Imaging Guides Efforts to Improve the Therapeutic Ratio

Acontinuing challenge for every specialty in oncology is to improve the therapeutic ratio, which is the balance of biological effectiveness of treatment and severity of treatment-related side effects. Targeted tumor imaging and therapy, based on tumor biology, have the goal of better identifying areas of tumor to limit surgical and radiation fields, and enable systemic therapies to limit their effects to tumor cells. This more targeted approach has the goal of improving tolerance to cancer treatment. Treatment-Related Toxicities Treatment-related toxicities significantly compromise response to cancer therapy by interrupting and extending the treatment schedule, reducing the doses administered, or by causing patients to fail to complete the planned course of therapy. For example, among 273 patients who were randomized and received postoperative chemoradiotherapy for gastric cancer, 41% experienced grade 3 toxicity, 32% had a grade 4 toxicity, and three patients (1%) died from toxic effects of chemoradiotherapy.[1] Only 64% (181 patients) completed the planned treatment; 17% stopped treatment because of a medical determination about treatment-related toxicity, 8% declined treatment after further consideration, and an additional 2% declined to continue treatment. Despite the toxicity and failure to complete treatment in more than one-third of chemoradiotherapy patients, the median overall survival time in the chemoradiotherapy arm of this inter-institutional trial was significantly higher than that of the surgery-only group. Unfortunately, inability to control treatment-related symptoms in more than one-third of chemoradiotherapy patients probably also significantly impacted survival rates among patients treated with chemoradiotherapy. If symptoms had been better controlled, allowing an additional 36% of patients to complete the planned postoperative chemoradiotherapy, the survival difference probably would have been even more significant. Ironically, the percentage of patients who benefited from the radiotherapy portal quality-assurance program is about the same as the percentage of patients who did not complete treatment because of toxicity from chemoradiotherapy; patients who do not complete therapy because of symptoms cannot be cured even if their radiation portals are correct. Horiot emphasized the negative impact of toxicity on survival.[2] A radiation treatment interruption of just 1 day may reduce disease-control rates by 1.4%; a treatment break of 1 week will reduce control rates by more than 10%.[2-4] The importance and ethics of quality assurance to reduce treatment- related toxicities through aggressive symptom management, using already available therapies, cannot be underscored enough in the development of clinical trials and standards of practice. Targeted Tumor Imaging and Therapy Radiation therapy fields historically were large to treat tumor, areas of potential microscopic involvement beyond visible tumor, and regional nodal drainage. Radiation treatment fields have decreased significantly with the concurrent administration of chemotherapy during radiation therapy, as clinicians are now depending more on systemic therapy to treat microscopic extensions of disease. Radiation portals generally now encompass the visible tumor and a limited margin around it. This evolution in radiotherapy planning also requires greater dependence on imaging information. Research in the past year has focused on improved imaging techniques that allow more precise radiation treatment volumes. As reported at the 2004 Radiological Society of North America (RSNA) meeting, magnetic resonance spectroscopy, dynamic contrast-enhanced MR imaging, and ultrasmall paramagnetic contrast medium improved the accuracy of diagnosis and staging of prostate cancer, making a significant impact on therapeutic decisions. With endorectal coil-assisted MRI and 3D MR spectroscopy, Vilanova was able to confirm the diagnosis of prostate cancer in 10 of 27 patients with persistent elevations of prostate-specific antigen levels after a negative biopsy (see report on page 14). Likewise, dynamic contrastenhanced MRI found recurrent prostate cancer earlier after radiation therapy. The sensitivity rates in all of these studies are equal to or greater than 75%. Positron emission tomography is like MR spectroscopy in that it involves imaging based on biological principles. The most exciting development is the anatomic and functional fusion of CT, MR, and PET images; fusion of these imaging techniques overcomes the limitations of each. Specifically, the fusion of CT/MR with PET overcomes the lack of anatomic detail in PET scans. PET has been shown to have a higher sensitivity and at times a higher specificity than CT and/or MRI in staging and post-treatment evaluation for recurrence in a wide range of tumors. Multiple studies have consistently shown that addition of PET to routine CT scanning impacted therapeutic decisions in almost one out of six cancer patients. Changes in therapeutic decisions were manifested in a variety of ways, from a change in cancer staging to modification of radiation portals. Studies like these are instrumental to match technology with reimbursement. Although PET has a 2% to 3% detection rate for unsuspected malignancies, the cost of PET scanning and the procedures performed subsequent to false-positive cases make it economically unfeasible for cancer screening. Screening issues aside, Blodgett and colleagues report that Medicare and most third-party payers do not reimburse for PET imaging with carcinoma arising from an unknown primary site, accounting for 5% of cancer diagnoses (see report on page 3). In addition, Medicare and most third-party payers do not reimburse the use of PET imaging to differentiate whether a nodule in the lung or other visceral structure is benign or malignant. An important distinction needs to be made, however, in the economics of procedures done for cancer staging and cancer screening. Economic models need to incorporate the savings of averting the need for biopsy or surgery to determine malignancy, and the cost of less-effective therapeutic approaches taken because the primary site is neither detected nor treated. Other costs of cancer and its care include the costs of disability to the patient and his or her family, whether they be temporary expenses related to a procedure or cumulative costs incurred over the long term. These costs are profound in financial and human terms. A Broadened Challenge More targeted approaches, which improve the therapeutic ratio by improved therapeutic tolerance, have evolved in every specialty of oncology. These approaches include receptor-specific systemic therapies, sentinel lymph node-based dissections, and intensity-modulated radiation therapy (IMRT). IMRT has allowed more specific radiation dose deposition to spare normal structures and increase the radiation dose within the tumor. At the 2004 RSNA meeting, fused ProstaScint and CT images were used to deliver 75.6 Gy over 42 fractions to the entire prostate, and the tumor was boosted to 82 Gy using IMRT techniques (see report on page 15). Doses of this magnitude were not possible without the use of IMRT, but the addition of Prosta Scint/CT image fusion reduced side effects even further. At 3 months, only 1 of 38 patients experienced a grade 3 genitourinary toxicity, which resolved after 1 month of follow-up. Development of respiratory gating during PET/CT can reduce uncertainties about tumor location for radiation treatment planning. In the past, large radiation fields were constructed for lung cancer therapy because of concerns that the tumor would move outside the radiation field during the respiratory cycle. New technology, by precisely accounting for movement of the tumor during the respiratory cycle, has significantly reduced the size of the radiation portal (see reports on pages 10 and 11). Respiratory gating during radiation can reduce the volume of lung included in radiation portals even further, which is especially important for patients with limited pulmonary reserve. These exciting technological advancements take the next step toward tumor-specific therapies that were popularized by the term,"magic bullet." The goal has always been to eradicate cancer without harm to the patient. Much work still must be done to achieve that goal. Improved control of disease and treatment-related symptoms is possible with available means and must be standardized in protocols and practice. Avoidance of treatment-related symptoms by more limited surgical approaches, and through targeted systemic agents and radiation therapy, will continue to reduce the burden of cancer treatment and its long-term sequelae, including subsequent treatment-induced cancer. The study of a new therapeutic approach should also include a comprehensive cost-benefit analysis to address the realities of health care demographics and economics. The challenge of oncology has broadened beyond curing cancer. For almost 2 decades, we have recognized the profound impact of the consequences of cancer treatment and cure. The specialty must not only relieve suffering by curing cancer, but it also must relieve suffering from pain, fatigue, and other symptoms while curing cancer. The challenge now facing us is to cure cancer without incurring side effects, and to improve the cost-effectiveness of cure. In short, these technological advancements in cancer therapy must provide a meaningful difference in response and minimize treatmentrelated toxicity, while reducing the burden of care and cost of cancer to society as a whole. Nora A. Janjan, MD
Professor of Radiation Oncology
The University of Texas
M. D. Anderson Cancer Center