Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer

Polymers can be conjugated to anticancer drugs and proteins to improve their therapeutic index. Some such conjugates are in routine clinical use and there are exciting advances in development, such as polymer-based combination therapies.

Polymer conjugates as anticancer nanomedicines

The era of chemotherapy began in the 1940s with the first uses of nitrogen mustards and antifolate drugs. Cancer drug development since then has transformed from a low-budget, government-supported research effort to a high-stakes, multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply. This article chronicles the history of modern chemotherapy and identifies remaining challenges for the next generation of researchers.

Timeline: Chemotherapy and the war on cancer.

Neoplasms are microcosms of evolution. Within a neoplasm, a mosaic of mutant cells compete for space and resources, evade predation by the immune system and can even cooperate to disperse and colonize new organs. The evolution of neoplastic cells explains both why we get cancer and why it has been so difficult to cure. The tools of evolutionary biology and ecology are providing new insights into neoplastic progression and the clinical control of cancer.

Cancer as an evolutionary and ecological process.

DNA repair pathways can enable tumour cells to survive DNA damage that is induced by chemotherapeutic treatments; therefore, inhibitors of specific DNA repair pathways might prove efficacious when used in combination with DNA-damaging chemotherapeutic drugs. In addition, alterations in DNA repair pathways that arise during tumour development can make some cancer cells reliant on a reduced set of DNA repair pathways for survival. There is evidence that drugs that inhibit one of these pathways in such tumours could prove useful as single-agent therapies, with the potential advantage that this approach could be selective for tumour cells and have fewer side effects.

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DNA repair pathways as targets for cancer therapy

ContextIn the past, cancer patients entering phase 1 studies confronted the
prospects of high risk and unlikely benefit. Over the last decade, cancer
drugs under development have become more targeted, and the clinical research
environment has become more scrutinized. The impact of these changes on the
risks and benefits to patients who participate in phase 1 cancer trials is
unknown.ObjectiveTo determine trends in the rates of treatment-related (toxic) death,
objective response, and serious toxicity and to identify factors associated
with these outcomes.Data SourcesWe searched abstracts and journal articles reporting the results of
phase 1 cancer treatment trials originally submitted to annual meetings of
the American Society of Clinical Oncology (ASCO) from 1991 through 2002.Study SelectionWe focused on published single-agent trials that enrolled patients with
advanced solid tumors and excluded studies testing agents already approved
by the US Food and Drug Administration at the time of the ASCO presentation.Data ExtractionMultiple observers independently extracted information on trial design,
location, sponsorship, types of tumors treated, drug class, route of administration,
and clinical outcomes.Data SynthesisThe overall toxic death rate for 213 studies (involving 6474 cancer
patients) published in peer-reviewed journals was 0.54%, while the overall
objective response rate was 3.8%. Toxic death rates decreased over the study
period, from 1.1% over the first 4 years of the study (1991-1994) to 0.06%
over the most recent 4-year period (1999-2002) (P<.01).
Response rates also decreased but by proportionally much less. After adjusting
for characteristics of the experimental trials and the investigational agents,
the odds of a patient dying from an experimental treatment while participating
in a trial submitted during the most recent 4-year period were less than one
tenth those of a patient participating in a trial submitted during the first
4-year period (odds ratio, 0.09; 95% confidence interval, 0.01-0.67; P = .009). In comparison, the adjusted odds of
a patient experiencing an objective response over the same time periods decreased
by approximately half (odds ratio, 0.46; 95% confidence interval, 0.32-0.66; P<.001).ConclusionsThe level of risk experienced by cancer patients who participate in
phase 1 treatment trials appears to have improved over the 12-year period
from 1991 through 2002. Because toxic death rates have decreased more quickly
than have objective response rates, the ratio of risk to benefit may have
also improved. These changes relate in part to the targeted and less-toxic
nature of newer cancer drugs and are coincident with the increased attention
that has been paid to the safety of clinical research over the time period
we analyzed.

Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials.

Purpose: There has been interest in using biomarkers that aid the evaluation of new anticancer agents. We evaluated trends in the use of biomarkers and their contribution to the main goals of phase I trials. Experimental Design: We did a systematic review of abstracts submitted to the American Society of Clinical Oncology annual meeting from 1991 to 2002 and the publications related to these abstracts. We analyzed the use of biomarkers and their contribution to published phase I trials. Results: Twenty percent of American Society of Clinical Oncology phase I abstracts (503 of 2458) from 1991 to 2002 included biomarkers. This proportion increased over time (14% in 1991 compared with 26% in 2002; P Conclusions: The use of biomarkers in phase I trials has increased over the period from 1991 to 2002. To date, biomarker utilization has made a limited and primarily supportive contribution to dose selection, the primary end point of phase I studies. Additional studies are needed to determine what type of biomarker information is most valuable to evaluate in phase I trials.

https://clincancerres.aacrjournals.org/content/clincanres/13/22/6719.full.pdf

Trends in the Use and Role of Biomarkers in Phase I Oncology Trials

Purpose: To review characteristics of contemporary phase III oncology trials and create an explicit framework to help clinical researchers prioritize novel therapies for phase III testing. Methods: We searched the MEDLINE and EMBASE databases for all reviews of phase III trials; cataloged all phase III trials in two national clinical trial databases; and reviewed approval criteria of recently approved oncology drugs from public data provided by the US Food and Drug Administration. Industry data not available elsewhere in the medical literature were obtained from a sourcebook published by a large contract research organization. Results: Phase III oncology trials are the most expensive and time-consuming aspect of the drug development process. The results of these trials continue to exert the greatest influence on the treatment decision of oncologists and remain pivotal to the granting of drug approval. Making optimal decisions about which agents to advance to phase III testing may decrease the overall cost...

The Phase III Trial in the Era of Targeted Therapy: Unraveling the “Go or No Go” Decision

In recent years, the Food and Drug Administration (FDA) has granted fast-track approval for cancer treatments that are effective in only 10 to 15 percent of patients, without requiring sponsors to identify the patients who are most likely to benefit. In this article, the authors propose that the FDA make rapid approval of new molecularly targeted cancer therapies contingent on sponsors' agreement to invest in research designed to identify subgroups of patients who are likely to have a response to treatment.

Thomas G. Roberts

Papers

Timeline: Chemotherapy and the war on cancer.

Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials.

Trends in the Use and Role of Biomarkers in Phase I Oncology Trials

The Phase III Trial in the Era of Targeted Therapy: Unraveling the “Go or No Go” Decision

Beyond fast track for drug approvals