Purpose: Clinicians may have reservations about using strontium-89 for the treatment of bone metastases because of concerns that it may limit future use of chemotherapy. We assessed the rate of bone marrow failure in patients with prostate cancer who had received a dose of strontium-89. Patients and Methods: This subgroup analysis involved 34 patients with androgen-independent prostate cancer who had been given a dose of strontium-89 and six weekly doses of doxorubicin after response to induction chemotherapy. We assessed subsequent hematotoxicity in terms of bone marrow failure and the ability to tolerate additional treatments during a median of 25 months (range, 7 to 76 months) after the strontium-89 was administered. Results: No patients developed bone marrow failure within 6 months of receiving strontium-89. Five (15%) of 34 patients developed bone marrow failure at a median 23 months (range, 6 to 53 months) after the strontium-89 treatment. Bone marrow biopsy performed in two of these five patients showed complete replacement of the marrow by tumor. Thirty-one patients (91%) received subsequent cytotoxic treatments at a median 11 months (range, 1 to 33 months) after the strontium-89 treatment. Conclusion: This analysis demonstrated that a single dose of strontium-89 combined with chemotherapy did not affect the delivery of subsequent courses of chemotherapy in a select group of patients. However, a majority of these therapies were given off protocol and were administered at a dose schedule that might be considered inappropriate or inadequate. The clinical role and safety profile of radiopharmaceuticals combined with chemotherapy in prostate cancer therapy deserve further exploration.

BACKGROUND: Ductal or endometrioid adenocarcinoma of the prostate may be a subtype of prostate cancer that is amenable to aggressive local therapeutic strategies. The authors of this report investigated the clinical outcome of patients who had prostate ductal adenocarcinoma after primary radical prostatectomy or radiotherapy.METHODS: The clinical features of 108 patients with locally confined or advanced prostate ductal adenocarcinoma who had undergone primary radical prostatectomy (surgical group, n = 76 men) or no surgery (nonsurgical group, n = 32 men) were evaluated retrospectively. Clinical records were reviewed, and Gleason scores, clinical/pathologic stages, and preoperative prostate‐specific antigen levels were examined. The clinical features that were assessed included local recurrence, distant metastasis, and progression‐free and overall survival after primary therapy.RESULTS: In the surgical group, patients who had pure ductal prostate cancer survived longer (median, 13.8 years; 95% confidence interval [CI], from 13.8 years to not attained) than patients who had mixed ductal prostate cancer (median, 8.9 years; 95% CI, from 7.1 years to not attained; P = .05). In addition, the median time to local progression was shorter (2.8 years vs 4.9 years) and the median time to distant metastasis was longer (3.9 years vs 2.0 years) for patients who had pure ductal adenocarcinoma than for patients who had mixed ductal adenocarcinoma of the prostate after surgery, respectively.CONCLUSIONS: The results of this preliminary study suggested that pure ductal prostate adenocarcinoma tends to pursue an indolent clinical course and poses an increased risk for local recurrence. Local control (particularly prostatectomy) may improve the clinical outcome of patients with pure prostate ductal adenocarcinoma. These results need to be confirmed in prospective studies. Cancer 2009. © 2009 American Cancer Society.

Purpose Samarium-153 (153Sm) lexidronam is a bone-targeting radiopharmaceutical with a short physical half-life and a favorable toxicity profile. We evaluated the safety and feasibility of a concurrent combination of weekly docetaxel with repeated 153Sm-lexidronam in patients with castration-resistant prostate cancer (CRPC). Patients and Methods A conventional 3 + 3 dose-escalation design was used for this study. Patients were treated in three cohorts comprising two cycles of weekly docetaxel at 25, 30, and 35 mg/m2, respectively, on days 1, 8, and 15 of a 28-day cycle in combination with 153Sm (1 mCi/kg) on day 1. Unacceptable hematologic toxicity (UHT) was defined as more than 7 days delay in therapy for inadequate counts: an absolute neutrophil count (ANC) more than 1,000/μL and platelets more than 70,000/μL were required at days 8 and 15 and ANC more than 1,500/μL and platelets more than 100,000/μL were required at cycle 2, day 1. If counts had not recovered by day 56 of either combination cycle, UHT was declared. Results Eighteen patients were treated in three cohorts. Two patients in separate cohorts experienced UHT; the maximum-tolerated dose for this regimen was not reached. The median interval between 153Sm doses was 35 days (range, 27 to 57 days). The only significant toxicity was mild, transient myelosuppression. Five patients (28%) experienced grade 3 hematologic toxicity. There were no grade ≥ 4 hematologic or nonhematologic toxicities. Conclusion Two dosing cycles consisting of weekly docetaxel and monthly 153Sm-lexidronam were well tolerated and feasible in this CRPC population.

BACKGROUND: Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype.METHODS: In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next‐generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations.RESULTS: Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac‐seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected.CONCLUSIONS: The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836–43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

In many respects, heterogeneity is one of the most striking revelations and common manifestations of a stem cell origin of cancer. We observe heterogeneity in myriad mixed tumors including testicular, lung, and breast cancers. We recognize heterogeneity in diverse tumor subtypes in prostate and kidney cancers. From this perspective, we illustrate that one of the main stem-ness characteristics, i.e., the ability to differentiate into diverse and multiple lineages, is central to tumor heterogeneity. We postulate that cancer subtypes can be meaningless and useless without a proper theory about cancer’s stem cell versus genetic origin and nature. We propose a unified theory of cancer in which the same genetic abnormalities, epigenetic defects, and microenvironmental aberrations cause different effects and lead to different outcomes in a progenitor stem cell versus a mature progeny cell. We need to recognize that an all-encompassing genetic theory of cancer may be incomplete and obsolete. A stem cell theory of cancer provides greater universality, interconnectivity, and utility. Although genetic defects are pivotal, cellular context is paramount. When it concerns tumor heterogeneity, perhaps we need to revisit the conventional wisdom of precision medicine and revise our current practice of targeted therapy in cancer care.

Stem cells have long been implicated in prostate gland formation. The prostate undergoes regression after androgen deprivation and regeneration after testosterone replacement. Regenerative studies suggest that these cells are found in the proximal ducts and basal layer of the prostate. Many characteristics of prostate cancer indicate that it originates from stem cells. For example, the putative androgen receptor-negative (AR(-)) status of prostate stem cells renders them inherently insensitive to androgen blockade therapy. The androgen-regulated gene fusion TMPRSS2-ERG could be used to clarify both the cells of origin and the evolution of prostate cancer cells. In this review, we show that the hypothesis that distinct subtypes of cancer result from abnormalities within specific cell types-the stem cell theory of cancer-may instigate a major paradigm shift in cancer research and therapy. Ultimately, the stem cell theory of cancers will affect how we practice clinical oncology: our diagnosis, monitoring, and therapy of prostate and other cancers.