Inl J Radialron Oncology RIO/ Phv Vol. 24, pp. I-2 Pnnted I” the U.S.A. All rights reserved
0360.3016192 $5.00 t Oil Copyright = 1992 Pergamon Press Ltd.
EDITOR’S NOTE Thesis and antithesis-these are the sounds of the dominant themes of this issue’s reports dealing with the challenges presented by lung cancer management. The lead article by Dosoretz, Katin, Blitzer et al. presents a positive result for modern radiation oncology utilizing current linear accelerators and computerized treatment planning in early localized stages and explodes the myth that irradiation alone cannot control this disease. In one of the largest series of medically inoperable lung cancer patients with technically operable stages, the authors advocate definitive radiation treatment alone (65 Gy median dose) which proved to yield results comparable to surgical series. That is, for tumors < 3 cm, the 3-year survival is 59% and for larger lesions 3-6 cm, it was 49%. Unfortunately, no survivors were found for tumors exceeding 6 cm in diameter. For the T 1 category, the probability of long-term survival remains at 60% although local failure is still high at 30%. Evidence of a dose effect is demonstrated by 10 Gy increments ranging from 50-70 Gy with higher doses yielding the best results. In his editorial, Haffty explores the real issue-“Can lung cancer be cured by irradiation alone?’ By contrast, a disappointing result for advanced intrathoracic lung cancers was found in a randomized trial of the North Eastern Italian Oncology Group reported by Trov6, Minatel, Franchin ef al. combining daily low dose CisPT (6 mgm/M2) and irradiation (45 Gy/15 fractions/3 weeks) versus irradiation alone in terms of response rates, progression sites and survival. The use of CisPt as a radiosensitizer remains promising but the search for an optimum scheduling remains and needs to be directed by radiobiological and/or pharmacological bases. Slight improvement in local control was shown for the combined CisPt and RT when compared to irradiation alone, but Komaki in her editorial notes the radiotherapy regimen was suboptimal and gains were modest; randomized clinical trials are required to detect any future advances. Utilizing chemoradiation (5-FU + CisPt ? VP16) in preoperative Phase 11lung cancer trials, Reddy, Lee, Bonomi et al. sought to improve resectability and hopefully long-term control in Stage III patients. Although no firm conclusions can be drawn when resected specimens were examined for residual disease, 76% were recurrence-free at 3 years when no cancer was found compared to 34% when gross disease persisted. Despite 75% resectability, local failure occurred in the majority of patients. Also in this issue are a series of lung cancer reports from University of Penn investigators dealing with adverse circumstances or prognostic factors. The topic of managing post-resection loco-regional recurrence in NSC lung cancer is addressed by Curran, Herbert, Stafford ei al. comparing 37 patients with 759 unresected Stage III cancers, newly diagnosed. Surprisingly, the median survival time of 12 months, the 2 year actuarial survival of 22-26% and freedom from local regional tumor progression at 2 years of 30%, was virtually identical for both groups. As known, bronchial stump failures do better than nodal or chest wall failures with a median survival of 36 versus 9 months, respectively. In another offering, Curran, Moldofsky, and Solin show a predictive value of perfusion lung scans in both resectable and non-operable patients to estimate the degree of subsequent pulmonary function due to surgical resection or lung irradiation. Fortunately, only the minority of patients decline in pulmonary function6-10%. The adverse influence of age is shown by Herbert, Curran, Rosenthal ei al. when comparing those < 50 years to > 50 years, i.e., median survival of 7.8 months versus 12.4 months and attributed to more poorly differentiated cancers and greater metastatic potential, particularly to the brain. One of the most controversial subjects in oncology is the value of prophylactic brain irradiation often associated with chemotherapy in lung cancer, ALL and in malignant gliomas-both from the view of micro-tumor eradication and complications. The value of prophylactic cranial irradiation (PCI) in small cell lung cancer is the subject that forms the basis of retrospective review of two consecutive series as reported by Kosenstein, Armstrong, Kris et al. who argue that the usefulness of PC1 would be best demonstrated in patients with local control of chest disease who remain free of thoracic failure. Their subset analysis in matched pairs, one with PC1 (+) and one without PC1 (-), strongly suggests PC1 (+) does reduce brain failures and adds to survival. The brain failures were 20% of PC1 (+) versus 58% of PC1 (-) and survival at 2 years was 42% of PC1 (+) versus 13% for PC1 (-). Clearly, clinical trials are required to see if this gain is real. Unfortunately, 3/6 or 50% of the 5-year survivors had neurotoxicity expressed as short term memory deficit, ataxia, dementia and optic nerve atrophy. In an
I. J. Radiation
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interesting communication from Spain, Giralt, Ortega, Olive et al. assessed the long-term neyropsychologic sequelae of childhood leukemia treatment in comparing two CNS prophylactic regimens, i.e., PC1 (24 Gy) and intrathecal methotrexate (i.t. MTX) versus Ara-C and i.t. MTX. Both forms of therapy-irradiation (PCI) and chemotherapy (Ara-C&lead to statistically significant differences in IQ and other cognitive functions when added to i.t. MTX, particularly before 5-years of age when compared to siblings and other solid tumor patients. By contrast. in the Phase I/II study section, Bouffet, Bernard, Frappaz et al. warn that avoiding prophylactic supratentorial irradiation in newly diagnosed medulloblastomas is ill-advised. Only 3/ 16 patients ( 18%) are alive and 69% failed supratentorially. A variety of interesting subjects can be found in this issue related to accelerated radiotherapy. Svoboda, Krawczyk, and Krawczyk utilized a variety of fractionation regimens and dose/time factors and found total dose was more important than overall time in treating breast cancer. Tumor cell kinetics and accelerated schedules (CHART) are analyzed by Lochrin, Wilson, McNally et al. using BrdUdR in 90% of their head and neck squamous cell carcinoma patients. No significant influence of any cell kinetics parameters measured correlated with immediate or longer term local control but their data are still compatible with overcoming cellular repopulation by acceleration of radiotherapy. In the hyperthermia section, Emami, Myerson, Cardenes et al. found no difference between once a week and twice a week heatings in a study of 240 superficially located recurrent/metastatic malignant lesions, i.e., complete response rate was 54.7% versus 57.8%. Two brief communications worth noting and reading are the subject of gonadal tumors-seminomas in cryptorchid testes (Gauwitz and Zagars) and advanced dysgerminomas (Zaghoul and Khattab). My final comment relates to the recent research efforts unraveling the molecular biology mechanisms in radiation induced late effects. Rubin, Finklestein and Shapiro have uncovered the immediate early release of trophic factors and an elaborate intercellular communication between cells both in viva and in vitro to explain the fibrogenic process. Autocrine and paracrine effects among the alveolar macrophage, the fibroblast, the type II pneumocyte and the endothelial cell are being studied. The concept of target cell is being supplemented by the multicellular nature of late injury expression. In their editorial, Fuks and Weichselbaum offer their perspective on radiation tolerance and the new biology of growth factor expression. They intriguingly note that the pattern of response seems to be specific for ionizing radiation, as its manifestations and kinetics are apparently distinct from other stress responses such as heat shock, hypoxia or alklation and further suggest that active intervention in specific pathways of such processes may favorably alter therapeutic ratios of tumor versus normal tissues. Phillip Rubin, M.D.