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.

Molecular pathways that modify tumor radiation response.

Aberrant expression of signal transduction molecules in pathways controlling cell survival, proliferation, death, or differentiation are a common feature of all tumors. The identification of the molecules that are involved allows the development of novel tumor-specific strategies. Not surprisingly, targeting these pathways often also results in radiosensitization. The efficacy of such directed therapies may, however, be limited by the heterogeneity and the multiple mutations that are associated with the cancerous state. A more robust alternative may be to target global mechanisms of cellular control. The ubiquitin/proteasome degradation pathway is one candidate for such therapeutic intervention. This pathway is the main posttranscriptional mechanism that controls levels of many short-lived proteins involved in regulation of cell cycle progression, DNA transcription, DNA repair, and apoptosis. Many of these proteins are involved in various malignancies and/or radiation responses. In recent years, proteasome inhibitors have gained interest as a promising new group of antitumor drugs. PS-341, a reversible inhibitor of proteasome chymotryptic activity, is currently being tested in phase I clinical trials. In this study, we show that proteasome inhibition by PS-341 can alter cellular radiosensitivity in vitro and in vivo, in addition to having direct antitumor effects.

Biological aspects of conformal therapy.

Both conformal and intensity-modulated radiation therapy have great potential to further increase tumor control rates and decrease morbidity. A homogeneous escalation of 'biological' dose within a tumor should increase the likelihood of local cure, especially within the mid-range (e.g. 15% to 80%) of tumor control rates, and conversely, a lower control rate should follow a homogeneously reduced dose. However, when the dose to critical normal tissues is tightly constrained, the dose distributions within the treatment volume may necessarily be heterogeneous, and the effect on tumor control probability will depend upon the magnitude of over- or underdosage, and on the proportions of the tumor clonogen population receiving higher or lower than the nominal dose. Dose-volume histograms provide a measure of heterogeneity of dose within the planned treatment volume, but tumor control probability is also influenced by other variables, e.g. inherent tumor clonogen radiosensitivity and growth rates during a course of treatment, alpha/beta ratios, oxygenation and clonogen density throughout the target volume. Heterogeneity in these factors introduces heterogeneity in tumor responses and a less steep change in tumor control probability with change in dose, reducing the gains or losses that would be predicted to result from heterogeneity of dose. Similarly, modeling the effect of inhomogeneous dose distributions on estimates of probability of complications in normal tissues is hindered by uncertainty of estimates for alpha/beta ratios, especially for late-responding tissues, and lack of data on volume effects. Although the effects of dose inhomogeneity cannot be presented with sufficiently reliable quantitation to be directly applicable to dose prescriptions in radiation therapy, the relative influences of heterogeneities in dose and volume can be modeled to provide a framework for clinical decision-making. The magnitude of a dose reduction is the major determinant of decline in tumor control probability. A large dose reduction to even a small volume of tumor can profoundly decrease tumor control probability. Conversely, the most rapid improvement in tumor control probability occurs the closer to 100% the amount of tumor exposed to an increased dose. Escalation of dose is of little value unless it is distributed through most of the tumor: even very large increases in dose to small volumes are of little benefit.

Positron emission tomography: an independent indicator of radiocurability in head and neck carcinomas.

Positron emission tomography (PET) is a biochemical-imaging tool that uses the uptake of the glucose analog 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) to detect head and neck tumor proliferation. The aim of this study is to determine if quantitation of either primary tumor metabolic activity or tumor response using PET scans could predict local control and overall survival in patients with head and neck cancer undergoing primary radiotherapy. Twelve patients with squamous cell carcinomas of the head and neck underwent PET scans before and 6 weeks after completion of radiation therapy. Tumor metabolic activity was quantitated using the metabolic ratio method. Mean follow-up was 40 months (range: 18-55 months). In our series, tumors with metabolic rates greater than that of the cerebellum are associated with significantly better local control (p < 0.05) and survival. Posttreatment PET imaging was falsely positive in one patient with clinical signs of severe inflammation. Tumors with greater than 50% decrease in metabolic activity with irradiation had improved local control. Clinically, nine patients had excellent response to irradiation. These results suggest that pretreatment PET findings may have prognostic implications in determining which patients will achieve long-term local control with primary radiation therapy. This may help identify those at increased risk of recurrence that may benefit from more aggressive altered fractionation schemes or combined modality therapy.

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.

Gangliogliomas: experience with 34 patients and review of the literature.

Ganglioglioma is an uncommon central nervous system tumor. The role of adjuvant postoperative radiation therapy is undefined. The authors retrospectively reviewed the clinicopathologic features and results of therapy for 34 patients with ganglioglioma treated at the University of California at Los Angeles. There were 18 women and 16 men. Median age was 18 years. Twenty-five tumors were low grade. Twenty-one patients underwent gross total resection. Three patients received adjuvant radiotherapy. The 4-year actuarial progression free and overall survival rates were 67% and 75%, respectively. The median time to progression was 14 months and all relapses were local. Factors significantly influencing progression-free or overall survival according to univariate analysis included degree of resection and tumor grade. Survival and relapse were not significantly influenced by any factor according to multivariate analysis. The progression-free survivals after gross total resection of low- and high-grade tumors were 78% and 75%, respectively. Respective rates after subtotal resection were 63% and 25%. Review of the literature demonstrates no role for radiotherapy after total resection of ganglioglioma or after partial removal of low-grade tumor. Radiation therapy appears to reduce the relapse rate after partial removal of high-grade lesions. A dose in excess of 5,000 cGy is necessary for ganglioglioma.

A non-parametric method of reconstructing single-dose survival curves from multi-fraction experiments.

PURPOSE: A method of estimating the single-dose curve from designed multifraction experiments is described and applied to three datasets. MATERIALS AND METHODS: The method, which is non-parametric and based on standard statistical regression techniques, can be used for functional endpoints which are either continuous or binary. The datasets are concerned with wound healing on mice, myelopathy in guinea pigs and spermatogenesis in mice. The results are compared with the results from fitting the linear quadratic model. The statistical methods of Bootstrapping and residual plots are illustrated. RESULTS: The method is based in part on an assumed statistical model, however, exact knowledge of the correct statistical model is not necessary to obtain an estimate of the shape of the single-dose survival curve. We find no good evidence from the reconstructed single-dose survival curve of an "induced repair" phenomena at low doses for the wound healing and spermatogenesis experiments. For the myelopathy experiment the data are consistent with the LQ model with a low alpha-beta ratio down to doses of at least 1.5 Gy per fraction. CONCLUSIONS: A robust statistical method of estimating the shape of the single-dose survival curve is demonstrated using standard statistical software on three datasets.

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.

Applying radiobiological principles to combined modality treatment of head and neck cancer--the time factor.

PURPOSE: Combined modality treatment is indicated for most advanced stage head and neck cancers. It is postulated that the efficacy of combined modality regimens could be enhanced by applying principles derived from radiotherapy fractionation studies to optimize the time factor in treatment scheduling. METHODS AND MATERIALS: The premise that tumor clonogens surviving a therapeutic intervention undergo accelerated repopulation in a time-dependent fashion as their numbers are depleted is used as a model to interpret the results of various chemoradiotherapy and postsurgical radiotherapy protocols and to suggest ways in which future combined modality regimens can be more rationally designed. RESULTS: Meta-analyses of chemoradiotherapy trials show the general superiority of concomitant vs. neoadjuvant sequential protocols. There is also emerging evidence that both the duration of postoperative radiotherapy and the delay in its instigation affect treatment outcome. These results are compatible with the hypothesis that the overall duration of the "package deal" of combined modality treatment is an important determinant of outcome. However, a large decrease in duration of the "package deal" does not necessarily translate into a therapeutic gain because the total dose has to be lowered to prevent intolerable acute reactions. In these circumstances tumor control will improve only if the reduced treatment time circumvents more tumor cell regeneration than the cytoreduction that could be achieved by the extra dose tolerable in a longer time period. More modest reductions in treatment time can be accomplished without dose reduction and so avoid this risk. The design of new protocols should take account of the fact that regeneration of tumor clonogens can be predicted to be nonuniform with time. Thus, the greatest therapeutic gain should be achieved by targeting periods of maximal regenerative capacity for shortening or, alternatively, for intensification of treatment. These periods are the latter part of a course of radiotherapy or chemotherapy and the early postoperative phase after surgery. CONCLUSIONS: The rational design of combined modality protocols should include principles concerning the time factor derived from radiotherapy fractionation studies. Periods of maximal tumor cell regeneration should be targeted for shortening or for treatment intensification. Any dose sacrifice necessitated by reducing treatment duration must be less than the dose equivalent of regeneration during the same time period.

Sensitization of renal carcinoma to radiation using alpha interferon (IFNA) gene transfection.

The rationale for this study was that local delivery of interferon-alpha (IFN-alpha) by gene transfection may be of value during radiotherapy. To investigate the feasibility of this approach, cells of the human renal carcinoma cell line R11 were transfected with the IFNA gene and evaluated for radiation responses in vitro by clonogenic assays. R11 cells expressing IFN-alpha after gene transfection were more sensitive to radiation than R11 control cells (SF2 = 0.33 and 0.51, respectively). In addition to increasing radiosensitivity, IFNA gene transfection slowed cellular growth and reduced the plating efficiency in clonogenic assays. The addition of exogenous rhIFN-alpha to cells at different times relative to irradiation showed that its presence during the postirradiation period was critical for radiosensitization, but repair of sublethal damage did not seem to be affected. No apoptosis of R11 cells was found 1-5 days after exposure to 2-25 Gy with or without IFN-alpha. Extensive formation of multinuclear giant cells was present beginning 2 days after irradiation; however, IFN-alpha did not cause any major alterations in the yield of radiation-induced giant cells. These studies suggest that gene transfection might be an effective means of delivering IFN-alpha for clinical use in radiotherapy of cancer.