To determine whether [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) can delineate patients with esophageal cancer who may not benefit from esophagectomy after chemoradiotherapy.
Patients and Methods
We reviewed records of 163 patients with histologically confirmed stage I to IVA esophageal cancer receiving chemoradiotherapy with or without resection with curative intent. All patients received surgical evaluation. Initial and postchemoradiotherapy FDG-PET scans and prognostic/treatment variables were analyzed. FDG-PET complete response (PET-CR) after chemoradiotherapy was defined as standardized uptake value ≤ 3.
Eighty-eight patients received trimodality therapy and 75 received chemoradiotherapy. Surgery was deferred primarily due to medical inoperability or unresectable/metastatic disease after chemoradiotherapy. A total of 105 patients were evaluable for postchemoradiotherapy FDG-PET response. Thirty-one percent achieved a PET-CR. PET-CR predicted for improved outcomes for chemoradiotherapy (2-year overall survival, 71% v 11%, P < .01; 2-year freedom from local failure [LFF], 75% v 28%, P < .01), but not trimodality therapy. On multivariate analysis of patients treated with chemoradiotherapy, PET-CR is the strongest independent prognostic variable (survival hazard ratio [HR], 9.82, P < .01; LFF HR, 14.13, P < .01). PET-CR predicted for improved outcomes regardless of histology, although patients with adenocarcinoma achieved a PET-CR less often.
Patients treated with trimodality therapy found no benefit with PET-CR, likely because FDG-PET residual disease was resected. Definitive chemoradiotherapy patients achieving PET-CR had excellent outcomes equivalent to trimodality therapy despite poorer baseline characteristics. Patients who achieve a PET-CR may not benefit from added resection given their excellent outcomes without resection. These results should be validated in a prospective trial of FDG-PET–directed therapy for esophageal cancer.
A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial.
The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm.
The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up.
This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen.
Patients with diabetes mellitus (DM) can have altered sugar transport into cells, potentially affecting the results of 18-FDG PET scans. The specific aim of this study was to determine the effect of DM on pre- and post-treatment standard uptake value (SUV) scores in patients undergoing chemoradiotherapy for esophageal cancer.
Patients with locally advanced esophageal carcinoma undergoing preoperative or definitive chemoradiotherapy underwent pre- and posttreatment 18-FDG PET scans. Maximum SUV score was measured from the tumor before chemoradiotherapy and 3 to 4 weeks after chemoradiotherapy (preoperatively). Patients were identified as having DM by medical record review. Random serum glucose measurements were obtained prior to 18-FDG PET scans. The Wilcoxon signed-rank test was used to test for differences in SUV scores between patients with and without DM, and a generalized linear model with backward selection was applied to search for significant predictors of initial and posttreatment SUV scores.
Sixty-three patients underwent 18-FDG PET scans during the course of treatment for esophageal malignancies between 6/02 and 8/05. Fifty-four patients received chemotherapy. The median radiation dose was 46.8 Gy. Eighteen patients had DM, six were insulin-dependent DM (IDDM). There was no difference in initial SUV scores between DM and non-DM patients (P > .05). There was also no difference in initial SUV scores between IDDM and non-IDDM groups. Patients with tumors at the gastroesophageal junction had lower initial SUV scores compared to patients with tumors in the lower or mid-esophagus (P = .05). T stage was associated with initial SUV score (T2 lower than T3, P = .014). Older age (P = .03), diabetes (P = .007), higher T stage (P = .002), and presence of nodes (P = .05) were each positively associated with posttreatment SUV scores. Blood glucose levels prior to 18-FDG PET scan, endoscopic tumor length, and tumor location were not predictive of posttreatment SUV scores. Patients with DM had significantly lower posttreatment SUV scores compared to patients without DM (P = .04). Pathologic complete response or percent SUV decrease did not differ between patients with or without DM.
Regardless of glucose levels, DM and IDDM do not influence pretreatment SUV scores in patients with localized esophageal cancer. However, DM may influence posttreatment SUV scores and thus complicate interpretation of treatment response. Further confirmatory study in a larger cohort of DM patients to evaluate the relationship of posttreatment SUV score to pathologic response is warranted.
Since the introduction of multimodal therapy regimens, the prognosis of esophageal cancer has improved. There is undoubtedly true for patients with surgically resected tumors in the case of a response to neoadjuvant chemotherapy or chemoradiation. Important conclusions can be drawn from this regarding the indication for perioperative therapies, the radicality of surgery, or the surgical indications. Thus, most of the current research in this field is aimed at the early identification of this subset of patients, at the beginning of, or even before, neoadjuvant treatment. Conventional staging tools have failed to predict responses to neoadjuvant therapy. However, molecular imaging methods, e.g. positron emission tomography (PET)-scans, have shown promising results in the early selection of responders and non-responders during the course of neoadjuvant therapy, allowing physicians to alter the treatment plan accordingly. Even more desirable is the identification of potential responders before the start of neoadjuvant therapy. Preliminary molecular data on biopsy specimens demonstrate the possibility of early response prediction in these patients. We present the current knowledge on response evaluation and prediction in esophageal cancer and draw conclusions for future clinical practice and studies in this review.
Esophageal cancer; Response prediction; Individualized therapy
An epidemiologic shift in esophageal and gastric carcinomas has occurred in recent years in the Western world. Adenocarcinoma of the distal esophagus and gastroesophageal junction (GEJ) is now the predominant esophageal carcinoma, and proximal gastric cancers now account for nearly half of gastric carcinomas. Tumors involving the GEJ appear to be a distinct clinical entity that presents a challenge to oncologists due to issues in staging and classification and uncertainties regarding optimal treatment approach. Beyond surgical resection as the primary treatment modality, the roles of neoadjuvant or adjuvant therapies in GEJ cancers are not clearly defined. This article reviews the major randomized trials of combined-modality treatment in populations with esophageal and gastric cancers that included patients with GEJ carcinomas and discusses how the findings relate to and inform the management of GEJ tumors. In general, preoperative or perioperative chemotherapy appears to improve survival, and the addition of neoadjuvant or adjuvant chemoradiotherapy increases locoregional control and appears to improve survival. Although GEJ tumors account for only 20% to 35% of cancers in the most relevant randomized trials, the available data suggest that trimodality therapy with chemotherapy, radiation, and surgery is a reasonable treatment approach for GEJ tumors. Further clinical trials are needed to define the optimal sequencing and combinations of surgery, radiotherapy, and chemotherapy. These trials should include appropriate definitions and stratification of GEJ tumors in order to facilitate translation of findings to treatment practice.
This study was aimed 1) to investigate the predictive value of FDG PET/CT (fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography) for histopathologic response and 2) to explore the results of FDG PET/CT by molecular phenotypes of breast cancer patients who received neoadjuvant chemotherapy.
Seventy-eight stage II or III breast cancer patients who received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this study. FDG PET/CTs were acquired before chemotherapy and after the first cycle of chemotherapy for evaluating early metabolic response.
The mean pre- and post-chemotherapy standard uptake value (SUV) were 7.5 and 3.9, respectively. The early metabolic response provided by FDG PET/CT after one cycle of neoadjuvant chemotherapy was correlated with the histopathologic response after completion of neoadjuvant chemotherapy (P = 0.002). Sensitivity and negative predictive value were 85.7% and 95.1%, respectively. The estrogen receptor negative phenotype had a higher pre-chemotherapy SUV (8.6 vs. 6.4, P = 0.047) and percent change in SUV (48% vs. 30%, P = 0.038). In triple negative breast cancer (TNBC), the pre-chemotherapy SUV was higher than in non-TNBC (9.8 vs. 6.4, P = 0.008).
The early metabolic response using FDG PET/CT could have a predictive value for the assessment of histopathologic non-response of stage II/III breast cancer treated with neoadjuvant chemotherapy. Our findings suggest that the initial SUV and the decline in SUV differed based on the molecular phenotype.
FDG PET; breast cancer; neoadjuvant chemotherapy; molecular phenotype
Esophageal cancer tumor biology is best assessed clinically by FDG-PET. Both FDG-PET SUVmax and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in esophageal cancer. Interestingly, there is limited data examining the relationship between FDG-PET SUVmax and expression of these tumors markers in esophageal cancer. The purpose of this study was to determine the correlation of tumor markers with FDG-PET SUVmax in esophageal cancer.
FDG-PET SUVmax was calculated in 67 patients with esophageal cancer of which 59 (88%) had adenocarcinoma. Neoadjuvant radiotherapy and/or chemotherapy were administered to (28/67) 42% of patients. Esophageal tumor tissue and surrounding normal tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for 5 known esophageal cancer tumor markers (GLUT1, p53, cyclin D1, EGFR, and VEGF). Assessment of each tumor marker was made by two independent, blinded pathologists using common grading criteria of intensity and percentage of cells stained. A p-value < 0.05 was considered significant.
There were 55 men (82%) and 12 women (18%) with a median age of 63 years (range 40-83). Pathologic staging included stage I (N=29, 43%), stage II (N=19, 28%), stage III disease (N=18, 27%), and stage IV disease (N=1, 2%). PET SUVmax correlated with T stage (p=0.001). In patients undergoing surgery without induction therapy, increasing SUVmax values correlated with increased expression of GLUT1 transporter (p=0.01). There was no correlation between SUVmax and EGFR, cyclin D1, VEGF, or p53 expression in primary tumor.
FDG-PET SUVmax correlates with an increased expression of GLUT1 transporter in esophageal cancer specimens not subjected to induction therapy. No significant difference in tumor marker expression was noted between patients undergoing induction therapy or surgery alone except p53 expression decreased in primary tumors following induction therapy. Failure of SUVmax values to correlate with known prognostic esophageal cancer tumor markers suggests that FDG-PET may have limited clinical utility in assessing response to therapies targeting these markers.
esophageal cancer; tumor markers; FDG-PET
Background. Pleomorphic sarcoma is an aggressive soft tissue sarcoma. In patients with high-risk extremity sarcomas, the significant survival benefits conferred by an intense regimen of neoadjuvant chemoradiotherapy and surgery were reported. To our knowledge, this is the first report in the literature of the neoadjuvant use of trabectedin in a patient with high-grade pleomorphic sarcoma, ineligible for standard neoadjuvant combination therapy with an anthracycline-based regimen. Case Presentation. Here we present a 58-year-old White male with a large tumor in the left thigh, but with no signs of metastases. Owing to the history of severe heart attack, three cycles of neoadjuvant trabectedin were administrated to achieve surgically wide margins. After two cycles, an 18F-FDG-PET showed a large proportion of the central tumor area was without metabolic activity. According to RECIST and Choi criteria, the tumor was stable. After the third cycle of trabectedin, the patient underwent a complete resection, which revealed completely necrotic high-grade pleomorphic sarcoma (stage pT2b), with only a small vital area. Conclusion. The present paper on a promising treatment with neoadjuvant trabectedin of patients with high-grade pleomorphic sarcoma might suggest that such treatment approach may provide a greater chance of cure and survival of such patients.
The integral role of positron-emission tomography (PET) using the glucose analog tracer fluorine-18 fluorodeoxyglucose (FDG) in the staging of non-small cell lung cancer (NSCLC) is well established. Evidence is emerging for the role of PET in response assessment to neoadjuvant therapy, combined-modality therapy, and early detection of recurrence. Here, we review the current literature on these aspects of PET in the management of NSCLC. FDG-PET, particularly integrated 18F-FDG-PET/CT, scans have become a standard test in the staging of local tumor extent, mediastinal lymph node involvement, and distant metastatic disease in NSCLC. 18F-FDG-PET sensitivity is generally superior to computed tomography (CT) scans alone. Local tumor extent and T stage can be more accurately determined with FDG-PET in certain cases, especially in areas of post-obstructive atelectasis or low CT density variation. FDG-PET sensitivity is decreased in tumors <1 cm, at least in part due to respiratory motion. False-negative results can occur in areas of low tumor burden, e.g., small lymph nodes or ground-glass opacities. 18F-FDG-PET-CT nodal staging is more accurate than CT alone, as hilar and mediastinal involvement is often detected first on 18F-FDG-PET scan when CT criteria for malignant involvement are not met. 18F-FDG-PET scans have widely replaced bone scintography for assessing distant metastases, except for the brain, which still warrants dedicated brain imaging. 18F-FDG uptake has also been shown to vary between histologies, with adenocarcinomas generally being less FDG avid than squamous cell carcinomas. 18F-FDG-PET scans are useful to detect recurrences, but are currently not recommended for routine follow-up. Typically, patients are followed with chest CT scans every 3–6 months, using 18F-FDG-PET to evaluate equivocal CT findings. As high 18F-FDG uptake can occur in infectious, inflammatory, and other non-neoplastic conditions, 18F-FDG-PET-positive findings require pathological confirmation in most cases. There is increased interest in the prognostic and predictive role of FDG-PET scans. Studies show that absence of metabolic response to neoadjuvant therapy correlates with poor pathologic response, and a favorable 18F-FDG-PET response appears to be associated with improved survival. Further work is underway to identify subsets of patients that might benefit individualized management based on FDG-PET.
PET; non-small cell lung cancer; staging; response assessment; follow-up
Esophageal cancer is the eighth most common cancer worldwide, and especially in some areas of China is the fourth most common cause of death and is of squamous cell carcinoma (SCC) histology in >90% of cases. Surgery alone was the mainstay of therapeutic intervention in the past, but high rates of local and systemic failure have prompted investigation into multidisciplinary management. In this review, we discuss the key issues raised by the recent availability of esophageal SCC treatment with the addition of chemotherapy, radiotherapy, and chemoradiotherapy to the surgical management of resectable disease and discuss how clinical trials and meta-analysis inform current clinical practice. None of the randomized trials that compared neoadjuvant radiotherapy or chemotherapy with surgery alone in esophageal SCC has demonstrated an increase in overall survival in those patients treated with neoadjuvant radiotherapy or chemotherapy. Neoadjuvant chemoradiotherapy has been accepted recently for esophageal cancer because such a regimen offers great opportunity for margin negative resection, improved loco-regional control and increased survival. The majority of the available evidence currently reveals that only selected locally advanced esophageal SCC are more likely to benefit from the adjuvant therapy. The focus of future trials should be on identification of the optimum regimen and should aim to minimize treatment toxicities and effect on quality of life, as well as attempt to identify and select those patients most likely to benefit from specific treatment options.
Esophageal cancer; Squamous cell carcinoma; Neoadjuvant therapy; Adjuvant therapy; Chemotherapy; Radiotherapy; Chemoradiotherapy
Facilitation of margin-negative resection is the goal of neoadjuvant therapy regimens used in the treatment of borderline-resectable pancreatic cancer patients. Multiple treatment approaches have shown efficacy in this setting, including neoadjuvant GTX (gemcitabine [Gemzar], docetaxel [Taxotere], and capecitabine [Xeloda]) and radiotherapy (RT). Three-dimensional tumor response may be a more accurate method of assessment compared to traditional 1- and 2-dimensional techniques. We compared these 3 methods in a series of patients who underwent neoadjuvant GTX-RT and surgical resection.
Materials and Methods:
This retrospective review included borderline-resectable pancreatic cancer patients treated with neoadjuvant GTX followed by 5-FU chemoradiotherapy with the intent of downstaging to resectability. Tumor was contoured on computed tomography (CT) scans obtained at the following time points: (A) initial staging, (B) CT simulation, and (C) restaging. These contours were used to determine tumor response according to WHO, RECIST, and volumetric criteria.
Fourteen patients all experienced a measurable decrease in tumor volume following neoadjuvant therapy and were deemed suitable for at least surgical exploration. Radiotherapy was delivered to a median 50 Gy (range, 45–52 Gy) in 1.8–2.0 Gy fractions via 3-D conformal (21%) or IMRT (79%). The median percent volume changes before and after CT simulation were −3.4% and −52.6%, respectively. The overall median percent change was −54.5%. The corresponding absolute volume changes were −0.42 cm3 (range, 9.12 to −12.47), −5.31 cm3 (range, 2.06 to −15.93), and −6.72 cm3 (range, 0.53 to −15.47), respectively. Response according to WHO, RECIST, and volumetric methods was identical with the exception of 1 patient.
This is the first study to quantify volumetric tumor change objectively as a result of neoadjuvant chemoradiotherapy for the treatment of borderline resectable pancreatic cancer. Our data suggest that tumor response to neoadjuvant therapy is essentially equivalent between 1-, 2-, and 3-dimensional assessment methods.
The prognosis of advanced esophageal cancer patients is poor. Trimodality therapy of surgical resection plus neoadjuvant chemoradiotherapy (CRT) has been developed to improve survival through locoregional control, leading to prevention of micrometastasis. We investigated whether or not neoadjuvant CRT led to survival benefits in TNM stage II/III esophageal cancer patients. We retrospectively reviewed 62 patients with stage II or III esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant CRT. All patients received esophagectomy 4–7 weeks after CRT consisting of 40 Gy irradiation and chemotherapy (5-FU, 500 mg/m2/day, days 1–5 and cisplatin, 10–20 mg/body, days 1–5). Clinical response and survival rates were analyzed using Kaplan-Meier methods, with P<0.05 considered as significant. The clinical effect rate of CRT for both primary tumors and metastatic nodes was 82.3%. Operative and hospital mortality rates were 1.65 and 6.5%, respectively. The 3-year overall survival (OS) and disease-free survival (DFS) rates were 52.6 and 49.2%, respectively. A significant difference was noted between stages II and III for both OS and DFS. The 5-year OS rates were 64.2% for stage II, 33.1% for stage III (T4 and non-T4) and 46.9% for stage III (non-T4 only) patients. The depth of tumor invasion (T3 vs. T4), resectability (R0 vs. R1, R2), lymph node metastasis (positive vs. negative), and the effect of CRT were proven to be independent prognostic factors for univariate analysis, with resectability and the effect of CRT for multivariate analysis. These data suggest that CRT in stage II/III (non-T4) ESCC patient contributed to tumor shrinkage, leading to higher resectability and longer survival. Neoadjuvant CRT appears to be a promising option for these patients.
chemoradiotherapy; esophagectomy; survival
The incidence of adenocarcinoma of the distal esophagus or esophagogastric junction has increased considerably in Western countries during the past 3 decades, whereas the incidence of squamous-cell carcinoma has decreased slightly. In Japan, most esophageal cancers are squamous-cell carcinomas. Endoscopic examinations are more frequently performed in Japan for routine screening and diagnosis and treatment than in other countries, thereby increasing the detection rate of superficial esophageal carcinomas. In Europe and North America, many clinical trials have been conducted to assess the effectiveness of neoadjuvant chemoradiotherapy followed by surgery in patients with resectable, advanced esophageal cancer. In Japan, surgical resection had been the mainstay of treatment for esophageal cancer. Since the results of the Japan Clinical Oncology Group (JCOG) 9907 study were reported, neoadjuvant chemotherapy with cisplatin plus 5-fluorouracil followed by surgery has emerged as a new standard treatment. As for definitive chemoradiotherapy, cisplatin, 5-fluorouracil, and concurrent radiotherapy dosed to 50.4 Gy are used as standard treatment in a randomized clinical trial performed in North America. In patients who have T4 tumors and/or M1 lymph-node metastasis, chemoradiotherapy with cisplatin and 5-fluorouracil is considered standard treatment, but docetaxel, cisplatin, and 5-fluorouracil plus concurrent radiotherapy is also being studied. Controlled studies have not shown that palliative chemotherapy is superior to best supportive care, but cisplatin plus 5-fluorouracil is still considered standard therapy. Clinical trials of targeted agents are in progress. It is hoped that targeted agents will be effective for esophageal cancer.
A 56-year-old male patient with locally advanced mucinous rectal cancer underwent neoadjuvant chemoradiotherapy. Follow-up imaging with positron emission tomography-computed tomography (PET-CT) revealed a local response to chemoradiotherapy, whereas diffusion-weighted magnetic resonance imaging (DW-MRI) showed newly presented sacral bone metastasis. Histopathologically confirmed bone metastasis and the local tumor were surgically removed. Repeat DW-MRI revealed tumor recurrence in the sacral excision zone eight months after surgery, which was reconfirmed by histopathology. This case shows the superior imaging ability of DW-MRI in the diagnosis of mucinous tumors in comparison to PET-CT.
mucinous; colon cancer; positron emission tomography; diffusion-weighted magnetic resonance imaging
18-Fluorodeoxyglucose-PET (18F-FDG-PET) can be used for early response assessment in patients with locally advanced adenocarcinomas of the oesophagogastric junction (AEG) undergoing neoadjuvant chemotherapy. It has been recently shown in the MUNICON trials that response-guided treatment algorithms based on early changes of the FDG tumor uptake detected by PET are feasible and that they can be implemented into clinical practice.
Only 40%-50% of the patients respond metabolically to therapy. As metabolic non-response is known to be associated with a dismal prognosis, metabolic non-responders are increasingly treated with alternative neoadjuvant chemotherapies or chemoradiation in order to improve their clinical outcome. We plan to investigate whether PET can be used as response assessment during radiochemotherapy given as salvage treatment in early metabolic non-responders to standard chemotherapy.
The HICON trial is a prospective, non-randomized, explorative imaging study evaluating the value of PET as a predictor of histopathological response in metabolic non-responders. Patients with resectable AEG type I and II according to Siewerts classification, staged cT3/4 and/or cN+ and cM0 by endoscopic ultrasound, spiral CT or MRI and FDG-PET are eligible. Tumors must be potentially R0 resectable and must have a sufficient FDG-baseline uptake. Only metabolic non-responders, showing a < 35% decrease of SUV two weeks after the start of neoadjuvant chemotherapy are eligible for the study and are taken to intensified taxane-based RCT (chemoradiotherapy (45 Gy) before surgery. 18FDG-PET scans will be performed before ( = Baseline) and after 14 days of standard neoadjuvant therapy as well as after the first cycle of salvage docetaxel/cisplatin chemotherapy (PET 1) and at the end of radiochemotherapy (PET2). Tracer uptake will be assessed semiquantitatively using standardized uptake values (SUV). The percentage difference ΔSUV = 100 (SUVBaseline - SUV PET1)/SUVBaseline will be calculated and assessed as an early predictor of histopathological response. In a secondary analysis, the association between the difference SUVPET1 - SUVPET2 and histopathological response will be evaluated.
The aim of this study is to investigate the potential of sequential 18FDG-PET in predicting histopathological response in AEG tumors to salvage neoadjuvant radiochemotherapy in patients who do not show metabolic response to standard neoadjuvant chemotherapy.
Clinical trial identifier NCT01271322
The present study aimed to identify whether second mitochondria-derived activator of caspase (Smac), vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (Ki-67) expression in pre-treatment tumor biopsies are useful predictive markers of tumor response in patients with rectal cancer undergoing pre-operative chemoradiotherapy (CRT). Paraffin-embedded tissues obtained before and after therapy were evaluated by immunohistochemical staining for Smac, VEGF and Ki-67. The study evaluated the correlation of Smac, VEGF and Ki-67 immunoreactivity in tumor biopsies before treatment of tumor response to pre-operative CRT. Regarding Smac, patients with a favorable response to neoadjuvant CRT had higher pre-therapy levels (p=0.011). The level of Smac expression decreased after neoadjuvant therapy (p=0.044). However, VEGF expression was found to be negatively and significantly correlated with a favorable tumor response to neoadjuvant CRT (p=0.010). A transient increase in VEGF expression was detected in the resected specimens following neoadjuvant therapy (p=0.030). In addition, tumors with a low Ki-67 labeling index (Ki-67-LI) expression were found to be more sensitive to neoadjuvant therapy than those with a high expression of Ki-67-LI (p=0.034). In contrast to VEGF, the Ki-67 expression level decreased after neoadjuvant therapy. Smac, VEGF and Ki-67 expression levels, assessed immunohistochemically from pre-treatment tumor biopsies, may be useful predictive markers of rectal tumor response to pre-operative CRT.
rectal cancer; second mitochondria-derived activator of caspase; vascular endothelial growth factor; Ki-67; pre-operative chemoradiotherapy
Patients with locally advanced breast carcinoma (LABC) receive preoperative chemotherapy to provide early systemic treatment and assess in vivo tumor response. Serial positron emission tomography (PET) has been shown to predict pathologic response in this setting. We evaluated serial quantitative PET tumor blood flow (BF) and metabolism as in vivo measurements to predict patient outcome.
Patients and Methods
Fifty-three women with primary LABC underwent dynamic [18F]fluorodeoxyglucose (FDG) and [15O]water PET scans before and at midpoint of neoadjuvant chemotherapy. The FDG metabolic rate (MRFDG) and transport (FDG K1) parameters were calculated; BF was estimated from the [15O]water study. Associations between BF, MRFDG, FDG K1, and standardized uptake value and disease-free survival (DFS) and overall survival (OS) were evaluated using the Cox proportional hazards model.
Patients with persistent or elevated BF and FDG K1 from baseline to midtherapy had higher recurrence and mortality risks than patients with reductions. In multivariable analyses, BF and FDG K1 changes remained independent prognosticators of DFS and OS. For example, in the association between BF and mortality, a patient with a 5% increase in tumor BF had a 67% higher mortality risk compared with a patient with a 5% decrease in tumor BF (hazard ratio = 1.67; 95% CI, 1.24 to 2.24; P < .001).
LABC patients with limited or no decline in BF and FDG K1 experienced higher recurrence and mortality risks that were greater than the effects of clinical tumor characteristics. Tumor perfusion changes over the course of neoadjuvant chemotherapy measured directly by [15O]water or indirectly by dynamic FDG predict DFS and OS.
18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been used extensively to explore whether FDG Uptake can be used to provide prognostic information for esophageal cancer patients. The aim of the present review is to evaluate the literature available to date concerning the potential prognostic value of FDG uptake in esophageal cancer patients, in terms of absolute pretreatment values and of decrease in FDG uptake during or after neoadjuvant therapy.
A computer-aided search of the English language literature concerning esophageal cancer and standardized uptake values was performed. This search focused on clinical studies evaluating the prognostic value of FDG uptake as an absolute value or the decrease in FDG uptake and using overall mortality and/or disease-related mortality as an end point.
In total, 31 studies met the predefined criteria. Two main groups were identified based on the tested prognostic parameter: (1) FDG uptake and (2) decrease in FDG uptake. Most studies showed that pretreatment FDG uptake and postneoadjuvant treatment FDG uptake, as absolute values, are predictors for survival in univariate analysis. Moreover, early decrease in FDG uptake during neoadjuvant therapy is predictive for response and survival in most studies described. However, late decrease in FDG uptake after completion of neoadjuvant therapy was predictive for pathological response and survival in only 2 of 6 studies.
Measuring decrease in FDG uptake early during neoadjuvant therapy is most appealing, moreover because the observed range of values expressed as relative decrease to discriminate responding from nonresponding patients is very small. At present inter-institutional comparison of results is difficult because several different normalization factors for FDG uptake are in use. Therefore, more research focusing on standardization of protocols and inter-institutional differences should be performed, before a PET-guided algorithm can be universally advocated.
Changes in tumor metabolism from PET in locally advanced breast cancer (LABC) patients treated with neoadjuvant chemotherapy (NC) are predictive of pathologic response. Serial dynamic [18F]-FDG PET scans were used to compare kinetic parameters to the standardized uptake value (SUV) as predictors of pathologic response, disease-free survival (DFS) and overall survival (OS).
Seventy-five LABC patients underwent FDG PET prior to and at midpoint of NC. FDG delivery (K1), FDG flux (Ki), and SUV measures were calculated and compared by clinical and pathological tumor characteristics using regression methods and area under the receiver operating characteristic curve (AUC). Associations between K1, Ki, and SUV and DFS and OS were evaluated using the Cox proportional hazards model.
Tumors that were hormone receptor negative, high grade, highly proliferative, or of ductal histology had higher FDG Ki and SUV values; on average, FDG K1 did not differ systematically by tumor features. Predicting pathologic response in conjunction with estrogen receptor (ER) and axillary lymph node positivity, kinetic measures (AUC = 0.97) were more robust predictors compared to SUV (AUC = 0.84, P = 0.005). Changes in K1 and Ki predicted both DFS and OS, while changes in SUV predicted OS only. In multivariate modeling, only changes in K1 remained an independent prognosticator of DFS and OS.
Kinetic measures of FDG PET for LABC patients treated with NC accurately measured treatment response and predicted outcome compared to static SUV measures, suggesting kinetic analysis may hold advantage of static uptake measures for response assessment.
PET; FDG kinetics; SUV; breast cancer; neoadjuvant
This report presents a case of highly advanced gastric cancer that achieved a histologically complete response (CR) to preoperative chemoradiotherapy with S-1 plus low-dose Cisplatin. A 60-year-old male patient underwent FDG positron emission tomography (PET) during a routine health examination. The patient was found to have swollen paraaortic lymph nodes. Shortly thereafter, he was diagnosed with gastric carcinoma with a type 2 tumor in the antrum with paraaortic lymph node metastases based on FDG-PET, endoscopic examination and abdominal computed tomography. After the completion of chemoradiation therapy (CRT), the tumor and the paraaortic lymph node metastases disappeared. The patient underwent surgery 5 wk after the completion of CRT, including a subtotal gastrectomy with Roux-en-Y reconstruction, D3 lymph node dissection and a left adrenalectomy. No cancer cells were detected in the resected specimen either in the primary lesion or lymph nodes, thus confirming a pathologically CR to CRT (CR grade 3). The patient has been stable and well without any evidence of recurrence for 48 mo after surgery. Such a preoperative CRT regimen might therefore be very effective for treatment of some advanced gastric cancers.
Complete response; Gastric cancer; Cisplatin; Chemoradiation; Neoadjuvant therapy
Chemoradiotherapy for advanced esophageal cancer is a standard treatment alongside surgical treatment. Although numerous investigators have attempted to identify the predictive markers for chemoradiosensitivity, there appear to be few candidates that can be applied in clinical use. Using biopsy specimens, we investigated the apoptotic index (AI) prior to treatment and following a radiation dose of 10 Gy to detect the early response to chemoradiotherapy in 28 patients with esophageal squamous cell carcinoma. Molecular markers, including p53, p21, bax, bcl-2, HSP27, HSP70, HSP90, Ku70, Ku86 and HIF-1α, were also examined by immunohistochemical staining. The patients were divided into two groups depending on the response to chemoradiotherapy: a responder group (RG) (n=19) that included the patients with complete or partial response, and a non-responder group (NRG) (n=9), that included patients with stable or progressive disease. In the RG and NRG, the AI of pretreatment was 4.7±5.3 (mean ± SD, cells/1,000 cells) and 5.9±3.7, respectively. The apoptotic index ratio (AIR), which was determined by dividing the AI following 10 Gy radiation by the pretreatment AI, was higher in the RG compared to the NRG (4.7±4.5 versus 1.9±1.4, p=0.03). When the cut-off value of AIR was set at 2.4, the sensitivity, specificity and accuracy were 74, 78 and 76%, respectively. Among the molecular markers we examined immunohistochemically, a positive p53 expression in the pretreatment evaluation was associated with the efficacy of chemoradiotherapy (p=0.08). Regarding the expression of other molecular markers, no significant correlations were found in RG and NRG. In the present study, the results indicated that AIR is useful for the prediction of chemoradiosensitivity in esophageal squamous cell carcinoma.
apoptotic index; chemoradiotherapy; esophageal squamous cell carcinoma
Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG-PET) has increasingly been used to evaluate the efficacy of anticancer agents. We investigated the role of FDG-PET as a predictive marker for response to mammalian target of rapamycin (mTOR) inhibition in advanced solid tumor patients and in murine xenograft models.
Patients and Methods
Thirty-four rapamycin-treated patients with assessable baseline and treatment FDG-PET and computed tomography scans were analyzed from two clinical trials. Clinical response was evaluated according to Response Evaluation Criteria in Solid Tumors, and FDG-PET response was evaluated by quantitative changes and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Six murine xenograft tumor models were treated with temsirolimus. Small animal FDG-PET scans were performed at baseline and during treatment. The tumors were analyzed for the expression of pAkt and GLUT1.
Fifty percent of patients with increased FDG-PET uptake and 46% with decreased uptake had progressive disease (PD). No objective response was observed. By EORTC criteria, the sensitivity of progressive metabolic disease on FDG-PET in predicting PD was 19%. Preclinical studies demonstrated similar findings, and FDG-PET response correlated with pAkt activation and plasma membrane GLUT1 expression.
FDG-PET is not predictive of proliferative response to mTOR inhibitor therapy in both clinical and preclinical studies. Our findings suggest that mTOR inhibitors suppress the formation of mTORC2 complex, resulting in the inhibition of Akt and glycolysis independent of proliferation in a subset of tumors. Changes in FDG-PET may be a pharmacodynamic marker for Akt activation during mTOR inhibitor therapy. FDG-PET may be used to identify patients with persistent Akt activation following mTOR inhibitor therapy.
Neoadjuvant chemoradiotherapy followed by esophagogastrectomy has become the standard of care for patients with locally advanced esophageal cancer. This report analyzes our experience with this treatment approach.
From January 1998 through December 2003, all patients from a single institution receiving neoadjuvant chemoradiotherapy followed by esophagogastrectomy were reviewed for operative mortality, morbidity, long-term survival, and factors affecting survival. Only patients preoperatively staged with both computed tomographic scans and endoscopic ultrasound were included.
There were 162 patients (142 men, 20 women), and the median age was 61 years (range, 22 to 81 years). Histopathology was adenocarcinoma in 143 patients and squamous cell in 19. Pretreatment clinical stage was II in 28 patients (17%), III in 111 (68%), and IV (M1a) in 23 (14%). Ivor Lewis esophagogastrectomy was the most common procedure, occurring in 132 patients. Operative mortality and morbidity was 4.9% and 37%, respectively. Pathologic response was complete in 42 patients (26%), near complete in 27 (17%), partial in 88 (54%), and unresectable in 5 (3%). Five-year survival for overall, complete, near complete, and partial response patients was 34%, 55%, 27%, and 27%, respectively (p = 0.013). Patients whose lymph nodes were rendered free of cancer showed improved overall and disease-free survival compared with patients having persistently positive lymph nodes (p = 0.019).
Esophagogastrectomy after neoadjuvant chemoradiotherapy can be performed with low mortality and morbidity. Patients with complete pathologic response have significantly improved long-term survival compared with patients with near complete and partial responses. Future efforts should be directed at understanding determinants of complete responses.
Standard treatment for clinical stage I esophageal cancer with submucosal invasion (T1b) has been surgical resection. We conducted a Phase II trial to evaluate the efficacy and the safety of combined treatment of endoscopic mucosal resection (EMR) and chemoradiotherapy for clinical stage I (T1b) esophageal cancer. Patients diagnosed as having clinical stage I (T1b) esophageal cancer which is considered to be resectable by EMR are eligible. When pathological examination of the EMR specimen confirms T1b tumor with negative or positive resection margin, the patient undergoes chemoradiotherapy. The study continues until 82 patients with T1b tumor with negative resection margin are enrolled from 20 institutions. The primary endpoint is 3-year overall survival (OS) in pT1b cases with negative resection margin. The secondary endpoints are 3-year OS and progression-free survival in all eligible cases, OS in pT1a-MM cases with margin-negative, complications of EMR and adverse events of chemoradiotherapy. The data from this trial will be expected to provide a non-surgical treatment option to the patients with clinical stage I (T1b) esophageal cancer.
superficial esophageal cancer; endoscopic mucosal resection; chemoradiotherapy
The optimal roles for imaging-based biomarkers in the management of head and neck cancer remain undefined. Unresolved questions include whether functional or anatomic imaging biomarkers might improve mortality risk assessment for this disease. We addressed these issues in a prospective institutional trial.
Methods and Materials
Ninety-eight patients with locally advanced pharyngolaryngeal squamous cell cancer were enrolled. Each underwent pre-and post-chemoradiotherapy contrast-enhanced CT and FDG-PET/CT imaging. Imaging parameters were correlated with survival outcomes.
Low post-radiation primary tumor FDG avidity correlated with improved survival on multivariate analysis; so too did complete primary tumor response by CT alone. Although both imaging modalities lacked sensitivity, each had high specificity and negative predictive value for disease-specific mortality risk assessment. Kaplan-Meier estimates confirmed that both CT and FDG-PET/CT stratify patients into distinct high- and low-probability survivorship groups on the basis of primary tumor response to radiotherapy. Subset analyses demonstrated that the prognostic value for each biomarker was primarily derived from patients at high risk for local treatment failure (HPV-negative disease, non-oropharyngeal primary disease, or tobacco use).
CT- and FDG-PET/CT-based biomarkers are useful clinical tools in head and neck cancer-specific mortality risk assessment following radiotherapy, particularly for high-risk HPV-unrelated disease. Focus should be placed on further refinement and corroboration of imaging-based biomarkers in future studies.
Radiotherapy; head and neck cancer; PET; CT; survival