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A 66-year-old woman with a history of stage IA mixed endometrioid and serous endometrial cancer presented to our centre with 2 weeks of worsening headaches nearly 4 years after her initial surgery. At admission, she manifested bitemporal hemianopsia, difficulty walking and clinical and laboratory findings of panhypopituitarism, including diabetes insipidus. Magnetic resonance imaging of the brain revealed a 2.7 cm sellar/suprasellar mass compressing the optic chiasm and infiltrating the pituitary stalk. Computerised tomography documented mediastinal, lung, adrenal and liver involvement, including a 2.5 cm palpable left supraclavicular node that on excisional biopsy demonstrated metastatic endometrial adenocarcinoma. Due to the advanced stage of her cancer as well as the presence of multiple metastases, including lung and hepatic metastases causing post-obstructive pneumonia and coagulopathy, the sellar/suprasellar mass was treated with fractionated radiosurgery rather than surgical excision.

Could hydroxychloroquine and quinacrine antimalarial therapy for dermatomyositis later attributed to a paraneoplasic manifestation of an ovarian cancer enhance its subsequent response to chemotherapy? Five months after being diagnosed with dermatomyositis, while somewhat improved with hydroxychloroquine, quinacrine and methotrexate, this 63-year-old woman presented with an advanced intra-abdominal epithelial ovarian cancer documented (but not resected) at laparotomy. Neoadjuvant carboplatin/paclitaxel resulted in remarkable improvement of symptoms, tumour markers and imaging findings leading to thorough cytoreductive surgery at completion of five cycles. No tumour was found in the resected omentum, gynaecologic organs, as well as hepatic and nodal sampling thus documenting a complete pathologic response; a subcutaneous port and an intraperitoneal (IP) catheter were placed for two cycles of IP cisplatin consolidation. She remains free of disease 3 years after such treatment and her dermatomyositis is in remission in the absence of any treatment. We discuss a possible role of autophagy in promoting tumour cell survival and chemoresistance that is potentially reversed by antimalarial drugs. Thus, chemotherapy following their use may subsequently lead to dramatic potentiation of anticancer treatment.

Treatment with tumour necrosis factor (TNF) antagonists may lead to enhanced susceptibility to certain malignancies. In particular, an association is seen emerging between TNF antagonists and development of squamous cell carcinomas (SCCs) of the skin (in association with psoriasis), the oral cavity, and in the anogenital areas (possibly related to prior human papilloma virus infection). We present here a case of a 53-year old woman with a history of severe rheumatoid arthritis (RA), most recently treated with the TNF antagonist etanercept plus methotrexate, presented to our service after several months of increasing left pelvis and buttock pain. Evaluation with a computerised tomography (CT)-directed biopsy of a pelvic side wall mass revealed a metastatic SCC. On a fluorodeoxyglucose (FDG) positron-emission tomography (PET) an additional area of uptake was identified in the left posterior rectum corresponding to a 1 cm nodule palpable on digital exam. Colonoscopic biopsy revealed a basaloid SCC of the rectum as the likely primary site. Immunosuppression following TNF antagonist therapy may have given arise to this unrestrained neoplastic growth. It thereby underscores the need for an initial baseline study of risk factors and identification of patients who are at higher risk for development of a malignancy, in order to achieve a diagnosis at an early stage.

Background. Continuous-infusion topotecan with erlotinib has the potential to reverse topotecan resistance due to drug efflux mechanisms. We assessed the activity of such a regimen in ovarian cancer patients previously failing bolus topotecan. Assay for shed collagen epitopes recognized by antibody HU177 during treatment explored its ability to reflect tumor invasion. Methods. Topotecan 0.4 mg/m2 per day was administered by continuous infusion for 9–10 days every 3 weeks. Erlotinib, 150 mg orally, was administered on days 1–10 of each cycle. Cycles were repeated until progression or toxicity. Serum for shed HU177 collagen epitopes was collected weekly. This was a two-stage design to detect a CA-125 response rate of at least 20% in 30 patients after completing two treatment cycles. The trial would be terminated early if there were less than two CA-125 responses in 16 patients. Four or more CA-125 responses in 30 patients would justify further study of this regimen in prior topotecan treatment failures. Results. Six patients were enrolled, with four receiving three or more cycles and one achieving a partial response by cancer antigen 125 (CA-125) criteria. Shed epitope levels became undetectable on at least one measurement in all patients who received three or more cycles (Fig. 1A) and reappeared concomitantly with rises in CA-125 and clinical progression (Fig. 1B). After logistical delays, the trial was closed by the sponsor's decision to stop developing erlotinib in ovarian cancer. Conclusion. Continuous-infusion topotecan with erlotinib was found safe in six pretreated ovarian cancer patients; one met CA-125 criteria for partial response. Serial shed epitope levels to reflect invasiveness deserve further study.

Learning Objectives After completing this course, the reader will be able to: Compare the risk of secondary cancer versus benefits of maintenance therapy for women with ovarian cancer who have a complete response to pegylated liposomal doxorubicin.Explain the need to perform regular and frequent oral examinations in women with ovarian cancer who received treatment with pegylated liposomal doxorubicin. CME This article is available for continuing medical education credit at CME.TheOncologist.com Purpose. To describe occurrences of oral squamous cell carcinoma (SCC) in patients who had received long-term pegylated liposomal doxorubicin (PLD) for ovarian cancer. Patients and Methods. In our cohort of patients on maintenance PLD for ovarian and related mullerian epithelial malignancies, we encountered two patients with invasive SCC of the oral cavity (one of them multifocal) and one with high-grade squamous dysplasia. Review of patients at our institution receiving PLD for recurrent ovarian cancer identified three additional patients. The duration of treatment, cumulative PLD dose, human papillomavirus (HPV) positivity, BRCA status, stage at diagnosis, outcome, and other characteristics are reviewed. Results. All five cases were nonsmokers with no known risk factors for HPV and four were negative for p16 expression. Four of the patients had known BRCA mutations whereas one tested negative. Cumulative doses of PLD were >1,600 mg/m2 given over 30–132 months. Three had SCCs staged as T1N0 oral tongue, alveolar ridge (gingival), and multifocal oral mucosa; one had a T2N0 oral tongue; and one had dysplasia. After excision, two were given radiation but recurred shortly thereafter; the others remain well and have had no further exposure to cytotoxic drugs, including PLD. Conclusion. Awareness of this possible long-term complication during PLD treatment should enhance the likelihood of early detection of oral lesions in these patients. Decisions to continue maintenance PLD after complete response of the original cancer should perhaps consider the benefits of delaying ovarian cancer recurrence versus the possible risk for a secondary cancer.

A group of 16 patients with advanced malignancy were entered on a phase I trial of escalating doses of doxorubicin with ICRF-187 for cardioprotection and granulocyte/macrophage-colony-stimulating factor (GMCSF) for bone marrow protection. Patients received intravenous ICRF-187 (dose ratio 20:1 ICRF-187:doxorubicin) 30 min prior to doxorubicin. GMCSF at a dose of 15 micrograms kg-1 day-1 was self-administered subcutaneously on days 3-14 of the cycle. Doxorubicin was administered every 21 days. Substantial hematological and non-hematological toxicity was seen. Fever, malaise, and pulmonary symptoms, thought to be due to GMCSF, were not eliminated by reduction in the GMCSF dose to 10 or 5 micrograms kg-1 day-1. Severe hematological toxicity was seen despite GMCSF administration and it was not possible to escalate the doxorubicin dose above 72 mg/m2 with this combination. Dose escalation of doxorubicin may be more feasible with the use of other growth factors or growth factor combinations.

Pegylated liposomal doxorubicin (PLD, Doxil, Caelyx) is widely used for the treatment of ovarian cancer. It is a stable formulation encapsulating doxorubicin in a ‘Stealth’ (i.e., pegylated) liposome with a half-life of about 72 hours. This drastically altered pharmacology confers on it a considerably lower risk of cardiotoxicity, no acute emesis, and near absence of alopecia or problems with extravasation necrosis. On the other hand, PLD's dose-limiting toxicity is cutaneous. Since the original phase I report, cutaneous toxicities reported with PLD fall into four common categories: the well known hand-foot syndrome (also called palmoplantar erythrodysesthesia, or PPE), a diffuse follicular rash, intertrigo-like eruption, and hyperpigmentation including melanotic macules.

Background: We hypothesized that a response to pegylated liposomal doxorubicin (PLD, Caelyx/Doxil) followed by maintenance is beneficial and safe in recurrent ovarian cancer. Patients and methods: Sixteen patients have received PLD for more than 1 year for recurrent ovarian (14) or fallopian tube (2) cancer. All had stable disease or better responses to PLD + carboplatin (5) or topotecan (9) doublets or to PLD alone (2). PLD maintenance therapy 30–40 mg/m2 was given every 4–8 weeks. This analysis focuses on cardiac status, overall tolerance, and time to recurrence. Results: Termination of PLD was due to progression in all patients. Noteworthy was the lack of cumulative myelosuppression and, with one exception, clinical cardiac toxicity. This patient was hospitalized with cardiogenic shock and fever complicating grade 4 pancytopenia from topotecan ten months after discontinuation of PLD. Seven patients continue to receive PLD after a median of 1680 mg/m2 (1180–2460 mg/m2). Four of these had documented relapses after 3–6 years on maintenance occurring in the setting of lengthening of the treatment interval. Maintenance PLD was reinstituted after ‘reinduction’ with a platinum. Conclusions: PLD appears to be safe as long-term maintenance in ovarian cancer and may be important for a continued response.

Background: Distinct cryptic collagen epitopes are among the protein fragments exposed by collagen type IV remodeling, and recent data indicate that these cryptic epitopes may facilitate tumor migration and angiogenesis. In studies with melanoma patients we tested the hypothesis that melanoma can induce detectable changes in systemic levels of cryptic epitope shedding, specifically the HU177 epitope and were able correlate the levels of HU177 shedding with clinical and pathologic parameters (Ng et al Clin Can Res, 14:6253,2008). In addition in a follow-up study the increased shedding of the Hu177 epitope was shown to correlate with a worse prognosis in primary melanoma (Hamilton et al, J Trans Med8:19,2010). In this study we examined wether the serum levels of these unique cryptic epitopes may be useful to monitor, in a phase II study with ovarian patients, the course of the combination treatment of continuous infusion topotecan with erlotinib over multiple cycles of therapeutic intervention. Methods: We made use of our previously published ELISA serum assay (Ng et al) of which the key components involve the anchoring of the primary Hu177 directed antibody followed by blocking with albumin and then incubation with patient serum. The assay is further developed with a sandwich ELISA consisting of biotinylated anti-collagen IV and an anti-biotin antibody conjugated to horseradish peroxidase, followed by chromagenic color development. A parallel examination of the Hu177 epitope was also conducted with a humanized version of the Hu177 antibody (D93). Serial blood samples were monitored for weekly time periods ranging from 6-20 weeks from 5 patients enrolled in this study. Serum were collected and stored in multiple aliquots at –20oC. Results: All 5 patients demonstrated an eventual lowering of shed epitopes, with the time course for a sustained reduction varying with each patient. Once a nadir in the Hu177 epitope occurred it would last from 4-6 weeks. In one patient (KL) the nadir levels were the most sustained and developed late in the course of treatment who had remarkable decreased changes in CA125 that was previously rapidly increasing. This patient had platinum resistant peritoneal carcinomatosis without any dominant masses. Upon failure of topotecan erlotinib as demonstrated by rising markers and development of ascites and a pleural effusion, the shed epitopes rapidly recurred starting at week 18 of the treatment. Comparable serial data were found with the humanized D93 antibody although the sensitivity was more pronounced with the Hu177 antibody. Conclusions: Our interpretation is that this Hu177 determination may provide an indication of active invasion of extracellular matrix (such as in the peritoneum) and may be a useful indicator of a biological effect. We cannot exclude at this point that erlotinib may be contributing to such effects by changes in the matrix. Supported by a grant from the Chemotherapy Foundation Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4617. doi:1538-7445.AM2012-4617