Introducing FDG PET/CT-guided chemoradiotherapy for stage III NSCLC in low- and middle-income countries: preliminary results from the IAEA PERTAIN trial.

PURPOSE: Patients with stage III non-small-cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT) in low- and middle-income countries (LMIC) continue to have a poor prognosis. It is known that FDG PET/CT improves staging, treatment selection and target volume delineation (TVD), and although its use has grown rapidly, it is still not widely available in LMIC. CRT is often used as sequential treatment, but is known to be more effective when given concurrently. The aim of the PERTAIN study was to assess the impact of introducing FDG PET/CT-guided concurrent CRT, supported by training and quality control (QC), on the overall survival (OS) and progression-free survival (PFS) of patients with stage III NSCLC. METHODS: The study included patients with stage III NSCLC from nine medical centres in seven countries. A retrospective cohort was managed according to local practices between January 2010 and July 2014, which involved only optional diagnostic FDG PET/CT for staging (not for TVD), followed by sequential or concurrent CRT. A prospective cohort between August 2015 and October 2018 was treated according to the study protocol including FDG PET/CT in treatment position for staging and multimodal TVD followed by concurrent CRT by specialists trained in protocol-specific TVD and with TVD QC. Kaplan-Meier analysis was used to assess OS and PFS in the retrospective and prospective cohorts. RESULTS: Guidelines for FDG PET/CT image acquisition and TVD were developed and published. All specialists involved in the PERTAIN study received training between June 2014 and May 2016. The PET/CT scanners used received EARL accreditation. In November 2018 a planned interim analysis was performed including 230 patients in the retrospective cohort with a median follow-up of 14 months and 128 patients in the prospective cohort, of whom 69 had a follow-up of at least 1 year. Using the Kaplan-Meier method, OS was significantly longer in the prospective cohort than in the retrospective cohort (23 vs. 14 months, p = 0.012). In addition, median PFS was significantly longer in the prospective cohort than in the retrospective cohort (17 vs. 11 months, p = 0.012). CONCLUSION: In the PERTAIN study, the preliminary results indicate that introducing FDG PET/CT-guided concurrent CRT for patients with stage III NSCLC in LMIC resulted in a significant improvement in OS and PFS. The final study results based on complete data are expected in 2020.

Impact of 18F-fluorodeoxyglucose positron emission tomography in the staging and treatment response assessment of extra-pulmonary small-cell cancer.

The aim of this study was to retrospectively evaluate the value of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in extrapulmonary small-cell cancer (EPSCC). Patients with EPSCC who underwent PET for staging or response assessment between 1996 and 2007 were identified from a database. Patient records were reviewed. PET-based, and conventional staging and restaging results were compared. The binary staging classification of limited disease (LD) versus extensive disease (ED) was used. Patients with LD had tumours that could be encompassed within a tolerable radiation therapy (RT) volume. Of 33 eligible patients, 12 had staging PET scans, 11 had restaging scans and 10 had both. All known gross disease sites were FDG-avid. PET and conventional stage groupings were concordant in 21 of 22 cases. One patient was appropriately upstaged from LD to ED by PET. PET detected additional disease sites, without causing upstaging in three further patients. Restaging PET scans identified previously unrecognised persistent or progressive disease in 4 of 21 cases. In four further cases, persistent FDG uptake after treatment was either false positive (n = 2) or of uncertain (n = 2) aetiology. PPV was 100% for staging and 82% for restaging. In 8 of 43 imaging episodes (19%), PET appropriately influenced management in five cases by changing treatment intent from radical to palliative, and in three cases by altering the RT volume. PET has incremental value compared to conventional imaging for staging EPSCC, and may also be useful for restaging after therapy. PET influenced patient management in 19% of 43 imaging episodes.

Performance of sodium iodide based (18)F-fluorodeoxyglucose positron emission tomography in the characterization of indeterminate pulmonary nodules or masses.

The purpose of this study was to document the accuracy of (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) with sodium iodide detectors in characterizing indeterminate lung nodules or masses and in identifying additional extra-lesional findings. 50 consecutive patients without a confident diagnosis of malignancy on CT underwent (18)FDG PET with and without attenuation correction. The diagnosis of malignancy was made using visual diagnostic criteria, and tumour-to-blood pool ratios were calculated. The final diagnosis was established by surgery, biopsy or long-term follow-up. Any additional findings made at PET were recorded and similarly verified. Using blinded visual diagnostic criteria for the differentiation of malignant from benign nodules, sodium iodide PET achieved a sensitivity of 91% (30 of 33 cases), a specificity of 88% (15 of 17 cases), a positive predictive value for malignancy of 94% (30 of 32 cases) and a negative predictive value of 83% (15 of 18 cases). False positives occurred with active tuberculosis and sarcoidosis. False negatives were a 3 cm bronchoalveolar carcinoma, a 1.3 cm sarcoma metastasis and a 1 cm carcinoma. Use of tumour-to-blood pool ratios did not improve performance. PET suggested the presence of nodal or distant metastases in 13 of 33 patients with a malignant pulmonary lesion. These PET findings were confirmed in 11 patients. These results indicate that sodium iodide PET is an accurate tool for the characterization of indeterminate pulmonary masses or nodules and simultaneously provides non-invasive staging information that can alter patient management in up to one-third of such patients. Performance of sodium iodide PET is comparable with reported results for PET scanners using other detector materials.

The utility of (18)F-FDG PET for suspected recurrent non-small cell lung cancer after potentially curative therapy: impact on management and prognostic stratification.

UNLABELLED: After potentially curative therapy of non-small cell lung cancer (NSCLC), masses or symptoms suggestive of relapse are common but may be difficult to characterize. Early detection is important because salvage therapies are available for localized recurrence. This study evaluated whether (18)F-FDG PET is useful and predictive of outcome in this setting. METHODS: For 63 consecutive patients with suspected relapse >6 mo after definitive treatment of NSCLC, the apparent extent of disease on conventional restaging was compared with that on FDG PET. Patients with already confirmed systemic metastases were excluded unless locally aggressive treatment of these was being considered. Serial imaging and pathologic results were obtained during a median follow-up of 19 mo to validate diagnostic findings. Prognostic significance was tested using the Cox proportional hazards regression model. RESULTS: PET had positive findings in 41 of 42 patients with confirmed relapse (sensitivity, 98%). No disease was evident during a minimum follow-up of 12 mo in 14 of 15 patients with clinically suspected relapse but negative PET findings (negative predictive value, 93%). PET induced a major management change in 40 patients (63%), including 6 whose treatment was changed from curative to palliative, 3 whose treatment was changed from palliative to curative, and 9 for whom negative PET findings prevented active management. Both the presence (P = 0.012) and the extent (P < 0.0001) of relapse on PET were highly significant prognostic factors. There was also significant prognostic stratification based on the treatment delivered after the PET study (P = 0.011), but after adjustment for this treatment, PET status remained highly predictive of survival. CONCLUSION: PET better assesses the status of disease and stratifies prognosis than does conventional staging, affects patient management, and should be incorporated into paradigms for suspected recurrence of NSCLC.

(18)F-FDG PET provides high-impact and powerful prognostic stratification in staging newly diagnosed non-small cell lung cancer.

UNLABELLED: Survival of lung cancer patients remains poor despite increasingly aggressive treatment. Conventional staging has well-described limitations. (18)F-FDG PET has been shown to stage lung cancer more accurately than does CT scanning, but the impact on patient treatment and outcome is poorly defined. This study evaluated this impact in routine clinical practice within a tertiary oncology facility. METHODS: For 153 consecutive patients with newly diagnosed non-small cell lung cancer, the treatment plan based on conventional staging methods was compared with the treatment plan based on incorporation of PET findings. Survival was analyzed using the Cox proportional hazards regression model. RESULTS: For broad groupings of stage, 10% of cases were downstaged and 33% upstaged by PET. When assessable, the PET stage was confirmed in 89% of patients. PET had a high impact on 54 patients (35%), including 34 whose therapy was changed from curative to palliative, 6 whose therapy was changed from palliative to curative, and 14 whose treatment modality was changed but not the treatment intent. For 39 patients (25%), a previously selected therapy was altered because of the PET findings. The Cox model indicated that the pre-PET stage was significantly associated with survival (P = 0.013) but that the post-PET stage provided much stronger prognostic stratification (P < 0.0001) and remained significant after adjustment for treatment delivered. CONCLUSION: Staging that incorporated PET provided a more accurate prognostic stratification than did staging based on conventional investigations. Further, the additional information provided by PET significantly and appropriately changed management in the majority of patients.

Positron emission tomography in pulmonary masses where tissue diagnosis is unhelpful or not possible.

OBJECTIVE: To document the usefulness of positron emission tomography (PET) in diagnosing lung masses where tissue diagnosis is not possible or is unhelpful. DESIGN: Cohort study (partly retrospective). SETTING: Departments of positron emission tomography and diagnostic imaging of a tertiary referral dedicated cancer hospital in Melbourne. PATIENTS: 40 of 60 consecutive patients referred for evaluation of an indeterminate lung nodule or mass, comprising 15 in whom biopsy was not possible and 25 in whom biopsy had either failed or did not confirm malignancy or a specific benign diagnosis. MAIN OUTCOME MEASURES: Accuracy of blinded reading of PET scans in determining whether the lung lesion is benign or malignant (final diagnosis established either through surgical biopsy or from long term clinical and imaging follow-up). RESULTS: PET yielded 23 true positives, 13 true negatives, 3 false positives (2 tuberculosis, 1 sarcoidosis) and 1 false negative (an adenocarcinoma), giving a sensitivity of 96%, a specificity of 81%, a negative predictive value of 93%, and a positive predictive value of 88% (for malignancy). CONCLUSIONS: For lung nodules where tissue diagnosis was not possible or was unhelpful, the negative predictive power of PET was sufficiently high to avoid open biopsy, and to follow such patients with serial surveillance. On the other hand, most lesions that were positive on PET were either malignant or required specific active management determined from histological characterisation. PET therefore contributed to improved patient management and has reduced the need for open thoracotomy.

Management of localized low-grade follicular lymphomas.

Long-term follow-up data from Stanford and other centres suggest that 40-50% of patients with clinical stages I and II follicular low-grade lymphoma can be cured by radiotherapy (RT). Relapse generally occurs outside radiation fields and most relapsed patients ultimately die from lymphoma. No randomized data exist to support adjuvant chemotherapy but only one trial of low-intensity chemotherapy was sufficiently powerful to address the question. Nevertheless, data from a large phase-II study from MD Anderson suggest that combined chemotherapy and RT can produce progression-free survival results that are far superior to historical series, with survival at 10 years to be approximately 20% superior to radiation alone. These results have encouraged the development of a joint phase III study by the Trans Tasman Radiation Oncology Group (TROG) and the Australasian Leukaemia and Lymphoma Group (ALLG) in which patients with clinical stage I/II follicular lymphoma are randomized to involved field RT with or without six cycles of cytotoxic chemotherapy. In an era of rapid development in immunological and molecular therapies the potential for improved results with new combinations of more established treatment modalities should not be forgotten. This report reviews the literature on the management of localized low-grade lymphoma and discusses the rationale for the TROG/ALLG study, which began recruitment in early 2000.

High rate of detection of unsuspected distant metastases by pet in apparent stage III non-small-cell lung cancer: implications for radical radiation therapy.

PURPOSE: Most radical radiotherapy (RT) candidates with non-small-cell lung cancer (NSCLC) have Stage III disease and ultimately die with distant metastases. We tested the hypothesis that positron emission tomography (PET) using 18-F fluorodeoxyglucose (FDG) would detect more unsuspected metastases in apparent Stage III disease than in Stages I-II. METHODS AND MATERIALS: Staging FDG-PET was performed for 167 NSCLC patients, with Stage I-III by conventional workup, who were candidates for curative therapy with surgery (n = 8), radical chemo/RT or RT (n = 156), or preoperative chemo/RT (n = 3). Each patient was allocated a conventional "pre-PET stage" and a "post-PET stage" that relied on PET when discordance with conventional staging occurred. RESULTS: Stage distribution pre-PET was n = 39 (Stage I), n = 28 (Stage II), and n = 100 (Stage III). In 32 patients (19%), PET detected distant metastasis, most commonly abdominal with 17 cases (adrenal, n = 7; liver, n = 4; other, n = 6). Other sites included lung (n = 10) and bone (n = 6). PET-detected metastasis increased with increasing pre-PET stage from I (7.5%) through II (18%) to III (24%, p = 0.016), and, in particular, was significantly higher in Stage III (p = 0.039). Biopsy confirmation was not routine, but progression occurred at PET-detected metastatic sites or other metastatic sites in all but 3 of the 32 patients by last review. CONCLUSION: PET staging is recommended for radical RT candidates with NSCLC. The highest yield of unexpected distant metastases is observed in Stage III.

Clinical impact of (18)F fluorodeoxyglucose positron emission tomography in patients with non-small-cell lung cancer: a prospective study.

PURPOSE: To prospectively study the impact of (18)F fluorodeoxyglucose (FDG) positron emission tomography (PET) on clinical management of patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: One hundred five consecutive patients with NSCLC undergoing (18)F FDG PET were analyzed. Before PET, referring physicians recorded scan indication, conventional clinical stage, and proposed treatment plan. PET scan results were reported in conjunction with available clinical and imaging data, including results of computed tomography (CT). Subsequent management and appropriateness of PET-induced changes were assessed by follow-up for at least 6 months or until the patient's death. RESULTS: Indications for PET were primary staging (n = 59), restaging (n = 34), and suspected malignancy subsequently proven to be NSCLC (n = 12). In 27 (26%) of 105 of cases, PET results led to a change from curative to palliative therapy by upstaging disease extent. Validity of the PET result was established in all but one case. PET appropriately downstaged 10 of 16 patients initially planned for palliative therapy, allowing either potentially curative treatment (four patients) or no treatment (six patients). PET influenced the radiation delivery in 22 (65%) of 34 patients who subsequently received radical radiotherapy. Twelve patients considered probably inoperable on conventional imaging studies were downstaged by PET and underwent potentially curative surgery. PET missed only one primary tumor (5-mm scar carcinoma). CT and PET understaged three of 20 surgical patients (two with N1 lesions < 5 mm and one with unrecognized atrial involvement), and PET missed one small intrapulmonary metastasis apparent on CT. No pathological N2 disease was missed on PET. CONCLUSION: FDG PET scanning changed or influenced management decisions in 70 patients (67%) with NSCLC. Patients were frequently spared unnecessary treatment, and management was more appropriately targeted.

Imaging with F-18 FDG PET is superior to Tl-201 SPECT in the staging of non-small cell lung cancer for radical radiation therapy.

Thallium-201 (Tl-201) single photon emission computed tomography (SPECT) is funded for evaluation of malignancy in Australia and may have utility for staging of non-small cell lung cancer (NSCLC) if CT results are equivocal. Fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET) is superior to CT for staging NSCLC but is more expensive and less widely available than Tl-201 SPECT. Therefore, these techniques were prospectively compared in 27 radical radiation therapy candidates. Patients were allocated a conventional, PET and Tl-201 stage. Tumour to background ratios (TBR) were recorded for the primary on both techniques. Metastatic disease was confirmed by surgical pathology, serial imaging or clinical follow up. Tumour to background ratios were consistently higher for FDG PET than Tl-201 SPECT (P < 0.0001). Positron emission tomography detected all known primary tumours but Tl-201 failed to image four primary tumours (15%). In 10 of 18 cases of discordance between PET and Tl-201 SPECT regarding stage, corroboration was available from pathology or disease progression. Positron emission tomography was shown to have a 100% positive predictive value, including all three patients with PET-detected distant metastases (P=0.002). Results indicate that PET is superior to Tl-201 SPECT scanning in the staging of NSCLC for radical radiation therapy, and that the low sensitivity for detection of local and metastatic disease is likely to limit the clinical impact and cost-effectiveness of this technique despite its lower cost.

Spontaneous regression of metastatic renal cell carcinoma following palliative irradiation of the primary tumour.

A 58 years old man presented with a bulky renal primary tumour, paratracheal lymphadenopathy and multiple pulmonary metastases. Spontaneous regression of intrathoracic metastases occurred after low dose palliative irradiation of the primary tumour. Serum levels of Interleukin-2 receptor were elevated during the period of tumour regression but concentrations of other cytokines were normal. Progressive abdominal disease eventually caused death. Autopsy confirmed the presence of renal cell carcinoma with intrathoracic metastases.

Hypobaric hypoxia: a method for testing bioreductive drugs in vivo.

Hypobaric hypoxia has been used to induce tumor hypoxia for in vivo comparison of the anti-tumor effects of the bioreductive agents SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), RSU 1069 (1(2-nitro-1-imidazolyl)-3-aziridino-2-propanol), and Nitromin (methylbis(2-chloroethyl)amine N-oxide). BDF mice bearing the T50/80 mammary carcinoma were treated with these agents over a range of doses under normobaric (oxic) and hypobaric (hypoxic) conditions. The time taken for the tumor to double treatment volume (volume doubling time) was used as a measure of anti-tumor effect. Volume doubling time was plotted against log dose and dose response curves were fitted. A dose enhancement ratio (the ratio of drug doses required to give an equivalent anti-tumor effect under oxic and hypoxic conditions) was determined. The dose enhancement ratios for SR 4233 and RSU 1069 were 8.8 and 8.5, respectively, showing that these agents had an equivalent and substantial enhancement of their cytotoxicity when combined with hypobaric hypoxia. For Nitromin, no significant dose response effect was obtained under oxic conditions precluding the calculation of the dose enhancement ratio. SR 4233 was found to have increased systemic toxicity when combined with hypobaric hypoxia, suggesting that it is more readily activated than the other drugs tested. This in vivo test system will allow determination of the dose enhancement ratio for novel bioreductive agents and facilitate their comparison.

Misonidazole binding in murine liver tissue: a marker for cellular hypoxia in vivo.

The hepatic microcirculation is believed to cause variable cellular oxygenation within the organ. In this study a marker of cellular hypoxia was used to demonstrate liver oxygen tension gradients in vivo. Covalent binding of misonidazole adducts to cellular macromolecules is enhanced by hypoxia. Autoradiographs of liver from mice treated with radiolabeled misonidazole demonstrated enhanced binding of adducts within hepatocytes surrounding hepatic veins. Livers from both hypoxic and normal mice had characteristic autoradiographic grain patterns reflecting regional oxygen tension variation in vivo. Differential binding of misonidazole adducts formed in hypoxic cells could have an application in studies of liver physiology and biochemistry.

The effect of hypobaric hypoxia on misonidazole binding in normal and tumour-bearing mice.

The effect of hypobaric hypoxia on the in vivo binding of misonidazole was investigated in normal mice and mice bearing T50/80 or CA NT mammary carcinomas. After the intraperitoneal injection of radiolabelled misonidazole, mice were randomised to breathe either room air or air at 0.5 atmospheres. The distribution of misonidazole in liver, kidney, heart, spleen and tumour tissue, 24 h later, was studied by scintillation counting and by autoradiography. Significantly higher misonidazole binding occurred in the livers (x2.5), kidneys (x2.4), spleens (x2.9) and hearts (x1.8) of hypoxic mice compared to controls. Hypobaric hypoxia was associated with a greater than four-fold increase in misonidazole binding within T50/80 tumours. However, significantly higher binding was not demonstrated within CA NT tumours after exposure of tumour-bearing animals to hypoxic conditions. In autoradiographs of hypoxic liver, labelling was intense in regions near to hepatic veins but sparse in areas surrounding portal tracts. This pattern was striking and consistent. In hypoxic kidney, labelling was most intense over tubular cells, less intense over glomeruli and sparse in the renal medulla. It is likely that the hepatic and renal cortical distributions of misonidazole binding reflect local oxygen gradients.

Accuracy of blood glucose concentrations determined by four visually read reagent strips.

Two new reagent strips have recently been introduced for blood glucose measurement by direct visual reading. Results obtained with these strips (Glucostix and Hypogard GA) were compared with those obtained using other commonly employed strips (BM-Test-Glycemie 1-44 and Visidex II) and a standard laboratory method. Blood glucose estimations were performed on samples of venous blood drawn from 125 patients attending the diabetic clinic using each of the four strips and the laboratory method. Results obtained with the strips correlated with the laboratory values as follows: BM-Test-Glycemie 1-44, r=0.93; Glucostix r=0.93; Hypogard GA r=0.87 and Visidex II r=0.92. The lower correlation with Hypogard GA reflected consistent underestimation of the laboratory value (slope of regression line = 0.63). Readings in error by 20% or more were: BM-Test-Glycemie 1-44, 14%; Glucostix, 15%; Hypogard GA, 31%, and Visidex II, 14%. With Hypogard GA strips, 57% of readings above 16 mmol/l were inaccurate. We conclude that Hypogard GA strips cannot be recommended for direct visual reading. Acceptable results may, however, be obtained using the other three strips.Reagent strips allow reasonably accurate determinations of blood glucose concentrations when used with a reflectance meter.(1, 2) Nevertheless many diabetic patients prefer to read the reagent strips visually. This method avoids the problems associated with meter calibration, is cheaper and also is more portable. Direct visual readings with BM-Test-Glycemie 1-44 (Boehringer Corporation) and Visidex II (Ames) have been shown to be acceptable in the hands of medical and technical personnel.(3, 4) Recently two new reagent strips have been marketed, Hypogard GA (Hypogard UK Ltd) and Glucostix (Ames), and it is claimed that they are also suitable for direct visual reading. To test the validity of these claims, we have compared results obtained using the newer strips with readings from BM-Test-Glycemie 1-44 and Visidex II and with a standard laboratory method.