Select Excerpts from the Interview

Tracks 1-2

DR LOVE: What is your take on the plenary presentation at ASCO on the EORTC study of PCI for extensive-disease SCLC (Slotman 2007)?

DR CURRAN: PCI is a standard approach for patients with limited-stage SCLC who achieve a complete or near-complete response to chest radiation therapy and chemotherapy. At least two meta-analyses demonstrated an overall absolute increase in survival of five percent with that approach over a series of studies and, in general, approximately a 50 percent or greater reduction in the development of central nervous system metastases (Aupérin 1999; Fried 2004).

The decision was made by the EORTC to conduct a trial to determine whether PCI could confer the same level of benefit to patients with extensive-stage disease who had a response to chemotherapy (Slotman 2007; [1.1]). The random assignment of 286 patients was between the administration of PCI at an aggressive fractionation of 20 Gray in five 4-Gray fractions versus observation. An important factor was that no brain imaging was required to confirm eligibility, so it’s possible that patients already had asymptomatic metastases at the time of randomization. One interpretation of the study was: could this PCI have been early treatment of subclinical disease?

A statistically significant improvement was seen, not only in progression-free survival but also overall survival, which was a startling observation considering the fact that patients with extensive-stage SCLC, even those who experienced a good response to chemotherapy, have so many competing risks for mortality.

One can interpret these data in several ways: (1) It was a positive study, which defines a new paradigm of treatment for extensive-stage SCLC, (2) It was a positive study that is so counterintuitive that it needs confirmation or (3) It was a positive study that has to do with design methodology — for example, lack of careful restaging of the patients to assess response or evaluate the CNS and perhaps asymmetry in the actual randomization and stratification.

DR LOVE: How were you approaching these patients before the EORTC study was presented, and what are you doing now?

DR CURRAN: These patients have extensive-stage disease — that’s an old VA Lung Cancer Group definition based on being encompassable or not in a reasonable radiation field. Some have extensive-stage disease and what I call oligometastases with an excellent complete response or near-complete response to chemotherapy or chemoradiation therapy, with whom I have a discussion about an aggressive therapeutic approach, including PCI. However, this is dependent on them having a normal brain MRI after staging. I have been doing that for highly selected patients, and I will continue to. As far as the broader group of patients with extensive-stage SCLC, I have not changed my practice.

DR LOVE: What was the overall consensus within the RTOG regarding the EORTC study results?

DR CURRAN: The responses span the spectrum. Some members say it has changed how they approach these patients, whereas others found the design so different from our standards that they don’t know how to apply the data.

I have never used the specific radiation regimen from the EORTC study, nor has any American study ever used it for PCI. This was administered in a week in five 4-Gray fractions (1.2), and the only time I see that in the US is for patients with cerebral metastases who are in poor condition, for whom there’s a desire to complete treatment rapidly. For PCI, the usual treatment I administer is 2.5 Gray in 10 fractions.

Tracks 5-6

DR LOVE: What do you think about the clinical research strategy of combining radiation therapy with bevacizumab?

DR CURRAN: The landmark paper by Chris Willett and Rakesh Jain showed that in a small number of rectal cancer patients, bevacizumab alone had a physiologic effect in terms of the vasculature and showed clinical effect when combined with radiation therapy (Willett 2004).

DR LOVE: The other major discovery from that study was not only is there an anti-angiogenic effect, but there is also a normalization of the tumor vasculature, which has big implications in chemotherapy and radiation therapy.

DR CURRAN: Yes, because tumor hypoxia is thought to be one of the primary mechanisms of resistance to radiation therapy — you’re right. SWOG initiated a study in Stage III NSCLC that is integrating bevacizumab into chemoradiation therapy, dividing patients between high- and low-risk groups according to whether they have central tumors, squamous histology, history of hemoptysis and other factors (SWOG-S0533; [1.3]). Due to cautious enrollment, a small number of patients have enrolled. Episodes of tracheoesophageal (TE) fistula were reported in parallel ongoing studies in SCLC with bevacizumab and chemoradiation therapy. That required SWOG to stop S0533 and evaluate safety.

DR LOVE: What’s your perspective on the potential benefits and risks of bevacizumab combined with chemoradiation therapy in lung cancer?

DR CURRAN: My gut feeling is that it can be an active addition to chemoradiation therapy. My biggest concern is that people will become legitimately concerned about the risk of catastrophic complications, and that will slow the clinical development. TE fistulas are obviously serious, life-threatening events. Originally with thoracic malignancies, we saw these when we started combining chemotherapy with radiation therapy decades ago, and it made some people back away from that paradigm. However, once we learned how to administer it, it revolutionized the care for those patients.

Even further back in the radiation therapy-alone era of unresected thoracic malignancies, we were taught that if someone had a tumor potentially invading the esophagus, we were to use a lower dose per fraction to avoid a TE fistula. So I view the TE fistula as a surrogate for excellent tumor response. We just need to figure out how to calibrate the antitumor action so it doesn’t have a catastrophic effect.

Tracks 9-10

DR LOVE: Can you discuss what we know about predictors of response to EGFR tyrosine kinase inhibitors (TKIs), specifically erlotinib?

DR CURRAN: There are molecular and epidemiologic predictors of response to EGFR TKIs in second- and third-line treatment of NSCLC. Patients who are never smokers, women and of Asian descent have a higher likelihood of responding to a TKI than men who are heavy smokers and non-Asian.

In searching for predictors of response at the molecular level, the focus is on mutations in chromosomes 18 and 22. Work is also being conducted at Harvard, Sloan-Kettering and Colorado showing that EGFR mutational analysis is extremely helpful, in the right hands. The FISH-type analysis by Fred Hirsch and others has also been useful for predicting response (Cappuzzo 2005a, 2005b; Hirsch 2003, 2005, 2007).

Recently, we’ve seen interest in whether the presence of a K-ras mutation is a sufficiently adverse predictor of response to warrant not using TKIs. I reviewed data suggesting that, although the overall response rate using RECIST is lower in patients with K-ras mutation-positive disease, waterfall-type trends clearly suggest that the range of responses does not appear different in those patients with K-ras mutations from those with non-K-ras mutations.

DR LOVE: What do you see in terms of quality of life with chemotherapy versus erlotinib?

DR CURRAN: In general, erlotinib is better tolerated, especially compared to doublet-based chemotherapy. If erlotinib provides the same palliation and arrest of symptoms as doublet chemotherapy in the older, never smoker or oligosmoker with a poor performance status at diagnosis, I would like to have data to support erlotinib as initial treatment for that patient. That’s an option that many patients and families would prefer.

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