ORLANDO, FL, USA (UroToday.com) - In a rigorous and thoughtful Year in Review lecture at the 2015 ASCO Genitourinary Cancers Symposium Noel W. Clarke, ChM, FRCS (Urol), from The Christie Clinic and Salford Royal NHS Trust in the UK, focused his remarks on the advantages of centralized pathology reporting, since higher accuracy follows from more experienced pathologists; on issues relating to penile preservation and the use of chemotherapy in advanced disease; and on the value of specialized treatment sites for the rare cases of urethral cancer. In testicular cancer, Professor Clarke reviewed evidence supporting insertion of a testicular prosthesis at the time of radical orchidectomy; the use of surveillance rather than intervention in clinical stage 1 disease; and the use of observation rather than surgical intervention for small post-chemotherapy masses in non-seminomatous germ cell tumors.
Penile Cancer
Centralization of pathology
The appropriate care of patients with penile cancer, no less than in other forms of cancer, depends upon an accurate diagnosis, and this in turn relies upon accuracy in pathology reporting. Accuracy comes with experience, and experience is better enabled in high- versus low-volume pathology settings, such as in centralized systems.
Errors that occur in pathology reporting shed light on the important role of experience. In one published re-analysis of pathology reports of 155 penile cancers from urology departments in the northwest of England, the diagnosis was changed in a significant number of patients. There were changes of dysplasia--upgrades, upstaging, down-staging. “Errors that were fundamentally important to treatment choices had occurred,“ Professor Clarke reported.
Not only from human error, variations in staging of this disease may also arise from the TNM classification system itself, or from vagaries of interpretation. In a study to examine this possibility that was published in 2014, researchers asked a group of uropathologists and referral centers in Europe to conduct independent analyses of tissue microarrays (TMAs) of 90 primary penile cancers. The findings revealed “widely different ways of calling this disease,” according to Professor Clarke. For example, the variation from T1a to T1b was 41% to 87%, meaning that many patients were moved from the low-risk to high-risk category, …and some, inappropriately, into a surgical staging process.
Also, as Professor Clarke reminded, a classification that incorporates grade with stage is not beneficial for clinical decision-making. “The cut-offs for values tends to drivec (up) the assignation of an in-between grade – pushing it to surgical staging.”
Questions of treatment
The advantage of centralization of pathology includes a clinical decision-making process for treatment that is based on numbers—a supportive tool in, for example, arriving at the choice of treatment between conservation vs ablation in penile cancer. In the circumstance of carcinoma in situ, expert calls from a central pathology database can help with questions such whether to irradiate or treat with surgery.
In more advanced disease, a vital question physicians must resolve relates to organ preservation: glansectomy vs partial amputation. Informing this decision is a 2014 paper in the journal Urology addressing the care of 859 patients who were treated with local therapy for low-stage disease. The study confirmed a trend toward penile preservation. Its outcomes, however, showed a local recurrence rate of 27%, which Professor Clarke admitted sounded high, but pointed out that the investigators found no difference in long-term survival in this trial. Most patients who had recurrences were successfully salvaged with further treatment.
In patients with poorly differentiated disease, however “one has to be careful to discriminate between conservation and ablation. If you can conserve, the quality of life can be so much better,” Professor Clarke added. Body image is understandably a significant problem for patients who have undergone a partial amputation.
Radiation has its strong proponents with outcomes, in terms of continence, erectile function, and toxicity that are all highly acceptable. In published work from France, outcomes following brachytherapy are very good for early stage disease, he asserted. But despite these endorsements, radiation is not the predominant form of treatment for penile cancer in the United States (or in Europe). According to SEER data, most patients receive surgery alone; only a small proportion of approximately 2,500 U.S. patients receive external beam radiation therapy.
Sentinel node biopsy
Sentinel node biopsy techniques have revolutionized prognostication in lymph node disease, Dr. Clarke said. Far fewer lymph node dissections are performed today due to the success of sentinel node dissection in allowing for sub-stratification. But challenges remain for physicians caring for patients who present with advanced disease.
Neoadjuvant chemotherapy
The use of neoadjuvant chemotherapy in advanced penile cancer is controversial. Published conclusions regarding its usefulness differ. Of two papers to opine on this matter, one from the U.S. and one from Europe, Professor Clarke stated, “one says it’s positive and useful and one says that it is not and don’t bother.”
Findings from a U.S. data retrospective analysis of 61 patients who, over time, had received a variety of treatments (e.g., prior inguinal procedures, no treatment) found that a number of patients do respond. In this report, 65% had partial responses and CRs.
In the contrasting European study of patients with locally unresectable disease who were treated with platinum and 5-FU with docetaxel, the complete and partial responses were not dissimilar to the U.S. findings. However, progression-free survival was poor, at 12%, and most of patients died from the disease. Thus, the negative news of a poor survival rate was made worse by the occurrence of considerable toxicity. “I think we can conclude (from these data) that, (while) there are some patients who respond, the long-term outcome is poor. Case selection is critical and we need larger scale collaborative studies,” Professor. Clarke recommended.
Primary urethral cancer
Primary urethral cancer is a rare form of cancer for which there have been few advances in the last 10 years. Most treatment is directed by guidelines such as from the NCCN in the United States and by the European EAU guidelines.
Patient outcomes are roughly 29%, according to SEER (data), and 54% as reported by European sources. Although study data of typical cases indicates about a 70% complete response rate, about one-fifth of patients have no response at all, Professor Clarke said. “My take-home message from data such as this is (that) what we need is centralization of this disease in the way penile cancer is currently centralized.” Fortunately, usable data are now being gathered, he said, and are beginning to drive treatment.
A remaining need is for a systematic strategy for treatment and accumulation of information about this disease. “Shouldn’t we treat this disease in specialty centers?” Professor Clarke asked rhetorically. “I would put it to you that we should.”
Testis Cancer
Among new developments and contemporary trends in testis cancers are data from active interventions and surgery for small masses.
Epidemiology
In European countries and the Americas, the incidence of testis cancer is rising while mortality is declining. But for reasons that are not yet understood, while the incidence of this form of cancer is rising in poorer countries as in others, mortality rates remain unchanged. This pattern also exists for the Far East and Asia.
Management: nonseminoma
A significant question in the management of testis cancer is whether or not to insert a prosthesis at the time of primary surgery. One study from the UK may provide useful guidance, Professor Clarke suggested. The trial looked at 885 men undergoing orchidectomy. Of that number, about 230 underwent a prosthesis insertion at the same time.
“When we look at the complication rate between those who had the prosthesis insertion at the same time as surgery, and those who did not, we can see pretty clearly that putting in a prosthesis at the time of surgery is safe,” Professor Clarke stated.
Post-orchidectomy surveillance in clinical stage 1 disease has emerged globally as the preferred approach to care, rather than active treatment. “There is a quite strongly held belief from a number of centers across the world, involving big players in this cancer treatment field, Professor Clarke said, “that surveillance is the preferred approach.” He cited one well-read 2013 report showing that outcomes are unsurpassed by management strategies that rely on adjuvant therapies, and further, that intervention can only reduce the quality of survivorship.
Clearly, however, “progression on surveillance is the one thing we want to avoid,” Professor Clarke said. Along these lines, published evidence provides reassurance. Large-scale studies, including often-referenced Danish studies looking at nonseminoma and seminoma, indicate that most relapses occur within 2 years. Danish data on nonseminoma are based upon available information about risk factors—vascular invasion, embryonal carcinoma, and the combination of all of these and others. Thus, Professor Clarke said, “It is possible to risk stratify (these patients) quite accurately.”
Follow-up beyond 3 years should be considered carefully, Professor Clarke recommended. Reassuringly, virtually all late relapses were cured with standard chemotherapy according to available data. This is a “strong message,” Professor Clarke said, that intervention is unwarranted.
The broad conclusion from Danish investigator Dr. Daugaard and co-investigators’ work is that surveillance is safe, the cure rate is high, and the treatment burden for surveillance is low, perhaps with the exception of the post-chemotherapy failures. In these patients, unfortunately, the frequency of the necessity for RPLD is high, raising questions about whether they should be treated with adjunct chemotherapy at the outset.
Management: seminoma
Important recent data informing the management of patients with clinical stage 1 seminoma comes from the Spanish Testicular Group, in three studies involving over 744 consecutive patients with median follow-up of 18 months. In findings from these trials, the relapse rate was low; disease-free survival was excellent; and all patients who relapsed were effectively salvaged with further therapy.
These studies also produced reliable indicators for risk, such as tumor diameter, pathological stage, and rete testis invasion. According to Dr. Clarke, the authors also produced a useful nomogram combining these features, making it possible in seminoma to state with a high degree of accuracy who is at risk of relapse. Based on these reliable aids, appropriate patients can be placed into surveillance protocols with some confidence, rather than undergoing primary intervention.
For patients with residual retroperitoneal lesions less than 1 cm following chemotherapy, there remains a risk of cancer or teratoma. In cases where any residual mass is present, guidelines are ambiguous in their recommendations, with some suggesting that surgical resection is indicated. But in a meta-analysis looking at records of lesions of less than 1 cm in 455 patients, the finding was that relapse was “very low” and the overall mortality was even lower.
The hope is that these data will make their way into new guidelines. When guidelines are revised in 2015, Professor Clarke suggested, evidence is there to support a change. Hopefully, he said, the final drafts will say something like “in patients with lesions less than 1 cm, there is minimal risk of cancer or teratoma, and surgery should be considered only in exceptional circumstances.”
Personalized Care
In discussions with patients, Professor Clarke urged his colleagues to personalize information, to inform a patient fully, so that he can himself make a decision about his care.
Presented by Noel W. Clarke, ChM, FRCS (Urol) at the 2015 Genitourinary Cancers Symposium - "Integrating Biology Into Patient-Centric Care" - February 26 - 28, 2015 - Rosen Shingle Creek - Orlando, Florida USA
The Christie Clinic, Wilmslow Road, Manchester UK and Salford Royal NHS Trust and The Christie NHS Foundation Trust