FROM THE LITERATURE

Should Carboplatin Be Considered a Standard Management Option for Clinical Stage I Seminoma?

Testicular germ cell tumors (GCT) commonly present as clinical stage I seminoma, and approximately 15% to 20% of these patients have metastatic disease at presentation. The preferred management approach for these patients for the past 50 years has been adjuvant treatment with fractionated RT to paraaortic nodes (a dose of 20 Gy to 30 Gy). However, RT is associated with acute toxicity as well as an increased risk of delayed cardiovascular disease, infertility, and secondary malignancies, and its use has been declining in the United Kingdom and United States. The alternative in most cases is observation, but there are currently no evidence-based protocols to guide follow-up and the frequency of radiologic assessments, and noncompliance with long-term follow-up is a concern in light of the incidence of late recurrences. The Medical Research Council (MRC) has, therefore, been conducting a series of studies to determine whether a single dose of carboplatin is noninferior to standard RT. The third and largest of these trials is MRC TE19/EORTC 30982, conducted in collaboration with the European Organization for the Research and Treatment of Cancer. This study randomized 1447 patients between 1996 and 2001 to treatment with single dose of carboplatin (7 X AUC) or RT (20 Gy or 30 Gy) and was originally reported by Oliver et al (Lancet. 2005;366(9482):293-300.). The authors now report updated results at a median follow-up of 6.5 years.

The updated results of this study confirm the results reported in 2005, and show that carboplatin is noninferior to RT in terms of the relapse-free rate (RFR). At 5 years, the RFR was 95% for carboplatin and 96% for RT, and carboplatin was associated with a significant reduction in the rate of contralateral GCTs (2 versus 15 recurrences with RT; hazard ratio [HR] = 0.22). In addition, an exploratory analysis showed that patients with elevated pretreatment follicle-stimulating hormone levels (>12 IU/L) had a 9-fold increased risk of contralateral recurrence, suggesting that a risk-based approach to adjuvant therapy with carboplatin may be appropriate. Based on these results, the authors concluded that carboplatin should be considered a standard management option for clinical stage I seminoma alongside surveillance and RT. They stated that carboplatin offers a less toxic alternative that at least delays and may substantially reduce the incidence of contralateral GCT.

However, in an accompanying editorial, George Bosl and Sujata Patil from Memorial Sloan-Kettering Cancer Center take exception with these conclusions and argue that carboplatin should not be considered standard therapy in clinical stage I seminoma for a variety of reasons. Most importantly, the trial design by Oliver et al was not a two-sided test for equivalence with RT, and the RFR at 5 years favored RT. They also question the clinical benefit of carboplatin since retroperitoneal relapse was not prevented and the need for surveillance CT scans was not eliminated. Their position is that surveillance should be the management of choice for most patients with clinical Stage I seminoma because roughly 80% of patients will never need treatment. They favor a risk-based management approach, and advocate for prospective studies to identify and validate predictive factors for relapse. Such factors would facilitate risk-adapted trials to determine the benefit of chemotherapy in patients at greatest risk of relapse.

J Clin Oncol. 2011:29(8):957-962.

J Clin Oncol. 2011:29(8):949-956. (Editorial)

Tolerability of Platinum-Based Doublet Chemotherapy in Elderly Patients with Recurrent Ovarian Cancer

The Gynecologic Cancer Intergroup (GCIG) conducted the CAeLYx in Platinum Sensitive Ovarian cancer (CALYPSO) study to compare the efficacy and safety of carboplatin plus pegylated liposomal doxorubicin (C-PLD) with carboplatin plus paclitaxel (C-P) in patients with platinum sensitive recurrent ovarian cancer. The substudy was published in Annals of Oncology online in March (ahead of print) and examined the efficacy and safety of these two regimens in a subset of 157 patients ≥70 years of age, which represents 16% of the total study population. Similar to the overall study population, there was no difference in efficacy between these two regimens within the elderly cohort. Median progression-free survival (PFS) was 11.6 months in the C-PLD arm compared to 10.3 months in the C-P arm. In addition, elderly patients were able to complete planned treatment just as well as their younger counterparts, and elderly patients experienced fewer ≥grade 2 allergic reactions but more ≥grade 2 sensory neuropathy, whereas myelosuppression did not differ with age. However, C-P was associated with a significantly higher incidence of ≥grade 2 alopecia, sensory neuropathy, arthralgia/myalgia, severe leukopenia, and febrile neutropenia compared with C-PLD. Therefore, although C-PLD was associated with significantly more ≥grade 2 hand-foot syndrome, the authors concluded that C-PLD was better tolerated and has an improved therapeutic index compared with C-P in this patient population.

This report adds valuable information to the scarce evidence supporting the efficacy and safety of platinum-based doublet chemotherapy in elderly patients with platinum-sensitive recurrent ovarian cancer. However, the authors commented that the patients selected for this trial may not be representative of the broader population of elderly patients with recurrent ovarian cancer. Although not every elderly patient can be treated with platinum-based doublet chemotherapy, these results suggest that C-PLD should be the preferred regimen to use in those patients deemed fit enough.

Ann Oncol. 2011 March 14. [Epub ahead of print]

BRIEF REPORTS

Should Liver Metastases of Breast Cancer Be Biopsied to Improve Treatment Choice?

Treatment of primary breast cancer is guided by molecular subtypes, which are currently defined in clinical practice by expression of estrogen receptor (ER), progesterone receptor (PgR), and HER2. Choice of treatment for recurrent breast cancer is typically based entirely on evaluation of the molecular subtype of the primary tumor despite evidence in the literature suggesting that expression patterns can vary between the primary tumor and metastatic lesions. In this study, the authors retrospectively compared expression of ER, PgR, and HER2 in 255 consecutive patients with matched primary and liver tissue samples, and they found discordance between the primary tumor and liver metastases in terms of ER status in 14.5% of cases, PgR status in 48.6% of cases, and HER2 status in 13.9% of cases. They estimated that the observed discordance would likely have changed the choice of therapy for metastatic disease in 12.1% of patients. Based on these data, the authors suggest that biopsy of metastases and reassessment of biomarkers should be considered in all patients with breast cancer, as long as the biopsy can be safely and easily carried out, particularly when there is a long interval from initial diagnosis to diagnosis of metastatic disease. However, they point out that clinical judgment should be exercised when making such a decision, recognizing the risks associated with the biopsy and the potential for false-negatives when assessing biomarker expression in biopsy material. Ultimately, the decision should be made in careful consultation with the patient.

Ann Oncol. 2011 February 22. [Epub ahead of print]

21-Gene Recurrence Score Assay Is Changing Clinical Practice Patterns In the United States

For patients with ER-positive, node-positive (ER+/N+) early breast cancer, National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guidelines recommend adjuvant chemotherapy in addition to hormonal therapy, however some of these women may not need chemotherapy depending on their risk of recurrence. The Oncotype DX^® 21-gene recurrence score (RS) has been shown to accurately predict patients' risk for recurrence not only in node negative but also in N+ postmenopausal ER+ breast cancer and can identify patients for whom chemotherapy may not be needed. To assess the impact of Oncotype DX^® results on adjuvant treatment recommendations for patients with N+/ER+ breast cancer , the authors conducted a web-based, voluntary survey among practicing oncologists in the United States. Medical oncologists who ordered the Oncotype DX^® assay for at least one N+/ER+ patient were invited to complete a survey regarding their most recent patient, and responses were obtained from 160 (16%) of the surveyed oncologists. The results showed that nearly 90% of responding clinicians made a treatment decision before obtaining the RS, but half of them changed their initial treatment recommendation after obtaining the RS. In the majority of cases, the change involved eliminating chemotherapy from the adjuvant regimen. The RS result changed the treatment recommendation more often in patients with a primary tumor <5 cm in size and with 1-3 positive nodes. Although this study has limitations and the responding physicians may not be representative of the larger group of breast cancer specialists, the results suggest that oncologists are using Oncotype DX^® to make treatment decisions for their ER+/N+ patients in much the same way they have been using it for their ER+/node-negative patients, and they have confidence in the validity of the RS in both settings.

J Oncol Pract. 2011;7(2):94-100.

Trastuzumab Benefit After Four-Year Follow-Up of HERA Trial

The benefit of adding trastuzumab (Herceptin^®) to chemotherapy for the adjuvant treatment of HER2-positive early breast cancer has been established in a number of large clinical trials, but it is not yet clear how best to combine trastuzumab with chemotherapy and the optimal duration of adjuvant trastuzumab. The HERA trial is comparing trastuzumab for 1 or 2 years with observation after standard neoadjuvant and/or adjuvant chemotherapy. Two previous interim analyses of this trial (after 1 year and 2 years of follow-up) showed that adjuvant trastuzumab for 1 year improves disease-free survival (DFS) and overall survival compared with observation. The current report, at a median follow-up of 4 years, confirms the DFS benefit associated with trastuzumab. The 4-year DFS rate was 79% with trastuzumab versus 72% with observation (HR = 0.76; P<.0001). However, this analysis does not show a significant overall survival benefit, likely due to the fact that 52% of patients on the observation arm crossed over to trastuzumab. Patients randomized to observation, who were event-free after 1 year, were allowed to cross over. Those patients who crossed over had significantly fewer DFS events compared with patients who did not (adjusted HR = 0.68). In an accompanying editorial, Heikki Joensuu from Helsinki University commented that the sequential approach used in the HERA trial continues to show clinical benefit and a generally favorable safety profile with a low incidence of congestive heart failure. Although the best way to integrate trastuzumab with chemotherapy and the optimum duration of trastuzumab are not known yet, available evidence suggests that concomitant treatment with trastuzumab and chemotherapy may be more effective than sequential therapy. Unfortunately, extensive crossover has made interpretation of the HERA trial challenging.

Lancet Oncol. 2011;12(3):236–244.

Lancet Oncol. 2011;12(3):203-204. (Editorial)

ADDITIONAL PUBLICATIONS WORTH READING

• Denosumab Included in Updated ASCO Guidelines for Bone-Modifying Agents in Metastatic Breast Cancer. The updated guidelines recommend subcutaneous denosumab in addition to intravenous pamidronate or zoledronic acid for the prevention and treatment of skeletal-related events in breast cancer patients with bone metastases. The guidelines also recommend that all patients should receive a dental examination and appropriate preventive dentistry before initiating bone-modifying agent therapy and should maintain optimal oral health. J Clin Oncol. 2001;29(9):1221-1227.
• Management of Uncommon Chemotherapy-induced Emergencies. In rare cases, chemotherapy can cause potentially life-threatening adverse drug reactions, and there is sparse literature on the management of these medical emergencies. This review article describes uncommon, chemotherapy-induced, life-threatening adverse events, discusses their pathogenesis and management, and provides recommendations for rechallenge with chemotherapy after the event is resolved. Lancet Oncol. 2011 January 27. [Epub ahead of print]
• Review of Multiple Myeloma. This comprehensive review article describes the biology of multiple myeloma, diagnosis and staging, and current treatment strategies. In recent years, the introduction of autologous stem-cell transplantation and the availability of agents such as thalidomide, lenalidomide, and bortezomib have changed the management of myeloma and extended overall survival. N Engl J Med. 2011;364(11):1046-1060.
• Can Some Patients Avoid Adjuvant Chemotherapy for Early-stage Breast Cancer? This review article summarizes the wealth of clinical evidence supporting a variety of biomarkers and novel molecular tools including the intrinsic molecular subtypes and multigene assays that can augment standard clinicopathological factors used to determine a patient's risk of relapse and the likelihood that they will benefit from chemotherapy. These technological advances are helping to make treatment of early breast cancer more and more individualized. Nat Rev Clin Oncol. 2011 March 1. [Epub ahead of print]

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