HIPEC in advanced epithelial ovarian cancer: why is there controversy?

PURPOSE OF REVIEW: The randomized OVHIPEC study provided further evidence that adding heated intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery significantly improved recurrence-free and overall survival in stage III epithelial ovarian cancer (EOC) patients, who were ineligible for primary cytoreductive surgery due to extensive intraperitoneal disease. Because opinions have been divided as to whether HIPEC is now a new standard of care for advanced EOC, the pros and cons of this approach are examined. A comparison with the ongoing discussion about the role of intraperitoneal chemotherapy is made. RECENT FINDINGS: For both techniques, experience is crucial and a learning curve essential. Compared with intraperitoneal chemotherapy, intraoperative application of HIPEC provides superior distribution through the peritoneal cavity. HIPEC, as given in OVHIPEC, did not significantly increase adverse events, had no negative effect on quality of life and was cost-effective. SUMMARY: Despite the ongoing debate about HIPEC, an important first step in attempting to demonstrate the efficacy of HIPEC in the first-line setting has been made with OVHIPEC. Critics have been of value to optimize future trials with HIPEC in patients with EOC.

Clinical recommendations for defining platinum unsuitable head and neck cancer patient populations on chemoradiotherapy: A literature review.

Toxicities resulting from platinum based chemotherapy in head and neck cancer is a cause for much concern. There is a lack of clinical criteria for defining these patient populations, which has posed serious problems associated with increased morbidity and consequently an adverse effect on patients' quality of life. In addition, there is a lack of consensus on clinical criteria for defining such patient populations, who may be unsuitable for concurrent chemoradiotherapy. A group of experts in the field of head and neck cancer from the Asia Pacific Region convened in August 2014 in Korea to discuss the development of a set of clinical criteria in order to fill the knowledge gap and provide a reference tool for head and neck oncologists. This paper reports the final output from this meeting and the accompanying literature review, with the aim of aiding clinical decision making with the help of some clinical criteria to identify platinum unsuitable patient populations in head and neck cancer management. Some alternative treatment options are also discussed in this paper.

Cetuximab in the treatment of squamous cell carcinoma of the head and neck.

The majority of the head and neck cancers are squamous cell carcinomas, which commonly overexpress the EGF receptor (EGFR). Cetuximab is a chimeric monoclonal antibody that binds with high affinity to the extracellular domain of EGFR, and in addition induces antibody-dependent cellular cytoxicity. In a randomized Phase III trial in patients with locoregionally advanced squamous cell carcinoma of the head and neck, the addition of cetuximab to radiotherapy prolonged the median time of locoregional control from 14.9 to 24.4 months and increased the median overall survival from 29.3 to 49.0 months. In patients with platinum-refractory recurrent and/or metastatic disease, the objective response and disease-control rates in various studies ranged from 10 to 13% and from 46 to 56%, respectively. In the EXTREME trial, the addition of cetuximab to platinum/5-fluorouracil as first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck not only led to significant improvements in survival, response rate and disease control, but also induced a better symptom control in comparison with that observed with platinum/5-fluorouracil alone.

Current concepts for the management of head and neck cancer: chemotherapy.

Chemotherapy can be administered in patients with locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) either concurrently with irradiation or as induction chemotherapy prior to local treatment or as palliative therapy in patients with recurrent and/or metastatic disease. Cisplatin-based chemoradiation is still the standard for LA-SCCHN. TPF has emerged as the new standard regimen when induction chemotherapy is indicated. Areas of active investigation in LA-SCCHN are the sequential administration of induction chemotherapy followed by chemoradiation and the integration of targeted therapies. None of the combination chemotherapy regimens demonstrated an overall survival benefit when compared to single agent methotrexate, cisplatin or 5-fluorouracil in recurrent/metastatic disease. Combination chemotherapy in this setting is preferably used in younger patients with a good performance status and with symptomatic disease who require prompt symptom relief. However, a survival benefit was observed when cetuximab was combined with platinum-5-fluorouracil.

Pharmacokinetic evaluation of platinum derived from cisplatin administered alone and with pemetrexed in head and neck cancer patients.

PURPOSE: This phase I study characterized the pharmacokinetics of free and total platinum derived from cisplatin administered alone and in combination with pemetrexed. Secondary objectives were to assess the pharmacokinetics of pemetrexed when it is combined with cisplatin as well as to evaluate the safety profile and document antitumor activity associated with this combination. METHODS: An open-label, two-arm, cross-over phase 1 study was performed in patients with squamous cell carcinoma of the head and neck, age > or =18 years, an Eastern Cooperative Oncology Group performance status of 0-2, and adequate organ function. Blood samples were taken and pharmacokinetics evaluated for the first two cycles using noncompartmental analysis. Patients received either pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) administered in cycle 1 followed by cisplatin alone in cycle 2; or in the reverse order (i.e., cisplatin alone in cycle 1 followed by pemetrexed plus cisplatin in cycle 2). Each treatment cycle was 21 days and patients received folic acid, vitamin B(12) supplementation, and dexamethasone prophylaxis. After the first two cycles, patients continued study treatment with pemetrexed plus cisplatin every 3 weeks up to a maximum of six total treatment cycles. Toxicities were graded by the investigators according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 3.0. RESULTS: A total of 13 patients were treated; one patient was discontinued from the study after cycle 1 for failure to meet baseline eligibility criteria for renal function. The ratios and 90% confidence intervals (CI) comparing the pharmacokinetics for cisplatin administered with pemetrexed to those for cisplatin administered alone for free platinum were: C(max) = 1.08 (CI: 0.92, 1.27) and AUC = 0.93 (CI: 0.82, 1.06); and, total platinum were: C(max) = 0.97 (CI: 0.88, 1.06) and AUC = 0.87 (CI: 0.81, 0.93). These results indicate that platinum pharmacokinetics (free and total) are similar, whether cisplatin is administered alone or combined with pemetrexed. The pemetrexed pharmacokinetic results were consistent with those from previous single-agent pemetrexed studies and a previous study of pemetrexed in combination with cisplatin. The combination of pemetrexed and cisplatin did not show any unexpected toxicities. Consistent with the platinum pharmacokinetic results, co-administration with pemetrexed did not appear to enhance cisplatin-related toxicities. Of the 13 treated patients, 11 had stable disease as the best overall response and 2 had progressive disease. CONCLUSIONS: The pharmacokinetics of free platinum derived from cisplatin were not altered by co-administration with pemetrexed, and in agreement with this, no unexpected cisplatin-induced toxicities were observed when these drugs were combined.

Induction therapy in the modern era of combined-modality therapy for locally advanced head and neck cancer.

As therapy for locoregionally advanced head and neck cancer (HNC) has evolved, treatment has become increasingly aggressive and cure rates have risen. However, survival still remains poor. The evolving standard of care has focused on the concurrent use of chemotherapy with more aggressive radiotherapy; however, patients continue to recur locally and/or regionally, albeit at a diminished rate, and distant metastases have become a major site of fatal recurrence, while long-term local and acute systemic toxicities have increased. As a result of these changes in outcomes and a re-evaluation of earlier historical data by meta-analyses, interest in cisplatin and 5-fluorouracil (PF) induction chemotherapy has re-emerged and evolved. Most recently randomized studies comparing PF with PF plus a taxane, in particular docetaxel (TPF regimen), have demonstrated markedly superior survival with the three-drug regimens. TPF is now considered the standard of care for induction chemotherapy. Induction chemotherapy followed by chemoradiotherapy, known as sequential therapy, has been shown to be safe and effective. This approach is promising and may have a survival advantage over chemoradiotherapy alone. Both TPF induction and sequential therapy are considered appropriate platforms upon which the new molecularly targeted agents can be tested.

Neoadjuvant chemotherapy in head and neck cancer: should it be revisited?

Locally advanced SCCHN (LA-SCCHN) is generally treated by a combination of chemotherapy, irradiation and/or surgery. Timing of the chemotherapy has for long been a matter of debate but concurrent chemoradiation was widely adopted as standard of care for locally advanced squamous cell carcinoma of the head and neck after the publication of a large meta-analysis which demonstrated that concurrent chemoradiation confers an absolute survival benefit of 8% at 2 and 5 years. Induction chemotherapy has some appealing advantages including the opportunity of assessing tumor response and selecting the patients who are candidates for organ preservation. The cisplatin-fluorouracil combination has been the induction regimen of choice for two decades but has recently been superseded by a combination of cisplatin, fluorouracil and a taxane which can be considered the standard regimen when induction chemotherapy is appropriate. Multiple large randomized trials designed to compare sequential induction, i.e., chemotherapy followed by CRT to CRT alone are currently underway. New challenges are the integration of targeted therapies into the current treatment strategies and the identification of prognostic biomarkers and of factors predicting the response to treatment which would help to select patients who are likely to benefit most from induction chemotherapy.