Platinum ineligibility in squamous cell carcinoma of the head and neck: consensus from Central America and the Caribbean.

The high incidence of head and neck cancer in Central America and the Caribbean, together with limitations in the healthcare system for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) in this region necessitate a consensus of opinion based on a review of the literature on therapy with cisplatin plus radiation. Such an approach will ensure appropriate selection of patients who can benefit from therapy and reduce the incidence of related adverse events. Therefore, we recorded the opinion of experts in the region in order to identify needs and challenges in the treatment of LA SCCHN.

Synthesis, antiproliferative activity in cancer cells and DNA interaction studies of [Pt(cis-1,3-diaminocycloalkane)Cl2] analogs.

The search for more effective platinum anticancer drugs has led to the design, synthesis, and preclinical testing of hundreds of new platinum complexes. This search resulted in the recognition and subsequent FDA approval of the third-generation Pt(II) anticancer drug, [Pt(1,2-diaminocyclohexane)(oxalate)], oxaliplatin, as an effective agent in treating colorectal and gastrointestinal cancers. Another promising example of the class of anticancer platinum(II) complexes incorporating the Pt(1,n-diaminocycloalkane) moiety is kiteplatin ([Pt(cis-1,4-DACH)Cl2], DACH = diaminocyclohexane). We report here our progress in evaluating the role of the cycloalkyl moiety in these complexes focusing on the synthesis, characterization, evaluation of the antiproliferative activity in tumor cells and studies of the mechanism of action of new [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes wherein the cis-1,3-diaminocycloalkane group contains the cyclobutyl, cyclopentyl, and cyclohexyl moieties. We demonstrate that [Pt(cis-1,3-DACH)Cl2] destroys cancer cells with greater efficacy than the other two investigated 1,3-diamminocycloalkane derivatives, or cisplatin. Moreover, the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes show selectivity toward tumor cells relative to non-tumorigenic normal cells. We also performed several mechanistic studies in cell-free media focused on understanding some early steps in the mechanism of antitumor activity of bifunctional platinum(II) complexes. Our data indicate that reactivities of the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes and cisplatin with glutathione and DNA binding do not correlate with antiproliferative activity of these platinum(II) complexes in cancer cells. In contrast, we show that the higher antiproliferative activity in cancer cells of [Pt(cis-1,3-DACH)Cl2] originates from its highest hydrophobicity and most efficient cellular uptake.

Efficacy of cisplatin combined with topotecan in patients with advanced or recurrent ovarian cancer as second- or higher-line palliative chemotherapy.

The aim of this study was to evaluate the outcomes of patients with advanced or recurrent ovarian cancer treated with cisplatin combined with topotecan as second- or higher-line palliative chemotherapy.We retrospectively reviewed the medical records of patients with advanced or recurrent ovarian cancer, who were treated with cisplatin (50 mg/m on day 1) and topotecan (0.75 mg/m on days 1-3). Treatment response, progression-free survival (PFS) and overall survival (OS) were analyzed, and laboratory data were reviewed to evaluate toxicities.Thirty one patients were treated with cisplatin and topotecan. The objective response rate (ORR) was 22.6%, and the disease control rate (DCR) was 61.3%. The median PFS was 3.7 months (95% confidence interval [CI], 2.3-5.2 months) and the median OS was 44.5 months (95% CI, 35.5-53.5 months). The ORR (33.3% vs. 0%; P = .012) was significantly better in the platinum-sensitive group compared to the platinum-resistant group. The median PFS was significantly longer in the platinum-sensitive group compared to the platinum-resistant group (7.7 vs 2.5 months; P < .001), and the median OS was also significantly longer in the platinum-sensitive group (46.6 vs 19.3 months; P < .001). Almost all of the patients reported some degree of hematological toxicity. A high rate of grade 3-4 neutropenia (87.1%) was observed. Grade 3-4 thrombocytopenia (41.9%) and febrile neutropenia (19.4%) were also seen.The results showed that cisplatin combined with topotecan, as second- or higher-line palliative chemotherapy for patients with advanced or recurrent ovarian cancer, might be effective, especially in the platinum-sensitive group. However, attention should be paid to the high hematological toxicity associated with this drug combination.

Clinical efficacy of weekly cisplatin for treatment of patients with breast cancer.

BACKGROUND: We will investigate the efficacy and safety of weekly cisplatin (WC) for treatment of patients with breast cancer (BC) systematically. METHODS: This study will describe and critically appraise shared decision approaches used in randomized controlled trials of WC for treatment of patients with BC. We will comprehensively search the following databases: PubMed, EMBASE, Web of Science, Cochrane Library, CINAHL, PsycINFO, Allied and Complementary Medicine Database, Wanfang, and Chinese Biomedical Literature Database from inception through July 1, 2019. We will utilize RevMan V.5.3 software (London, UK) for statistical analysis. RESULTS: This study will systematically explore the efficacy and safety of WC for the treatment of patients with BC through evaluating primary outcomes of overall survival, pathological complete response; and secondary outcomes of cancer-specific survival, recurrence-free survival, disease-free survival, quality of life, and toxicities. CONCLUSION: This study will provide latest evidence of WC for the treatment of patients with BC. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019145358.

Current and future perspectives in advanced bladder cancer: is there a new standard?

The methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) regimen has been the standard treatment in patients with locally advanced and metastatic urothelial cancer for the past 15 years. The minimal or moderate survival benefit-depending on prognostic features-and the severe toxicity associated with the MVAC regimen have made the search for new drugs and drug combinations of utmost importance to increase efficacy and/or decrease toxicity. In this respect, the taxanes and gemcitabine are promising new drugs. Paclitaxel and docetaxel as single agents have yielded overall response rates of 7% to 56%, depending on whether the patients have received prior chemotherapy for metastatic disease. The combination of paclitaxel and cisplatin has been explored in three studies with a total of 104 evaluable patients, a pooled overall response (OR) rate of 61%, and a complete response (CR) rate of 20%. There are two studies of docetaxel and cisplatin with a total of 91 evaluable patients, an OR rate of 54%, and a CR rate of 16%. The OR rate for paclitaxel and carboplatin in six studies was 43%, with a CR rate of 13%; however, the reported median survival was only 8.5 to 9.5 months. The OR rate for single-agent gemcitabine based on five studies was 26%, with a CR rate of 9%, which was apparently independent of whether the patients had received prior chemotherapy. The OR rate for gemcitabine and cisplatin in four phase II studies ranged from 41% to 57%, with a CR rate of 15% to 22% and a median survival of 12.5 to 14.3 months. Based on the encouraging results for the combination of gemcitabine and cisplatin (GC), a randomized phase III trial comparing GC and MVAC was begun in late 1996. This study of 405 randomized patients showed that the two regimens were associated with similar response rates, time to progression, and overall survival, whereas GC was associated with less toxicity than MVAC. On the basis of this superior risk-benefit ratio, the GC regimen should be favored as a new standard treatment in patients with locally advanced and metastatic urothelial cancer. Other promising combinations include gemcitabine and paclitaxel, with or without cisplatin, and the combination of ifosfamide, paclitaxel, and cisplatin. The triple combination of gemcitabine, paclitaxel, and cisplatin has yielded an OR rate of 78%, a CR rate of 28%, and a median survival of 24 months. An international phase III trial comparing this triple combination with GC in patients with locally advanced and metastatic urothelial cancer has now been initiated.

Novel gemcitabine-containing triplets in the management of urothelial cancer.

Chemotherapy has been the cornerstone of treatment of advanced urothelial cancer. For a decade, the combination regimen of methotrexate/vinblastine/doxorubicin/cisplatin has been considered the standard for these patients. The need for improved efficacy and reduced toxicity of a predominantly palliative therapy has propelled efforts for new drug development. Of the newly identified agents with documented activity, both gemcitabine and paclitaxel have been evaluated with a platinum and have been incorporated into multiagent chemotherapy combinations. Phase II data from two gemcitabine-based triplets are currently available. Combination gemcitabine/paclitaxel/cisplatin and gemcitabine/paclitaxel/carboplatin have high levels of activity with overall and complete response rates of 76% and 26%, respectively, for the former and 68% and 32%, respectively, for the latter combination. The role of gemcitabine-based multiagent combinations compared with standard therapy awaits evaluation in prospectively randomized trials.

Advanced ovarian cancer in the elderly: results of consecutive trials with cisplatin-based chemotherapy.

From 1982 through 1996, 547 untreated advanced ovarian cancer patients were entered onto Gruppo Oncologico Nord-Ovest (GONO) consecutive randomized trials including cisplatin-based chemotherapy. End points of analysis included the influence of age on prognosis, toxicity, clinical/surgical response rates, progression-free survival and survival. Of the entire study group, 116 patients were 65 years of age or older at diagnosis. WHO main toxicity (any grade) consisted of: emesis (93% of patients), myelotoxicity (leukopenia in 52%, anemia in 51% and thrombocytopenia in 17% of patients), nephrotoxicity in 13% of patients and neurotoxicity in 10% of patients. No significant difference in toxicity was evident between patients > or = or <65 years. Refusal of CT and early (< or =2 courses) interruption of CT due to toxicity were more frequent in elderly patients (3.4 vs. 1.4%; 3.4 vs. 0.7%, respectively). After a median follow-up of 71 months no difference was observed in survival and progression-free survival between younger and older patients. Cox multiple regression analysis of the entire study population demonstrated that age >65 years per se was not a negative prognostic factor.

Toxicity and results of MVAC (methotrexate, vinblastine, adriamycin and cisplatin) chemotherapy in advanced urothelial carcinoma.

OBJECTIVE: The experience with MVAC (methotrexate, vinblastine, Adriamycin and cisplatin) chemotherapy in advanced urothelial cancer is reviewed with emphasis on toxicity and efficacy. METHODS: We report on 28 patients with advanced, progressive transitional cell carcinoma (TCC) of the bladder (27) or ureter (1), treated with MVAC. RESULTS: The average number of cycles was 4.5. Leucopenia was the most frequent and severe side effect (18% WHO grade I, 46% GII, 19% GII and 4% GIV). Other side effects were acceptable and could be treated successfully. One patient (complete responder) died of a toxic cause (sepsis), a second patient (partial responder) died of an intestinal bleeding (not drug- or cancer-related). Complete response was seen in 10 patients (36%), partial response and stable disease in 4 patients each (14%), progression in 8 patients (29%), and 2 patients were not evaluable for response. However, relapses were frequent (8 of 12 remaining responders, 66%). Median survival of the whole group was 9 months (0-52), without a significant difference for responders and nonresponders (p = 0.29). CONCLUSION: Our results are comparable to data from the literature with regard to efficacy and toxicity, although detailed toxicity data are unfortunately not always available.

Canine osteosarcoma: amputation and chemotherapy.

One of the most important advances in veterinary oncology during the past 10 years has been the use of adjuvant chemotherapy for treatment of the micrometastases of canine osteosarcoma. This article reviews the biologic behavior of osteosarcoma and discusses chemotherapy with the two agents known to be effective: cisplatin and doxorubicin.

Canine osteosarcoma: amputation and chemoimmunotherapy.

Canine osteosarcoma is a highly metastatic cancer commonly seen in large breed dogs. At the time of diagnosis, approximately 90% to 95% of the dogs have established micrometastases. Dogs undergoing amputation alone have a median survival time of 3 to 4 months. Amputation followed by cisplatin chemotherapy increases median survival times to 9 to 11 months. When dogs are treated with amputation and cisplatin, followed by immunotherapy (with liposome-encapsulated muramyl tripeptide phosphatidylethanolamine), median survival times increase to 14.4 months, the longest reported median survival time for dogs with osteosarcoma treated by amputation and any form of adjuvant therapy.

Comparison of sensitivities of cells to X-ray therapy, chemotherapy, and isotope therapy using a tumor spheroid model.

Numerous treatment modalities have been used in treating microscopic carcinoma confined to the peritoneal cavity. However, there is little information at the cellular level regarding which modality is most effective in eradicating small nests of tumor cells. In order to determine whether chemotherapy, X rays, or isotope therapy is most effective, we have compared in a three-dimensional spheroid model the survival of cells after treatment with cis-platinum, X ray, or the investigational high-energy isotope 212-bismuth (Bi-212). In this study, V-79 cells were grown to 100-microns diameter spheroids. In killing spheroids, high-energy isotopes were at least six times more effective than X rays at fractionated doses of up to 1300 cGy. High-energy isotopes appear also to be as efficient as cis-platinum. Regardless of exposure time to treatment, Bi-212 was more toxic to spheroids than the other treatment modalities. From this study we conclude that high-energy isotope therapy biologically is very effective in eradicating microscopic nests of cells.

Characteristics of patients with small-volume residual ovarian cancer unresponsive to cisplatin-based ip chemotherapy: lessons learned from a Gynecologic Oncology Group phase II trial of ip cisplatin and recombinant alpha-interferon.

The Gynecologic Oncology Group conducted a phase II trial of intraperitoneal (ip) cisplatin plus recombinant human alpha-interferon in patients with small-volume persistent/recurrent ovarian cancer. This study was based on the known single agent activity of the drugs administered by the ip route and experimental evidence of cytotoxic synergy between the agents. In 18 evaluable patients, only 1 partial response was observed (5.5% response rate). In an effort to explain these disappointing findings, patients were retrospectively divided into two groups; those with favorable disease (documented response to systemic platinum and absence of surgical findings of diffuse carcinomatosis at laparotomy prior to initiation of ip therapy) or unfavorable disease (no evidence of response to systemic platinum and/or laparotomy findings of diffuse carcinomatosis before ip treatment). The favorable patient population would be predicted to have a far greater chance of responding to local therapy, but only 3 of the evaluable patients fell into this category. In the 15 unfavorable patients, only 1 partial response was observed (7% response rate). We conclude that patients who have failed to demonstrate a response to systemic cisplatin or carboplatin or who have diffuse carcinomatosis at second-look laparotomy are poor candidates for second-line ip cisplatin-based therapy, even if they are considered to have small-volume residual disease (each individual tumor nodules less than 0.5-1 cm). Such patients should be considered for alternative therapeutic strategies.

Preliminary results of concurrent radiotherapy and chemotherapy with cis-platinum, vincristine, and bleomycin in bulky, advanced cervical carcinoma: a pilot study.

Twenty-four patients with bulky (greater than 4 cm), advanced (stages IIB-IVA) carcinoma of the uterine cervix were prospectively treated with a concurrent combination of radiotherapy (RT) and chemotherapy (CT). RT consisted of 4400 cGy (22 fractions) to the whole pelvis and a 1400-cGy boost to the parametrium. This was followed by two to three intracavitary brachytherapy courses. CT consisted of one to four course (median, three) of cisplatin (50 mg/m2) on Day 1, vincristine (1 mg/m2) on Day 2, and bleomycin (25 mg/m2) on Days 2-4. CT was started on the first day of external radiation and the scheduled course interval was 21 days. Among the 20 evaluable patients who completed at least one course of chemotherapy and a full course of radiation, 13 (65%) achieved complete response and 5 (25%) had partial response. Fatal complication occurred in 1 patient with stationary disease who died of septic shock due to ruptured pyometra. The other patient with primary stage IVA disease had progressive disease with ascites appearance after two courses of CT and later expired. Transient drug fever occurred in 19 (40.4%) of the 47 bleomycin-containing CT cycles. Grade 2 or 3 hematological toxicities occurred in 16 (30.2%) of a total of 53 CT cycles. Treatment delays of 1 to 7 days occurred in 15 (28.3%) CT cycles. Except for the case of septic shock, all of the other toxicities were generally tolerable and reversible. From this preliminary result we concluded that this particular combination of RT and CT in bulky, advanced cervical carcinoma is effective in enhancing local pelvic tumor control and well tolerated if strict selection of accrued patients is applied. Further investigation to assess its impact on long-term survival is in progress.

Stage III ovarian tumors of low malignant potential treated with cisplatin combination therapy (a Gynecologic Oncology Group study).

By serendipity we have had the opportunity to evaluate cis-platin-based chemotherapy in ovarian tumors of low malignant potential (LMP). Optimal (less than 1 cm residual disease) FIGO stage III ovarian carcinomas were randomly assigned to treatment with cisplatin plus cyclophosphamide with or without doxorubicin on a prospective Gynecologic Oncology Group Study. On review by the Gynecologic Oncology Group Pathology Committee, 32 of these cases were determined to represent low malignant potential tumors. Mean age of patients with these lesions was 48 years (range, 25-75 years). After initial cytoreduction, 19 patients had residual disease less than 1 cm and 13 had no residual. Twenty (62.5%) received cisplatin plus cyclophosphamide and 12 cisplatin, cyclophosphamide, and doxorubicin chemotherapy; 75% of patients received six or more courses. Second-look surgery was done in 15 cases; only six were negative. However, with a median follow-up of 31.7 months (range, 1-75), only 1 patient has died; no cancer was found at autopsy. The remaining patients are alive without clinical evidence of disease at a median of 30 months. The need for adjunctive therapy in patients with advanced LMP tumors remains speculative.