By W. Silvio. Touro College. 2018.

Sensory loss can occur in the peripheries of cisplatin chemotherapy discount 60 mg dapoxetine amex. Patients should be warned of the possibility of this Hemorrhagic cystitis happening and assessed periodically throughout the treatment as well order 30 mg dapoxetine overnight delivery. Patients with sensory neuropathy Hemorrhagic cystitis can occur with ifosfamide 30 mg dapoxetine overnight delivery. Doxorubicin plus ifosfamide is a chemothera- peutic regimen that is sometimes used in the treat- Table 3 Regimen for maintaining hydration and urinary ment of sarcoma of the uterus. The regimen is output during administration of cisplatin chemotherapy described in Table 4, illustrating how mesna and IV Fluid Volume Drug Time fluids are used to decrease the risk of hemorrhagic cystitis. Normal saline 1 litre Cisplatin 75 mg/m2 2 h Skin changes like pigmentation and darkening of 5. Normal saline 1 litre 20 mmol KCl 6 h the skin as well as nail abnormalities are sometimes seen with a number of chemotherapeutic agents. Table 4 Regimen with mesna and intravenous fluids to decrease the risk of hemorrhagic cystitis Fluid Volume Drug Time 1. Dextrose saline 1 litre 1/3 of ifosfamide 5 g/m2 8 h 1/3 of mesna 5 g/m2 5. Dextrose saline 1 litre 1/3 of ifosfamide 5 g/m2 8 h 1/3 of mesna 5 g/m2 6. Dextrose saline 1 litre 1/3 of ifosfamide 5 g/m2 8 h 1/3 of mesna 5 g/m2 7. Dextrose saline 1 litre Mesna 3 g/m2 8 h 399 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS Mucositis Hypersensitivity Mucositis can occur with methotrexate, 5-fluoro- Hypersensitivity can occur with a number of uracil, dactinomycin, doxorubicin, mitomycin C chemotherapeutic drugs like etoposide, cisplatin, and vincristine. The onset of mucositis is 5–7 days carboplatin, doxorubicin, cyclophosphamide/ following administration and will usually resolve ifosfamide, melphalan, methotrexate, paclitaxel, spontaneously within 2–3 weeks. Rarely, serious complications like angio-edema and hypotension can occur. Hypersensitivity is treated by discon- Extravasation tinuing treatment at once, maintaining an IV line Extravasation is a serious complication of a number with intravenous normal saline, antihistamines, of chemotherapeutic agents. Skin necrosis can corticosteroids, vasopressors and bronchodilators. It is now possible to greatly when extravasation occurs. Firstly, choose methasone, diphenhydramine (antihistamine) and large distal veins in the forearm, avoiding veins in cimetidine or ranitidine before administration of the joints and antecubital fossa as well as veins in the drug. Secondly, ensure that the as adjuvant treatment of ovarian cancer as well as intravenous line is free flowing. The schedule tering the chemotherapeutic drug, the IV lines below describes how this drug combination is should be flushed slowly with 100ml of normal administered with adequate pre-medication to saline. Initial administration of the chemotherapeu- decrease paclitaxel hypersensitivity: tic drug should be slow, at 1–2cc per min paying Carboplatin/paclitaxel regimen for epithelial ovarian cancer attention to the patient’s complaints at the same 1. While administering chemotherapy, the drip saline (N/S) over 15 min site must be continually monitored for redness, 2. Ranitidine 50mg slow bolus When extravasation occurs, the chemothera- 4. Granisetron 3mg IV bolus peutic drug must be stopped at once. Paclitaxel in 100ml N/S to run over 3h specific antidotes for some drugs. For doxorubicin 2 175 mg/m extravasation, dilute hydrocortisone 100mg per ml 6. Carboplatin in 500ml N/S AUC of 5 to run with 5 ml of saline and inject 1–2ml through the over 60 min IV line and inject the remaining solution into the extravasation site via 2 or 3 injections. Apply cold When hypersensitivity to a drug occurs, it is best compress. There are certain For dactinomycin extravasation, prepare a solu- situations, however, where the drug in question tion of sodium thiosulfate by mixing 4ml of 10% may be the best option for an individual patient, sodium thiosulfate with 6ml of sterile water for in- due to reasons like a good response to treatment jection. Inject 6 ml through the existing IV line and with that particular drug or lack of other good inject 2ml subcutaneously via multiple injections. When this occurs, a careful assessment The subcutaneous injection can be repeated hourly must be carried out of the benefits of the particular over the next few hours. If it is felt that the drug antidote is hyaluronidase; 1–6ml of a 150U/cc that has caused hypersensitivity is still the best solution is injected subcutaneously via multiple option, desensitization may be carried out by injections, repeating hourly over the next few administering SoluMedrol 100mg IV every 6h for hours. Bleomycin is associated with interstitial pneumoni- All other patients will benefit from six courses of tis which can lead to pulmonary fibrosis. The risk adjuvant chemotherapy administered 3-weekly of this complication is dose related. It is easy to administer Other side-effects of chemotherapeutic agents and the side-effects are manageable.

Firstly buy generic dapoxetine 60 mg, there is a loss of the normal cell cycle sometimes complete obstruction and anuria due to regulation control and secondly there is failure of blockage of the ureters by parametrial tumor exten- normal programmed cell death (apoptosis) buy generic dapoxetine 60mg on line. Sometimes patients with a partially obstructed It is useful to have an understanding of the nor- ureter may develop complete obstruction with the mal cell cycle dapoxetine 60 mg low price. There are four phases as described initiation of radiotherapy, as the radiotherapy can below (Figure 1). M-phase Chromosome division occurs (mito- partially obstructed ureters. G-1 phase Specialized functions of cell types are management is cystoscopy and stenting of the fulfilled and the cell’s machinery is prepared for ureters by a urologist or surgeon with the necessary DNA synthesis. Ureteric stents can be expensive and RNA synthesis and DNA repair occur in prep- the necessary trained personnel to perform these aration for cell division; G-1 cells can terminally procedures are not always available. An alternative differentiate into G-0 (non-cycling cells) or re-enter is to perform a nephrostomy and drain the urine the cell cycle after a period of quiescence. S-phase New DNA is synthesized (replication procedure can salvage existing renal function while of existing strand). G-2 period A short phase when the cell’s stenting of the ureter should be carried out with nucleus is being organized for mitosis. The cell radiological assistance at some stage later. When this happens after complete obstruction, the patient may go into a state of diuresis for many Normal and cancer cells are sensitive to chemo- days. Intravenous hydration will be necessary and therapy during the active cell cycling period and 395 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS achieve better chemotherapeutic effects compared to single drugs by two main mechanisms. Firstly, by using a number of drugs with different toxicities, increased anti-tumor effects can be obtained with limitation of the severity of individual drug toxici- ties. Secondly, as the different drugs used in combi- nation chemotherapy have different mechanisms of action, the risk of drug resistance developing is de- creased. Chemotherapy is used in a number of ways in gynecological cancers: • Induction chemotherapy is used up-front in certain situations in patients with metastatic disease where chemotherapy is the best option (e. There is an • Palliative chemotherapy is used when the patient initial pattern of rapid proliferation followed by has an advanced malignancy that is incurable to progressive delay in doubling time. When the tumor is small, in the In the administration of chemotherapy, the right initial phase of the growth curve, the relatively dose of drugs required must be calculated for each small number of tumor cells divide and grow individual patient. The tumor then enters a rapid growth phase and finally plateaus into a slower rate of growth • The patient’s weight in kilograms • The body surface area (BSA) in m2. This is a when the tumor is large and able to kill the host. A large tumor is more resistant to chemotherapy more difficult calculation but many internet because the proportion of cells that are actively tools are available, e. Another cause of resistance graph on epithelial ovarian cancer below. The doubling dose for each patient: underdosing will reduce the times can vary according to the tumor type and can effectiveness of the therapy, while overdosing may range from 1–6 months. For this reason it is a good prac- the cell cycle, please refer to: http://en. Combination chemotherapy Toxicity Gynecological cancers are often treated with com- All chemotherapeutic drugs have toxicities. In general, combinations clinician must be aware of the toxicities of 396 Basic Oncology including Treatment in Less-resourced Locations commonly used chemotherapeutic agents used in Table 1 Dose adjustment for carboplatin–paclitaxel in gynecological cancer. Toxicities may be classified leukopenia and thrombopenia (count at nadir) according to the common toxicity criteria (CTC) Platelets WBC count scale by the World Health Organization (WHO). Moderate 9 <75 × 10 /l Delay 1 week then Delay 1 week then 3. Life-threatening paclitaxel 100% 75% of paclitaxel 5. Dose reduction of chemotherapeutic most of the chemotherapeutic agents. Leukopenia agents may be required in this situation. Other usually occurs 10–14 days after treatment with agents like paclitaxel do not have cumulative toxi- most chemotherapeutic agents and may persist for city and can often be given for many cycles without 3–10 days. When the patient is leukopenic, she is at dose modification. Severe neutropenic septicemia is Table 1 gives an example of dose reduction for a life-threatening condition and prophylactic anti- the carboplatin/paclitaxel regimen, commonly biotics like ciprofloxacin plus amoxicillin/clavu- used as adjuvant treatment for ovarian cancer, uter- lanate may be considered. The counts must have returned to normal onset as well as recovery of thrombocytopenia usu- levels prior to administration of the next course of ally slightly lags behind that of leukopenia. Prophylactic platelet transfusion Febrile neutropenia is defined as an oral tempera- should be considered when the platelet count drops ture >38.

Thrombosis is a leading direct cause of death in cancer adenocarcinoma developed VTE in the first 6 months after diagno- patients with fatal pulmonary embolism buy dapoxetine 30 mg cheap, being 3 times more sis compared with 7 90mg dapoxetine visa. A prospective analysis of more than 800 patients with VTE revealed that the 12-month Various treatments also increase the risk of VTE buy 30mg dapoxetine. Surgery is a major cumulative incidence of recurrent VTE was significantly higher in provoking factor for VTE in patients without cancer, and underlying cancer patients compared with patients without cancer (20. That study estimated the total VTE-related health care VTE occurs in 8% to 27% of myeloma patients treated with costs to be $9247 per patient with VTE. Many risk factors for cancer-associated thrombosis have been Several large clinical trials and meta-analyses have demonstrated identified, including patient-related, cancer-related and treatment- that bevacizumab is associated with an 2-fold increased risk of arterial thromboembolic events19 and this agent may also increase related factors (Table 1). The evidence to support patient-related risk factors, including age, sex, and race, has been reviewed VTE risk (although this is controversial). A systematic review encompassing 37 trials and 6743 patients 684 American Society of Hematology Table 1. Risk factors and biomarkers for cancer-associated thrombosis Cancer-related factors Patient-related factors Primary site of cancer Older age Pancreas, stomach, brain, kidney, lung, and ovary Female sex Advanced stage of cancer Race (lower in Asians, higher in blacks) Initial period after diagnosis of cancer Comorbidities (Renal disease, obesity, infection) Histology Prior history of VTE Lower performance status Treatment-related factors Major surgery Candidate biomarkers Hospitalization Platelet count 350 000/mm3 Chemotherapy (particularly cisplatin) Leukocyte count 11 000/mm3 Hormonal therapy Hemoglobin 10 g/dL Anti-angiogenic agents (bevacizumab, sunitunib, sorafenib) Elevated tissue factor Immunomodulatory drugs (thalidomide, lenalidomide) Elevated D-dimer Erythropoiesis-stimulating agents Elevated soluble P-selectin Transfusions (platelets and red blood cells) Elevated C-reactive protein Central venous catheters Thrombin generation potential showed that erythropoietin-stimulating agents significantly in- patients from a prospective registry. Observed rates of VTE in the creased the risk of thrombotic complications in cancer patients development and validation cohorts were 0. This factors suggested there is also an increased risk of thrombosis with model has now been validated in several other studies (Table 2), the use of GM-CSF. Several consensus guidelines have outlined specific recom- Efforts to identify cancer patients at greatest risk of VTE have 32-35 mendations for prophylaxis in these situations. Many older focused on clinical factors, biomarkers, and risk prediction tools. A studies comparing placebo with heparin-based prophylaxis in more refined approach to VTE risk stratification will allow for more 36 surgical patients have been summarized in meta-analyses. A targeted prophylaxis, which is particularly important in cancer review of prophylaxis in patients undergoing gynecologic cancer patients, who have a heightened risk of bleeding complications. Several biomarkers have been identified as potentially predictive of VTE in multivariate analyses (Table 1). Prechemotherapy elevation in leukocyte and platelet count and low hemoglobin levels are all predictive for chemotherapy-associated VTE. The Khorana Risk Score Khorana Risk Score can accurately stratify cancer patients into low, was originally derived from a development cohort of 2701 ambulatory intermediate, and high risk for developing VTE (Figure 1). Rates patients and was then validated in an independent cohort of 1365 of VTE in the derivation and validation cohorts are shown at the top. Studies validating the Khorana risk model Study Design Population N VTE rate by risk group Mandala et al64 Prospective Cancer patients enrolled in various phase 1 clinical 1412 Low 1. A formal subgroup analysis of laxis in patients undergoing major abdominal surgery also showed a cancer patients from the MAGELLAN trial has not been reported. SAVE- efficacy between unfractionated heparin and LMWH prophylaxis, ONCO, the largest and most recent outpatient prophylaxis trial, but there is a nonsignificant trend toward decreased bleeding with compared once daily semuloparin with placebo in 3000 patients LMWH. The ENOXACAN38 study compared standard duration to with solid tumors and showed a significant reduction in VTE (1. A systematic review of extended prophylaxis in cancer in patients with “high-risk” sites of cancer, including those with patients also supports this approach in high-risk patients. A smaller but more prevention of VTE in nonsurgical hospitalized cancer patients. Two major prospective randomized studies have significantly higher than rates in matched controls without myeloma examined extended prophylaxis in medically ill patients. There decreased VTE events including asymptomatic deep vein thrombo- are no placebo-controlled trials of prophylaxis in multiple myeloma sis (2. A specific subgroup analysis of the LMWH, low-dose aspirin (acetylsalicylic acid [ASA]) or low-fixed- 15% of patients with active or prior cancer was not done, but the dose warfarin in 667 newly diagnosed myeloma patients. The recently published MAGELLAN trial,45 which concluded that LMWH, warfarin, and ASA are likely to be similarly included 7% cancer patients, demonstrated significant reduction in effective prophylactic regimens except in elderly patients, in whom VTE with extended oral rivaroxaban prophylaxis compared with warfarin showed less efficacy than LMWH. Current consensus 686 American Society of Hematology guidelines do not recommend routine outpatient VTE prophylaxis, but many do suggest prophylaxis in myeloma patients receiving high-risk regimens (Table 4). Myeloproliferative neoplasms such as essential thrombocythemia, polycythemia vera, and primary myelofibrosis are associated with increased risk of arterial and venous thrombotic events. In these patients, age 60 years, history of prior thrombosis, cardiovascular risk factors (hypertension, diabetes), leukocytosis, and Jak2 muta- tion are associated with higher risk of thrombotic complications. The Comparison of LMWH versus Oral anticoagulant Therapy for prevention of recurrent venous thromboembolism in patients with cancer (CLOT) study compared dalteparin with oral vitamin K antagonist therapy. Based largely on the results of the CLOT trial and other smaller trials summarized in a meta-analysis,60 long-term therapy with LMWH should be viewed as the standard of care in the management of patients with cancer-associated thrombosis. No clinical trials have yet prospectively examined the appropriate length of anticoagulant therapy in patients with cancer and VTE, but in patients with active cancer and minimal bleeding risk, it is reasonable to continue anticoagulation beyond 6 months.

Adults with 177 982 12 weeks PsARC ACR20 significantly Good 2011 MA placebo + PsA better outcomes methotrexate than placebo ALEFACEPT 24 weeks (12 Active PsA; Alefacept had Alefacept + weeks failed at least statistically Mease et al discount dapoxetine 90mg free shipping. ACR 50/70 dapoxetine 60mg without prescription, PASI dapoxetine 30mg with amex, 179 RCT 185 treatment, 12 ACR 20 1 DMARD; significantly Fair 2006 placebo + PGA weeks mean disease better ACR 20 methotrexate observation) duration: NR than placebo ETANERCEPT Etanercept had Etanercept + statistically Saad et al. ACR 20/50/70 Adults with 176 265 12-24 weeks PASI 50/75/90 significantly Good 2008 MA methotrexate + PsARC PsA better outcomes placebo than placebo Targeted immune modulators 58 of 195 Final Update 3 Report Drug Effectiveness Review Project Author Study Primary Secondary Quality Year design N Duration Comparisons outcome outcomes Population Results rating Etanercept had Etanercept + statistically Rodgers et al. Adults with 177 982 12 weeks PsARC ACR20 significantly Good 2011 MA placebo + PsA better outcomes methotrexate than placebo GOLIMUMAB Golimumab had ACR50/70, statistically Kavanaugh et al. Adults with 180 RCT 405 16 weeks ACR20 PsARC, DAS28, significantly Fair 2009 placebo PsA SF-36 better outcomes than placebo INFLIXIMAB Infliximab had Infliximab + statistically Saad et al. ACR 20/50/70 Adults with 176 304 12-24 weeks PASI 50/75/90 significantly Good 2008 MA placebo + PsARC PsA better outcomes methotrexate than placebo Infliximab had Infliximab + statistically Rodgers et al. Adults with 177 982 12 weeks PsARC ACR20 significantly Good 2011 MA placebo + PsA better outcomes methotrexate than placebo USTEKINUMAB Significantly more ustekinumab Gottlieb et al. Adults with patients 181,182 RCT 146 12 weeks ACR 20 PASI 75, DLQI Fair 2009. Targeted immune modulators 59 of 195 Final Update 3 Report Drug Effectiveness Review Project Study populations and outcome measures All patients suffered from active psoriatic arthritis. All trials consisted of patients who had previously failed a disease-modifying antirheumatic drug. All trials assessed response rates as defined by the American College of Rheumatology. In addition, most studies used the disease specific Psoriatic Arthritic Response Criteria which is composed of a patient global self-assessment, a physician global assessment, a swollen joint score, and a tender joint score. Further details of this scale are presented in Appendix D. In addition, the Psoriasis Area and Severity Index was used in some studies to measure improvements in both the amount of psoriatic plaque, as well as the severity of the disease. The Short Form 36 Health Survey and Health Assessment Questionnaire were used to assess quality of life. Sponsorship All trials, except the systematic review and meta-analysis, were funded by the pharmaceutical industry. Detailed assessment: Direct evidence on the comparative effectiveness We did not find any head-to-head trials for the treatment of psoriatic arthritis. One fair-quality prospective observational registry study from the United Kingdom (the British Society for Rheumatology Biologics Register) followed 596 psoriatic arthritis patients for 6 months and showed that adalimumab, etanercept, and infliximab have similar positive effects on quality of 183 life. For example, the mean improvements in Short Form 36 Health Survey mental component scale were: adalimumab 49. There were no statistically significant differences between the groups after adjusting for baseline variables such as sex, age, and severity of disease. Detailed assessment: Indirect evidence on the comparative effectiveness Two systematic reviews provided indirect evidence on the comparative effectiveness of adalimumab, etanercept, and infliximab for adults with moderate to severe plaque psoriatic 176,177 arthritis. The reviews employed different statistical techniques for the indirect comparisons; however the same six trials and 982 patients were included in both reviews. Both methods of 176 indirect comparison, adjusted indirect comparisons as proposed by Bucher and Bayesian 177 mixed treatment comparison, suggested that the three treatments are all more efficacious than placebo but that no statistically significant differences between adalimumab, etanercept, and infliximab exist. Using Bayesian analysis one group of reviewers calculated the probability of a psoriatic arthritis response criteria response for each comparator: 59% for adalimumab (95% CI, 44 to 71), 71% for etanercept (95% CI, 57 to 83), and 80% for infliximab (95% CI, 67 to 89). The second review came to a similar conclusion using an adjusted indirect comparison approach: the relative risk of an American College of Rheumatology 20 response for adalimumab compared with etanercept was 0. Table 12 summarizes the study conducting indirect comparisons. Targeted immune modulators 60 of 195 Final Update 3 Report Drug Effectiveness Review Project Table 12. Characteristics and results of studies conducting direct and adjusted- indirect comparisons Author, year Comparisons Primary Conclusion Quality outcome Adalimumab, etanercept, Adalimumab, 183 and infliximab have similar Saad et al. Detailed assessment: Evidence on the general efficacy Because of the lack of head-to-head trials, we reviewed placebo-controlled trials. We have summarized evidence on the general efficacy of targeted immune modulators in the treatment of psoriatic arthritis. This, however, does not provide evidence on the comparative efficacy and tolerability of targeted immune modulators. Abatacept We identified one fair-quality 6-month randomized controlled trial of abatacept compared with placebo in 170 patients with chronic psoriatic arthritis and one target skin lesion greater than 2 178 cm in diameter. All patients had failed prior therapy with a disease-modifying antirheumatic drug or another targeted immune modulator. Three doses of abatacept were used: 3 mg/kg, 10 mg/kg, or 30 mg/kg for two doses, followed by 10 mg/kg. Significantly more patients in the 30- 10 mg/kg group and the 30 mg/kg group achieved the primary endpoint, an American College of Rheumatology 20 response, compared with the placebo group.