Combination therapy definition

ACE inhibitors and angiotensin-receptor blockers (ARB) have definite benefits in patients with nephropathy and are believed to have renoprotective effects in most patients. Due to their ability to cause an initial bump in serum creatinine, these agents should be used cautiously when employed in combination with the calcineurin inhibitors. The dihydropyridine calcium channel blockers have demonstrated an ability to reverse the nephrotoxicity associated with cyclosporine and tacrolimus (Table 52-8). In general, antihypertensive therapy should focus on agents with proven benefit in reducing the progression of cardiovascular disease and should be chosen on a patient-specific basis.55 See Chapter 2 for further recommendations for treating HTN. 

Interferon-a2b has diverse mechanisms of action, including antiviral activity, impact on cellular metabolism and differentiation, and antitumor activity.42 The antitumor activity is due to a combination of direct antiproliferative effect on tumor cells and indirect immune-mediated effects.42 Interferon-a2b is currently approved by the Food and Drug Administration (FDA) as adjuvant therapy for patients who are free of disease after curative surgical resection but are at high risk of MM recurrence. This includes patients with bulky disease or regional lymph node involvement such as stage IIB, IIC, or III disease.43 It is controversial if interferon-a2b (IFN) should be offered as adjuvant therapy for every high-risk MM patient. The reason is because clinical trials with different doses of IFN have not proved definitively that IFN improves overall patient survival. 

Until definitive trials are published, it is appropriate to use either LHRH agonist monotherapy or combined androgen blockade as initial therapy for metastatic prostate cancer. 

Although the delivery of radiation and chemotherapy as sole modalities is definitely more complex than outlined above, there needs to be guiding principles that will allow for their successful integration in combined modality therapy. Peckham and Steele introduced several key concepts that govern the interactions of both radiation and chemotherapy when they are administered together in an attempt to improve the therapeutic effect of their separate administrations (27). 

Toxicity independence definitely emerges as a real concern in the planning of combined modality therapy. As originally outlined, if two partially effective agents can be combined without having to alter their levels substantially, an improved therapeutic... 

Prior clinical trials have attempted to discern the best manner in which to administer chemotherapy when combined with radiation. It may be given concurrently with standard radiotherapy, an alternating or split-course radiotherapy schedule, or in a sequential fashion as induction (prior to definitive treatment) or adjuvant (following definitive treatment) chemotherapy. Concomitant chemoradiotherapy is the use of both modalities simultaneously. Alternating chemoradiotherapy is the use of systemic chemotherapy for a definitive duration, followed by radiotherapy for a specified period followed by repeated alternations of the two modalities. Split-course chemoradio-therapy usually involves concomitant systemic doses of chemotherapy combined with radiation therapy for a specified duration followed by a rest period, and then the regimen is repeated. This approach allows planned treatment breaks for toxicity recovery. 

Obviously, this broad range of tumor extent requires an equally broad array of treatment approaches, ranging from surgery, with or without adjuvant radiation therapy (RT) or chemotherapy (ChT), to definitive chemoradiation combinations, to palliative... 

The first trial to address this question was a GOG trial (13) comparing concurrent hydroxyurea plus radiation therapy vs concurrent cisplatin and fluorouracil plus radiation therapy in patients with locally advanced disease who had negative para-aortic nodes at lymphadenectomy. An early analysis of this trial, which was completed in 1990, failed to yield definitive results. Publication of the study findings was delayed until more complete follow-up could be obtained. Ultimately, the study demonstrated a modest but significant advantage for the cisplatin-fluorouracil combination. 

In all, and despite the considerable differences between the cited studies, these results suggest that CT is an effective therapeutic procedure for ambulatory patients with mild to moderately severe depressions. It also appeal s that CT and drug therapy may have similar efficacy in these cases, although the small numbers typical of these trials leave the possibility of type 2 errors open. It remains to be determined whether a combination of CT with an antidepressant provides a significant additional benefit, and it is also unclear what the precise indications are for the two forms of therapy (see Hollon et al., 1991). Two more recent studies also have not provided definitive answers to these questions ... 

Of 206 postmenopausal women who took the oral combination of estradiol valerate plus norethisterone (5) eight withdrew because of bleeding during year 1 during years 2 and 3 there were no withdrawals because of bleeding. By the end of year 3, 133 patients had completed the study. There were serious adverse effects in 24, but there was no definite relation to therapy. The numbers of adverse events reported each year by the patients who completed the study are shown in Table 1. The authors concluded that this combination was effective in the majority of patients and was well tolerated. 

The specific choice of treatments to be used in combination with hypothermia could be based on a variety of different approaches. First, there could be a direct synergistic effect between hypothermia and the other proposed treatment modality, presumably as a result of a complementary mode of action. For example, combining hypothermia with thrombolytic therapy might be an appropriate pairing in which the hypothermia prolongs the therapeutic window for subsequent definitive reperfusion. Similarly, hypothermia could be used just after thrombolysis, to prevent reperfusion induced injury and prolonging the viability of injured but not irreversibly damaged tissue. 

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