Prognosis for men with newly diagnosed germ cell tumors is generally excellent; at present, more than 90% of these men will be cured. However, some treatment controversies remain. Three experts discussed these issues during Friday’s Education Session “Controversies in the Management of Germ Cell Tumors.”
George J. Bosl, MD, of Memorial Sloan Kettering Cancer Center, chaired the session. “Do I think it’s possible to do better? I think, obviously, we can,” he said.
Depending on the tumor type, rates of relapse for germ cell tumors can be very low, thus minimization of management-related toxicities is a priority. Alan Horwich, MD, PhD, of the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, discussed the use of surveillance and adjuvant therapy in these patients.
Dr. George J. Bosl discusses future directions in germ cell tumors.
Surveillance, in particular in the early days of use, was relatively intensive, Dr. Horwich said, but the usefulness of more scans has been called into question. One prospective study published in 2007 looked at whether aggressive surveillance improves outcomes. In this trial, 414 patients with stage I nonseminomas were randomly assigned to either five scans at 3, 6, 9, 12, and 24 months, or two scans at 3 and 12 months. The trial found no significant differences with regard to outcome.
Dr. Horwich said that in nonseminoma, the relapse rate in unselected case series is between 26%-30% overall. The most important prognostic factor has been shown to be lymphovascular invasion (LVI) in several studies. In one trial published last year of 1,139 men who underwent surveillance, 44% of patients who were LVI-positive relapsed, compared with only 14% of patients who were LVI-negative. The median time to relapse was 6 months, and 90% of relapses occurred within 2 years. Notably, only 17% of patients treated with surveillance were LVI-positive, substantially fewer than in earlier published series. Dr. Horwich said this could reflect a change in treatment practices, as patients who are LVI-positive are now treated with adjuvant chemotherapy more frequently.
With regard to seminoma, most published series have found relapse rates with surveillance to be between 15%-19%. Establishing prognostic factors for these patients is especially important, Dr. Horwich said. A trial in 2002 found that the two most important risk factors for relapse on surveillance were tumor size and rete testis involvement: patients with tumors greater than 4 cm and rete testis involvement had a 31.5% relapse rate, compared to only 15.9% with one factor and 12.2% with neither of these factors.
A combined analysis from the Spanish Oncology Group confirmed the importance of these factors. In 744 men diagnosed between 1994-2008, 396 were treated with surveillance, and 15% relapsed. Patients with a tumor size of 4 cm and rete testis involvement had a relapse rate of 27%. Dr. Horwich pointed out that rete testis involvement can at times be difficult to discern, but these may be useful factors for determining the appropriateness of surveillance.
For nonseminomas, retroperitoneal lymph node dissection (RPLND) is an option, as is adjuvant chemotherapy with a single cycle of bleomycin, etoposide, and cisplatin (BEP). For seminoma, adjuvant radiotherapy and one or two cycles of carboplatin therapy are possibilities.
In the case of seminoma, a 2008 trial of 382 patients found that 99% were recurrence free at 2 years with BEP, compared with 92% of patients treated with RPLND. Radiotherapy for seminoma, meanwhile, appears to increase the rate of second malignant neoplasms later in life. In one trial of 2,543 patients performed over more than 30 years, after 20 years the second cancer incidence in patients treated with RT was twice that in age-matched population controls.
“It’s clear that the cure rate should be very high,” Dr. Horwich said. “Our challenge for research is more precise risk classifications and clarification of whether a single cycle of chemotherapy has any long-term toxicities.”
In patients whose testicular cancer is treated with initial chemotherapy but then relapses, guidelines on salvage therapy are not particularly clear, said Lawrence H. Einhorn, MD, of Indiana University School of Medicine.
“There are some pitfalls in salvage therapy,” Dr. Einhorn said. “One should never institute salvage chemotherapy unless we are 100% certain that the patient really needs it.” Elevated tumor markers including HCG and AFP do not necessarily reflect a relapse—marijuana usage, mononucleosis, and other factors can influence these readings.
If relapse does occur, salvage chemotherapy still may not be ideal. “Not only is this the most chemo-curable disease among all the solid tumors, it’s also the most surgically curable disease with a retroperitoneal lymph node dissection,” Dr. Einhorn said. For patients whose disease is confined to the retroperitoneum, salvage surgery is better than salvage chemotherapy.
When salvage chemotherapy is more appropriate, patients are classified according to whether they are platinum-refractory or not; those who progress within 4 weeks of their initial treatment with a platinum-based combination are refractory, and others are platinum-sensitive.
With regard to specific regimens, Dr. Einhorn said clinicians should “preferably give the patient drugs that [the patient] has not seen before.”
In one study by Dr. Einhorn’s group that started in 1996, 184 consecutive patients received high-dose chemotherapy with peripheral blood stem cell transplantation. Of that cohort, 116 patients (63%) are continuously disease free and 18 of the 40 patients (45%) who were deemed platinum-refractory are disease free. There are two types of high-dose chemotherapy in use, but Dr. Einhorn said no data suggest one type is better than the other.
No prospective trials will directly compare the high-dose and standard-dose approaches. A retrospective review of 1,594 patients (773 standard dose, 821 high dose) published in 2010, however, found significantly better 2-year PFS with high-dose chemotherapy (49.6% vs. 27.8%, respectively; p < 0.001). The 5-year OS rates were also better with high-dose therapy (53.2% vs. 40.8%; p < 0.001).
There is a phase III planned, known as the TIGER trial, that will look at which high-dose regimen is better.
Finally, Dr. Bosl spoke about management of late toxicities. Although the cure rate for germ cell tumors is very high, there are other issues to address. “We have to remember that survivors of [germ cell tumors] now account for a substantial fraction of all cancer survivors,” Dr. Bosl said. “These survivors, and there are a few hundred thousand of them, all will have late events.”
The treatment of survivors is one area that needs attention in the coming years, Dr. Bosl said. Survivors of germ cell tumors often have persistent peripheral neuropathy, ototoxicity, and hypogonadism, although less obvious problems such as cardiovascular disease and second malignant neoplasms are among the most important, life-threatening issues.
In a study of 932 patients receiving cisplatin published in 2011, 18% experienced some thromboembolic event. Most were pulmonary embolism, but 11% of the events were arterial. Dr. Einhorn noted that germ cell tumors are considered high risk for thromboembolism.
The treatment used for these malignancies matters with regard to vascular events. The risk of coronary artery disease, according to one 2010 study, is similar for those who receive radiotherapy or chemotherapy (but lower for surgery alone), but the two seem to have a synergistic effect when patients receive both.
With regard to secondary malignant neoplasms, the replacement of radiotherapy with surveillance in many patients has reduced the risk somewhat. Still, before 2005 most patients with seminoma received radiotherapy, and thus should be monitored carefully.
With regard to neoplasms, as well as other problems in patients with germ cell tumors, Dr. Einhorn stressed that “we need to have a long time horizon looking at the various forms of late toxicity.” According to a 2005 paper, testicular cancer survivors are at increased risk of other solid tumors for at least 35 years.
Dr. Bosl also discussed the biology of germ cell tumors and its clinical relevance. He said that although work continues in the search for actionable mutation targets in these malignancies, few have been found. Small studies have found limited or no efficacy of drugs targeting KRAS, BRAF, and other mutations. Some recent work, however, has suggested that certain p53 mutations may be actionable targets.
Dr. Bosl concluded by urging participation in large international trials, such as the TIGER trial mentioned by Dr. Einhorn, that could further improve the treatment of these tumors.
Watch the entire session, on the ASCO Virtual Meeting website.