Japanese Journal of Clinical Oncology

To the Editor:

I have enjoyed a fruitful and very positive experience learning many different aspects of clinical practice and multimodality management of non-small cell lung cancer patients (NSCLC), which will be very useful to think over now that I have returned home. First of all, on behalf of the Spanish Lung Cancer Group I would like to say many thanks for giving me the opportunity and honor of this fellowship. We spent a lot of time discussing different approaches mainly for stage IIIAN2 disease and a lot of pros and cons on the issue of whether or not surgery is required as part of treatment; for example, Dr Kubota et al.'s study of chemoradiotherapy yielded 29% survival at 3-years (J Clin Oncol, 1994).

A randomized trial is being designed comparing chemoradiotherapy administered concomitantly, followed by surgery versus preoperative chemotherapy followed by surgery. The drugs to be used are triplets of vindesine with either cisplatin or carboplatin and mitomycin. This is an important and relevant study that may well answer the crucial question of whether or not preoperative radiotherapy enhances the chemotherapy effect on survival in still resectable stage IIIAN2 patients. What can be predicted for such a study? First, complete resection rate will possibly be the same, about 60-75%. Second, the percentage of pathologic complete response could be strikingly different, from less than 10% with only preoperative chemotherapy up to 30% with preoperative concurrent chemoradiotherapy. Third, a significant difference is also expected to be found in downgrading frequencies, approximately 60-70% N2 to N0 in the combined preoperative group and 35% in the preoperative chemotherapy group. Fourth, more radiographic responses are predicted in the combined preresectional modality, around 80% in contrast with 60% with only preoperative chemotherapy. The main objective of this trial is to compare survival and disease-free survival.

We can also focus on the treatment of stage IIIAN2 using new drug combinations. The ECOG study (Bonomi et al., ASCO 1996, 1997) showed that taxol/cisplatin was better than cisplatin-etoposide in terms of response rate, time to progression and survival. We have already demonstrated that in advanced or metastatic NSCLC, gemcitabine-cisplatin yielded a 41% objective response rate in 69 patients in contrast with only 22 % in 66 cisplatin/etoposide treated patients (P = 0.002). Differences also surface on time to progression (6.9 months versus 4.6 months, P < 0.001 by logrank test). I am strongly in favor of using such new drugs.

More recently we have been involved in detecting occult micrometastases by means of PCR techniques directly from patients' serum. DNA was extracted from the sera of 22 NSCLC resected patients and analyzed with 4 dinucleotide markers of chromosome 3p. In 6 of them, we detected the presence of circulating tumor DNA; LOH was observed in the serum as well as in the DNA from the corresponding resected tumor. In one case, a squamous cell carcinoma T2N0M0, circulating tumor DNA was identified; the patient developed huge liver metastases 10 months later and died two months after that (Sanchez-Cespedes et al., Ann Oncol, 1998).

One interesting approach for neoadjuvant multimodality treatment could be to become involved in a large international study, based on the Japanese experience with taxotere and the European and American experience with cisplatin/gemcitabine.

First, stage IIIA N2 patients would be randomized to receive either cisplatin/taxotere/gemcitabine every 21 days for 3 cycles followed by surgery, or weekly cisplatin/taxotere/gemcitabine plus radiotherapy followed by surgery.

Second, only patients attaining complete resection, would be randomized to receive only observation, or 3 cycles of the same chemotherapy regimen, or delayed postoperative chemotherapy with the same regimen (cisplatin/taxotere/gemcitabine) administered 3 months after resection. This second randomization would focus on detecting differences in disease free survival time, with the hypothesis that delayed chemotherapy could attain a better control of occult micrometastases.

The primary end-point is survival. Secondary end-points are differences in complete resection rates, downstaging and pathologic complete responses, and toxicity.

We focused our interest on whether surgery is warranted in stage IIIAN2. The issue has not been completely solved and we are still awaiting the results of large randomized studies.

We compared Eberhardt et al.'s study (JNCI, 1998) of preoperative cisplatin/-etoposide plus radiotherapy followed by surgery. Kubota's trial of chemoradiotherapy versus chemotherapy and Roth's trial (JNCI, 1994) of preoperative chemotherapy plus surgery versus surgery alone, revealed several seemingly relevant points:

1. Median survival time was 20 months in the preresectional chemoradiotherapy study, 21 months in the Roth study, and 12 months in the Kubota study, while on the surgery alone arm in the Roth study, median survival was 14 months.
2. Overall survival was 31% at 4 years in the Eberhardt study of preoperative chemoradiotherapy and 36% at 5 years in the Roth study (without using preoperative radiotherapy). Intriguingly, a 29% 3-year survival rate was found in Kubota et al.'s study. However, survival in the Kubota study bottomed out to nearly 14% at 5 years.
3. Long-term survival in the Eberhardt and Roth trials was very similar (the latter not yet published). Median survival for patients attaining complete resection was 42 months in the Eberhardt study and not yet reached in the Roth study, though median survival was 18.8 months on the surgery randomized arm. Eberhardt et al. reported 46% 4-year survival, as compared to about 53% in the Roth study of preresectional chemotherapy without preoperative radiotherapy. On the surgery arm of the latter study for completely resected patients, 24% 5-year survival was attained.

What can be learnt from such relevant studies? Stage IIIAN2 disease is experienced in a rather limited subset of patients in which further randomized trials are required. However, surgery is indicated, as other studies have also demonstrated that the best survival is in the group of patients who attained complete resection.

We are planning to establish some kind of clinical and laboratory cooperation in the near future.

Rafael Rosell
Chief, Medical Oncology Service
Hospital Germans Trias i Pujol
Barcelona, Spain

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