Clinical Implications of Antiangiogenic Therapies
Clinical Implications of Antiangiogenic Therapies
Vascular endothelial growth
factor (VEGF) is a potent
stimulator of angiogenesis.
It is expressed throughout the angiogenic
process and is crucial for tumor
growth and metastatic spread.[1-3]
VEGF expression is upregulated in a
broad array of tumor types, and this
overexpression translates into poorer
survival in many human cancers.
Given the multiple targets in the
VEGF pathway and the potential for
improving outcomes in a broad range
of human malignancies, numerous
anti-VEGF agents are in development.
These include antibodies to VEGF,
soluble VEGF receptors (VEGFRs),
antibodies to some or all of the VEGF
receptors, antisense oligonucleotides,
and small-molecule inhibitors
One anti-VEGF therapy, a humanized
monoclonal antibody to VEGF
(bevacizumab [Avastin]), has been
approved by the US Food and Drug
Administration (FDA). The clinical
success (ie, increased patient survival)
of this agent in conjunction with
chemotherapy in the treatment of patients
with colorectal cancer demonstrates
that angiogenesis inhibition,
and specifically VEGF inhibition, is a
viable therapeutic approach.
Maximizing the potential of agents
that target the VEGF pathway involves
investigating a range of doses and administration
schedules in combination
with chemotherapy. In this article,
we explore concepts related to the
integration of anti-VEGF agents into
chemotherapy regimens and postulate
that these agents may alter tumor
growth in a manner consistent with
the Norton-Simon hypothesis, resulting
in improved cytotoxicity, reduced
regrowth between cycles, and
At the dawn of the modern chemotherapy
era, much of the rationale for
administering chemotherapy came
from kinetic modeling of the response
of murine leukemia L1210 to curative
chemotherapy. L1210 is a rapidly
and almost exponentially growing
tumor, with all of its cells progressing
through the cell cycle at any given
time. The cytotoxic effects of chemotherapy
follow log-kill kinetics in this
model. If a dose of chemotherapy reduced
the tumor burden from 109 to
108, the same dose would therefore
reduce the burden from 104 to 103
(Figure 1). Although the vast majority
of human tumors have a smaller
growth fraction than that of rodent
leukemia L1210, this work fostered
widely held beliefs that the ratio of
proliferating cells to total cells remains
constant, tumor growth is logarithmic,
and cell kill is proportional regardless
of tumor burden.
While the exponential growth model
is attractive for its simplicity, most
human cancers do not exhibit purely
exponential growth. Rather, human
cancers appear to follow a Gompertzian
model of growth. Here,
the ratio of proliferating cells to total
cells decreases with increasing tumor
size. The growth fraction declines exponentially
over time, and a plateau
phase can be observed in some malignancies.[
10] As a result, the tumor
growth curve has three distinct regions:
a slow initial phase, a middle
phase characterized by rapid growth,
and a slow plateau phase (Figure
2). In a Gompertzian model, chemotherapy,
which targets rapidly proliferating
cells, kills a small fraction
of cells when the cancer is advanced
and the tumor is large, but a higher
fraction of cells when the tumor is
small or when the cancer is clinically
undetectable. This explains, in part,
the relatively greater effectiveness of
adjuvant therapy compared with treatment
for metastatic disease.
Another important consideration
with Gompertzian growth is the impact
of residual tumor cells on tumor
regrowth. The regrowth of residual
cells is fastest at small tumor volumes,
meaning that clinically significant
regrowth might occur between
cycles of conventionally scheduled
chemotherapy. This growth property
may explain the challenges inherent
in designing curative adjuvant chemotherapy
regimens for many types
of cancer, including breast cancer.
Attempts to eliminate residual disease
and improve survival by increasing chemotherapy
dose intensity through dose
escalation have not proven particularly
effective. However, with the advent
of colony-stimulating factors, it
became possible to decrease the time
interval between chemotherapy cycles
Based on his extensive work with
Gompertzian kinetics, Norton proposed
that administering an appropriate
and effective dose of
chemotherapy more frequently would
limit tumor regrowth between cycles,
thereby providing a more effective
way of treating residual disease (Figure
3). Building on a series of
pilot studies, the Cancer and Leukemia
Group B (CALGB) tested this
hypothesis in Intergroup trial
C9741. In this randomized clinical
trial, treatment with dose-dense
chemotherapy improved survival relative
to standard chemotherapy when
administered in the adjuvant setting
for the treatment of patients with
node-positive breast cancer. Treatment
was generally well tolerated.
Severe neutropenia was less common
for patients in the dose-dense arm,
who received prophylactic colonystimulating
factor support with each
cycle as part of the treatment regimen.
With the proof of principle established,
other cooperative group trials
are currently including dose-dense
chemotherapy in randomized trials,
eg, Southwest Oncology Group
(SWOG) trial 0221, National Surgical
Adjuvant Breast and Bowel Project
(NSABP) trial B-38, and CALGB
40101. Dose-dense chemotherapy has
been hailed as an important incremental
advance in treatment for early-stage
breast cancer. Results from additional
trials are needed to determine
the ability of dose-dense chemotherapy
to improve survival for patients
with other malignancies.
With Anti-VEGF Therapy
Potential Effects on
Tumor Growth Patterns
The Norton-Simon hypothesis predicts that the addition of any effective anticancer agent to chemotherapy could produce improved results by limiting tumor regrowth between cycles. Anti-VEGF agents are not believed to be cytotoxic on their own, but rather inhibiting tumor growth through their effects on neoangiogenesis is one underlying mechanism of action. Specifically, anti-VEGF agents are thought to starve tumors by inhibiting their ability to maintain newly developed vasculature and to recruit a blood supply. These steps are necessary for continued tumor growth. By altering the growth pattern of the tumor and preventing regrowth of a regressing tumor, the addition of anti-VEGF agents to chemotherapy regimens may result in improved clinical outcomes, without requiring a reduction in the chemotherapy dosing interval. Moreover, anti-VEGF agents likely enhance the cytotoxic effects of chemotherapy. Anti-VEGF therapy has been demonstrated to normalize the disorganized and dysfunctional tumor vasculature, resulting in increased intratumoral chemotherapy levels.[14,15] In addition, the demonstrated ability of anti-VEGF agents to reduce the high interstitial fluid pressure of the tumor may result in improved chemotherapy delivery to the tumor center where this pressure is highest. By improving chemotherapy delivery to the tumor, anti-VEGF agents could increase tumor cell kill rates. In the pivotal trial conducted in patients with colorectal cancer, survival was improved for patients receiving IFL (irinotecan [Camptosar], fluorouracil, leucovorin) chemotherapy plus bevacizumab relative to those receiving IFL alone. Theoretical tumor regression curves illustrate the hypothesis that adding anti-VEGF agents alters the tumor growth pattern, improves intratumoral chemotherapy delivery, and results in improved rates of minimal residual disease and possibly disease eradication (Figure 4). Dose-Dense Chemotherapy Combined With Anti-VEGF Therapy Potential Therapeutic Synergies
There are provocative theoretical reasons to evaluate the combination of anti-VEGF agents and dose-dense chemotherapy. Dose-dense therapy is being applied in the adjuvant setting because the mathematical cell kill curves suggest greatest benefit with early intervention. Similarly, VEGF may be especially important during the early stages of neoplastic progression.[ 18,19] Because VEGF signaling is a rate-limiting step for tumor angiogenesis, the use of anti-VEGF agents early in the course of disease and prior to the development of metastases would be expected to yield the greatest benefit. In theory, anti- VEGF agents would aid in keeping tumor volumes small, while dosedense chemotherapy would eradicate the small but mitotically active residual tumor cells. Another possible synergy between dose-dense chemotherapy and anti- VEGF agents relates to the induction of VEGF expression. Dose-dense chemotherapy may increase the proportion of tumor cells undergoing mitosis while it reduces tumor burden through its cytotoxic action. Hypoxia occurs during rapid tumor growth and is a signal for the tumor to produce VEGF. In the absence of anti- VEGF agents, it is possible that dosedense chemotherapy could actually increase signals for tumor angiogenesis. Treatment with anti-VEGF agents could counteract any increase in VEGF levels found in the tumor environment as a result of rapid cell growth and hypoxia. Overall, it is likely that the cell-kill curve produced by an anti-VEGF/dose-dense chemotherapy regimen would be steeper than that by chemotherapy alone, which could result in the eradication of residual disease with fewer courses of therapy. Potential Effects of Chemotherapy on Angiogenesis
Another intriguing hypothesis is the possibility of synergy between anti-VEGF agents and chemotherapy, with respect to the inhibition of angiogenesis. Chemotherapy likely targets dividing endothelial cells found in newly forming blood vessels; however, these cells are relatively slow growing, and conventional cycle lengths may allow for repair and recovery from some of the chemotherapy- induced damage. Researchers have devised antiangiogenic or metronomic chemotherapy dosing schedules in order to apply continuous pressure on the newly forming tumor vasculature and possibly overcome acquired chemotherapy resistance.[ 21,22] This approach involves either continuous chemotherapy infusion or regular, frequent chemotherapy administration, generally with lower chemotherapy doses to avoid excess toxicity. Indeed, there is evidence in humans that this approach overcomes drug resistance, as patients resistant to conventional taxane therapy have been found to respond subsequently to lower-dose weekly treatment. In animal models, metronomic chemotherapy has generally produced tumor control, including regression in chemotherapy-resistant models.[ 21,24,25] However, superior results have consistently been seen in these models when metronomic chemotherapy was combined with a putative angiogenesis inhibitor, such as TNP-470 or experimental anti-VEGF antibodies.[21,24-26] Indeed, complete, sustained regressions were seen in a neuroblastoma model and a lung cancer model when metronomic chemotherapy and angiogenesis inhibitors were combined.[21,24] Combined antiangiogenic therapy has been taken a step further by Pietras and colleagues, who evaluated a combination of standard chemotherapy followed by metronomic chemotherapy with multitargeted inhibition of VEGF and pericytes (through platelet- derived growth factor receptor [PDGFR] inhibition). Given the pronounced efficacy of the combination in this murine model of neuroendocrine cancer, they proposed a clinical trial schematic consisting of standard chemotherapy followed by maintenance therapy with an oral, lowdose chemotherapeutic agent plus bevacizumab to target the endothelial compartment and imatinib (Gleevec) to target the pericytes, which along with endothelial cells are important regulators of blood vessel formation and function. Evaluating Chemotherapy and Anti-VEGF Combinations in the Clinic The possibility that anti-VEGF agents enhance dose-dense and metronomic chemotherapy warrants evaluation in clinical trials. The effect of bevacizumab on metronomic lowdose cyclophosphamide (Cytoxan, Neosar)/methotrexate therapy is currently being evaluated in a randomized phase II trial in women with metastatic breast cancer. Similarly, the combination of low-dose continuous oral cyclophosphamide plus bevacizumab is under investigation in women with metastatic or recurrent ovarian cancer. Additional data may be needed before moving forward with dose-dense chemotherapy and anti-VEGF combinations in randomized clinical trials. For example, given the potential for anti-VEGF agents to enhance intratumoral chemotherapy concentrations, it may be possible to reduce the dose of chemotherapy when given in combination with these agents. Reduced- dose chemotherapy could improve the tolerability of dose-dense regimens, and perhaps even obviate the need for routine CSF support. Furthermore, reduced-dose, dosedense chemotherapy with anti-VEGF agents may begin to resemble metronomic therapy, producing enhanced cytotoxicity through improved delivery to the tumor and enhanced and prolonged targeting of the endothelial compartment. A logical dose-dense regimen with which to evaluate combined therapy with anti-VEGF agents is dose-dense doxorubicin/cyclophosphamide followed by paclitaxel, as used in Intergroup trial C9741. The benefits of this regimen have been demonstrated in patients with node-positive, operable breast cancer. Moreover, research suggests a role for anti-VEGF agents in breast cancer. VEGF is highly expressed in breast carcinomas, and VEGF expression is a prognostic marker in breast cancer in that it is correlated with decreased relapse-free and overall survival.[1,30,31] Indeed, bevacizumab monotherapy has shown promising activity in metastatic breast cancer in a phase I/II trial, although data are currently lacking in the adjuvant setting. Of note, recent data from a phase III trial comparing capecitabine with or without bevacizumab in heavily pretreated patients with metastatic breast cancer showed significant improvement in overall response rate. However, overall survival was not increased in the bevacizumab arm. Results from studies such as Eastern Cooperative Oncology Group (ECOG) trial 2100, a randomized trial comparing paclitaxel with or without bevacizumab in first-line treatment of metastatic breast cancer, will help identify the clinical benefit of bevacizumab and will likely guide patient selection for future clinical trials. In addition, evaluation of bevacizumab in combination with metronomic and dose-dense chemotherapy regimens will provide key information that can be used to optimize the therapeutic benefits of anti-VEGF agents. Conclusion The success of bevacizumab in the treatment of patients with metastatic colorectal cancer demonstrates the utility of targeting a tumor's collateral support system rather than the tumor itself. The mechanism of action of anti-VEGF agents suggests that these agents complement traditional chemotherapy regimens in a way that could especially augment the most effective existing regimens such as dosedense therapy. There is evidence that frequently administered chemotherapy enhances the antiangiogenic activity of bevacizumab and that bevacizumab enhances the cytotoxic effects of chemotherapy. The clinical development of anti- VEGF agents represents a major opportunity for the evaluation of novel combination regimens in a broad range of tumor types. Optimizing the use of anti-VEGF agents will require additional studies that evaluate how best to integrate these agents into chemotherapy regimens, particularly those designed to achieve maximal benefit in the Gompertzian model of tumor growth and those designed to maximize the antiangiogenic potential of chemotherapy itself. The potential for maintenance metronomic/antiangiogenic therapy to potentiate the effects of standard chemotherapy is also worthy of further evaluation.
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