Six-drug Regimen Research Articles

A LONG FORGOTTEN DIAGNOSIS – A CASE OF MALIGNANT HYPERTENSION

Objective: Malignant hypertension is a severe form of hypertension (HTN) classified as a hypertensive emergency, whose occurrence is rather rare given compared to the time it entered the medical lexicon, given the nowadays ample blood pressure (BP) lowering therapeutic arsenal. We present the case of a patient with acutely decompensated heart failure due to malignant HTN. Design and method: A 66 years old diabetic, chronic renal disease, obese, female patient presented to the emergency department for a five days onset of hallucinations and confusion. She described dyspnea on mild-moderate efforts, headache and vertigo for the past six months, lacking BP control for the past two years on a four-drug regimen including perindopril, amlodipine, bisoprolol, and furosemide. Clinical evaluation found no signs of stroke, but significant systemic and pulmonary congestion, BP levels 250/160 mmHg (equal both arms), and bilateral flame haemorrhages and papilloedema on fundoscopy. CT scan was positive for cerebral edema and echocardiography showed left ventricle hypertrophy with an ejection fraction of 40%, diffuse hypokinesis, with no significant valvulopathy. Upon admission the patient received urapidil during the first 24 h, on top of high dose loop diuretic and a six-drug regimen including an ACE inhibitor, calcium channel blocker, spironolactone, betablocker and two central acting antihypertensives. 24 h and 72 h control CT scan did not reveal any changes; nephrotic range proteinuria (17 g/24 h) was also noted along with a moderate increase in creatinine levels once BP control was obtained. Results: Congestion and neurological symptoms were significantly improved during the two-week course of above mentioned therapy and patient was discharged. Control at one month revealed an asymptomatic patient with good BP control at 110/90 mmHg and improved cardiac function, persistent but lower proteinuria, however with significantly increased serum creatinine levels. This led to a step-down in antihypertensive therapy aiming for a systolic BP of 130–139 mmHg. Conclusions: This is a case of refractory hypertension aggravated by inertia to seek medical advice and secondary poor BP control. This led to a severe form of malignant hypertension in which adequate control was obtained with difficulty and over a long period of time.

Broader Implications of a Stage-Guided Stratified Therapeutic Approach for AIDS-Related Kaposi's Sarcoma

Kaposi sarcoma (KS) remains the most common illness in people living with HIV (PLWH), although its incidence has declined dramatically since the introduction of combination antiretroviral therapy (cART). Unlike most malignancies that are staged using the TNM system, which takes into account tumor size and extent of spread, staging for AIDS-related KS must account for the presence of other AIDS-related effects, such as the severity of immunosuppression and presence of opportunistic infections. The AIDS Clinical Trials Group (ACTG) staging system considers three factors, notably, the extent of the tumor (T), the status of the immune system as measured by the CD4 count (I), and the extent of systemic illness. Each factor is further subgrouped into either good risk (0) or poor risk. T0 disease is defined as KS that is limited to the skin but without edema or ulceration, lymph node disease, or flat palatal lesions. T1 disease is defined as the presence of tumor-associated edema or ulceration, or extensive oral/GI KS or other non-nodal visceral lesions. Although this system has helped to clinically categorize patients, until now there has been no clear, universally adopted treatment algorithm that is based on disease stage. As with other HIV-associated malignancies, the challenge for health care professionals treating AIDS-related KS has revolved around the ability to effectively treat without causing the patient further immunocompromise and, if possible, to concomitantly reconstitute the immune system. Therefore, it is not surprising that the introduction of cART has led to a remarkable improvement in median overall survival (OS) of affected patients, which was less than 18 months in the pre-cART era. In addition to improving prognosis and time to disease progression in KS, cART can lead to lesion regression, and this applies to both protease inhibitor and non-nucleoside reverse transcriptase inhibitor– based regimens, the major categories of antiretroviral regimens. However, the resolution of KS with cART usually follows the recovery of cellmediated immunity in the host and can therefore be a slow process over several months, complicated in some instances, for example, by an immune reconstitution inflammatory syndrome. Furthermore, there is the complex paradox of how best to treat patients already receiving cART who have maintained a high CD4 count and low viral load, but who still develop KS. In the pre-cART era, chemotherapy was the mainstay of treatment for suitable patients with AIDS-related KS, and this has remained the major therapeutic modality despite the advent of cART in 1996. In the pre-cART era, chemotherapy was adopted as an accepted treatment modality in AIDS-related KS on the basis of the results of a number of clinical trials that assessed the efficacy and safety of combination regimens. In one study, 18 consecutive patients with socalled disseminated KS received a six-drug regimen of doxorubicin, vinblastine, bleomycin (ABV), dactinomycin, vincristine, and dacarbazine, with a partial or complete response observed in 13 individuals. Opportunistic infections were the most common cause of death. Another study compared the use of recombinant interferon alpha or ABV/dactinomycin, vincristine, and dacarbazine in the 18 consecutive patients with disseminated disease, and responses were similar in the two groups and were comparable with the results of earlier trials. Subsequent studies in the preand post-cART era have provided strong evidence in support of the use of single-agent anthracyclines or taxanes, particularly pegylated liposomal doxorubicin (PLD) and paclitaxel. In a study reported in 1998, Northfelt et al randomly assigned 258 patients with advanced AIDS-related KS to receive either PLD (20 mg/m) or ABV every 14 days for six cycles. PLD was more effective and less toxic than ABV (overall response rates, 45.9% v 24.8%; P .001). In 2010, Cianfrocca et al reported a study comparing paclitaxel with PLD in patients with advanced AIDS-related KS and demonstrated comparable response rates (56% v 46%; P .49), median progression-free survival of 17.5 v 12.2 months (P .66), and 2-year survival rates of 79% v 78% (P .75), although paclitaxel was associated with more grade 3 to 5 toxicity (84% v 66%; P .077). PLD has thus become the current standard first-line therapy for advanced disease in many centers in the developed world, with paclitaxel reserved as a second-line agent. However, this is not the case in less developed countries, where HIV remains endemic. Given the complexity of the ACTG staging system, there is no clear international consensus on what constitutes advanced disease, and therefore, no clear algorithm exists to determine which patients should receive cART alone and which should receive cART plus chemotherapy, or chemotherapy alone, given that interactions between protease inhibitors and chemotherapy may lead to worse neutropenia. In the article that accompanies this editorial, Bower et al answer these issues in part for the first time and present an elegantly JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 5 FEBRUARY 1

Randomized Comparison of Intensified Six-Drug Versus Standard Three-Drug Chemotherapy for High-Risk Nonmetastatic Rhabdomyosarcoma and Other Chemotherapy-Sensitive Childhood Soft Tissue Sarcomas: Long-Term Results From the International Society of Pediatric Oncology MMT95 Study

MMT95 was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial. From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m(2) (both arms), epirubicin 450 mg/m(2), etoposide 1,350 mg/m(2) (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other arm. Delivery of radiotherapy was determined according to site and/or response to chemotherapy with or without surgery. Overall survival (OS) for all patients was 81% (95% CI, 77% to 84%) at 3 years. No significant difference in outcome in either OS or event-free survival was noted between the two arms (3-year OS: 82% [95% CI, 76% to 86%] for IVA and 80% [95% CI, 74% to 85%] for the six-drug arm). Toxicity was significantly greater (infection, myelosuppression, and mucositis) in the six-drug arm. Overall burden of local therapy was consistent with data from previous SIOP studies and showed no difference between the two chemotherapy regimens. Intensification of chemotherapy for nonmetastatic RMS and other chemotherapy-sensitive STS provides no survival advantage or reduction in the intensity of local therapy and adds toxicity.

Neoadjuvant chemotherapy for Ewing's tumour of bone: recent experience at the Rizzoli Orthopaedic Institute

The results achieved in 157 patients with non-metastatic Ewing's sarcoma of the bone treated at a single institution between 1991 and 1997 according to a new protocol (REN-3) are reported. Induction chemotherapy consisted of two cycles of ‘VAC’: vincristine (V), doxorubicin (A), cyclophosphamide (C) alternated with one cycle of ‘VIAc’: V, ifosfamide (I), actinomycin (Ac). After local treatment, patients received three more cycles of VAC, two of VIAc, three cycles of I plus etoposide (E) and two cycles with V, C and Ac. Local treatment was surgery in 53% of patients, surgery+radiotherapy in 25% and radiotherapy only in 22%. With a follow-up ranging between 4 and 10 years (mean: 7 years), 110 patients (70%) remained continuously event-free, 2 patients died of toxicity and 45 patients relapsed: 33 due to metastases and 12 due to local recurrence always associated with metastases. The 5-year event-free survival (EFS) and overall survival (OS) were 71.0 and 76.5% respectively. These results are significantly better that the ones achieved in our previous three studies in which a three-drug VAC regimen (REA-1), and 4-drug VACAc regimen (REA-2 and REN-1) was used, and in our most recent study (REN-2) which was based on a six-drug regimen as in the present study, but where I and Ac were used only after the local treatment. However, since REN-3 surgery was used in a significantly larger number of patients, we cannot say whether the better outcome of this study was due to the use of a six-drug regimen with an early delivery of ifosfamide and actinomycin, or to the wider use of surgery as local treatment or both.

A Six-Drug Regimen (Mapeco) for Intermediate or High-Grade Non-Hodgkin's Lymphoma

Forty-eight patients with intermediate and high-grade NHL were treated with an intensive weekly six-drug regimen of methotrexate, doxorubicin, prednisolone, etoposide, cyclophosphamide and vincristine (MAPECO) between 1982-1988 and now have a median follow-up of 4.8 years. Nineteen of these patients received an intensified derivative of this regimen with the incorporation of bleomycin. Histological sub-type showed intermediate grade in 28 and high grade in 20 patients. Forty-five patients received the 4 planned cycles, and all patients achieved an objective response, of whom 36 (75%) entered complete remission. At 5 years, the actuarial survival of the 48 patients was 50%. Of the 36 patients achieving complete remission, the relapse-free survival at 5 years was 62%. The 5-year time to treatment failure was 48% for the whole group and 40% for the 22 stage III+IV patients. Histological sub-type had no effect on survival and time to failure curves. Neutropenic fever occurred in 15 patients and grade 3/4 mucositis was seen in 25. The MAPECO combination is an effective intensive regimen with acceptable toxicity for intermediate and high-grade lymphoma.

The place of third-generation regimens in the treatment of adult aggressive non-Hodgkin's lymphoma

Diffuse large cell lymphoma, the most common form of aggressive non-Hodgkin's lymphoma, has been known to be curable with combination chemotherapy for almost 20 years. Although occasional patients were cured with regimens like COP (cyclophosphamide/vincristine/prednisone) the development of four-drug regimens made cure possible in a significant percentage of patients. Subsequently, newer, so-called third-generation regimens incorporated even more drugs with an apparent increase in the cure rate. However, the identification of important clinical and biologic features in the patient or the tumor that predict for treatment outcome (prognostic factors) has complicated comparison between nonrandomized and nonconcurrent trials. Recently, the Southwest Oncology Group presented data from pilot studies showing that patients treated with ProMACE-CytaBOM (procarbazine/methotrexate/doxorubicin/cyclophosphamide/etoposide- cytarabine/bleomycin/vincristine/methotrexate), m-BACOD (methotrexate-bleomycin/doxorubicin/cyclophosphamide/vincristine/dexa met hasone) , and MACOD-B (methotrexate/doxorubicin/cyclophosphamide/vincristine/dexamethasone- ble omycin) did not seem to do better than patients treated in the past with CHOP cyclophosphamide/doxorubicin/vincristine/prednisone). Also, the Eastern Cooperative Oncology Group has presented a study in which patients treated with a six-drug regimen did no better than those treated with a CHOP-like regimen. Some have interpreted these reports to mean that all patients with diffuse large cell lymphoma should receive CHOP, since they feel it to be safer. I believe this is not a good interpretation of the available data for the following reasons: (1) when administered at maximum tolerated doses, CHOP has the same approximate 5% treatment-related mortality seen with all regimens; (2) when CHOP is given at reduced (ie, safer) doses, it is not as effective; and (3) it is not yet clear that all patients with diffuse large cell lymphoma are the same in their response to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase II Trial with Alternating Two Drug Schedules, CAP/MEC', For Advanced (Stage III Mo/Ml) Non-Small-Cell Lung Cancer

Sixty-eight evaluable patients with advanced squamous cell carcinoma (48), large cell carcinoma (2) and adenocarcinoma (18) of the lung were treated with a six-drug regimen delivering two monthly alternated combinations. The combinations were cisplatin, adriamycin and cyclophosphamide (CAP) and methotrexate, etoposide and CCNU (MEC'). Following a minimum of two courses, the overall response rate was 22% (confidence limits, 12% to 32%) (15/68, 2 complete responses and 13 partial responses); 47% (32/68) had stable disease and 31% (21/68) had progressive disease. The responses lasted a median of 3 months (range, 1-15 months). The actuarial median survival was 11 months in responsive patients, 10 months in stable disease patients, and 5 months in progressive patients. The overall median survival obtained was 9 months (range, 2-28+ months). Toxicity was minimal, and subjective tolerance of the treatment appeared good. However, this alternating program did not improve response rate or survival.

Combination chemotherapy of disseminated kaposi's sarcoma in patients with the acquired immune deficiency syndrome

Two clinical trials were conducted to assess the efficacy and safety of a combination chemotherapy regimen for the treatment of Kaposi's sarcoma in patients with the acquired immune deficiency syndrome (AIDS). Eighteen consecutive patients with disseminated Kaposi's sarcoma were treated with a six-drug regimen of doxorubicin (Adriamycin), vinblastine, bleomycin/actinomycin D, vincristine, dacarbazine (ABV/ADV). A brief partial or complete response was achieved in 13 patients. Most patients died of opportunistic infections. Eighteen consecutive patients with disseminated Kaposi's sarcoma were then randomly assigned to therapy with either recombinant alpha interferon or ABV/ADV. The treatment responses in these two groups were comparable to results of earlier trials, and the incidence of opportunistic infections during therapy did not differ between the two treatment arms. It is concluded that chemotherapy is effective and safe for use in palliative management of Kaposi's sarcoma in patients with AIDS.

Etoposide (VP-16) and cisplatin in previously treated small-cell lung cancer: clinical trial and in vitro correlates.

Treatment of patients with relapsed small-cell lung cancer (SCLC) has been uniformly unsuccessful. Recently, the combination of etoposide (VP-16) and cisplatin in this setting has been reported to result in up to 50% response rates. We treated 29 patients with relapsed SCLC with this combination and found only a 12% response rate. The discrepancy between our results and those of others is most likely due to differences in prior treatment of the patients, although the effect of dose and schedule modifications are considered. Our patients had received a six-drug regimen over a median of 7 months and had a median drug-free interval before this treatment of only 3 weeks. Evidence is presented that suggests that this aggressive initial therapy affected both host tolerance to further treatment and the development of tumor resistance at the cellular level.

Effectiveness of a six-drug regimen (APO) without local irradiation for treatment of mediastinal lymphoblastic lymphoma in children.

Fourteen children with mediastinal lymphoblastic lymphoma (MLL) were treated with the six-drug APO protocol. This regimen includes aggressive intermittent chemotherapy and prophylactic central nervous system therapy. Mediastinal irradiation was given only for emergency relief of mediastinal compression (two children) or for incomplete resolution of mediastinal widening with chemotherapy (one child). All 14 patients achieved complete remission; only 1 has relapsed. Toxicities were not severe. APO is effective therapy for children with MLL. APO should receive further trials in children and adults with T-cell lymphoblastic lymphomas.

Prolonged remissions of metastatic breast cancer achieved with a six-drug regimen of relatively low toxicity.

A combination of six chemotherapeutic agents was used to treat 30 women with unresectable metastatic carcinoma of the breast. In the first year five drugs (Cytoxan, methotrexate, 5-fluorouracil, vincristine, and prednisolone [CMFVP]) were given using a weekly schedule for administration of intravenous drugs. During the next year, a seven-week treatment cycle was introduced, with CMFVP given for four weeks, followed by an Adriamycin combination (Adriamycin, cyclophosphamide, and prednisone [ACP]) for three weeks and then the cycle repeated. Treatment was continued for three years or to time of relapse. Overall response rate was 66.7% (20/30). The median duration of response was 40 months and the median survival 39 months. Premenopausal women fared better than postmenopausal women with comparable response rates, duration of response and survival being 81.5%, 41 months, 56 months versus 50%, 20 months and 27 months. Of 16 premenopausal patients treated 7 achieved a complete response (CR) and, of these, 5 remained free of disease at 3 years. For these five individuals all treatment was then stopped. Disease recurred in two patients by five months but three remain disease-free after 43, 40 and 34 months, respectively without therapy. Toxicity was generally limited to heartburn and modest hair loss. This regimen appears to be more effective than those previously employed for metastatic breast cancer. However, comparative trials will be necessary to confirm its advantages.

Small Cel Carcinoma of the Lung. Experience with a six-drug Regimen

Small Cel Carcinoma of the Lung. Experience with a six-drug Regimen

Medical management of refractory hematuria in sickle-cell trait

Hematuria secondary to sickle-cell trait has on occasion proved refractory to medical management. We have adopted a new six-drug regimen to deal with this difficult problem. Herein is reported our experience with this protocol in 2 patients. Our results have been excellent, with hematuria clearing within twenty-four hours. The drug regimen is used in an attempt to alter the conditions that are favorable for sickling in the renal medulla.

Clinical evaluation of combination chemotherapy of solid tumors with five or six anticancer drugs.

The clinical effects of combination chemotherapy with five or six anticancer drugs were investigated on the patients with the advanced cancer which originated mainly from the gastrointestinal tract. The five-drug regimen was found effective in 15 of 21 patients (71%) and the six-drug regimen in 29 of 43 patients (67%). The incidence of the cases which showed favorable clinical responses was higher in the five- and six-drug regimens than in the one-, two- and three-drug regimens. Leukopenia, which occurred in almost half of the patients, was observed more frequently in cases of the six-drug regimen than in cases of the five-drug regimen. Gastrointestinal disturbances were found frequently during and after treatment, and seemed to be aggravated mainly by 5-FU and SP-G in these regimens. The main reasons for the discontinuation of these therapies were firstly leukopenia and secondly gastrointestinal upsets. The cases treated with the five- or six-drug regimen survived only slightly longer than the non-treated. However, there were few remarkable differences in the survival period between the cases of the five- or six-drug regimen and the cases of other regimens.