To determine if escalated radiation dose using hypofractionation significantly reduces biochemical and/or clinical disease failure (BCDF) in men treated primarily for prostate cancer.
Between June ...2002 and May 2006, men with favorable- to high-risk prostate cancer were randomly allocated to receive 76 Gy in 38 fractions at 2.0 Gy per fraction (conventional fractionation intensity-modulated radiation therapy CIMRT) versus 70.2 Gy in 26 fractions at 2.7 Gy per fraction (hypofractionated IMRT HIMRT); the latter was estimated to be equivalent to 84.4 Gy in 2.0 Gy fractions. High-risk patients received long-term androgen deprivation therapy (ADT), and some intermediate-risk patients received short-term ADT. The primary end point was the cumulative incidence of BCDF. Secondarily, toxicity was assessed.
There were 303 assessable patients with a median follow-up of 68.4 months. No significant differences were seen between the treatment arms in terms of the distribution of patients by clinicopathologic or treatment-related (ADT use and length) factors. The 5-year rates of BCDF were 21.4% (95% CI, 14.8% to 28.7%) for CIMRT and 23.3% (95% CI, 16.4% to 31.0%) for HIMRT (P = .745). There were no statistically significant differences in late toxicity between the arms; however, in subgroup analysis, patients with compromised urinary function before enrollment had significantly worse urinary function after HIMRT.
The hypofractionation regimen did not result in a significant reduction in BCDF; however, it is delivered in 2.5 fewer weeks. Men with compromised urinary function before treatment may not be ideal candidates for this approach.
Active surveillance (AS) has gained acceptance as a management strategy for localized renal masses.
To review our large single-center experience with AS.
From 2000 to 2016, we identified 457 patients ...with 544 lesions managed with AS from our prospectively maintained kidney cancer database. A subset analysis was performed for patients with ≥5-yr follow-up without delayed intervention (DI).
Linear growth rates (LGRs) were estimated using linear regression for the initial LGR (iLGR) AS interval and the entire AS period. Overall survival (OS) and cumulative incidence of DI were estimated with Kaplan-Meier methods utilizing iLGR groups, adjusting for covariates. DI was evaluated for association with OS in Cox models.
Median follow-up was 67 mo (interquartile range IQR 41–94 mo) for surviving patients. Cumulative incidence of DI (n=153) after 1, 2, 3, 4, and 5 yr was 9%, 22%, 29%, 35%, and 42%, respectively. Median initial maximum tumor dimension was 2.1cm (IQR 1.5–3.1cm). Median iLGR and overall LGR were 1.9 (IQR 0–7) and 1.9 (IQR 0.3–4.2) mm/yr, respectively. Compared with the no growth group, low iLGR (hazard ratio HR 1.25, 95% cumulative incidence CI 0.82–1.91), moderate iLGR (HR 2.1, 95% CI 1.31–3.36), and high iLGR (HR 1.87, 95% CI 1.23–2.84) were associated with DI (p=0.003). The iLGR was not associated with OS (p=0.8). DI was not associated with OS (HR 1.34, 95% CI 0.79–2.29, p=0.3). Five-year cancer-specific mortality (CSM) was 1.2% (95% CI 0.4–2.8%). Of 99 patients on AS without DI for >5 yr, one patient metastasized.
At >5 yr, AS±DI is a successful strategy in carefully managed patients. DI often occurs in the first 2–3 yr, becoming less likely over time. Rare metastasis and low CSM rates should reassure physicians that AS is safe in the intermediate to long term.
In this report, we looked at the outcomes of patients with kidney masses who elected to enroll in active surveillance rather than immediate surgery. We found that patients who need surgery are often identified early and those who remain on active surveillance become less likely to need surgery over time. We concluded that active surveillance with or without delayed surgery is a safe practice and that, when properly managed and followed, patients are unlikely to metastasize or die from kidney cancer.
Active surveillance (AS)±delayed intervention (DI) for localized renal masses is safe at >5 yr of follow-up. Many patients can safely avoid DI, and its likelihood decreases over time. Disease progression is unlikely when remaining on AS for >5 yr.
Standard therapy for an enhancing renal mass is surgical. However, operative treatment may not be plausible in all clinical circumstances. Data on the natural history of untreated enhancing renal ...lesions is limited but could serve as a decision making resource for patients and physicians. We examined available data on the natural history of observed solid renal masses.
A Medline review of the literature was performed from 1966 to the present regarding untreated, observed, localized solid renal masses. To these data we added our institutional experience with a total of 61 lesions observed in 49 patients for a minimum of 1 year. Variables examined were initial lesion size at presentation, growth rate, duration of followup, pathological findings and progression to metastatic disease. Overall weighted mean estimates were calculated for lesion size at presentation, growth rate and followup based upon combining single institutional series with complete information.
We identified 10 reports from 9 single institutional series in the world literature regarding the natural history of untreated solid localized renal lesions. The series included 6 to 40 patients (mean 25) with a mean followup of 30 months (range 25 to 39). When combined with our institutional data, a total of 286 lesions were analyzed, of which 234 could be included in the meta-analysis. Mean lesion size at presentation was 2.60 cm (median 2.48, range 1.73 to 4.08). Meta-analysis revealed a mean growth rate of 0.28 cm yearly (median 0.28, range 0.09 to 0.86) at a mean followup of 34 months (median 32, range 26 to 39) in all series combined. Pathological confirmation was available in 46% of the cases (131 of 286) and it confirmed 92% (120 of 131) as RCC variants. Evaluable data in this subset of confirmed RCC demonstrated a mean growth rate of 0.40 cm yearly (median 0.35, range 0.42 to 1.6). Lesion size at presentation did not predict the overall growth rate (p = 0.46). Progression to metastatic disease was identified in only 1% of lesions (3 of 286) during followup.
The majority of small enhancing renal masses grow at a slow rate when observed. Although metastatic and cancer specific death are low, serial radiographic data alone are insufficient to predict the true natural history of these lesions. Therefore, physicians and patients assume a calculated risk when following these tumors. Basic biological data are needed to assess the natural history of untreated renal masses.
Abstract Objectives Evaluate the efficacy and safety of valrubicin for bacillus Calmette-Guérin (BCG)–refractory carcinoma in situ (CIS) of the bladder based on updated phase III pivotal trial ...efficacy data together with efficacy and safety data from a supportive phase II/III study. Materials and Methods In a phase II/III open-label study (A9303), BCG refractory/intolerant adults with CIS (≥1 previous course of BCG or could not complete a BCG course owing to toxicity or contraindication) were randomized to receive 6 or 9 weekly intravesical valrubicin (800 mg) instillations. In the pivotal phase III open-label study, BCG-refractory/recurrent adults with CIS (≥2 previous courses of intravesical therapy, including ≥1 BCG course) received 6 weekly intravesical valrubicin (800 mg) instillations. Patients with muscle-invasive disease were excluded. Patients underwent a primary disease evaluation (PDE) at 3 months (∼6 weeks after last dose) that included cytoscopy, biopsy, and cytology. Disease recurrence was monitored at 3-month intervals. Complete response (CR) was defined as no evidence of disease at the PDE (month 3) and follow-up (month 6). Efficacy data from the pivotal trial reflect updated information based on US Food and Drug Administration review. Safety assessments in A9303 included local bladder adverse events (LBAEs) and other adverse events (AEs). Results Eighty patients enrolled and 78 completed treatment and underwent the PDE in study A9303; in the pivotal trial, the respective numbers were 90 and 87 patients. In study A9303, 39% of patients had received ≥2 previous courses of BCG and 11% had received ≥3 courses vs. 70% and 28%, respectively, in the pivotal trial. In both studies, the CR rate was 18%. In A9303, LBAEs were the most common AEs, reported by 86% of patients during treatment and 45% during follow-up; most treatment-related LBAEs were mild to moderate. 2 serious AEs in 1 patient (azotemia/reflux nephropathy) were judged as definitely or possibly treatment related; none of the patient deaths were judged to be related to valrubicin. Conclusions Two trials of valrubicin in patients with CIS demonstrate a consistent degree of efficacy in highly pretreated patients (pivotal trial; BCG-refractory patients) and those with fewer previous therapies (A9303; BCG-refractory/intolerant patients).
Abstract Background Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25–50% of patients expected to achieve a ...pathologic response. Validated biomarkers predictive of response are currently lacking. Objective To discover and validate biomarkers predictive of response to NAC for MIBC. Design, setting, and participants Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments–certified laboratory. Outcome measurements and statistical analysis The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. Results and limitations Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery ( p = 0.024) and validation ( p = 0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM , RB1 , and FANCC predicted pathologic response ( p < 0.001; 87% sensitivity, 100% specificity) and better overall survival ( p = 0.007). This test remained predictive for pathologic response in the validation set ( p = 0.033), with a trend towards better overall survival ( p = 0.055). These results require further validation in additional sample sets. Conclusions Genomic alterations in the DNA repair-associated genes ATM , RB1 , and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. Patient summary Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.
Abstract Background Counseling patients with enhancing renal mass currently occurs in the context of significant uncertainty regarding tumor pathology. Objective We evaluated whether radiographic ...features of renal masses could predict tumor pathology and developed a comprehensive nomogram to quantitate the likelihood of malignancy and high-grade pathology based on these features. Design, setting, and participants We retrospectively queried Fox Chase Cancer Center's prospectively maintained database for consecutive renal masses where a Nephrometry score was available. Intervention All patients in the cohort underwent either partial or radical nephrectomy. Measurements The individual components of Nephrometry were compared with histology and grade of resected tumors. We used multiple logistic regression to develop nomograms predicting the malignancy of tumors and likelihood of high-grade disease among malignant tumors. Results and limitations Nephrometry score was available for 525 of 1750 renal masses. Nephrometry score correlated with both tumor grade ( p < 0.0001) and histology ( p < 0.0001), such that small endophytic nonhilar tumors were more likely to represent benign pathology. Conversely, large interpolar and hilar tumors more often represented high-grade cancers. The resulting nomogram from these data offers a useful tool for the preoperative prediction of tumor histology (area under the curve AUC: 0.76) and grade (AUC: 0.73). The model was subjected to out-of-sample cross-validation; however, lack of external validation is a limitation of the study. Conclusions The current study is the first to objectify the relationship between tumor anatomy and pathology. Using the Nephrometry score, we developed a tool to quantitate the preoperative likelihood of malignant and high-grade pathology of an enhancing renal mass.
The authors systematically reviewed the literature and conducted a pooled analysis of studies on small renal masses who underwent active surveillance to identify the risk progression and the ...characteristics associated with metastases.
A search of the MEDLINE database was performed to identify all clinical series that reported the surveillance of localized renal masses. For studies that reported individual-level data, clinical and radiographic characteristics of tumors without progression were compared with the characteristics of tumors that progressed to metastases.
Eighteen series (880 patients, 936 masses) met screening criteria; and, among these, 18 patients were identified who had tumors that progressed to metastasis (mean, 40.2 months). Six studies (259 patients, 284 masses) provided individual-level data for pooled analysis. At a mean (± standard deviation) follow-up of 33.5 ± 22.6 months, the mean initial greatest tumor dimension was 2.3 ± 1.3 cm, and mean linear growth rate was 0.31 ± 0.38 cm per year. Sixty-five masses (23%) exhibited zero net growth under surveillance, and none of those masses progressed to metastasis. A pooled analysis revealed increased age (age 75.1 ± 9.1 years vs 66.6 ± 12.3 years; P = .03), an initial greatest tumor dimension (4.1 ± 2.1 cm vs 2.3 ± 1.3 cm; P < .0001), initial estimated tumor volume (66.3 ± 100.0 cm(3) vs 15.1 ± 60.3 cm(3) ; p = .0001), linear growth rate of (0.8 ± 0.65 cm per year vs 0.3 ± 0.4 cm per year; P = .0001), and a volumetric growth rate of 27.1 ± 24.9 cm(3) per year (vs 6.2 ± 27.5 cm(3) per year; P < .0001) in the progression cohort.
A substantial proportion of small renal masses remained radiographically static after an initial period of active surveillance. Progression to metastases occurred in a small percentage of patients and generally was a late event. The current results indicated that, in patients who have competing health risks, radiographic surveillance may be an acceptable initial approach, and delayed intervention may be reserved for patients who have tumors that exhibit significant linear or volumetric growth.
Purpose Compared to T1a lesions the natural history of untreated renal masses larger than 4 cm is poorly understood. We assessed the growth kinetics and outcomes of cT1b/T2 cortical renal tumors ...managed by an initial period of active surveillance. We compared these cases to those treated with definitive delayed intervention. Materials and Methods We reviewed our institutional, prospectively maintained renal tumor database to identify enhancing solid and cystic masses managed expectantly. Included in analysis were clinically localized tumors greater than 4.0 cm (T1b or greater) that were radiographically followed for more than 6 months. Tumor size at presentation, annual linear tumor growth rate, Charlson comorbidity index, followup and clinical outcomes were compared in patients who remained on active surveillance and those who underwent delayed surgical intervention. Results We identified 72 tumors 4 cm or greater in diameter in a total of 68 patients. Active surveillance was the only treatment in 45 patients (66%) while 23 (34%) progressed to intervention. Median tumor size at presentation was 4.9 cm and the mean linear growth rate was 0.44 cm per year. Of the masses 14.7% demonstrated no growth with time. Comparing patients treated exclusively with active surveillance and those who progressed to definitive intervention revealed no difference in median tumor size at presentation (4.9 vs 4.6 cm, p = 0.79) or the median Charlson comorbidity index (3 vs 2, p = 0.6) but significant differences were seen in median age at presentation (77 vs 60 years, p = 0.0002) and the mean linear growth rate (0.37 vs 0.73 cm per year, p = 0.02). After adjustment younger patients (OR 0.91, 95% CI 0.86–0.97) and tumors with a faster linear growth rate (OR 9.1, 95% CI 1.7–47.8) were more likely to be treated with delayed surgical intervention. At a mean ± SD 38.9 ± 24.0 months of followup (median 32, range 6 to 105) 9 patients (13%) had died of another cause and none had progressed to metastatic disease. Conclusions Localized cT1b or larger renal masses show growth rates comparable to those of small tumors managed expectantly with a low rate of progression to metastatic disease at short-term followup. An initial period of active surveillance to determine tumor growth kinetics is a reasonable option in select patients with significant competing risks and limited life expectancy.
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