Assessing Response to Therapy

Introduction

Cancer continues to be a major health problem, as one in four deaths in the United States is attributed to cancer. However, we continue to see incremental improvements over time, with the relative 5-year survival rate for cancer in the United States at 68%, up from 50% in the mid-1970s. Cancer death rates fell 21.0% among men and 12.3% among women from 1991 to 2006 in the United States. The American Cancer Society estimates that the cancer incidence decreased 1.3% per year among men from 2000 to 2006 and 0.5% per year from 1998 to 2006 among women. This decline is attributed mainly to falling smoking rates, improved cancer treatments, and earlier detection of cancer.

Oncologic imaging is recognized as an integral part of the management of cancer patients. Continued improvement in survival and the introduction of novel and multimodality therapies demand greater contributions from imaging to assess the presence of tumor, its extent, and response to therapy.

Improved understanding of the basic mechanisms of tumor biology, immunology, carcinogenesis, and genetics provides a rich foundation for translating these findings into enhancing efforts to reduce the impact of cancer. Some of these areas include understanding inherited or acquired genetic mutations or malfunctions; elucidating the molecular pathways of cell proliferation; acknowledging the effects of immune response and vascular proliferation; and taking advantage of more effective clinical cancer detection modalities, including magnetic resonance imaging (MRI), computed tomography (CT), and molecular imaging techniques paired with gene screening arrays to identify molecular abnormalities in individual patients’ cancer cells.

The challenges to imaging are continuously evolving as novel personalized therapies and multimodality regimens are developed. However, scientific limitations and economic realities mean there is a need to provide proof of principle of the ways in which imaging can be an integral part of daily care and the design of various clinical trials to treat cancer patients.

The ability of imaging to provide indices to response such as tumor size and perfusion, as well as the more recent advent of functional imaging, makes imagining a standard component of clinical practice and the assessment of novel therapies. This central role is best exemplified by the multidisciplinary approach to the management of cancer patients. The integration of surgery, pathology, imaging, medical oncology, radiation oncology, and medical physics to cancer patient care attests to the complex nature of the disease and the need to bring together the expertise of a group in lieu of the traditional models on which individual patient–physician relationships are developed, followed by subspecialist referrals.

The traditional subspecialty designations in diagnostic imaging have and continue to be anatomic regions—for example, neuroradiology (head and/or neck), thoracic (chest), body (abdomen/pelvis), and others. However, cancer imaging demands expertise not only of specific anatomic areas but also in other modalities such as ultrasound, MRI, CT, x-ray plain films, and nuclear medicine, including positron emission tomography (PET)/CT. This multimodality ability is now supported by the ready availability of images via picture archiving and communication systems and electronic medical records and, when necessary, ready access to other imaging specialists, because it may be difficult to manage expertise in so many modalities. Easier access to referring physicians for consultation is also aided by fast communications via smartphones, the web, or the traditional page and phone system. Finally, the availability and use of voice-recognition systems and web access allows rapid turnaround of report results to both referring physicians and patients. The transparency of these imaging reports should remind us all to avoid causing unnecessary anxiety by ensuring the proper use of language that is accurate and concise and hopefully answers the clinical question being posed.

For both the individual patient and clinical trial patients, close communication between the interpreting doctor and the referring physician is necessary for deciding the most appropriate imaging technique to use and when to perform a follow-up study to assess response. Appropriate care in planning the imaging component of clinical trials is essential, and may include proper imaging techniques, analysis, reporting, image transfer, and the design of forms that may need to be filled out for these studies. Ideally, these imaging modalities and measurements are identical in both individual and trial patients, which may make it easier to perform clinical imaging research or even to incorporate an individual patient into a clinical trial. Such planning will avoid added costs of repeat imaging or the need to go back and reanalyze images. Many of these imaging strategies could be made easier by accreditation of the imaging facility by the American College of Radiology, which ensures that the imaging equipment and the staff and physicians’ qualifications are registered, which then makes it easier to participate in collaborative groups that carry out clinical imaging trials such as the American College of Radiology Imaging Network. Ensuring the high quality of imaging primarily benefits our patients but also allows easy participation in clinical research, which is the foundation of continuing improvement in our various specialties.

General Imaging Strategies

Why Do We Need To Monitor Tumor Response?

The need for monitoring response became apparent in the early days of chemotherapy, particularly for conducting clinical comparative trials for various experimental chemotherapeutic agents in multiple cancer types. The typical development pathway for cancer therapeutic drugs is evolution from phase I to phase II and to phase III clinical trials. In phase I trials, the toxicity of the agent is assessed to determine what dose is appropriate for subsequent trials. In phase II trials, evidence of antitumor activity is obtained. Phase II trials can be done in several ways. One way is to examine tumor response rate versus a historical control population treated with an established drug. New drugs with a low response rate are typically not moved forward to advanced clinical testing under such a design. In such trials, tumor response has traditionally been determined with anatomic imaging techniques. An alternative approach is to use a larger sample size and have a randomized phase II trial, in which the new treatment is given in one treatment arm and compared with a standard treatment. Once drug activity is shown in phase II, phase III trials are then performed. Phase III trials are larger and usually have a control arm treated with a standard therapy. Therefore, imaging is expected to have a major role not only in the individual patient care but also in designing clinical trials to select which therapies should be advanced to progressively larger trials and become standard of care.