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Looking at new studies dealing with the most frequent tumours like NSCLC, breast cancer and colorectal cancer does not induce enthusiasm. But there are some important data confirming that there has been made considerable progress in recent years that might lead to further improvement in the near future.

Metastatic NSCLC

One of the most important studies presented at this year´s ASCO meeting was the ECOG 1594 trial which compared four different treatment regimens (table 1) assuming that there might be some clinically relevant differences with regard to survival in patients with metastatic NSCLC. It was the largest study ever conducted in NSCLC and predominantly included stage IV patients.

The results of this study, however, have been disappointing to a certain extent, because there was no significant difference favouring one of these regimens as far as survival is concerned - since most patients received secondline
treatment, the survival of the 4 arms is difficult to compare. Response rates were very similar across treatment groups, although there was a trend suggesting that carboplatin + paclitaxel (15%) and cisplatin + docetaxel (17%) might be less effective compared to cisplatin + paclitaxel (21%), which was defined as the standard arm and was given in a 24-hour regimen.
But this difference in response rates had no impact on overall survival (table 2). The only significant advantage in this study as to efficacy was demonstrated for the gemcitabine + cisplatin regimen which produced an increase in progression free survival compared to the control group (table 2).

	1 Year  Survival	Median Survival (mo.)	PFS (mo.)*
cisplatin + paclitaxel 31% 7,8 3,5 cisplatin + gemcitabine 36%  8,1 4,5 (sign. diff.) cisplatin + docetaxel 31% 7,4 3,6 carboplatin + paclitaxel 35% 8,2 3,3
* progression free survival Table 2: Major results of ECOG 1594

As far as tolerability is concerned, there were some significant differences favouring the carboplatin + paclitaxel regimen, while gemcitabine + cisplatin was associated with an increased toxicity compared to the control group. But the latter was mainly due to a higher cis-platin-dose (100 mg/m² versus 75mg/m²) and the 28-day schedule, and should be avoidable when a lower cis-platin-dose is used in a 21-day schedule.

Summarizing the results of ECOG 1594 (and other new studies) leads to the conclusion that platin-based regimens seem to remain the golden standard in the treatment of NSCLC. But it is interesting that a new treatment standard was not recommended.
Frances Sheperd said in her comments that she thought Gem-Cis had won by a nose in a "foto-finish".

Breast Cancer

Reviewing the presented studies on the treatment of breast cancer does not allow to talk about major breakthroughs in this field, but there were some interesting papers that might induce a change of treatment strategies in the future. One of the most exciting studies was performed by the NSBAP, comparing radiotherapy, tamoxifen and the combination of radio-therapy + tamoxifen in the adjuvant setting. Interestingly enough, tamoxifen was far from being as effective as radiotherapy, while
the combination of radiotherapy + tamoxifen proved to be the most effective regimen in preventing recurrence of ipsilateral breast cancer (fig. 1). Analyzing the overall recurrence rate shows a similar trend with the combination therapy being the
most effective treatment (6%) compared to tamoxifen alone (26%) and radiotherapy alone (13,6%).

Fig. 1: Incidence of ipsilateral breast cancer after 5 years of follow-up 
(NSPAB trial B21)

Another important study was presented by an Italian group investigating continuing longterm treatment with tamoxifen over 5 years compared to a switch to aromatase inhibitor therapy (amino-glutethimid) after an initial tamoxifen therapy over 3 years in the adjuvant setting. Analyzing the results during the randomized phase of the study does not show any relevant differences with regard to tumour recurrence or second malignomas. But there was a striking difference in mortality favouring aminoglutethimid (12 cases versus 28) that was mainly due to a decreased incidence of progressive breast cancer (8 versus 16), cardiac events (1 versus 6) and strokes (0 versus 2). What makes this study so important is the fact that it confirms the potential role of aromatase inhibitors as alternative to tamoxifen. In the light of these data one can look
forward to the results of ongoing studies with newer aromatase inhibitors, which have the advantage of an improved tolerability compared to aminoglutethimid.

HER2-positive breast cancer

Management of patients with HER2-positive breast cancer is a challenging task. This is due to a worse prognosis and a decreased success rate under treatment with chemotherapy. Since the introduction of the monoclonal antibody herceptin, treatment options have looked more promising because efficacy of chemotherapy is en-hanced when combined with herceptin and this can be translated into prolonged survival in patients with metastatic disease. So far, the most important combination studies have used anthracyclines and taxanes as cytotoxic agents and only limited information is available on
other combination regimens incorporating herceptin. Therefore a study from Burstein et al. deserves special attention,
which investigated herceptin in combi-nation with vinorelbine in 34 patients with metastatic HER2-positive breast
cancer. The vast majority of the patients had received prior chemotherapy which had been applied in the adjuvant setting
(56%) or during metastatic disease (62%) and had consisted mainly of an-thracyclines and taxanes. Patients with
herceptin pre-treatment were not included in this study.

The results so far are very encouraging, showing a response rate of 71%. Although the patient number included is pretty small it seems of note that a high response rate was even seen in patients who had received prior chemotherapy in the metastatic setting (fig. 2). This is in contrast to the results of a large phase III study in which a substantial decrease of efficacy was seen in patients who had received pretreatment with anthracyclines in the adjuvant setting and had therefore been allocated to a combination of herceptin and taxanes that turned out to be less effective than the combination of nthracyclines and herceptin in patients who had had no prior AC therapy. It is needless to say that no valid conclusions can be drawn from the present study, but it is at least exciting that there might be a treat-ment option with an efficacy that is not diminished in the second-line setting.

Fig. 2: Response rates under a combination treatment with 
herceptin and vinorelbine depending on the pre-treatment 
status in the metastatic setting

Looking at other studies dealing with the treatment of HER2-positive breast cancer does not provide too much new information. What seems important is the observation that the benefit of herceptin is confined to patients with HER2/3+ or FISH-positive tumours. This was shown for patients treated with herceptin combined with chemotherapy and herceptin monotherapy as well. Especially the data of a monotherapy study of Vogel et al. look pretty promising because of the high response rate in HER2/3+ and FISH-positive patients (35% and 40% respectively).
On the other hand, this study has shown that herceptin does not provide a substantial benefit in patients with HER2/2+ breast cancer.

Colorectal cancer

For decades treatment of metastatic colorectal cancer was a domain of 5-FU/LV. Nowadays we have a variety of new agents that have led to promising results, especially in combination regimens. In first-line therapy, oxaliplatin combined with 5-FU/LV has proven to be more effective than 5-FU/LV alone in two large studies (de Gramont, Giac-cetti) and so has ralitrexed in the Saltz study. Another promising approach is the combination of new agents like ralitrexed and oxaliplatin as has been shown in two recent trials by Douillard and Scheithauer (table 3). These studies lead to the conclusion that combining two new agents is at least as effective as 5-FU/LV-based regimens.

As to second/third-line therapy, there are also some promising data confirming that the newer cytotoxic agents represent an important and valuable treatment tool. This has been shown for irinotecan and oxaliplatin in combination with 5-FU/LV and for the combination of irinotecan and oxaliplatin as well.
The response rates in these studies were around 20%, while stabilization could be achieved in 50%. The median survival reached one year and is thus underlining the importance of these new regimens.

ASCO meeting 20.-24. May 2000,
New Orleans, USA

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