Faculty Bibliography

In this article, the discussions about concepts involved in anticancer therapy, including cell death pathways and the variables that guide clinical management, such as intents and types of anticancer therapy regimens and modalities, are a prelude to the review of FDG PET/CT imaging parameters used in the evaluation of response to therapy. The review also includes brief discussions about differences between evaluation of cytostatic and cytotoxic therapy regimens and induction and neoadjuvant therapy regimens.

This article discusses evaluating response after and during therapy in various settings and for the types of cancers for which ample evidence demonstrates that PET imaging with flourodeoxyglucose provides a valuable surrogate for response to therapy. It also briefly discusses pitfalls in obtaining an optimal assessment of response and issues that need further attention for this modality to become established as an independent predictor of response to anticancer therapy.

FDG PET/CT, an established imaging modality for staging and restaging workup of malignancies, also demonstrates increased uptake in infectious or inflammatory conditions, including both infectious and noninfectious granulomatous processes. A 65-year-old man with a history of hepatocellular carcinoma status post-wedge resection and chemoembolization of the primary tumor referred for evaluation of extrahepatic metastases for determining the surgical eligibility for a liver transplantation. The patient underwent FDG PET/CT imaging associated with a separately acquired contrast enhanced CT (CECT) of the chest, abdomen, and pelvis. FDG PET/CT imaging revealed multiple FDG-avid pulmonary nodules that were subsequently confirmed to represent Mycobacterium avium intracellular infection on histology.

PURPOSE/OBJECTIVE:To develop guidelines for performing and interpreting positron emission tomography (PET) imaging for treatment assessment in patients with lymphoma both in clinical practice and in clinical trials. METHODS:An International Harmonization Project (IHP) was convened to discuss standardization of clinical trial parameters in lymphoma. An imaging subcommittee developed consensus recommendations based on published PET literature and the collective expertise of its members in the use of PET in lymphoma. Only recommendations subsequently endorsed by all IHP subcommittees were adopted. RECOMMENDATIONS/CONCLUSIONS:PET after completion of therapy should be performed at least 3 weeks, and preferably at 6 to 8 weeks, after chemotherapy or chemoimmunotherapy, and 8 to 12 weeks after radiation or chemoradiotherapy. Visual assessment alone is adequate for interpreting PET findings as positive or negative when assessing response after completion of therapy. Mediastinal blood pool activity is recommended as the reference background activity to define PET positivity for a residual mass > or = 2 cm in greatest transverse diameter, regardless of its location. A smaller residual mass or a normal sized lymph node (ie, < or = 1 x 1 cm in diameter) should be considered positive if its activity is above that of the surrounding background. Specific criteria for defining PET positivity in the liver, spleen, lung, and bone marrow are also proposed. Use of attenuation-corrected PET is strongly encouraged. Use of PET for treatment monitoring during a course of therapy should only be done in a clinical trial or as part of a prospective registry.

PURPOSE/OBJECTIVE:Based on prostate-specific membrane antigen (PSMA) expression on the vasculature of solid tumors, we performed a phase I trial of antibody J591, targeting the extracellular domain of PSMA, in patients with advanced solid tumor malignancies. This was a proof-of-principle evaluation of PSMA as a potential neovascular target. The primary end points were targeting,toxicity, maximum-tolerated dose, pharmacokinetics (PK), and human antihuman antibody (HAHA) response. PATIENTS AND METHODS/METHODS:Patients had advanced solid tumors previously shown to express PSMA on the neovasculature. They received 111Indium (111ln)-J591 for scintigraphy and PK, followed 2 weeks later by J591 with a reduced amount of 111In for additional PK measurements. J591 dose levels were 5, 10, 20, 40, and 80 mg. The protocol was amended for six weekly administrations of unchelated J591. Patients with a response or stable disease were eligible for re-treatment. Immunohistochemistry assessed PSMA expression in tumor tissues. RESULTS:Twenty-seven patients received monoclonal antibody (mAb) J591. Treatment was well tolerated. Twenty (74%) of 27 patients had at least one area of known metastatic disease targeted by 111In-J591, with positive imaging seen in patients with kidney, bladder, lung, breast, colorectal, and pancreatic cancers, and melanoma. Seven of 10 patient specimens available for immunohistochemical assessment of PSMA expression in tumor-associated vasculature demonstrated PSMA staining. No HAHA response was seen. Three patients of 27 with stable disease received re-treatment. CONCLUSION/CONCLUSIONS:Acceptable toxicity and excellent targeting of known sites of metastases were demonstrated in patients with multiple solid tumor types, highlighting a potential role for the anti-PSMA antibody J591 as a vascular-targeting agent.

Radioimmunotherapy (RIT) with tositumomab and iodine 131 tositumomab can produce durable and complete responses in relapsed/refractory low-grade Non-Hodgkin's lymphoma. Patients with bone marrow involvement (BMI) with tumor >25% of the intertrabecular space are generally excluded from RIT because of risk of excessive hematologic toxicity. The authors conducted a dose-escalation study of tositumomab and iodine 131 tositumomab to determine whether RIT is feasible in this population. Patients had baseline BMI of >25% and platelet count of >or=150,000/mm3. In contrast to the usual 75 cGy total body dose of radiation, dose escalation of Iodine I 131 tositumomab began at a total body dose of 45 cGy, and increased to 55 cGy in a second cohort. Dose-limiting toxicity (DLT) was defined as absolute neutrophil count <500 cells/mm3 or platelets <25,000/mm3 for >17 days, or absolute neutrophil count <750/mm3 or platelets <50,000/mm3 for >24 days. Eleven subjects were enrolled (8 at 45 cGy and 3 at 55 cGy). Estimated BMI ranged from 30 to 65% (median approximately 40%). Patients had received a median of three prior chemotherapies (range 1 - 6). One of the six evaluable patients treated at 45 cGy experienced DLT. Three patients received 55 cGy, one had hematologic DLT concurrent with lymphoma progression and extensive BMI at relapse. Three of 11 (27%) patients received hematologic supportive care. Two patients had objective responses of 1 and 42.4+ months, respectively. RIT with attenuated dose iodine 131 tositumomab for patients with >25% BMI has acceptable toxicity and can result in lymphoma responses.

BACKGROUND:Early prediction of response to therapy may offer the potential to identify patients who will benefit from standard conventional therapy. The objective of this study was to determine the predictive value of FDG-PET as an early response indicator after 1 cycle of chemotherapy for progression-free survival (PFS) in diffuse large cell lymphoma (DLCL) and classic Hodgkin disease (HD). METHODS:FDG-PET was performed before, after 1 cycle, and after completion of chemotherapy in 47 patients. The patients were followed with a median follow-up of 21 months (range, 3-47 months). PFS was compared between PET-positive and PET-negative patients after 1 cycle and after completion of therapy. RESULTS:All PET-negative patients after 1 cycle (n = 31) had sustained complete remission with a median follow-up of 28 months. Fourteen of 16 PET-positive patients after 1 cycle had refractory disease or relapsed (median PFS, 5.5 months). There were 2 false-positive results, 1 with an active infection at the biopsy site and the other in a patient who had been in remission after radiation therapy. There was good agreement between the results obtained after 1 cycle and at completion of therapy (kappa, 0.80); however, the negative predictive value was higher for FDG-PET after 1 cycle than after completion of chemotherapy (100% vs 91.4%), although not statistically different (P = .40). CONCLUSIONS:FDG-PET had a high prognostic value after 1 cycle of chemotherapy, thus it can be a valid alternative for posttreatment evaluation of DLCL and HD and may offer the potential for change in treatment paradigms.

The identification of refractory or nonresponding tumors at an early period during therapy may lead to abbreviation of the current therapy regimen or timely institution of an alternative therapy protocol. Nevertheless, evaluation of treatment response is consequential clinically if the tumor potentially is curable and if effective treatment alternatives exist, so that change in treatment ultimately may increase the probability of response and survival. Hodgkin disease (HD) and diffuse large cell lymphoma (LCL) fit in this model well. However, a subset of patients is either refractory to first-line treatment or develops recurrent disease after an initial remission. Improvements in the treatment of these diseases rely not only on new therapy modalities and accurate assessment of disease extent but also on the assessment of disease extent and on timely and accurate therapy response to enable a more effective management plan. Although the International Prognostic Score for HD and International Prognostic Index for LCL have proved valuable for the stratification of patients in clinical trials, there is variability in outcome within the individual risk groups. Recently, positron emission tomography using (18)F-labeled fluoro-2-deoxy-D-glucose (FDG-PET) imaging has been suggested as a sensitive and relatively more specific means to reflect tumor biologic changes after therapy. With increasingly compelling evidence, early FDG-PET provides a reliable means to assess tumor response accurately that may lead to better management with an effective therapeutic approach.