The continuing challenge for every specialty in oncology is to improve the therapeutic ratio, which is the balance of the biological effectiveness of the treatment and the severity of treatment-related side effects.
The continuing challenge for every specialty in oncology is to improve the therapeutic ratio, which is the balance of the biological effectiveness of the treatment and the severity of treatment-related side effects. The goal of targeted tumor imaging and therapy based on tumor biology is to better identify tumor in order to limit surgical and radiation fields and restrict the effects of systemic therapies to tumor cells. This more targeted approach has the potential to improve tolerance to cancer treatment.
Treatment-related toxicities can significantly compromise response to cancer therapy, as they may interrupt and extend the treatment schedule, cause reductions in the doses administered, and result in failure to complete the planned course of therapy. In one study, 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 the toxic effects of the chemoradiotherapy.1 Only 181 patients (64%) completed the planned treatment; 17% stopped treatment because of a medical determination about treatment-related toxicity, and 10% of patients declined to continue treatment.
Despite the toxicity and failure to complete treatment in more than one-third of the chemoradiotherapy patients, the median overall survival in the chemoradiotherapy arm of this interinstitutional trial was significantly higher than the surgery-only group. Unfortunately, the inability to control treatment-related symptoms in more than one-third of chemoradiotherapy patients probably also had a substantial impact on the 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 notable.
It is ironic that 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 one day may reduce disease control rates by 1.4%, while a treatment break of a 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 available therapies, cannot be overemphasized in the development of future clinical trials and standards of practice.
Radiation therapy fields have historically been large to treat the tumor, the areas of potential microscopic involvement beyond visible tumor, and regional nodal drainage. Radiation treatment fields have decreased considerably with the concurrent administration of chemotherapy during radiation therapy. Generally, depending more on systemic therapy to treat microscopic extensions of disease, radiation portals now usually encompass the visible tumor and a limited margin around the tumor. 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 earlier diagnosis and more precise radiation treatment volumes. As reported at the 2004 RSNA meeting, MR spectroscopy, dynamic contrast-enhanced MR imaging, and ultrasmall paramagnetic contrast media improved the accuracy of diagnosis and staging of prostate cancer and affected therapeutic decisions (p. 8). With endorectal-coil-assisted MR imaging and 3D MRS, Dr. Juan 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. Likewise, dynamic contrast-enhanced MRI found recurrent prostate cancer earlier after radiation therapy (p. 8). The sensitivity rates in all of these studies equaled or were greater than 75%.
PET is similar to MR spectroscopy in that it involves imaging based on biological principles. An exciting development is the anatomic and functional fusion of CT, MR, and PET images, which overcomes the limitations of each. Specifically, the fusion of CT or 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 MR in staging and post-treatment evaluation of recurrence of a wide range of tumors. Multiple studies have consistently shown that the addition of PET to routine CT scanning had an impact on therapeutic decisions in almost one out of six cancer patients. Changes in therapeutic decisions have ranged from a change in cancer staging to modification of radiation portals.
Studies such as 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 subsequent procedures resulting from false-positive cases is not economically feasible for routine cancer screening. Although the costs associated with PET scanning as a screening procedure may be prohibitive, Blodgett and colleagues report that Medicare and most third-party payers do not reimburse for PET imaging of carcinoma arising from an unknown primary site, which accounts for 5% of cancer diagnoses (p. 2). Medicare and most third-party payers also do not reimburse for PET imaging when it is used to determine whether a nodule in the lung or other visceral structure is benign or malignant.
An important distinction must be made, however, in the economics of procedures done for cancer staging and for cancer screening. Economic models should incorporate the savings when biopsy or surgery is avoided to determine malignancy. These economic models should also consider the cost of less effective treatments that result in disability. Disability, whether temporary or long-term, incurs profound financial and human costs to the patient and family.5
More targeted approaches that improve the therapeutic ratio by improving therapeutic tolerance have evolved, including receptor-specific systemic therapies, sentinel lymph node-based dissections, and intensity-modulated radiation therapy. IMRT has allowed more specific radiation dose deposition to spare normal structures and increase the radiation dose within the tumor. In a study reported 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 dose to the tumor was boosted to 82 Gy using IMRT techniques. Doses of this magnitude were not possible without the use of IMRT, but the addition of ProstaScint/CT image fusion reduced side effects even further. At three months, only one of 38 patients had experienced a grade 3 genitourinary toxicity, which resolved after one month of follow-up.
Development of respiratory gating during PET/CT can reduce the uncertainties about the tumor location for radiation treatment planning. Large radiation fields have been constructed for lung cancer in the past because of concerns that the tumor would move outside the radiation field during the respiratory cycle. Precisely accounting for movement of the tumor during the respiratory cycle allows reduction of the size of the radiation portal. Respiratory gating during radiation can reduce the volume of lung included in radiation portals even further, which is especially important among patients with limited pulmonary reserve.
FINDING THE MAGIC BULLET
These exciting technological advancements take the next step toward tumor-specific therapies that used to be popularized by the term "the magic bullet." The goal has always been to eradicate cancer without harm to the patient. Despite tremendous advancements, much remains to be done to achieve that goal. Improved control of disease and treatment-related symptoms is possible with available means that 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 such as fatigue, cardiac dysfunction, and subsequent treatment-induced cancer. The study of a new therapeutic approach should also include a comprehensive cost-benefit analysis to address the realities of current and future healthcare demographics and economics.
The challenge of oncology has broadened beyond curing cancer. For almost two decades, we have recognized the profound impact of the consequences of cancer treatment and cure. Oncologists acknowledge that their specialty must not only relieve suffering by curing cancer, but it must also relieve suffering from pain, fatigue, and other symptoms while curing cancer. The challenge now is to achieve the cure without incurring side effects and to improve the cost-effectiveness of cure.
In short, technological advancements in cancer therapy must provide a meaningful difference in response, minimize the treatment-related toxicity for the patient, and reduce the burden of care and cost from cancer to society as a whole.
1. Macdonald JS, Smalley SR, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. NEJM 2001;345:725-730.
2. Horiot JC. Prophylaxis versus treatment: is there a better way to manage radiotherapy-induced nausea and vomiting? Int J Radiation Oncology Biol Phys 2004;60:1018-1025.
3. Fowler J, Lindstrom M. Loss of local control with prolongation in radiotherapy. Int J Radiation Oncology Biol Phys 1992;23:457-467.
4. Robertson C, Robertson AG, Hendry JH, et al. Similar decreases in local tumour control are calculated for treatment protraction and for interruptions in the radiotherapy of carcinoma of the larynx in four centres. Int J Radiation Oncology Biol Phys 1998;40:319-329.
5. Emanuel EJ, Fairclough DL, Slutsman J, Emanuel LL. Understanding economic and other burdens of terminal illness: the experience of patients and their caregivers. Ann Intern Med 2000;132:451-459.
Dr. Janjan is a professor of radiation oncology at the M.D. Anderson Cancer Center in Houston, TX, and the guest editor for Imaging and Oncology.