Evaluation of Efficacy and Tolerance of Radical Radiotherapy and Radiochemotherapy in Treatment of Locally Advanced, Unresectable Rectal Cancer.

Background: A retrospective evaluation of tolerance and efficacy of two schemes of neoadjuvant treatment in patients (pts) with unresectable rectal cancer: radiochemotherapy (CRT) and radiotherapy (RT), including conventional and accelerated hyperfractionation. Material and Method: A total of 145 consecutive pts with unresectable, locally advanced rectal cancer. The schemes used are RT in 73 (50%) or CRT in 72 (50%). In CRT, 54 Gy in 1.8 Gy fractions was given with chemotherapy, In the RT group, conventional fractionation (CFRT) and hyperfractionated accelerated radiotherapy (HART). HART was introduced at first as an alternative to CFRT, after radiobiological studies suggesting a therapeutic gain of hyperfractionation in other cancers, and second to administer relatively high dose needed in unresectable cancer, which is not feasible in hypofractionation because of critical organs sensitivity to high fraction doses (fd). HART was an alternative option in pts with medical contraindications to chemotherapy and to shorten overall treatment time with greater radiobiological effectiveness than CFRT. Results: Objective response (OR) in the RT and CRT group was 60% versus 75%. Resection rate (RR) in RT and CRT: 37% versus 65%. Tumor mobility and laparotomy-based unresectability were significant factors for OR. Performance status (PS), tumor mobility, and neoadjuvant treatment method were significant for RR.

Long-course preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study.

BACKGROUND: This trial evaluated whether preoperative short-course radiotherapy and consolidation chemotherapy (CCT) were superior to chemoradiation in rectal cancers with clinical (c)T4 or fixed cT3. Previously, we reported early results showing no differences in the radical surgery rate (primary end point). In the short-course/CCT group, we observed lower acute toxicity of preoperative treatment and better overall survival (OS). We updated results to determine whether the benefit in OS was sustained and to evaluate late complications. PATIENTS AND METHODS: Patients with cT4 or fixed cT3 rectal cancer were randomized either to preoperative 5 × 5 Gy and three cycles of FOLFOX4 or to chemoradiation (50.4 Gy with bolus 5-Fu, leucovorin and oxaliplatin). RESULTS: Patients (N = 515) were eligible for analysis, 261 in the short-course/CCT group and 254 in the chemoradiation group. The median follow-up was 7.0 years. The difference in OS was insignificant [hazard ratio (HR) 0.90; 95% confidence interval (CI) 0.70-1.15; P = 0.38). However, the difference in early OS favouring short-course/CCT previously reported was observed again, being 9% at 3 years (95% CI 0.5% to 17%). This difference disappeared later; at 8 years OS was 49% in both groups. There was no difference in disease-free survival (HR 0.95; 95% CI 0.75-1.19; P = 0.65) at 8 years 43% versus 41% in the short-course/CCT group versus the chemoradiation group, respectively. The corresponding values for cumulative incidences of local failure and distant metastases did not differ and were HR = 1.08, 95% CI 0.70-1.23, P = 0.60, 35% versus 32% and HR = 1.10, 95% CI 0.68-1.23, P = 0.54, 36% versus 34%, respectively. The rate of late complications was similar (P = 0.66), grade 3+ being 11% versus 9% in the short-course/CCT group versus the chemoradiation group, respectively. CONCLUSION: The superiority of preoperative short-course/CCT over chemoradiation was not demonstrated. CLINICAL TRIAL NUMBER: The trial is registered as ClinicalTrials.gov number NCT00833131.

Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients.

BACKGROUND: PPM1D (WIP1) negatively regulates by dephosphorylation many proteins including p53 tumour suppressor. The truncating mutations (nonsense and frameshift) in exon 6 of PPM1D were found recently in blood cells of patients with breast, ovarian or colorectal cancer. These mutants code for gain-of-function PPM1D with retained phosphatase activity. Their significance in carcinogenesis is unknown. METHODS: The exon 6 of PPM1D was sequenced in blood DNA of 543 non-small-cell lung cancer patients (NSCLC). The functional significance of selected PPM1D alterations (Arg458X, Lys469Glu) was compared with the wild-type gene and examined by recombinant DNA techniques, immunoblotting and luciferase reporter assays. RESULTS: The frameshift mutations were found in five NSCLC patients (5/543; 0.92%), all of them had squamous cell carcinomas (5/328; 1.5%). All patients with the mutations were exposed, before the blood collection, to the DNA damaging agents as a part of chemotherapeutic regimen. Functional tests demonstrated that truncating mutation Arg458X causes enhancement of dephosphorylation activity of PPM1D toward serine 15 of p53, whereas Lys469Glu version is equivalent to the wild-type. Neither version of PPM1D (wild-type, Arg458X, Lys469Glu) significantly modulated the ability of p53 to transactivate promoters of the examined p53-target genes (BAX and MDM2). CONCLUSIONS: The truncating mutations of PPM1D are present in blood DNA of NSCLC patients at frequency similar to percentage determined for ovarian cancer patients. Our findings raise a question if the detected lesions are a result of chemotherapy.

Stereotactic radiotherapy (SBRT) as a sole or salvage therapy in non-small cell lung cancer patients.

The aim of this study is to present evaluation of treatment toxicity and the rate of local control in non-small cell lung cancer patients (NSCLC) treated with stereotactic body radiotherapy (SBRT). The analysis was performed on heterogenous group of 61 NSCLC patients, treated with SBRT between 2005 and 2008. It included 26 patients in clinical stage I, 5 in stage II, 22 in III and 8 in stage IV. In 30 patients SBRT was the only treatment, in 20 patients SBRT was a salvage therapy and in 11 patients SBRT was used as a boost after conventionally fractionated radiotherapy (CRT). The mean age was 67 yrs. Fifteen patients received chemotherapy in the course of treatment. Radiation doses were converted into Linear Quadratic Equivalent Dose at 2Gy per fraction (LQED2). The survival curves were plotted using Kaplan-Maier estimator and analyzed using log-rank test and Cox method. The LQED2 doses administered in stereotactic technique ranged from 8 Gy to 150 Gy and the fraction doses from 5 Gy to 24 Gy. The rate of 2 years local control correlated with LQED2: it was 81% in a group of patients who received over 110 Gy, compared to 51% and 33% in a group of patients who received 60-110 Gy and less than 30 Gy respectively. Prior radiotherapy and advanced clinical stage correlated with lower doses at SBRT and hence lower rate of local control. The tolerance of SBRT was satisfactory: there was no RTOG grade 3 - 4 toxicity. The results are consistent with findings of other authors and indicate that LQED2 doses delivered by SBRT in the treatment of NSCLC should be higher than 110 Gy whenever clinically feasible. SBRT used as a salvage therapy was less effective, because use of high doses was precluded due to consideration of normal tissue tolerance.

Time factor and treatment strategies in subclinical disease.

Rational biological development of treatment strategies for subclinical metastases has lagged behind such efforts with primary cancers: most adjuvant therapies for subclinical disease have been developed empirically, based on clinical observation. This paper reviews recent studies that point to rapid growth of subclinical disease. The effect of rapid growth of occult metastases and undetectable extensions of primary cancer is to increase the radiation dose necessary for their elimination if treatment duration is extended. This increase may be evident even when changes are made to short courses of treatment, consistent with no lag time between the start of treatment and rapid growth or regrowth of subclinical tumour deposits. This provides a strong rationale for avoiding gaps or delays in adjuvant treatments and suggest that accelerated regimens of radiation or chemoradiation may be advantageous in the treatment of subclinical disease provided that the total dose can be maintained or not greatly reduced from those used conventionally. Conversely, an escalation of total dose with a concomitant increase in overall treatment duration may not result in improved control rates because the rapid growth of small clonogen deposits might counterbalance the effect of the higher dose.

Estimation for paired binomial data with application to radiation therapy.

We compare and contrast several different methods for estimating the effect of treatment when responses are paired binomial observations. The ratio of binomial probabilities is the parameter of interest, while the binomial probabilities are nuisance parameters which may vary between pairs. The application is a meta-analysis of the treatment of rectal cancer, with observations in each study indicating the number of recurrences of the cancer in each of two groups, one with radiation therapy and one without. The ratio of the probabilities of recurrence in the radiation to non-radiation groups is of substantive interest, and is modelled as a logistic or complementary log-log function of an unknown linear combination of the covariates. The three methods we consider are maximum likelihood, a Bayesian approach and an approach based on estimating equations. For the MLE and Bayesian approach the potentially large number of nuisance parameters are estimated together with the parameters of interest, whereas for the estimating equation approach only the parameters of interest are estimated. A simulation study is performed to compare the methods and evaluate the impact of overdispersion.

[Radiobiologic basis for using 131I to treat patients with thyroid cancer]. / Radiobiologiczne podstawy leczenia jodem promieniotwórczym 131I chorych na raka tarczycy.

The basic biological principle for 131I treatment of patients with thyroid cancer is the ability of well-differentiated tumor cells to uptake iodine. The absorption of adequate activities of radioiodine may sterilize primary tumor cells and the metastatic deposits. The basic factors which determine the effectiveness of radioiodine treatment include the effective half-life of 131I, the discrete energy of its beta decay, the effective range of emitted beta-rays, the activity of individual therapeutic doses, the intrinsic ability of tumor to uptake radioiodine, and the absorbed total radiation dose. The biological factors, which contribute to the effectiveness of radioiodine treatment, can be referred to "five Rs" of radiobiology: radiosensitivity, repair, redistribution, reoxygenation, and repopulation. The theoretical radiobiological considerations suggest that improvements in therapeutic indexes of radioiodine treatment are possible, e.g. by unconventional fractionation of 131I, or by combining the radionuclide therapy with external-beam irradiation. The net effect of such strategies in the clinic is, however, often unpredictable, and remains investigational and controversial. This illustrates the need for improved design of new research in clinical and experimental radiobiology of radioiodine treatment.

Tumor volume and growth kinetics in hypothalamic-chiasmatic pediatric low grade gliomas.

Pediatric low grade gliomas evidence a tendency towards quiescent growth, thus complicating the clinical management of nonresected tumors whose clinical behavior may be difficult to predict. We decided to explore the hypothesis of possible correlation in pediatric low grade glioma between tumor volume and growth rate. We identified 6 children with hypothalamic chiasmatic lesions. Five of these patients were treated only with biopsy and 1 with repeated partial tumor resection. All of 6 patients had 10-15 sequential brain MRI over a time span of 3-8 years. Tumor volume was determined using Sigma Scan Image software. The results were analyzed utilizing two equations for modeling tumor growth: exponential and Gompertz. In 4 patients whose tumor volume was approximately 80-100 cm(3) at the time of diagnosis, slow spontaneous partial regression was observed. In the other patients deceleratory or exponential tumor growth was volume-dependent. Our results suggest that growth of pediatric low grade glioma decelerates as tumor becomes large and that the Gompertz model for tumor growth is useful for understanding the growth kinetics of pediatric low grade glioma.

The effect of heterogeneity in tumor cell kinetics on radiation dose-response. An exploratory investigation of a plateau effect.

PURPOSE: To investigate the effect of heterogeneity in tumor cell kinetics on radiation dose-response curves for a population of patients. MATERIALS AND METHODS: A series of exploratory calculations have been performed using an improved geometric-stochastic model of tumor cure. RESULTS: Radiation therapy dose-response curves may plateau, or nearly so, at tumor control levels well below 100%, if a proportion of tumors would grow sufficiently fast to counterbalance the effect of fractionated radiotherapy. If the model assumptions of doubling time heterogeneity are correct, the difference between a short and protracted radiation regimen would be not only in the position and steepness of the radiation dose-response curve, but also in the level of the predicted plateau. CONCLUSIONS: For a given rate of dose accumulation, the one-sided flattening in dose-response curves at high doses is predicted from the modeling, and determined by the proportion of most radioresistant and rapidly growing tumors. This shows that empirical models of tumor control probability which assume a symmetric sigmoid relationship from 0 to 100% have apparent limitations, seemingly not well acknowledged in the literature.

Rapid growth of microscopic rectal cancer as a determinant of response to preoperative radiation therapy.

PURPOSE: To quantify the dose-time fractionation factors in preoperative radiation therapy for microscopic pelvic deposits of rectal cancer. This provides a biologic basis for understanding and improving the results of adjuvant therapies for this disease. METHODS: The reduction in incidence of pelvic relapses as a function of radiation dose and overall treatment time was determined from the literature. The displacement of dose-response curves to higher doses reflects the growth during radiation treatment of subclinical pelvic deposits which are beyond the future surgical margins. RESULTS: Dose-response curves are steep if the effect of overall duration of radiation therapy is accounted for. The time-related displacement of these steep dose-response curves is consistent with a median doubling time for malignant clonogenic cells of about 4 or 5 days, much faster than the growth rate of the average primary tumor at diagnosis. This rapid growth is evident within the first few days of irradiation, implying that the natural growth rate of these microscopic deposits if fast, and/or that an acceleration of growth follows initiation of radiation injury with a very short lag time. CONCLUSION: Subclinical pelvic deposits of rectal cancer grow rapidly during preoperative radiation therapy with an adverse influence on the rate of pelvic tumor control from protracting the duration of adjuvant treatment. Low doses only offer clinically relevant reduction in risk of pelvic relapses if the overall radiation treatment time is short. For a given overall treatment duration there is a relatively steep dose-response curve, predicting that significant improvements in tumor control are possible.

Dose-response relationship for elective neck irradiation of head and neck cancer--facts and controversies.

The aim of this study is to assign dose-response relationship for subclinical neck metastases of squamous cell head and neck cancer based on extensive survey of 24 data sets collected from the literature. Neck relapse rates (NRR) without and after elective (ENI) or preoperative irradiation were estimated for each site and stage of primary tumor and the reduction in neck relapse rate was calculated. An average NRR without ENI was 22% (12-35%) and only 2.5% (0-10%) after the ENI with total dose of 46-50 Gy which gives high reduction rate in the risk of neck recurrences being on the average 89% and 42% (0-46%) after preoperative irradiation using 22-30 Gy. Dose response curve for elective and preoperative irradiation have shown that 50 Gy in 2 Gy fraction reduces the incidence of neck relapses in the N0 patients by more than 90% and only by less than 50% after total doses lower than 30 Gy. No correlation between the risk of neck metastases without ENI and the reduction in neck relapses after ENI was found.

Radiation dose response for subclinical metastases.

The development of adjuvant therapies for subclinical metastases has been empiric. Decades of experience showed that 45 to 50 Gy resulted in high control rates for subclinical lymph node involvement.1 By analogy with the response of macroscopic tumors, in which doses below a threshold yield no benefit, it was commonly believed that doses lower than 40 to 50 Gy would not be useful in elective treatment of subclinical disease. Biological phenomena, such as presumed metastatic tumor cell burden and growth rate of micrometastases, which could guide the oncologist, had little or no role in the empirical development of adjuvant cytotoxic therapies. In this article, some assumptions regarding the biology of subclinical metastases are discussed and examined in the light of treatment responses reported from clinical experience. In particular, the importance of early initiation of adjuvant therapy can be appreciated as well as the significant reductions in the incidence of metastases that can be achieved even when doses less than 45 to 50 Gy have to be accepted if necessitated by normal tissue tolerance.

Dose-response relationship for prophylactic cranial irradiation in small cell lung cancer.

PURPOSE: To determine the dose-response relationship for prophylactic cranial irradiation (PCI) in small cell lung cancer, to quantify the growth kinetics of subclinical metastases, and to determine the influence of time-delay in initiating PCI on its utility. METHODS AND MATERIALS: Published reports of brain relapse rates in small cell lung cancer with and without PCI were collected. The reduction in brain relapse rate as a function of radiation dose was analyzed. The time interval between treatment of the primary tumor and the initiation of PCI was analyzed as a factor potentially influencing dose-response. RESULTS: A shallow dose-response curve without any threshold in the dose intercept was demonstrated for control of subclinical brain metastases in "early PCI" (delay between initiation of treatment for primary tumor and PCI less than 60 days). By contrast "late PCI" (delay over 60 days) was associated with a significant displacement of the dose intercept. Doses over 30-35 Gy in 2-Gy fractions did not result in a further reduction in brain relapse rate, but there were too few high-dose studies to draw any definite conclusion. CONCLUSIONS: The nearly linear dose-response relationship for reduction in brain relapses demonstrated for "early PCI" in the range of doses from zero up to 35 Gy given in 2-Gy fractions supports the model of a fairly logarithmically uniform distribution of metastatic cell number within a series of patients. When PCI is delayed, a significant threshold in dose-response was observed, consistent with a fast growth rate of untreated subclinical brain metastases from small cell lung cancer. The exact shape and locations of dose-response curves is not well established by this retrospective analysis of diverse data. A high probability of eliminating brain relapses following PCI requires a dose of about 30-35 Gy in 2-Gy fractions. Control rates in brain can be enhanced if PCI is applied early.

Randomized clinical trial on accelerated 7 days per week fractionation in radiotherapy for head and neck cancer. Preliminary report on acute toxicity.

PURPOSE: Toxicity of an accelerated 7 days per week fractionation schedule (arm A) was evaluated and compared with a conventional 5 days per week treatment (arm B) in a randomized trial. MATERIALS AND METHODS: Forty-four patients with squamous cell carcinoma of the head and neck in stage T2-4Nzero-1Mzero were included in the study. Total dose and dose per fraction of 2.0 Gy given once-a-day at 24 h intervals were the same in both arms of the trial. The only difference was the overall treatment time being 5 weeks in arm A and 7 weeks in arm B. RESULTS: Analysis of severe mucosal reactions shows significant difference between arm A and B, with regard to both maximum score and duration of severe mucositis. Confluent mucositis (score > 15 according to the Dische system) lasting longer than 3 weeks developed in 48% of patients in arm A and only in 5% in arm B. In group A seven (30%) late effects (osteo- and soft tissue necrosis) occurred during 7-12 month follow-up with two reactions (10%) in group B being suspected as late effects. There was significant association between acute reactions and late effects in arm A, suggesting that the late effects are consequential. CONCLUSION: The high incidence of severe acute reactions and consequential late effects suggests that the accelerated treatment in arm A (using daily fractions of 2.0 Gy, 7 days per week) gives unacceptable toxicity.

Sequential combination of radio-chemotherapy (5-fluorouracil, cis-platinum and irradiation) in the management of locally advanced head and neck cancers.

Thirty-seven previously untreated patients with advanced, inoperable head and neck were treated with a sequential courses combining hypofractionated irradiation with chemotherapy (5-fluorouracil and cis-platinum). Each course was repeated every 4 weeks. Tumor response was evaluated and for 15 patients (41%) with a partial or complete regression after 3 radio-chemotherapy courses conventional radiotherapy was added. Eleven percent of all patients were in complete remission at the end of a treatment. This tumor response rate and the 50% rate of pain subside after first course for symptomatic patients contributed for a good palliative effect in the present study. However, the median survival of 7.2 months was considered unsatisfactory.