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• W2019903563 abstract "This phrase “The Best-Laid Plans … Often go Awry …” is adapted from a line in the poetry of Robert Burns—“To a Mouse.” Here, it seems apropos as we consider the work by Arrieta et al.1Arrieta O Gallardo-Rincón D Villarreal-Garza C et al.High frequency of radiation pneumonitis in patients with locally advanced non-small-cell lung cancer treated with concurrent radiotherapy and gemcitabine after induction with gemcitabine and carboplatin.J Thorac Oncol. 2009; 4: 845-852Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Alas, our ability in the last decade to improvise better therapies for patients with inoperable stage III non-small cell lung cancer, has been limited. Here, the investigators attempt to combine a potent radiation sensitizer, gemcitabine, with a definitive course of thoracic radiation. In doing so, the authors observed an encouraging overall response rate of 68% and a provocative median survival of 21 months. Although this study is limited to 19 patients, the results would suggest this combination may have activity. Unfortunately, the authors report that 32% of patients experienced a grade 3 to 5 pulmonary toxicity. Although we can debate what is an acceptable level of toxicity–in a cohort of patients with a very limited possibility of cure, what we must accept is the very narrow therapeutic ratio when combining gemcitabine and a course of definitive thoracic radiation. As reflected in Figure 1, with the addition of a radiation sensitizer, we hope to increase the tumor-control rate using the same or lower dose of radiation (shifting the green curve to the left). This has to be balanced with monitoring the risk of a normal tissue injury (not shifting the blue curve to the left). A number of clinical trials, including the work from Arrieta et al., would suggest that the radiation sensitization is not selective and both curves are being shifted to the left. For gemcitabine in particular, achieving an acceptable therapeutic ratio has been more than challenging. In the first reported study of concurrent gemcitabine and thoracic radiation, the trial was terminated early after the first eight patients were accrued.2Scalliet P Goor C Galdermans D et al.Gemzar (Gemcitabine) with thoracic radiotherapy-A phase II pilot study in chemonaive patients with advanced non small cell lung cancer (NSCLC).Proc Am Soc Clin Oncol. 1998; 17 (Abstract 1923)Google Scholar Although Scalliet et al. observed an 88% response rate, this study also determined a 75% grade 3 to 4 pneumonitis rate with 38% patients succumbing to treatment related toxicities. One concern was that full-dose (1000 mg/m2) gemcitabine weekly was administered with the 60 Gy of thoracic radiation. Several experiences used moderated doses of gemcitabine and still the concern for toxicity remains. With preclinical data indicating that gemcitabine possessed radiation sensitizing properties at much lower doses, Blackstock et al.3Blackstock AW Ho C Butler J et al.Phase Ia/Ib chemo-radiation trial of gemcitabine and dose-escalated thoracic radiation in patients with stage III A/B non-small cell lung cancer.J Thorac Oncol. 2006; 1: 434-440Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar completed a phase Ia/Ib study of twice-weekly gemcitabine given at a dose of 10 to 50 mg/m2 with 66 to 74 Gy thoracic radiation. Again, an impressive 88% response rate was observed in the 39 patients accrued, but grade 3–4 pneumonitis was seen 24% of the patients treated. The first Cancer and Leukemia Group B (CALGB 9431) study evaluating thoracic radiation and concurrent gemcitabine, used a dosing scheduled that delivered 350 mg/m2 given on days 1 and 8 every 21 days–not weekly.4Vokes EE Herndon II, JE Crawford J et al.Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: cancer and leukemia group B study 9431.J Clin Oncol. 2002; 20: 4191-4198Crossref PubMed Scopus (345) Google Scholar The grade III/IV pneumonitis rate was an acceptable 14%. This moderate pulmonary toxicity may have to do with the gemcitabine being dosed only 3 to 4 times during the thoracic radiation. However, the 74% response rate and 18.3 month median survival while encouraging were not interesting enough for further study. In a subsequent CALGB trial (30105), in which the radiation volumes were prospectively mandated, 37% of patients receiving concurrent twice-weekly gemcitabine and thoracic radiation experienced a grade 3 to 5 pulmonary event.5Socinski MA Blackstock AW Bogart JA et al.Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105.J Clin Oncol. 2008; 26: 2457-2463Crossref PubMed Scopus (155) Google Scholar This arm of the randomized phase II study was terminated early because of unexpected toxicity. It should be noted that the V20 (percent of normal lung receiving greater than 20 Gy) for 2 patients experiencing grade 5 pulmonary events exceeded 40%; a lung volume that would be considered excessive by most radiation oncologists. Data from Zinner et al.6Zinner RG Komaki R Cox JD et al.Dose escalation of gemcitabine is possible with concurrent chest three-dimensional rather than two-dimensional radiotherapy: a phase I trial in patients with stage III non-small-cell lung cancer.Int J Radiat Oncol Biol Phys. 2009; 73: 119-127Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar would support the importance of the radiation volumes used with gemcitabine. In this phase I study, the investigators were unable to dose escalate the gemcitabine until 3-dimensional treatment volumes were mandated. The Arrietta manuscript does not provide the details of the thoracic radiation, but one would speculate a relationship between the normal lung irradiated (V20) and the observed unacceptable pulmonary toxicity. It must be noted that several trials evaluating this combination of gemcitabine and thoracic radiation have consistently reported high response rates but with significant nonhematologic toxicities that were not pulmonary.7Choy H Jain AK Moughan J et al.RTOG 0017: a phase I trial of concurrent gemcitabine/carboplatin or gemcitabine/paclitaxel and radiation therapy (“ping-pong trial”) followed by adjuvant chemotherapy for patients with favorable prognosis inoperable stage IIIA/B non-small cell lung cancer.J Thorac Oncol. 2009; 4: 80-86Crossref PubMed Scopus (17) Google Scholar, 8Zwitter M Kovac V Smrdel U Strojan P Gemcitabine, cisplatin, and hyperfractionated accelerated radiotherapy for locally advanced non-small cell lung cancer.J Thorac Oncol. 2006; 1: 662-666Abstract Full Text Full Text PDF PubMed Google Scholar These manuscripts, however, do not provide a great deal of detail about the delivery of the radiation in terms of treatment volumes and V20 restrictions. It seems reasonable that “culpability” for the narrow therapeutic window of gemcitabine is in part, that the threshold for toxicity is sensitive to the volume of normal lung treated. In retrospect, perhaps we should have anticipated this strategy had the potential to “go awry” from the preclinical studies. The radiation sensitizing properties of gemcitabine have been well described with a number of mechanisms proposed.9Lawrence TS Chang EY Hahn TM Hertel LW Shewach DS Radiosensitization of pancreatic cancer cells by 2′,2′-difluoro-2′-deoxycytidine.Int J Radiat Oncol Biol Phys. 1996; 34: 867-872Abstract Full Text PDF PubMed Scopus (291) Google Scholar, 10Blackstock AW Lightfoot H Case LD et al.Tumor uptake and elimination of 2′,2′-difluoro-2′-deoxycytidine (gemcitabine) after deoxycytidine kinase gene transfer: correlation with in vivo tumor response.Clin Cancer Res. 2001; 7: 3263-3268PubMed Google Scholar With data from Fields et al.11Fields MT Eisbruch A Normolle D et al.Radiosensitization produced in vivo by once- vs. twice-weekly 2′2′-difluoro-2′-deoxycytidine (gemcitabine).Int J Radiat Oncol Biol Phys. 2000; 47: 785-791Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar suggesting a lower dose given more frequently provides superior radiation sensitization. However, Mason et al.12Mason KA Milas L Hunter NR et al.Maximizing therapeutic gain with gemcitabine and fractionated radiation.Int J Radiat Oncol Biol Phys. 1999; 44: 1125-1135Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar in a jejunal mucosal animal model was able to demonstrate that gemcitabine delivered with radiation to normal tissues resulted in a disadvantageous shift in the therapeutic ratio, more normal tissue injury with the combination. In conclusion, Arrieta et al. provide additional data indicating gemcitabine delivered concurrent with a course of definitive thoracic radiation is an active regimen for patients with stage III non-small cell lung cancer. But these results and this discussion should remind us that some chemotherapeutic agents are less forgiving than others as they relate to normal tissue toxicity. Furthermore, current studies combining biologics, such as the epidermal growth factor receptor inhibitors, to standard chemoradiation strategies should be carefully evaluated, in terms of a potential reversal of the radiation sensitization properties of the conventional chemotherapeutics or for potential unanticipated toxicities. Moving forward, all clinical trials combining radiation with radiation sensitizing agents, should mandate detailed radiation planning parameters and reporting. This represents our only opportunity for developing the “best laid plans.”" @default.
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