Edward Y. Cheng

Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development

2-[18F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) assesses a fundamental property of neoplasia, the Warburg effect. This molecular imaging technique offers a complementary approach to anatomic imaging that is more sensitive and specific in certain cancers. FDG-PET has been widely applied in oncology primarily as a staging and restaging tool that can guide patient care. However, because it accurately detects recurrent or residual disease, FDG-PET also has significant potential for assessing therapy response. In this regard, it can improve patient management by identifying responders early, before tumor size is reduced; nonresponders could discontinue futile therapy. Moreover, a reduction in the FDG-PET signal within days or weeks of initiating therapy (e.g., in lymphoma, non–small cell lung, and esophageal cancer) significantly correlates with prolonged survival and other clinical end points now used in drug approvals. These findings suggest that FDG-PET could facilitate drug development as an early surrogate of clinical benefit. This article reviews the scientific basis of FDG-PET and its development and application as a valuable oncology imaging tool. Its potential to facilitate drug development in seven oncologic settings (lung, lymphoma, breast, prostate, sarcoma, colorectal, and ovary) is addressed. Recommendations include initial validation against approved therapies, retrospective analyses to define the magnitude of change indicative of response, further prospective validation as a surrogate of clinical benefit, and application as a phase II/III trial end point to accelerate evaluation and approval of novel regimens and therapies.

Lumbosacral chordoma. Prognostic factors and treatment.

STUDY DESIGN Retrospective analysis. OBJECTIVES To analyze the prognostic factors in patients with chordomas, the success of various treatments, the diagnostic value of open versus needle biopsy, the neurologic impairment after sacral nerve resection, and the clinical presentation and site of origin. SUMMARY OF BACKGROUND DATA Staging of chordomas has not been of much value, compared with other bone tumors, because for chordomas, grade is similar, metastasis is infrequent at presentation, and the prognostic significance of size is uncertain. METHODS A review of patients with chordoma from 1965 through 1996 found 23 cases (mean age of patients, 55 years). The mean follow-up was 84 months. Mean tumor size was 81 mm (range, 35-135 mm), location was lumbar (n = 6), S1 (n = 4), S2 (n = 3), S3 (n = 7), S4 (n = 2), and S5 (n = 1). RESULTS No tumors were found in the higher sacrum (S1-S2) alone, without involvement of the lower sacrum. Survival analysis at 5 years showed overall survival (OS) 86%, continuous disease-free survival (CDFS) 58%, and local recurrence-free survival (LRFS) 60%. The location of tumor, defined by highest level of involvement (lumbar vs. sacrum) was of prognostic significance for OS (P = 0.01; log-rank test), CDFS (P = 0.036), but not for LRFS (P = 0.189). Results of multivariate regression showed that location was significant for OS (P = 0.007), CDFS (P = 0.008), and LRFS (P = 0.001). For patients with positive margins (n = 16), initial radiation correlated with longer CDFS (P = 0.002; Mantel-Cox) and LRFS (P = 0.005, Mantel-Cox), but was not significant for OS (P = 0.41). For patients who received no radiation, a positive margin correlated with a shorter CDFS (P = 0.04), a trend to shorter LRFS (P = 0.08), but no difference in OS. Therefore, both a tumor-free margin and initial radiation correlated with a longer survival. No patients had urinary or bowel dysfunction when both S3 nerves were preserved. If one S3 nerve was preserved, 1 of 3 patients had partial urinary incontinence and 2 of 3 patients required bowel medications. If both S3 nerves were resected, all patients required intermittent urinary catheterization and bowel medications. If both S2 nerves were resected, there was complete urinary and bowel incontinence. CONCLUSIONS The highest level of tumor involvement was prognostically significant for OS, CDFS, and LRFS. Radiation was of value when complete excision was not achieved. Bilateral S3 nerve preservation is necessary to ensure retention of normal urinary and bowel function.

Soft tissue sarcomas: Preoperative versus postoperative radiotherapy

External beam radiation may be given either before or after excision of a primary soft tissue sarcoma. This study was undertaken to determine whether or not the timing of radiotherapy was associated with any difference in either local control, survival, or incidence of complications. The files of 112 patients with a primary, nonmetastatic, extremity soft tissue sarcoma, treated with limb salvage surgery and irradiation were evaluated. Data regarding tumor stage, grade, site, surgical margin, dosage and timing of radiotherapy, treatment complications, disease relapse, and relapse‐free survival (RFS) were analyzed. Kaplan‐Meier lifetable analysis was used to determine survival estimates. There was no significant difference in the 5‐year RFS between patients receiving radiotherapy (RT) preoperatively versus postoperatively; 56 ± 15% and 67 ± 12% (P = 0.12, Mantel‐Cox), respectively. There was no significant difference in the overall survival between patients receiving RT preoperatively versus postoperatively; 75 ± 15% and 79 ± 11% (P = 0.94), respectively. Actuarial local control at 5 years for preoperative versus postoperative RT patients was not statistically different; 83 ± 12% versus 91 ± 8% (P = 0.41), respectively. Wound complications were more frequent in preoperative RT patients (31%) compared to postoperative RT patients (8%) (P = 0.0014, chi‐square). Preoperative irradiation was not associated with any benefit in terms of relapse‐free survival, overall survival or actuarial local control in this series. A higher incidence of major wound complications was found among patients treated with preoperative irradiation. We recommend that patients with a resectable extremity soft tissue sarcoma be treated with postoperative irradiation, reserving preoperative irradiation for those situations in which either the tumor is initially thought to be unresectable or the original tumor boundaries are obscured.

Factors Influencing Early Rehabilitation After THA: A Systematic Review

AbstractA wide variation exists in rehabilitation after total hip arthroplasty (THA) in part due to a paucity of evidence-based literature. We asked whether a minimally invasive surgical approach, a multimodal approach to pain control with revised anesthesia protocols, hip restrictions, or preoperative physiotherapy achieved a faster rehabilitation and improved immediate short-term outcome. We conducted a systematic review of 16 level I and II studies after a strategy-based search of English literature on OVID Medline, PubMed, CINAHL, Cochrane, and EMBASE databases. We defined the endpoint of assessment as independent ambulation and ability to perform activities of daily living. Literature supports the use of a multimodal pain control to improve patient compliance in accelerated rehabilitation. Multimodal pain control with revised anesthesia protocols and accelerated rehabilitation speeds recovery after minimally invasive THA compared to the standard approach THA, but a smaller incision length or minimally invasive approach does not demonstrably improve the short-term outcome. Available studies justify no hip restrictions following an anterolateral approach but none have examined the question for a posterior approach. Preoperative physiotherapy may facilitate faster postoperative functional recovery but multicenter and well-designed prospective randomized studies with outcome measures are necessary to confirm its efficacy. Level of Evidence: Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Osteonecrosis of the femoral head after solid organ transplantation: a prospective study.

Background: The reported prevalence of osteonecrosis of the femoral head in patients who have undergone a solid organ transplant has ranged from 3% to 41%. The wide variation is due to the retrospective nature of most studies and the inability to capture data on asymptomatic patients. The primary goals of this study were to determine the true prevalence of osteonecrosis of the femoral head following solid organ transplantation, the time to the development of the osteonecrosis, and whether findings on magnetic resonance imaging precede the onset of symptoms.Methods: Beginning in 1997, patients who had undergone a solid organ transplant were asked to participate in a prospective study in which they would be screened for osteonecrosis of the femoral head. Inclusion criteria included an age of greater than fourteen years, a first-time transplant, and magnetic resonance imaging performed within six months after the transplant. Exclusion criteria were pre-existing osteonecrosis of the femoral head in the hip included in the study, a history of inflammatory arthritis, previous hip surgery, any contraindication to magnetic resonance imaging, a prior organ transplant, prior systemic corticosteroid treatment, and mental health issues preventing adequate follow-up. Screening magnetic resonance imaging was performed every four months. Survivorship analysis was used to determine the prevalence of osteonecrosis of the femoral head.Results: Fifty-two patients (103 hips) were enrolled in the study. Their ages ranged from twenty-four to sixty-five years (mean, forty-three years). Sixteen patients were dropped from the study, but the data collected on them before they were dropped were included in the analysis. Osteonecrosis of the femoral head was diagnosed in eight of the 103 hips. Survivorship analysis revealed that, at one year after the transplant, 89% ± 7% of the hips and 80% ± 13% of the patients were free of osteonecrosis of the femoral head; thus the prevalence of osteonecrosis one year after transplantation was 11% or 20%, respectively. The mean duration of follow-up of the remaining hips was 2.3 years. In two hips the osteonecrosis of the femoral head was seen on the initial screening magnetic resonance imaging, and in the other six it developed after the initial magnetic resonance imaging revealed negative findings. All cases of osteonecrosis of the femoral head developed within ten months after the transplant. Seven of the eight hips were asymptomatic at the time of diagnosis. There was a significant difference in the one-year osteonecrosis-free survival rate between the patients who were less than forty years old (78%) and those who were at least forty years old (97%) (p = 0.011). Diabetes, smoking, and rejection episodes were not risk factors for osteonecrosis of the femoral head.Conclusions: Our study of patients who had had a solid organ transplant revealed that the true prevalence of osteonecrosis of the femoral head in such patients is lower than that reported in most previous studies, osteonecrosis of the femoral head develops prior to the onset of symptoms, an age of less than forty years is a risk factor for osteonecrosis of the femoral head, and osteonecrosis of the femoral head develops within one year after transplantation. We recommend that magnetic resonance imaging be used to screen for osteonecrosis of the femoral head within one year after transplantation. The utility of additional magnetic resonance imaging after one year has not been established.

Quantifying the extent of femoral head involvement in osteonecrosis.

Background: There are numerous methods for quantifying the extent of osteonecrosis of the femoral head. However, there is no consensus regarding which method is the most reliable. The purpose of this study was to determine the reliability and prognostic accuracy of three commonly used methods for quantifying the extent of osteonecrosis of the femoral head.Methods: Thirty-nine hips in twenty-five patients who had stage-I or II osteonecrosis of the femoral head, according to the grading system of the Association Research Circulation Osseous, were independently examined on two separate occasions by three observers of different specialty backgrounds and experience. Each observer used three methods to quantify the extent of osteonecrosis of the femoral head: (1) the index of necrotic extent, (2) the modified index of necrotic extent, and (3) the percentage of femoral head involvement. The interobserver and intraobserver agreement was determined for each method, and the ability of each method to predict the time to subchondral collapse was analyzed statistically.Results: There was significantly valid agreement among the observers for all three methods (p < 0.001 for all three). The correlation coefficients demonstrated substantial agreement among raters when they measured the index of necrotic extent and the percent involvement and nearly perfect agreement when they measured the modified index of necrotic extent. Survivorship analysis revealed that the percent involvement (p < 0.05), index of necrotic extent (p < 0.007), and modified index of necrotic extent (p < 0.04) were prognostically significant predictors of subchondral fracture.Conclusions: Our results indicate that the index of necrotic extent, modified index of necrotic extent, and estimation of the percentage of involvement of the femoral head are reproducible and reliable methods for quantitatively evaluating the extent of osteonecrosis of the femoral head. We believe that the three methods can be utilized with confidence. Furthermore, they are clinically useful for identifying hips at greatest risk for subchondral collapse.

NCI, NHLBI/PBMTC First International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation: Endocrine Challenges—Thyroid Dysfunction, Growth Impairment, Bone Health, & Reproductive Risks

The endocrine system is highly susceptible to damage by high-dose chemotherapy and/or irradiation before hematopoietic cell transplantation (HCT) during childhood. The specific endocrine organs most affected by HCT include the thyroid gland, the pituitary, and the gonads. In addition, hormones that support development and stability of the skeletal system are also affected. Insufficiency of thyroid hormone is 1 of the most common late sequelae of HCT, and occurs more often in young children. Deficiency in the pituitarys production of growth hormone is a problem of unique concern to the pediatric population. The reproductive risks of HCT depend on the patients gender and pubertal status at the time of HCT. Pubertal or gonadal failure frequently occurs, especially in females. Infertility risks for both genders remain high, whereas methods of fertility preservation are limited in all but postpubertal males. Bone health post-HCT can be compromised by low bone mineral density as well as avascular necrosis, but the data on both problems in the pediatric HCT population are limited. In this paper, the current state of knowledge, gaps in that knowledge, and recommendations for future research are addressed in detail for each of these systems.

Ewing Sarcoma Family of Tumors

The Ewing sarcoma family of tumors (ESFT) consists of a group of tumors characterized by morphologically similar round‐cell neoplasm and by the presence of a common chromosomal translocation. Although rare, such tumors constitute the third most frequent primary sarcoma of bone after osteosarcoma and chondrosarcoma. ESFT most commonly affects young children and adolescents. Because most patients with clinically apparent localized disease at diagnosis may also have occult metastatic (ie, systemic) disease, multidrug chemotherapy as well as local disease control with surgery and/or radiation therapy are indicated for all patients. Despite marked improvements in survival during the past 40 years for patients with localized disease, lesser improvements have been seen in patients with metastatic or recurrent disease. A better understanding of the complex biology of ESFT may lead to the successful development of biologically targeted therapies. As the regulatory pathways responsible for transformation, growth, and metastasis of ESFT become more refined, the number of potential therapeutic targets will expand.

Results of treatment for metastatic osteosarcoma with neoadjuvant chemotherapy and surgery.

The purpose of the current study was to define the survival outcome variables for the 85 patients with Stage IIB osteosarcoma treated with neoadjuvant chemotherapy at the authors’ institution from 1982 to 1997. A minimum 4-year followup or death was a requisite for inclusion. Forty-three patients were relapse-free survivors and 14 had no evidence of disease at followup for an overall survival of 67%. Twenty-nine patients had thoracotomy and nine have no evidence of disease with a minimum 4-year followup from last thoracotomy. The mean time to metastasis after diagnosis for patients presenting with Stage IIB disease was 12.8 months. There was no difference in the survival for any of the three chemotherapy protocols, used during the 15 years included in this analysis. There was a significant relation between length of time to relapse and survival. For each additional year without relapse, there is an 18% increase in chance of survival. In patients who were treated with thoracotomy, the number of metastatic nodules was a significant predictor of survival; specifically, each nodule increased the risk of death by 43%. A favorable outcome in this cohort of patients is related to the length of time between initiation of therapy and diagnosis of metastasis, and the number of metastatic foci.

Spontaneous Resolution of Osteonecrosis of the Femoral Head

BACKGROUND The decision to proceed with surgical treatment of asymptomatic osteonecrosis of the femoral head is controversial. The purpose of the present study was to determine (1) if spontaneous resolution of osteonecrosis of the femoral head occurs, (2) how long it takes for resolution to occur, and (3) if there are predictors of spontaneous resolution. METHODS Patients with asymptomatic osteonecrosis of the femoral head were identified from two National Institutes of Health-funded screening studies: a prospective screening study for osteonecrosis of the femoral head after organ transplantation and a study in which patients who had had surgical treatment of symptomatic osteonecrosis of the femoral head were screened for osteonecrosis of the contralateral, asymptomatic hip. The cohort of patients with asymptomatic osteonecrosis of the femoral head was then analyzed. RESULTS Thirteen asymptomatic hips in ten patients were identified in the prospective screening study for osteonecrosis after organ transplantation, and seventeen hips in seventeen patients were identified in the contralateral hip-screening study. Three hips, all from the group of patients who had had organ transplantation, had Association Research Circulation Osseous stage-I disease with spontaneous resolution occurring later as evidenced by serial magnetic resonance imaging scans. In these three hips, the modified index of necrotic extent measured 11.10, 12.72, and 20.83, with the estimated percentage of femoral head involvement being 15% to 30% in two of the hips and <15% in the third. Resolution on magnetic resonance imaging was complete in two of the three hips and was nearly complete in the third. Resolution was not observed when the contralateral hip had symptomatic disease. CONCLUSIONS Spontaneous resolution of osteonecrosis of the femoral head can occur. The factors that appear to be related to resolution are early, asymptomatic disease (Association Research Circulation Osseous stage I) and small lesion size (a modified index of necrotic extent of <25). A larger series is necessary before these factors can be verified as being independent predictors of resolution. Initial signs of resolution may take as long as one year to occur. LEVEL OF EVIDENCE Prognostic study, Level I-1 (prospective study). See Instructions to Authors for a complete description of levels of evidence.