic
of SD" which elapses from the best response, PR or CR, to agents oxaliplatin and CPT11.
PD, in "responders". Preliminary reports of SD are usually
based on short follow-up (only 8-12 weeks) and only References
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