Case report: Multidrug resistant gestational trophoblastic neoplasia: focus on failure of immunotherapy and success of high-dose chemotherapy.

Gestational trophoblastic neoplasia (GTN) is extremely rare, but has a very good prognosis, with a cure rate close to 100%, for low-risk diseases. This article describes the case of a healthy 28-year-old nulliparous patient with GTN resistant to multiple lines of treatment. The era of immunotherapy is revolutionizing oncology, having already proved its worth in the treatment of many cancers. This article will have a specific focus on the emerging role of immunotherapy in the treatment of GTN. Unfortunately, the use of an immune checkpoint inhibitor (ICI) failed in our case, emphasizing on the necessity to clearly define the future role of immune therapy in GTN. Finally, given the rapid progression of the disease after hysterectomy, induction with Paclitaxel- Ifosfamide and then intensification with high-dose Carboplatin and Etoposide with peripheral blood stem cell support was given as a rescue therapy with still curative intent.

Efficacy and Safety of Lanreotide Autogel in the Treatment of Clinical Symptoms Associated With Inoperable Malignant Intestinal Obstruction: A Prospective Phase II Study.

PURPOSE: Inoperable malignant intestinal obstruction (IMIO) is a severe complication in patients with cancer, usually gastrointestinal or gynecologic in origin. For patients with IMIO, there is a need to relieve symptoms and limit nasogastric tube (NGT) use. Previous studies have suggested the efficacy of somatostatin analogues in relieving obstruction-related symptoms, such as nausea, vomiting, and pain. The purpose of this study was to assess the efficacy of lanreotide autogel 120 mg (LAN 120 mg) in the management of symptoms resulting from IMIO in patients with advanced cancer. METHODS: This single-arm, multicenter study enrolled 52 patients mostly with advanced gastrointestinal or ovarian malignant tumors (35 patients with NGT and 17 patients without NGT). Patients received 1 deep subcutaneous injection of LAN 120 mg. Evaluations were performed on days 7, 14, and 28. The primary end point was the percentage of responding patients before or at day 7. Response was defined as ≤2 vomiting episodes per day (for patients without NGT at baseline) or no vomiting recurrence (after NGT removal) during at least 3 consecutive days at any time point between treatment and day 7. Responders at day 28 were offered a second LAN 120 mg injection and followed up until day 56. FINDINGS: The proportion of responders in the intention-to-treat population was 24 of 52 (46.2%), which was significantly greater than the reference proportion of 30% (P = 0.0055). Patients without NGT had a higher response (88.2%) than patients with NGT (25.7%) and had a steady trend for clinical improvement that led to sustainable responses. Median time to response was 9 days for the overall population, 3 days for patients without NGT, and 14 days for patients with NGT (P < 0.0001). IMPLICATIONS: Our study is the first to use long-acting LAN 120 mg in patients with IMIO and suggests an effect in controlling clinical symptoms in patients with and without NGT at baseline. The safety profile of LAN 120 mg was similar to that reported in other indications. ClinicalTrials.gov identifier: NCT02275338.

Central diabetes insipidus induced by temozolomide: A report of two cases.

INTRODUCTION: Central diabetes insipidus is a heterogeneous condition characterized by decreased release of antidiuretic hormone by the neurohypophysis resulting in a urine concentration deficit with variable degrees of polyuria. The most common causes include idiopathic diabetes insipidus, tumors or infiltrative diseases, neurosurgery and trauma. Temozolomide is an oral DNA-alkylating agent capable of crossing the blood-brain barrier and used as chemotherapy primarily to treat glioblastoma and other brain cancers. CASES: Two men (aged 38 and 54 years) suddenly developed polyuria and polydispsia approximately four weeks after the initiation of temozolomide for a glioblastoma. Plasma and urine parameters demonstrated the presence of a urinary concentration defect. MANAGEMENT: The clinical and laboratory abnormalities completely resolved with intranasal desmopressin therapy, allowing the continuation of temozolomide. The disorder did not relapse after cessation of temozolomide and desmopressin and relapsed in one patient after rechallenge with temozolomide. DISCUSSION: Our report highlights the importance of a quick recognition of this exceptional complication, in order to initiate promptly treatment with desmopressin and to maintain therapy with temozolomide.

A phase I/II trial of the safety and clinical activity of a HER2-protein based immunotherapeutic for treating women with HER2-positive metastatic breast cancer.

The objectives of this phase I/II study (NCT00140738) were to evaluate the safety and clinical activity of a cancer immunotherapeutic agent (recombinant HER2 protein (dHER2) and the immunostimulant AS15) in patients with HER2-overexpressing metastatic breast cancer (MBC). Forty HER2-positive MBC patients received up to 18 doses (12q2w, 6q3w) of dHER2 immunotherapeutic, as first- or second-line therapy following response to trastuzumab-based treatment as maintenance. Toxicity was graded by the Common Terminology Criteria for Adverse Events (CTCAE) and clinical activity was evaluated by target lesion assessment according to the Response Evaluation Criteria in Solid Tumors (RECIST). Immunogenicity was assessed. The dHER2 immunotherapeutic was well tolerated: grade 1/2 adverse events (AEs) were most common. No cardiac events were observed and one patient experienced an asymptomatic decrease of left ventricular ejection fraction below the normal range (47 %). Both humoral and cellular immunogenicity to the dHER2 antigen was observed. No patient discontinued the immunizations because of AEs but 35/40 withdrew prematurely, 34 because of disease progression (24/34 before or at the tumor assessment after dose 6). One patient achieved a complete response lasting 11 months and one patient had a partial response lasting 3.5 months. Ten patients experienced stable disease ≥26 weeks with 4/10 still in stable disease at the last tumor assessment after 47 weeks. Immunization of MBC patients with the dHER2 immunotherapeutic was associated with minimal toxicity and no cardiac events. Clinical activity was observed with two objective responses and prolonged stable disease for 10/40 patients.

Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer.

PURPOSE: We performed a dose-escalation study to investigate the safety of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Six patients were included per dose level. Following docetaxel infusion on day 1 (75 mg/m(2)/q3 weeks), sorafenib was administered at 200 mg BID on days 2-19 (dose level 1), at 200 mg BID on days 1-21 (dose level 2), at 400 mg BID on days 2-19 (dose level 3), at 400 mg BID on days 1-21 (dose level 4). Maximal tolerated dose (MTD) was exceeded if ≥2 patients experienced dose-limiting toxicities (DLT) during cycle 1. The recommended phase 2 dose for sorafenib was defined as one dose level below MTD. If MTD was not reached, the highest feasible dose would be selected to treat an expanded cohort to confirm safety. RESULTS: Two DLTs were observed during sorafenib dose-escalation consisting of grade 4 febrile neutropenia (dose level 2) and grade 3 hand-foot syndrome (HFS) (dose level 3). Our pharmacokinetic results showed an increased exposure to docetaxel across all dose levels during sorafenib comedication. The main grade ≥3 toxicities were neutropenia (35 %), HFS (27 %), and febrile neutropenia (19 %). The prostate-specific antigen (PSA) response rate was 74 %. Median overall survival was 25.2 months. CONCLUSION: Three-weekly docetaxel and prednisone could be combined with sorafenib at 400 mg BID on days 1-21 without reaching MTD. However, we observed a pharmacokinetic interaction between sorafenib and docetaxel, associated with significant toxicities, raising concerns about the safety of this combination in mCRPC.

Nonadherence to imatinib treatment in patients with gastrointestinal stromal tumors: the ADAGIO study.

AIM: To determine imatinib nonadherence rates in patients with gastrointestinal tumors (GIST) over 90 days. PATIENTS AND METHODS: A prospective 90-day observational, open-label, multicenter study was carried out of 28 evaluable GIST patients on imatinib. Nonadherence behavior was measured using a 4-item patient interview. Clinicians, patients, and collaterals rated perceived patient adherence on a 0-100 VAS scale. RESULTS: Nonadherence rates in the 4 weeks prior to baseline and follow-up were 29% (95% CI=26-32) and 24% (95% CI=21-27, p>0.05). Mean VAS ratings of perceived adherence ranged from 95.2 ± 10.2 to 97.3 ± 4.8 (p>0.05 for time and source of rating). Correlations between perceptions of and actual adherence behavior were negative. CONCLUSION: In this first study on imatinib nonadherence in GIST patients, rates were similar to those observed in patients with chronic myeloid leukemia, higher than clinically expected and exceeding meta-analytic estimates for cancer. Nonadherence rates were consistent across the 90-day period. Nonadherence behavior should be assessed by clinicians.

Prospective randomized study comparing docetaxel, estramustine, and prednisone with docetaxel and prednisone in metastatic hormone-refractory prostate cancer.

PURPOSE: To assess the efficacy and toxicity of the addition of estramustine to docetaxel (D) for the treatment of metastatic hormone-refractory prostate cancer. PATIENTS AND METHODS: One hundred fifty patients were randomly assigned to D alone (35 mg/m(2) on days 2 and 9, every 3 weeks) or D in combination with estramustine (D/E; 280 mg orally three times a day on days 1 to 5 and 8 to 12, every 3 weeks). All patients received prednisone (10 mg/d). The primary end point was prostate-specific antigen (PSA) response rate, which was defined as a decrease in PSA > or = 50% from baseline. The study was powered to test the hypothesis that D/E would improve the PSA response rate by 25%. RESULTS: The PSA response rate was not statistically different between the two groups. PSA of less than 4 ng/mL occurred in 29 (41%) of 71 patients receiving D/E and in 17 (25%) of 69 patients receiving D (P = .05). No significant differences were found for median time to PSA progression (D/E, 6.9 months; D, 7.3 months) or median overall survival time (D/E, 19.3 months; D, 21 months). More patients had at least one grade 3 or 4 toxicity with D/E (45%) compared with D (21%; P = .005), mainly as a result of grade 3 or 4 GI toxicity (P = .05). Serious adverse events were more frequent with D/E (n = 20) than with D (n = 9; P = .04). CONCLUSION: The addition of estramustine to weekly D does not provide any clinically relevant advantage. Both regimens are well tolerated, although the toxicity profile favors D without estramustine.

Primary combined squamous and small cell carcinoma of the larynx: Report of two cases and discussion of treatment modalities.

Combined small cell carcinoma (SMCC) of the larynx consists of SMCC admixed with a component of squamous cell carcinoma or adenocarcinoma. These tumors are very rare and, to date, only a few cases have been fully described. This points out the lack of information available about the correct management of these patients. Here, we describe two additional cases of combined SMCC of the larynx that illustrate the difficulties that we can encounter to diagnose correctly these patients and, by consequence, to treat them adequately.

Phase I/II study of cetuximab in combination with cisplatin or carboplatin and fluorouracil in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

PURPOSE: This was an open, randomized, multicenter, phase I/II study to investigate the safety and tolerability of cetuximab in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Treatment comprised cetuximab (initial dose 400 mg/m2 with subsequent weekly doses of 250 mg/m2) in combination with 3-week cycles of either cisplatin (100 mg/m2) or carboplatin (area under the curve, 5), each in combination with a 5-day infusion of fluorouracil (FU) at escalating doses of 600, 800, and 1,000 mg/m2/d. The study was divided into two phases: A, the first two cycles (6 weeks) focusing on the safety and tolerability of combination therapy; and B, the remaining time for those benefiting from therapy until disease progression or intolerable toxicity. RESULTS: Fifty-three patients were enrolled onto the study. The incidence of dose-limiting toxicities in phase A was acceptable. The most common grade 3/4 adverse events in both groups were leucopenia (38%), asthenia (25%), vomiting (14%), and thrombocytopenia (15%), which are consistent with the known safety profiles of cetuximab, cisplatin/carboplatin, and FU. The overall response rate among patients was 36%, with no clear trend toward an increased efficacy at the highest dose of FU, and no impact of the concomitant chemotherapy regimens on cetuximab pharmacokinetics. CONCLUSION: The combination of cetuximab, cisplatin/carboplatin, and FU was reasonably well tolerated and active in recurrent/metastatic SCCHN, and merits additional investigation. An FU dose of 1,000 mg/m2/d in combination with cisplatin or carboplatin can be recommended for additional studies.

Imatinib for the treatment of patients with unresectable or metastatic malignant KIT-positive gastrointestinal stromal tumours: an open-label Belgian trial.

BACKGROUND: Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. They are defined immunohistologically as KIT positive tumours. The only effective treatment for malignant GIST was surgery until 2000. Imatinib mesylate (STI571, Glivec) has shown substantial anticancer activity in patients with metastatic or unresectable GIST. PATIENTS AND METHODS: 57 patients who were diagnosed with unresectable or metastatic malignant GIST were entered into this study. The patients were given 400 mg Glivec orally once daily. The dose could be increased to 600 mg orally once daily and then to 400 mg twice daily if tumour progression was noticed. Daily treatment was interrupted or dose was decreased only in the case of limiting toxicities. We evaluated the tumour response and the safety of the drug. RESULTS: 85% of GIST patients showed a partial response or stable disease after 8 weeks of treatment with imatinib. The main side effects were nausea, vomiting, anorexia, skin rash, periorbital oedema and diarrhea. CONCLUSION: This study confirms that imatinib is an active agent against malignant GIST with manageable toxicities.

Osteomalacia due to chemotherapy-induced Fanconi syndrome in an adult patient.

BACKGROUND: Chemotherapy-induced Fanconi syndrome is a dangerous condition that could lead to severe electrolyte disturbances and rarely to osteomalacia. CASE: A patient treated with ifosfamide for a metastatic cervix squamous-cell carcinoma was admitted for diffuse, symmetric bilateral pain in bones and articulations. The diagnosis work-up revealed that she suffered from osteomalacia due to a chemotherapy-induced Fanconi syndrome. The patient recovered completely with oral calcitriol supplements. CONCLUSIONS: This very rare chemotherapy-complication suggests that detection of potential tubular dysfunction, by regular serum electrolyte monitoring of patients receiving ifosfamide, may be a reasonable approach to diagnose early chemotherapy-induced Fanconi syndrome, even in adults.

Unusual metastatic features in a patient with concomitant malignant orbital melanoma and prostate carcinoma.

A 73-year-old man with a history of malignant orbital melanoma and prostate carcinoma was admitted for progressive visual disturbance. Brain magnetic resonance imaging showed a suprasellar enhancing nodular lesion with major impingement on the anterior optical ways and sellar invasion. The extensive imaging work-up could not demonstrate with certainty its origin. Surprisingly, the transphenoidal biopsy of this patient revealed a prostate cancer metastasis outlining the importance of a histopathological diagnosis of cerebral metastases in patients with multiple malignancies when there is a doubt about the nature of the lesion.

Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy in patients with primarily unresectable, advanced-stage ovarian cancer.

OBJECTIVE: The aim of this review is to report our experience and the feasibility of neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer. METHODS: Forty-five patients with primarily unresectable advanced-stage epithelial ovarian cancer were treated in our center between 1995 and 2002 by platinum-based neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy. Their files were reviewed retrospectively. RESULTS: At the end of neoadjuvant chemotherapy, according to RECIST criteria, 1 patient (2.2%) had achieved a clinical complete response (CR), 33 (73.4%) a partial response (PR), and 8 (17.8%) had stable disease (SD). Only 3 (6.6%) patients showed disease progression (PD). Surgery was performed in patients with objective response or SD after a median number of 4 courses (range: 2-6) of induction chemotherapy. A complete macroscopic debulking was achieved in 24 (53.3%) out of 39 patients in whom cytoreductive surgery was performed. For the entire group, median overall survival was 29 months. Survival was significantly improved in patients with optimal debulking compared to patients with persistent tumor after surgery: 41 months versus 23 months (P = 0.0062). Median survival for patients responding to neoadjuvant chemotherapy (CR and PR) was 44 months compared to 27 months for patients with SD or PD after initial chemotherapy (P = 0.01). Neither treatment-related deaths nor significant toxicities were observed. CONCLUSION: Neoadjuvant chemotherapy followed by optimal debulking may be a safe and valuable treatment alternative in patients with primarily unresectable advanced-stage bulky ovarian cancer. Patients with an objective response to chemotherapy or absence of macroscopic residual tumor after surgery have a better outcome. This approach is currently being tested in large, prospective randomized clinical trials.