Management of Anxiety and Depression in Adult Survivors of Cancer: ASCO Guideline Update.

PURPOSE: To update the American Society of Clinical Oncology guideline on the management of anxiety and depression in adult cancer survivors. METHODS: A multidisciplinary expert panel convened to update the guideline. A systematic review of evidence published from 2013-2021 was conducted. RESULTS: The evidence base consisted of 17 systematic reviews ± meta analyses (nine for psychosocial interventions, four for physical exercise, three for mindfulness-based stress reduction [MBSR], and one for pharmacologic interventions), and an additional 44 randomized controlled trials. Psychological, educational, and psychosocial interventions led to improvements in depression and anxiety. Evidence for pharmacologic management of depression and anxiety in cancer survivors was inconsistent. The lack of inclusion of survivors from minoritized groups was noted and identified as an important consideration to provide high-quality care for ethnic minority populations. RECOMMENDATIONS: It is recommended to use a stepped-care model, that is, provide the most effective and least resource-intensive intervention based on symptom severity. All oncology patients should be offered education regarding depression and anxiety. For patients with moderate symptoms of depression, clinicians should offer cognitive behavior therapy (CBT), behavioral activation (BA), MBSR, structured physical activity, or empirically supported psychosocial interventions. For patients with moderate symptoms of anxiety, clinicians should offer CBT, BA, structured physical activity, acceptance and commitment therapy, or psychosocial interventions. For patients with severe symptoms of depression or anxiety, clinicians should offer cognitive therapy, BA, CBT, MBSR, or interpersonal therapy. Treating clinicians may offer a pharmacologic regimen for depression or anxiety for patients who do not have access to first-line treatment, prefer pharmacotherapy, have previously responded well to pharmacotherapy, or have not improved following first-line psychological or behavioral management.Additional information is available at www.asco.org/survivorship-guidelines.

Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update.

PURPOSE: To update the American Society of Clinical Oncology (ASCO)-Society of Surgical Oncology (SSO) guideline for sentinel lymph node (SLN) biopsy in melanoma. METHODS: An ASCO-SSO panel was formed, and a systematic review of the literature was conducted regarding SLN biopsy and completion lymph node dissection (CLND) after a positive sentinel node in patients with melanoma. RESULTS: Nine new observational studies, two systematic reviews and an updated randomized controlled trial (RCT) of SLN biopsy, as well as two randomized controlled trials of CLND after positive SLN biopsy, were included. RECOMMENDATIONS: Routine SLN biopsy is not recommended for patients with thin melanomas that are T1a (non-ulcerated lesions < 0.8 mm in Breslow thickness). SLN biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or <0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure. SLN biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of >1.0 to 4.0 mm). SLN biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm. In the case of a positive SLN biopsy, CLND or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathological factors. For higher risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. Important qualifying statements outlining relevant clinicopathological factors, and details of the reference patient populations are included within the guideline.

Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update.

Purpose To update the American Society of Clinical Oncology (ASCO)-Society of Surgical Oncology (SSO) guideline for sentinel lymph node (SLN) biopsy in melanoma. Methods An ASCO-SSO panel was formed, and a systematic review of the literature was conducted regarding SLN biopsy and completion lymph node dissection (CLND) after a positive sentinel node in patients with melanoma. Results Nine new observational studies, two systematic reviews, and an updated randomized controlled trial of SLN biopsy, as well as two randomized controlled trials of CLND after positive SLN biopsy, were included. Recommendations Routine SLN biopsy is not recommended for patients with thin melanomas that are T1a (nonulcerated lesions < 0.8 mm in Breslow thickness). SLN biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or < 0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure. SLN biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of > 1.0 to 4.0 mm). SLN biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm. In the case of a positive SLN biopsy, CLND or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathological factors. For higher-risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. Important qualifying statements outlining relevant clinicopathological factors and details of the reference patient populations are included within the guideline. Additional information is available at www.asco.org/melanoma-guidelines and www.asco.org/guidelineswiki .

Brachytherapy for Patients With Prostate Cancer: American Society of Clinical Oncology/Cancer Care Ontario Joint Guideline Update.

Purpose To jointly update the Cancer Care Ontario guideline on brachytherapy for patients with prostate cancer to account for new evidence. Methods An Update Panel conducted a targeted systematic literature review and identified more recent randomized controlled trials comparing dose-escalated external beam radiation therapy (EBRT) with brachytherapy in men with prostate cancer. Results Five randomized controlled trials provided the evidence for this update. Recommendations For patients with low-risk prostate cancer who require or choose active treatment, low-dose rate brachytherapy (LDR) alone, EBRT alone, and/or radical prostatectomy (RP) should be offered to eligible patients. For patients with intermediate-risk prostate cancer choosing EBRT with or without androgen-deprivation therapy, brachytherapy boost (LDR or high-dose rate [HDR]) should be offered to eligible patients. For low-intermediate risk prostate cancer (Gleason 7, prostate-specific antigen < 10 ng/mL or Gleason 6, prostate-specific antigen, 10 to 20 ng/mL), LDR brachytherapy alone may be offered as monotherapy. For patients with high-risk prostate cancer receiving EBRT and androgen-deprivation therapy, brachytherapy boost (LDR or HDR) should be offered to eligible patients. Iodine-125 and palladium-103 are each reasonable isotope options for patients receiving LDR brachytherapy; no recommendation can be made for or against using cesium-131 or HDR monotherapy. Patients should be encouraged to participate in clinical trials to test novel or targeted approaches to this disease. Additional information is available at www.asco.org/Brachytherapy-guideline and www.asco.org/guidelineswiki .

Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: an American Society of Clinical Oncology guideline adaptation.

PURPOSE: A Pan-Canadian Practice Guideline on Screening, Assessment, and Care of Psychosocial Distress (Depression, Anxiety) in Adults With Cancer was identified for adaptation. METHODS: American Society of Clinical Oncology (ASCO) has a policy and set of procedures for adapting clinical practice guidelines developed by other organizations. The guideline was reviewed for developmental rigor and content applicability. RESULTS: On the basis of content review of the pan-Canadian guideline, the ASCO panel agreed that, in general, the recommendations were clear, thorough, based on the most relevant scientific evidence, and presented options that will be acceptable to patients. However, for some topics addressed in the pan-Canadian guideline, the ASCO panel formulated a set of adapted recommendations based on local context and practice beliefs of the ad hoc panel members. It is recommended that all patients with cancer be evaluated for symptoms of depression and anxiety at periodic times across the trajectory of care. Assessment should be performed using validated, published measures and procedures. Depending on levels of symptoms and supplementary information, differing treatment pathways are recommended. Failure to identify and treat anxiety and depression increases the risk for poor quality of life and potential disease-related morbidity and mortality. This guideline adaptation is part of a larger survivorship guideline series. CONCLUSION: Although clinicians may not be able to prevent some of the chronic or late medical effects of cancer, they have a vital role in mitigating the negative emotional and behavioral sequelae. Recognizing and treating effectively those who manifest symptoms of anxiety or depression will reduce the human cost of cancer.

Improving IMRT-plan quality with MLC leaf position refinement post plan optimization.

PURPOSE: In intensity-modulated radiation therapy (IMRT) planning, reducing the pencil-beam size may lead to a significant improvement in dose conformity, but also increase the time needed for the dose calculation and plan optimization. The authors develop and evaluate a postoptimization refinement (POpR) method, which makes fine adjustments to the multileaf collimator (MLC) leaf positions after plan optimization, enhancing the spatial precision and improving the plan quality without a significant impact on the computational burden. METHODS: The authors' POpR method is implemented using a commercial treatment planning system based on direct aperture optimization. After an IMRT plan is optimized using pencil beams with regular pencil-beam step size, a greedy search is conducted by looping through all of the involved MLC leaves to see if moving the MLC leaf in or out by half of a pencil-beam step size will improve the objective function value. The half-sized pencil beams, which are used for updating dose distribution in the greedy search, are derived from the existing full-sized pencil beams without need for further pencil-beam dose calculations. A benchmark phantom case and a head-and-neck (HN) case are studied for testing the authors' POpR method. RESULTS: Using a benchmark phantom and a HN case, the authors have verified that their POpR method can be an efficient technique in the IMRT planning process. Effectiveness of POpR is confirmed by noting significant improvements in objective function values. Dosimetric benefits of POpR are comparable to those of using a finer pencil-beam size from the optimization start, but with far less computation and time. CONCLUSIONS: The POpR is a feasible and practical method to significantly improve IMRT-plan quality without compromising the planning efficiency.

Verification of MLC based real-time tumor tracking using an electronic portal imaging device.

PURPOSE: The authors have developed a novel technique using an electronic portal imaging device (EPID) to verify the geometrical accuracy of delivery of dose-rate-regulated tracking (DRRT). This technique, called verification of real-time tracking with EPID (VORTE), can potentially be used for both on-line and off-line quality assurance (QA) of MLC-based dynamic tumor tracking. METHODS: The shape and position of target as a function of time, which is assumed to be known, is projected onto the EPID plane. This projected sequence of apertures as a function of time (target motion) is then used as the reference. The accuracy of dynamic MLC tracking can then be assessed by how well the delivered beam follows this projected target motion without the use of a physical moving phantom. The beam apertures controlled by DRRT (aperture motion) is detected by the EPID as a function of time. The aperture motion is compared to the target motion to evaluate tracking error introduced by DRRT. The accuracy of VORTE was measured using film measurements of ten static fields. The VORTE for dynamic tumor tracking was tested with several target motions, including (1) rigid-body two-dimensional (2-D) cyclic motion in the superior-inferior direction with various period and amplitude; (2) the above 2-D cyclic motion plus cyclic deformation; and (3) 2-D cyclic motion with both deformation and rotation. For each target motion, the controlled aperture motion resulting from DRRT was acquired at approximately 8 Hz using EPID in the continuous-acquisition mode. Leaf positions in all captured frames were measured from the EPID and compared to their expected positions. The passing rate of 2 mm criteria for all leaves from all frames was calculated for each of the four patterns of tumor motion. Additionally, the root-mean-square (RMS) deviations of the centroid of the apertures between the designed and delivered beams were calculated for all three cases. RESULTS: The accuracy of MLC-leaf position determination by VORTE is 0.5 mm (1 standard deviation) by comparison to film measurements. With DRRT, the passing rates using the 2 mm criteria for all acquired frames are 100% for the 2-D displacement, 99% for the 2-D displacement with deformation, and 88% for the 2-D displacement combined with both deformation and rotation. The RMS deviations are 0.6 mm for the 2-D displacement, 1.0 mm for the 2-D displacement with deformation, and 1.1 mm for the 2-D displacement combined with both deformation and rotation. CONCLUSIONS: The VORTE can measure the accuracy of MLC-based tumor tracking without the necessity of employing a moving phantom. Moreover, it can be used for complex target motion (i.e., 2-D displacement combined with deformation and rotation) that is difficult to create with physical moving phantoms. Therefore, the VORTE and the novel QA process illustrated by this study have a great potential for verifying real-time tumor tracking.

Usefulness of guided breathing for dose rate-regulated tracking.

PURPOSE: To evaluate the usefulness of guided breathing for dose rate-regulated tracking (DRRT), a new technique to compensate for intrafraction tumor motion. METHODS AND MATERIALS: DRRT uses a preprogrammed multileaf collimator sequence that tracks the tumor motion derived from four-dimensional computed tomography and the corresponding breathing signals measured before treatment. Because the multileaf collimator speed can be controlled by adjusting the dose rate, the multileaf collimator positions are adjusted in real time during treatment by dose rate regulation, thereby maintaining synchrony with the tumor motion. DRRT treatment was simulated with free, audio-guided, and audiovisual-guided breathing signals acquired from 23 lung cancer patients. The tracking error and duty cycle for each patient were determined as a function of the system time delay (range, 0-1.0 s). RESULTS: The tracking error and duty cycle averaged for all 23 patients was 1.9 +/- 0.8 mm and 92% +/- 5%, 1.9 +/- 1.0 mm and 93% +/- 6%, and 1.8 +/- 0.7 mm and 92% +/- 6% for the free, audio-guided, and audiovisual-guided breathing, respectively, for a time delay of 0.35 s. The small differences in both the tracking error and the duty cycle with guided breathing were not statistically significant. CONCLUSION: DRRT by its nature adapts well to variations in breathing frequency, which is also the motivation for guided-breathing techniques. Because of this redundancy, guided breathing does not result in significant improvements for either the tracking error or the duty cycle when DRRT is used for real-time tumor tracking.

Real-time tumor tracking with preprogrammed dynamic multileaf-collimator motion and adaptive dose-rate regulation.

The authors have developed a new method for real-time tumor tracking with dynamic multileaf-collimator (MLC) motion under condition of free breathing. Unlike other previously proposed tumor-tracking methods, their new method uses a preprogrammed dynamic MLC sequence in combination with real-time dose-rate control. This new scheme circumvents the technical challenge in MLC-based tumor tracking of having to control the MLC motion in real time, based on real-time detected tumor motion. With their new method, the movement of the tumor, as a function of breathing phase, amplitude, or tidal volume, is reflected in the preprogrammed MLC sequence. The irregularity of breathing during treatment is handled by real-time regulation of the machine dose rate, which effectively speeds up or slows down the delivery of radiation as needed. This method is based on the fact that all of the parameters in dynamic radiation delivery, including MLC motion, are enslaved to the cumulative dose, which, in turn, can be accelerated or decelerated by varying the dose rate. Because commercially available MLC systems do not allow the MLC delivery sequence to be modified in real time based on the patient's breathing signal, previously proposed tumor-tracking techniques using a MLC cannot be readily implemented in the clinic today. By using a preprogrammed MLC sequence to handle the required motion, the task for real-time control is greatly simplified. With their new scheme, which they call dose-rate-regulated tracking (DRRT), it is possible to use existing linear accelerators that have dynamic MLC capability to achieve real-time tumor tracking, provided that the beam dose rate can be controlled externally. Tracking-error evaluation for 13 patients out of 14 resulted in a tracking error of less than 1 mm (1 sigma), if the effect of the response time of the treatment machine on the dose-rate modulation can be neglected. Film measurements on a moving phantom with variable breathing patterns and DRRT delivery showed that 97% of the measurement points have gamma values less than 1 (for 3% and 2-mm criteria), while non-DRRT delivery showed only 87%. This study shows that real-time tracking is feasible with DRRT even when the patient breathing frequency is irregular. Effects of the variation of breathing amplitude and of base line drift on the tracking error with DRRT are discussed; pending further study, a criterion is suggested for patient selection in the application of this new technique in the clinic.

Phase 1 study of escalating-dose OncoGel (ReGel/paclitaxel) depot injection, a controlled-release formulation of paclitaxel, for local management of superficial solid tumor lesions.

OncoGel is a novel depot formulation of paclitaxel designed for intralesional injection with a sustained paclitaxel delivery over approximately 6 weeks from a single administration. This phase 1 study was designed to characterize the toxicity, pharmacokinetics and preliminary antitumor activity associated with OncoGel administered directly into solid tumors. OncoGel was injected into 18 superficially accessible advanced solid cancerous lesions among 16 adult patients for whom no curative therapy was available. Four dose cohorts were evaluated, ranging from 0.06 to 2.0 mg paclitaxel/cm3 tumor volume. OncoGel injections were generally well tolerated. There was one report of grade 3 injection site pain for a patient in the 0.25 mg paclitaxel/cm3 tumor volume dose cohort. Other adverse events considered related to the study drug included mild to moderate local responses to the injection itself. Systemic levels of paclitaxel were detectable only in 3.3% of the samples analyzed (range: 0.53-0.71 ng/ml). For the 14 patients evaluable for disease progression, stable disease was noted among six patients and progressive disease among eight patients. Although the maximum tolerated dose was not identified, the planned maximum dose was administered in the study. OncoGel delivered intralesionally at doses up to 2.0 mg paclitaxel/cm3 tumor volume was well tolerated and paclitaxel remained localized at the injection site, confirming design principles to minimize systemic exposure. Therefore, localized paclitaxel administration using OncoGel merits continued clinical development.

Phase I Trial of sequential administration of recombinant DNA and adenovirus expressing L523S protein in early stage non-small-cell lung cancer.

L523S is an immunogenic lung cancer antigen that has demonstrated preclinical safety when the gene is injected intramuscularly as an expressive plasmid (pVAX/L523S) and when delivered following incorporation into an E1B-deleted adenovirus (Ad/L523S). We performed a phase I clinical trial in 13 stage IB, IIA, and IIB non-small-cell lung cancer patients. pVAX/L523S (8 mg on days 0 and 14 in all cohorts) and Ad/L523S (1, 20, 400 x 10(9) vp on days 28 and 56, cohorts 1, 2, and 3, respectively) were administered to 3 patients in each of three cohorts. No significant toxic effect was identified. All but 1 patient demonstrated greater than or equal to twofold elevation in anti-adenovirus antibodies. One of 10 evaluable patients demonstrated L523S-specific antibody by direct IgG ELISA. Two patients developed disease recurrence and all remain alive after a median of 290 days follow-up. Results suggest a high level of safety but evidence of L523S-directed immune activation was limited, suggesting a need for modification of dose, schedule, and site of vaccination (i.e., intradermal) with further clinical testing.

Spatial distribution of radiation-induced double-strand breaks in plasmid DNA as resolved by atomic force microscopy.

Atomic force microscopy (AFM) has been used to directly visualize, size and compare the DNA fragments resulting from exposure to low- and high-LET radiation. Double-stranded pUC-19 plasmid ("naked") DNA samples were irradiated by electron-beam or reactor neutron fluxes with doses ranging from 0.9 to 10 kGy. AFM scanning in the tapping mode was used to image and measure the DNA fragment lengths (ranging from a few bp up to 2864 bp long). Double-strand break (DSB) distributions resulting from high-LET neutron and lower-LET electron irradiation revealed a distinct difference between the effects of these two types of radiation: Low-LET radiation-induced DSBs are distributed more uniformly along the DNA, whereas a much larger proportion of neutron-induced DSBs are distributed locally and densely. Furthermore, comparisons with predictions of a random DSB model of radiation damage show that neutron-induced DSBs deviate more from the model than do electron-induced DSBs. In summary, our high-resolution AFM measurements of radiation-induced DNA fragment-length distributions reveal an increased number of very short fragments and hence clustering of DSBs induced by the high-LET neutron radiation compared with low-LET electron radiation and a random DSB model prediction.

Irofulven demonstrates clinical activity against metastatic hormone-refractory prostate cancer in a phase 2 single-agent trial.

BACKGROUND: The primary objective of this study was to assess the antitumor activity of irofulven in patients with hormone-refractory prostate cancer by measuring a sustained decrease of 50% or greater in serum prostate-specific antigen (PSA) levels. PATIENTS AND METHODS: Forty-two patients (median age, 73 years) received at least 1 dose of 10.6 mg/m2 irofulven per day on days 1-5 of a 28-day course. Eligible patients had pathologically confirmed metastatic hormone-refractory adenocarcinoma of the prostate and had not received prior cytotoxic chemotherapy. RESULTS: Forty-two patients received a median of 3 courses of irofulven. Thirty-two patients received at least 2 courses of therapy and were evaluable for efficacy. Four patients (13%) achieved partial response, with a median duration of 2.9 months (range, 2.6-5.8 months). Twenty-seven patients (84%) had disease stabilization and 1 patient (3%) progressed on study. Median progression-free survival was 3.2 months (95% confidence interval, 2.3-4.2 months), with a median progression-free survival of 4.2 months (range, 3.5-6.9 months) for responders. Grade 4 toxicities consisted of thrombocytopenia, anemia, and neutropenia, occurring in 1 patient each. The most common treatment-related grade 3 nonhematologic toxicities included asthenia (19% of patients), vomiting (14%), nausea (12%), and infection without grade 3/4 neutropenia (10%). CONCLUSION: Irofulven shows activity in hormone-refractory prostate cancer and has an acceptable safety profile, warranting further investigation of this drug, particularly in combination therapies.