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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.

The i.p. administration of topoisomerase I (Topo I) inhibitors has a pharmacologic advantage over intravenous application, including preservation of the biologically active lactone form. In our ongoing study, patients have received 9-amino-20(S)-camptothecin (9-AC) i.p. on days 1, 3, 5, 8, 10, and 12, repeated every 4 weeks. The daily dose has been escalated to level IV of 1.5 mg/m2 (9.0 mg/m2 per course), median of 3 cycles, range 1-4, with a reversible Grade 3 neutropenia in one patient. Responses included one CR (resolution of a pleural effusion), two patients without progressive disease (PD), two not evaluable, and two patients too early for evaluation. The area under the curve (AUC)i.p./AUCpl ratio (pharmacologic advantage) ranged from 7.6 to 16.5 on average, and, using nonlinear modeling, the pharmacologic decay data were fit to one- or two-compartmental models. Overall, a 9-AC i.p. application is well tolerated and anticipated to be an active regimen against i.p. malignancies, particularly those known to be sensitive to systemic Topo-I inhibitors.

The purpose of this study was (i) to determine the maximum tolerated dose (MTD) of docetaxel that can be administered in combination with Doxil, given without and with granulocyte colony stimulating factor (G-CSF), (ii) to define the pharmacokinetics (PK) of docetaxel when used in combination with Doxil, and (iii) to make preliminary observations on the anti-tumor activity of this combination in patients with metastatic solid tumors. Thirty-seven patients with metastatic cancer were enrolled. Courses were repeated every 3 weeks. Patients received a fixed dose of Doxil 30 mg/m(2) in combination with escalating doses of docetaxel ranging from 40 to 100 mg/m(2). After encountering dose-limiting febrile neutropenia, subsequent escalation was accomplished with G-CSF support. Selected patients at the recommended phase II dose underwent PK evaluation. The most common toxicity observed was neutropenia. Dose-limiting toxicity (30 mg/m(2) Doxil + 80 mg/m(2) docetaxel) was febrile neutropenia in three of six patients treated without G-CSF. Major non-hematological toxicities included alopecia, mucositis and hand-foot syndrome, and were observed after cumulative doses of chemotherapy. Objective responses (complete/partial) were documented in eight of 37 patients (four with breast cancer) and stable disease was seen in 17 patients. PK studies showed an increased tissue retention (decreased clearance) of docetaxel when given with Doxil. The recommended phase II dose of Doxil/docetaxel is 30/60 mg/m(2), q3 weeks, without G-CSF. Further dose escalation to 30/80 mg/m(2) is safe with G-CSF support. Anti-tumor activity, particularly against breast cancer, was observed at various dose levels. Our observations should provide evidence for phase II studies of this combination in patients with breast cancer and other anthracycline/taxane-sensitive cancers.

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.

Ovarian cancer arising in women with BRCA mutations is known to have a more favorable outcome and to be more responsive to platinum-based regimens than in those without a hereditary background. We analyze our previously published intraperitoneal (IP) studies in relation to BRCA mutation status and update their outcomes. Among 62 patients with ovarian cancer enrolled in IP platinum doublet studies in clinical trials (with etoposide (n = 18), with floxuridine (n = 30), and with topotecan (n = 14)), a deleterious BRCA mutation was eventually identified in 10 patients. The outcomes in these BRCA mutation carriers are described and compared with survival of others in respective trials. Ten patients that were confirmed to have BRCA mutations—all with high-grade and stages IIC to IV disease—survived a median of 10 years (range: 4–18+) after receiving IP cisplatin-based regimens. Two continue with no evidence of disease since their IP treatment, while four others remain alive with recurrences after 8, 9, 10, and 11 years, respectively. This experience suggests that IP cisplatin leads to favorable long term outcomes in advanced ovarian cancer in women with defective homologous recombination (i.e., with deleterious BRCA mutations). Whether such cisplatin dose-intensification from IP relative to (intravenous) IV drug administration leads to superior results in these mutation carriers requires further study.

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 Few studies have evaluated concomitant pegylated liposomal doxorubicin (PLD) plus trastuzumab as therapy for HER2-overexpressing metastatic breast cancer (MBC). This open-label, prospective, phase II trial assessed the safety and efficacy of this regimen, with cardiac tolerance as the principal focus. Patients and Methods Women with HER2-overexpressing recurrent MBC, baseline left ventricular ejection fraction ≥ 55%, and no history of serious cardiac illness were eligible; preexisting cardiac risk factors, including previous anthracyclines and previous trastuzumab for MBC, were allowed. Patients received weekly trastuzumab and every-3-week PLD until progression, prohibitive toxicity, or patient refusal. Left ventricular ejection fraction was assessed during and after therapy. Grade 3/4 congestive heart failure (CHF) was monitored for premature closure. Results The trial closed after 2.5 years for slow accrual. Twelve patients were enrolled: 7 had received adjuvant anthracyclines; 9 had received previous MBC treatment, of whom 7 had received trastuzumab in combination with chemotherapy. Patients received a mean of 4.8 cycles of PLD; 8 patients experienced stable disease; 4 patients experienced progression. Mean left ventricular ejection fraction levels did not change substantially: 60.4%, 57%, 60.3%, and 56.8% at baseline, after cycle 2, after cycle 4, and after completion of treatment, respectively. No patients experienced grade 4 CHF. One patient discontinued treatment after grade 3 CHF. Three patients experienced grade 2 left ventricular dysfunction, of whom 2 discontinued treatment. Cardiac function improved in all 4 patients after going off study. Other adverse events were generally mild (grade 1/2) and infrequent. Conclusion Pegylated liposomal doxorubicin plus trastuzumab might be an option for heavily pretreated patients with recurrent HER2-overexpressing MBC.

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.

PURPOSE A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen. PATIENTS AND METHODS Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity. RESULTS Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose-limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy. CONCLUSION The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients.

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

5548 Background: PLD activity in platinum-resistant OC is modest. B, with its activity in platinum(Plat)-sensitive and Plat-resistant patients (pts), has not been combined with PLD. PLD intratumoral concentrations, if affected by B, might be reflected in PLD PK. This phase II study of PLD + B was started in 2007 to accrue 48 pts, unless 4 serious (> grade 3) adverse events (AEs) supervened. Methods: Improvement in progression-free survival (PFS) at 6 m from 25 to 40% at 6 m in Plat-resistant OC is primary endpoint. PK of PLD alone at 1h, d 7 and d 21 (cycle 1) vs with B (cycle 2), safety, and response rates (RECIST and CA125 criteria) were secondary endpoints. Dosing: PLD 30 mg/m2 followed by B 15 mg/kg on cycles 2–7 (with option to continue) d 1 every 3 w. Pts recurring within 6 m of platinum-based treatment for OC after < 3 prior regimens (but no PLD or B) were eligible. Exclusions: bowel obstruction, prior perforation, uncontrolled hypertension, or vascular disease. Hematologic, mucocutaneous and renal toxicities were evaluated prior to each cycle, MUGA scans every third cycle; disease status by CA125 and/or RECIST every third cycle. Results: 21 of 24 pts enrolled to date are evaluable. Median age is 65, range 52–83; most had 2 prior chemotherapy regimens. Median 6 (range 3–12) cycles were given with 6 off study with progression at 3–7 cycles. RECIST and CA125 responses are under review; in 11 pts with baseline CA125 of > 40 IU/mL, median increase was 31% by cycle 2; later falling to -57%. AEs did not exceed grade 3; hand-foot syndrome led to PLD dose reduction in 8 pts (33%); asymptomatic decreases in left ventricular ejection fraction (LVEF) >10% in 3 pts were noted, with treatment discontinuation in 1. The mean (±SEM) secondary PK parameter estimates for Cmax, AUC, and elimination half life were 4.5 ± 0.5 ug/mL, 651.7 ± 61 ug/mL x h, and 93.3 ± 19.7 h, respectively. Conclusions: Cycles 1 and 2 PLD PK do not differ. PLD + B is tolerable with PLD dose modifications. Declines in LVEF in 1 institution have uncertain causality. Midway into the trial, safety and time on study encourage completion for study primary endpoint. [Table: see text]

14020 Background: Mucinous peritoneal carcinomatosis is most commonly associated with primariy tumors of the appendix and colon. Typically, spread remains confined to the abdominal cavity. Imaging assessment of these mucinous lesions is difficult, and tumor markers (CEA and CA19.9) are often used as a surrogate for extent of disease. Patients (pts) often undergo surgical debulking, sometimes coupled with intraperitoneal (IP) drug delivery, but recurrence is common. Since mucin genes are regulated by EGFR, our two institutions initiated this study. Methods: Between Sept 2004 and Dec 2005, weekly cetuximab (loading 400 mg/m2 on first dose, followed by 250 mg/m2/week thereafter) was given to 20 pts (4 men, 16 women): 17 of appendiceal origin were entered a median 3 y (6 m-7 y) after diagnosis; 3 were unknown primaries 24, 23, and 2 m after diagnosis. Prior treatment included surgery (18), systemic (17), and intraoperative (4) or subsequent IP therapy (2). Results: Pts received a median of 12 doses (0–51) of cetuximab. No major objective responses were observed; transient > 25% decreases in CEA and CA19.9 were noted in 4/19 pts; markers were never elevated in 1. Stable disease was best response in 3 of 15 evaluable (5 too early). The most common toxicities, as expected, were skin rash, dryness, and nail fragility. Hypersensitivity reactions in 2 patients did not preclude repeated dosing with premedications. The median time to progression from the start of treatment was 3 m. Conclusions: Brisk accrual by two institutions in this rare clinical entity is noteworthy. In this heavily pretreated population, transient decrease in tumor markers and time on study with stable disease were encouraging, prompting plans for a future study of cetuximab with the addition of systemic irinotecan. [Table: see text]

5055 Background: Liposomal doxorubicin (Doxil [D]) has activity in ovarian (OC), tubal (TC), and endometrial (EC) cancers. Since 2nd responses in OC are shorter than the 1st and always followed by relapse, patients achieving maximal response after D-containing doublets or monotherapy, were then continued on D. Methods: 18 patients (after platinum-based induction: 14OC, 2TC, 1EC; or after radiation: 1EC) were treated with D + carboplatin (3), topotecan (9) or taxane (1) doublet trials, or D alone (5). Treatment consisted of D 30–40 mg/m2 given every 4–6 weeks (adjusted to skin tolerance); routine cardiac status (MUGA, ECHO) follow-up was obtained at cumulative doses > 300 mg/m2; duration of treatment and its tolerance are analyzed. Results: 5 continue in complete response (4 OC, 1EC) with D as 2nd line to cumulative doses of 750+, 750+, 760+, 1515+ mg/m2 for 4OC & 390+ mg/m2 for 1EC; time on monotherapy maintenance lasting 22+, 24+, 25+, 57+ & 11+ m vs 34, 13, 8, 7, & 5 m, respectively, for 1st unmaintaine...