This is the second trial, a French study. Control arm here was cisplatin with vindesine, an 80’s type of platinum Vinca, versus cisplatin, Navelbine versus Navelbine alone. And this is the outcome: median survival 40 weeks with cisplatin, vinorelbine versus 30 weeks with cisplatin, vindesine. And of note, vinorelbine as a single agent very similar. Of course, vinorelbine as a single agent, I just mentioned in the elderly, coming to similar outcome of about 27 weeks median survival. So this is the second trial that established cisplatin and vinorelbine as a possible standard regimen, slightly better than those of the 1980’s.

There is a third trial that did not show that difference but it really didn’t have a control arm. The only control arm with this one was vinorelbine versus cisplatin, vinorelbine and it showed a median survival for both of about 33 weeks.

So let’s move on to Taxol then. This is probably the best of the U.S. trials. This was an ECOG trial early on. The control arm was cisplatin, etoposide. It was compared with cisplatin, Taxol low dose versus cisplatin, Taxol high dose with GCSF. Of note, and I think this is the only such trial, the Taxol here was given as a 24 hour infusion. Not as we would do now, one or three hours. Median survival: 7.6 months with cisplatin, etoposide and close to 10 months with the two Taxol arms, and there was no dose response curve. Meaning that there is probably a threshold value for this drug but not a dose response curve. So this is a trial that suggested that cisplatin, Taxol could also be a standard regimen. This trial has not yet been published, even though it is a few years old. But supposedly it is going to come up pretty soon.
Cancer
This is a European trial, cisplatin, Taxol versus cisplatin, VM-26. This is a drug that is not available in the United States, teniposide, but these two are also a standard doublet. Published in JCO by _ in 2006. It’s a large study. You see the doses here; cisplatin 80 plus either teniposide or paclitaxel as a three hour infusion. Look at response rate; 28% versus 40% with paclitaxel. And median survival not different but very good on both arms at almost 10 months. One year survival of 41% and 43%. So this trial was actually not positive for survival, although encouraging on both arms, and here the Taxol was chosen as the future arm because it was felt to be less toxic and provide better quality of life, but had some late neuropathy. This is the outcome. You see no difference between the two but somewhat better median survival.

And you see there are at least four, all asking basically the same thing and all coming to the same conclusion. This is the best one, British Medical Journal, 1995. Median survival six months with supportive care, eight months with chemotherapy. One year survival, 16% versus 26%. All four concluded that chemotherapy improved survival by a little. This is a more recent example. MIC, standing for mitomycin, ifosfamide, cisplatin; the British trial, published this month in JCO. And here four cycles of MIC versus best supportive care: median survival, five versus seven months, statistically significant. I show this trial and the data are in the Journal because they looked at quality of life and it was improved with chemotherapy over best supportive care. This had also been addressed in previous trials, but addresses this issue where frequently it was meant that yeah, you only improve survival a little and are patients really benefiting from it? Well, they do.

What about elderly? This is a disease that frequently occurs in the elderly. So patients 70-years-old, or in the past it would be argued, “Well, let’s not treat that patient anymore. It’s too old.” Well, 191 patients were randomized to either vinorelbine single agent or best supportive care. Median survival with chemo: 27 weeks versus 21 weeks. Sort of showing the same thing in this group of patients. Six months survival: 54% versus 39%, statistically significant. One year: 27% versus 5%. Quality life here too was analyzed – this was published in JMCI last year, or early this year rather – improved with chemotherapy. Finally, cost-effectiveness has been looked at, particularly with one of these trials, the so-called Canadian trial. And to not go into great detail, just to make the case, that even though the chemotherapy costs some money they felt that this was well within the range of any other interventions and that cost or cost-effectiveness should not be a barrier to offering chemotherapy. So looking at this information, you can summarize that chemotherapy is an active modality in stage IV disease, that it prolongs survival by a little, that it improves quality of life – and it does so at acceptable cost – and as a consequence should be offered to these patients. The debate is done. That’s the literature of the 80’s.

So what we want to move onto then is in the 90’s, not much any more do we want to use chemotherapy but can we identify better chemotherapy? I mentioned that there were five drugs that came out during this decade. They have now been somewhat evaluated and let’s go over that a little bit, in sequence at least. The first two trials will focus on vinorelbine. That was the first drug that came out. It’s a Vinca alkaloid. This is the definitive trial done by SWOG, Tony Wosniak published in JCO. Cisplatin alone is the control arm, cisplatin, vinorelbine was the experimental arm. Median age 63 years as a standard. Most patients male, as is the case, and most had stage IV disease. So this is a poor prognostic group of patients. Some other trials have more patients with stage IIIb disease in there. You can look at response. So what’s the single agent response rate to cisplatin? It’s 12% and to cisplatin and vinorelbine it’s 26%. Here’s the overall survival: median survival six months with cisplatin alone and about eight months with cisplatin and vinorelbine and statistically significantly improved. So this is the trial, or one of them, that got vinorelbine approved by the FDA for non-small cell lung cancer, and cisplatin, vinorelbine then as a possible standard regimen.

There are some other pretreatment prognostic factors, and most of these are established in patients with stage IV disease, so those are treated with chemotherapy. There are some large trials that have looked at retrospective evaluation of large numbers. There are newer references for this but they all show the same. Stage is the predominant clinical pretreatment prognostic factor. Performance status is a very strong next, pretreatment weight loss and then adverse effects of male gender and age. For patients with stage IV disease in particular, the number of metastatic sites matters and the use of chemotherapy, in particular cisplatin-based chemotherapy. Now in earlier stage disease, those who have surgery we can also look at molecular abnormalities. These are the two that over the years have been established as negative prognostic factors. That’s the K-ras mutation that’s frequently seen in adenocarcinomas, and absence of blood group antigen A which probably correlates with something else missing. It’s not the absence of the antigen that is harmful to the patient, but there may be loss of a tumor suppresser gene associated with that.

So let’s focus then, for non-small cell lung cancer, on therapy and since most of you are medical oncologists that’s what we want to focus on. About 50% of patients present with stage IV disease. They are treated for palliation, and as I will show you, chemotherapy improves survival and quality of life at acceptable cost. It is now accepted therapy for stage IV disease. If you look back to the 1980’s, then the platinum and Vinca regimens have all similar activity, and the same is true for cisplatin and carboplatin which have similar single agent activity. So this is a disease where either one could be used. The current dogma is that doublets are as good as anything. Adding a third or fourth drug has not been shown to be beneficial. There may be exceptions but that’s the rule. There is probably no dose response curve for survival but there may be threshold doses and that’s coming out particularly with the novel agents that you need to get to a certain dose, but from then on there is no further benefit. That is, of course, softer knowledge but nevertheless it looks like that, particularly for the taxines. Activity for single agent therapy in non-small cell lung cancer has been defined historically as 15% or more. Well, it isn’t always even 15%. Some of these are more like 10%.

There are two groups. These are the older drugs that were available a decade ago and typical regimens then consisted of cisplatin in combination with vinblastine or cisplatin in combination with etoposide. There was also a so-called MVP regimen of cisplatin, mitomycin and vinblastine. That was a triplet. Since 1990 we have at least five new drugs with significant single agent activity, and I will focus on some of that: vinorelbine, Taxol, paclitaxel, docetaxel, gemcitabine and CPT-11 or irinotecan.
Cancer
So let’s look at the literature of the 1980’s first because what was established during that decade is that chemotherapy is useful for non-small cell lung cancer. Response rates were around 20-30% with most regimens, median survival times around eight months, so how good really was chemotherapy? What was done then is combine, do a randomized trial, comparing chemo alone versus no chemo. Just supportive care. A large number of trials but usually few patients and if you looked at outcome, only three were statistically positive supporting the use of chemotherapy. You can, however, look into this column and what you’ll see – this is median survival in weeks – is usually 25 to the low 30’s and if you look at best supportive care you usually see 15-17. So that’s a poor-mans metaanalysis. Right out of this you could make some conclusions and then have three trials that have statistically positive results and all the others showing the same thing. So metaanalyses were of course done then.

Lung cancer is smoking-related. This is a totally preventable disease if patients do not smoke. And all of what we talked about wouldn’t be necessary if not for cigarettes. So it is the second most common malignancy in both sexes. Head and neck cancer was 40,000, this is 172,000 cases per year and it’s the most common cause of death in either sex. Meaning that in males it is a more common cause of death than prostate cancer, and in females more common a cause of death than breast cancer. Eighty percent of cases at least attributed to smoking. There may be some other risk factors and a genetic predisposition – largely, we think, because there is no familial clustering outside of smoking – in terms of how individual patients metabolize or otherwise handle the carcinogens contained in the smoking.

Let’s look at some of the incidence figures. These are incidence, cancer rates. This is prostate cancer shooting up when PSA becomes available then down. This is lung cancer in terms of incidence, slightly going down in males for the last 20 years or so. This is incidence rates for females and you see it’s still rising, as far as lung cancer is concerned. This is breast cancer – more common. Now let’s look at the death rates. These are the death rates in males. This is lung cancer. Exceeding everything else by far with somewhat of a reverse trend in the last few years. And this is the same in women, exceeding everything else with what still appears to be a rising incidence of lung cancer deaths in women. So that is where smoking prevention is more important than anything we can talk about in this kind of lecture. This is way too late and conceptually of course, not in an epidemiological sense, the primary thing to do.
Pharmacy
Now what about the histologic types? Seventy-five percent are non-small cell, that’s what we will cover here. The others are small cell and non-small cell, divided up into these cancers: in the United States now adenocarcinoma is the most common, squamous carcinoma is next. This used to be different 20 years ago but now adenocarcinomas are the common ones and we are not sure why that is. Then this is stage-specific survival. Stage I is a confined disease. These patients are treated with curative intent by resection. Stage II is very similar, with at most, hilar lymphadenopathy. Many patients can be cured although you are down now to about 30%. Stage III, we will talk about a bit more in detail, includes regionally advanced disease. So that is disease in the chest involving large primaries or lymph nodes, mediastinal lymph nodes or supraclavicular lymph nodes, but no distant metastases. Then stage IV is distant metastases. We can also look at this is a sense of how far along can we use surgery. For metastatic disease we wouldn’t, and for stage I or II we would. Because these patients can be cured surgically, at least in some cases. Then stage III is split. Where usually IIIa is, at least in theory, resectable whereas IIIb is considered un-resectable. So that is the split from a surgical point of view.

Although uncontrolled studies and anecdotal reports of high-dose chemotherapy with marrow reconstitution appear promising, the highly selected nature of the patients and the expense of the procedures mandate that randomized, comparative trials demonstrate the superiority of this approach over standard therapy before it can be considered a valid part of the therapeutic armamentarium. Such a study is underway with very poor accrual.

Intraperitoneal administration of drug, although under study for over a decade, still has no defined role in management. In the salvage setting, it appears to have no advantage over intravenous therapy. In the setting of first-line treatment, two large randomized trials in patients with small-volume disease show small advantages but have major design problems. The final determination of the role, if any, for intraperitoneal therapy awaits the completion of the current trial comparing intravenous paclitaxel-platinum to intraperitoneal paclitaxel-platinum. If a role for intraperitoneal therapy exists, data show that it will be in only those patients with extremely small-volume disease or perhaps no residual disease; hence, its role will be a very narrow one.
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In conclusion, the future holds the promise of continuing advances in the management of patients with celomic epithelial carcinoma of the ovary. Although the explosion of knowledge of the basic nature of the disease holds the greatest potential for improvement, the identification of an effective screening technique, the clarification of the role of surgery in advanced disease, and the introduction of exciting new agents such as Taxol offer the promise of better treatment in the immediate future. The great promise of dose-intense regimens, still worthy of further investigation, suffers from a growing body of evidence that no advantage is obtained at least over the clinically achievable range of doses unsupported by marrow reconstitution.

Third, although the efficacy of initial surgical cytoreduction in patients with stage III disease has been accepted on the basis of retrospective analyses, prospective trials are needed to address several important questions. One such study suggests an advantage for interval surgical cytoreduction at the midpoint of a series of chemotherapy courses. Prospective randomized trials of initial or secondary surgical cytoreduction have not been completed. Investigations of the relative merits of each of these approaches versus no surgery are needed, as well as trials evaluating which of these points in the therapy represents the optimal time to introduce surgical resection into the management of advanced disease. Such studies are difficult to conduct because of the widespread acceptance of the role of surgical cytoreduction in ovarian carcinoma. A confirmatory trial of interval cytoreduction is nearing completion, but further study is needed.

Fourth, efforts continue to investigate the role of new agents in the management of ovarian carcinoma. Current interest continues to center on further delineation of the role of paclitaxel. The plethora of new agents with activity in patients who are clinically resistant to the platinum compounds and paclitaxel, however, opens the possibility for the addition of clinically non-cross-resistant drugs to front-line paclitaxel-platinum therapy. Defining the role of these new agents is of paramount importance.

Finally, dose intensity continues to command significant interest. Three basic ways to enhance the dose intensity have been proffered: escalation of dose within the range that can be achieved without marrow reconstitution, high-dose chemotherapy with support of autologous bone marrow transplant or peripheral stem cell transfusion, and, in the case of ovarian carcinoma, intraperitoneal administration of drug. Eight randomized trials of dose escalation over a standard range of doses have been completed. Six show no advantage to a doubling of dose intensity, and the other two have major design problems. Further exploration of this approach seems unwarranted.

FUTURE DIRECTIONS

The development of additional information about the nature and management of germ cell cancers and rarer malignant tumors of the ovary as well as fallopian tube cancer will continue to be restricted by the low frequency of these lesions. With regard to celomic epithelial carcinomas of the ovary, however, progress should continue to be rapid. Current and future investigational efforts focus on several distinct areas: biology of ovarian carcinoma, screening and early detection, the proper role of surgery, new agents and their role in systemic therapy, and the value of approaches to achieve greater dose intensity.
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First, with regard to the biology of ovarian carcinoma, specific studies are seeking (1) to characterize factors associated with ovarian carcinoma and its outcome such as specific genetic defects associated with hereditary ovarian carcinoma, various oncogenes, and DNA ploidy; (2) to identify features predictive of the likelihood of developing ovarian carcinoma; and (3) to ascertain the biologic reasons for the observation that more aggressive disease is associated with older patients. As these and other investigations expand the understanding of the basic nature of ovarian carcinoma, the development of better and more specific methods for early detection and treatment of the disease should be possible. Where this line of work will ultimately lead is speculative but exciting.

Second, the evolution of effective techniques for screening for and early detection of ovarian carcinoma has a high priority in ovarian carcinoma, the only one of the major gynecologic cancer for which early detection is not the rule. Most interest centers on the potential for transvaginal sonography, especially when enhanced by color flow Doppler, to permit earlier detection of disease. Studies are currently directed at improving the specificity of the technique and at demonstrating an impact on the morbidity and mortality of the disease. Ultimately, confirmation of the value of the procedure will depend on a large screening trial of high-risk women (one or more first-order relatives), a study now planned but as yet unfunded.