This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jeremic, B. Articles by Koning, C. Search for Related Content PubMed PubMed Citation Articles by Jeremic, B. Articles by Koning, C.

Induction Chemotherapy Before Chemoradiation in Locally Advanced Non–Small-Cell Lung Cancer: Failure After Failure, Again and Again

International Atomic Energy Agency, Vienna, Austria

Caro Koning

Radiotherapy Department, Academic Medical Center, Amsterdam, the Netherlands

To the Editor:

We read with great interest a Review Article by Glynne-Jones and Hoskin¹ on failure of neoadjuvant cisplatin chemotherapy (CHT) before chemoradiotherapy in a number of solid tumors. Authors should be congratulated for such an effort, which we see as a timely one. While we can only happily agree with the review findings, their implications, and also favor proposals for more appropriate terminology, we would like to offer additional data (we believe not presented due to space limitation) in the case of non–small-cell lung cancer (NSCLC), which may be of a value to the readership of the Journal of Clinical Oncology.

While induction CHT followed by radical radiation therapy (RT) alone was shown to be superior to the same radical RT given alone, subsequent intensification in a way of using additional concurrent radiochemotherapy (RT-CHT) and, in a few cases, followed also by an additional (posterior, adjuvant, consolidation) CHT unequivocally failed. Several clinical trials clearly showed that any intensification of the latter/major part of the combined treatment approach via concurrent RT-CHT is not effective, once you have started with induction CHT. Studies of CALGB such as 9130 or 39801 or 30105,^2-4 showed that there is no compensation for insufficient start (with CHT). Other attempts, such as the use of three daily fractions of RT,⁵ also proved to be ineffective. All in all, whatever you do after you start with CHT, failure is inevitable and comes fast. With this approach, you can only achieve more toxicity,³ and even if you use the modern RT tools such as 3-dimensional RT and attempt treatment intensification by escalating the total dose, again, one cannot achieve better outcome. Indeed, impressive 12% mortality in the most recent CALGB(30,105)⁴ attempt to combine induction CHT with subsequent RT-CHT led investigators to early stopping the trial.

While the nature of the work of medical oncologists/pulmonologists dealing with lung cancer remains the domain of CHT from the onset, with a paradigm, "the more of it, the better of it", radiation oncologists have unintentionally added to these failures by accepting the policy that we should "do something" while patient is waiting for a radiation therapy planning computed tomography (CT) scan, as part of the preparation before the radiotherapy will start. We have indeed "done" something! This can easily be materialized in a recently identified fact (supporting one of those that Glynne-Jones and Hoskin¹ identified) of never-achieved improvement in local control in locally advanced NSCLC treated with induction CHT. The elegant study of El-Sharouni et al⁶ has compared CT scans pre- and postinduction CHT with emphasis on the time from the last induction CHT cycle to the time of radiation therapy planning CT was actually done. That way, they have been able to measure an increase in gross tumor volumes and subsequently define volume doubling times. During the waiting period (for the radiation therapy planning CT scan and start of RT), a total of 41% of all tumors became incurable, with the ratio of gross tumor volumes being in the range of 1.1 to 81.8! Tumor doubling times ranged 8.3 to 171 days, with a median of 29 days. This important finding for radiation biologists and clinicians clearly speak about accelerated repopulation of tumor clonogens; or better said, even if you may have thought (due to insufficient CT-based imaging) that response occurs (and that it matters), there is actually an opposing development: surviving tumor clonogens repopulate. They do it fast and tumors regrow to the state of incurability.

Finally, similarly to Glynne-Jones and Hoskin's proposal for adapted terminology (with which we can only completely agree), we would like to suggest more appropriate terminology for a combination of concurrent RT and CHT as radiochemotherapy. If one gives 65 to 70 Gy of RT and either daily low-dose CHT or weekly CHT or even more protracted CHT (ie, cisplatin, 100 mg/m² every 3 weeks), how this can be called chemoradiotherapy? Perhaps chemoradiotherapy was more appropriate term in ancient times, when one started with CHT. Since this sequencing is inferior to one including RT from the onset, the term "chemoradiotherapy" should be put into the museum of history of failures (in the year 2008). RT is the mainstay of the treatment and CHT is used to support these effects. Therefore, radiochemotherapy should be preferentially used as the term appropriate for all concurrent regimens, deemed today as standard of treatment in locally advanced NSCLC, as recently shown by the largest ever meta analysis.⁷ Although concurrent radiochemotherapy had been frequently accused of being more toxic, it relates only to the acute toxicity in terms of oesophagitis and/or neutropenia, while the late toxicity was not increased. An increase in acute toxicity, however, largely depends on the way CHT has been added to the RT, unequivocally being high-dose CHT. This was not the case when a low (daily) CHT dose has been used.^8-10 On the other side, the latter seems to be a preferable method of providing sustained, protracted low levels of CHT (ie, platinum) necessary to enhance RT effects on a locoregional tumor level and subsequently improve overall survival as several clinical trials had successfully shown.^8-10

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Glynne-Jones R, Hoskin P: Neoadjuvant cisplatin chemotherapy before chemoradiation: A flawed paradigm? J Clin Oncol 25:5281-5286, 2007[Abstract/Free Full Text]

2. Clamon G, Herndon J, Cooper R, et al: Radiosensitization with carboplatin for patients with unresectable stage III non–small-cell lung cancer: A phase III trial of the Cancer and Leukemia group B and the Eastern Cooperative Oncology Group. J Clin Oncol 17:4-11, 1999[Abstract/Free Full Text]

3. Blackstock AW, Socinski MA, Bogart J, et al: Induction (Ind) plus concurrent (Con) chemotherapy with high-dose (74 Gy) 3-dimensional (3D) thoracic radiotherapy (TRT) in stage III non-small cell lung cancer (NSCLC): Preliminary report of Cancer and Leukemia Group B (CALGB) 30105. Proc Am Soc Clin Oncol 24:18S, 2006 (suppl; abstr 7042)

4. Vokes EE, Herndon JE, Kelley MJ, et al: Induction chemotherapy followed by concurrent chemoradiotherapy (CT/XRT) versus CT/XRT alone for regionally advanced unresectable non-small cell lung cancer (NSCLC): Initial analysis of a randomized phase III trial. Proc Am Soc Clin Oncol 22:14S, 2004 (suppl; abstr 7005)

5. Belani CP, Wang W, Johnson DH, et al: Phase III study of the Eastern Cooperative Oncology Group (ECOG 2597): induction chemotherapy followed by either standard thoracic radiotherapy or hyperfractionated accelerated radiotherapy for patients with unresectable stage IIIA and B non-small-cell lung cancer. J Clin Oncol 23:3760-3767, 2005[Abstract/Free Full Text]

6. El Sharouni SY, Kal HB, Battermann JJ: Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy. Br J Cancer 89:2184-2189, 2003[CrossRef][Medline]

7. Rolland E, Le Pechoux C, Curran WJ, et al: Concomitant radio-chemotherapy (CT-RT) versus sequential CT-RT in locally advanced non-small-cell lung cancer (NSCLC): A meta analysis using individual patient data (IPD) from randomized clinical trials (RCTs). Int J Radiat Oncol Biol Phys 69:S5, 2007 (suppl; abstr 9)

8. Schaake-Koning C, van der Bogaert W, Dalesio O, et al: Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326:524-530, 1992[Abstract]

9. Jeremic B, Shibamoto Y, Acimovic LJ, et al: Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer : A randomized study. J Clin Oncol 14:1065-1070, 1996[Abstract/Free Full Text]

10. Jeremic B, Shibamoto Y, Acimovic LJ, et al: Hyperfractionated radiation therapy and concurrent low-dose, daily carboplatin/etoposide with or without week-end carboplatin/etoposide chemotherapy in stage III non-small-cell lung cancer: A randomized trial. Int J Radiat Oncol Biol Phys 50:19-25, 2001[CrossRef][Medline]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jeremic, B. Articles by Koning, C. Search for Related Content PubMed PubMed Citation Articles by Jeremic, B. Articles by Koning, C.