Combined Modality Regimens Research Articles

Changing role and decreasing size: current trends in radiotherapy for Hodgkin's disease.

Radiotherapy, the first cancer treatment modality that offered cure, is still considered to be the most effective "single agent" in treating Hodgkin's disease (HD). Yet, the role of radiotherapy in HD has changed dramatically with the advent of effective combination chemotherapy and the rising concern of long-term complications associated with successful treatment of HD. The new principles of integrating radiotherapy into a combined-modality regimen for HD at different prognostic stages are reviewed here, along with the effect of this new role on radiation field size and design.

Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity.

Recent studies of human immunodeficiency virus type 1 (HIV-1) infection in humans and of simian immunodeficiency virus (SIV) in rhesus monkeys have shown that resolution of the acute viral infection and control of the subsequent persistent infection are mediated by the antiviral cellular immune response. We comparatively assessed several vaccine vector delivery systems-three formulations of a plasmid DNA vector, the modified vaccinia Ankara (MVA) virus, and a replication incompetent adenovirus type 5 (Ad5) vector-expressing the SIV gag protein for their ability to elicit such immune responses in monkeys. The vaccines were tested either as a single modality or in combined modality regimens. Here we show that the most effective responses were elicited by a replication-incompetent Ad5 vector, used either alone or as a booster inoculation after priming with a DNA vector. After challenge with a pathogenic HIV-SIV hybrid virus (SHIV), the animals immunized with Ad5 vector exhibited the most pronounced attenuation of the virus infection. The replication-defective adenovirus is a promising vaccine vector for development of an HIV-1 vaccine.

Chemotherapy- and radiotherapy-induced mucositis in head and neck cancer patients: new trends in pathophysiology, prevention and treatment.

Mucositis is the intensity-limiting toxicity in the management of locally advanced non-resectable head and neck cancer with radiotherapy and chemotherapy. New radiation modalities (hyperfractionation and/or acceleration) as well as combined modality regimens in this situation induce higher rates of acute toxicity. Hyperfractionation, for example, allows higher control rates, with few late toxicities, but it slightly increases acute mucositis. The addition of chemotherapy introduces systemic toxicity and can exacerbate local tissue reactions when used concurrently with radiotherapy. Mucositis is recognized as the principal limiting factor to further treatment intensification. As local regional control and overall survival are related to dose-intensity in this case, further research into the assessment, analysis, prevention and treatment of mucosal toxicity is not only crucial to improvement in quality of life, but certainly also to improved rates of disease control. Several topical and systemic treatments are directed to the decrease and the acceptance of this acute toxicity, but few have shown a significant preventive effect. The efficacy of low-level laser therapy in the management of such toxicity could hence yield important developments with this method in the field of oncology.

Irinotecan (CPT-11): recent developments and future directions--colorectal cancer and beyond.

Since its approval in the United States in 1996, irinotecan (CPT-11, Camptosar, Pharmacia Corp.; Peapack, NJ) has undergone extensive clinical evaluation. In the past five years, the focus of development has evolved from evaluation of single-agent activity in refractory disease settings to evaluation of front-line irinotecan-based combination chemotherapy regimens and integration of irinotecan into combined modality regimens. Important studies have been performed clarifying the role of irinotecan in treating colorectal and other gastrointestinal cancers, small cell and non-small cell lung cancer, and a variety of other malignancies. Preclinical studies performed in conjunction with these clinical trials have also provided significant insights into the pharmacology, metabolism, mechanisms of resistance, and molecular determinants of response. This review summarizes that progress, focusing on the achievements of the past five years.

Immunotherapy (recombinant interleukin 2), hormone therapy (medroxyprogesterone acetate) and antioxidant agents as combined maintenance treatment of responders to previous chemotherapy

An open, non-randomized phase II study was carried out including all patients treated with whatever chemotherapy or combined modality regimen for whatever cancer who were in clinical objective response or stable disease (SD) for more than three months, to receive maintenance treatment with recombinant interleukin-2 (rIL-2) plus medroxyprogesterone acetate (MPA) plus antioxidant agents alpha-lipoic acid (ALA) and N-acetyl cysteine (NAC). The main study endpoints were clinical outcome and toxicity. The secondary endpoints were effects of treatment on cancer-related anorexia/cachexia syndrome (CACS) symptoms, on serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin as well as the evaluation of quality of life (QL). rIL-2 was administered at a dose of 1.8 MIU subcutaneously three times/week on alternate days for the first two weeks of every month and MPA was given orally at a dose of 500 mg once a day at alternate days without interruption. ALA 300 mg/day orally and NAC 1800 mg/day orally were also administered. The treatment was administered until progression of disease or appearance of toxicity. From July 1998 to May 2000, 16 patients were enrolled in the study (M/F ratio: 15/1; mean age: 62 years, range 45-71). The median duration of maintenance treatment was 10 months (range 5-22). The response to maintenance treatment at September 2000 was: CR (persistent throughout the treatment) 4 patients (25%); SD 1 patient (6.2%); PD 11 patients (68.8%). The median duration of response was 9.8 months (range: 5-22+). The median follow-up duration was 19 months (range: 8-102). The median OS was not reached. The median PFS was 14 months (range 1-29). The 1-year survival rate was 25%. At September 2000, 9 patients are still surviving. No grade 3/4 toxicity was observed. One Grade 2 skin toxicity was observed and Grade 1: 2 fever, 2 thrombocytopenia, 1 neutropenia and 1 skin were observed. The ECOG PS did worsen significantly, the body weight and BMI increased significantly after treatment, whereas the appetite did not change significantly. The QL evaluation showed a significant amelioration of cognitive functions and a borderline significant amelioration of emotional functions after treatment, whereas a borderline worsening of dyspnea was observed. The absolute lymphocyte count increased significantly after the maintenance treatment, as well as the serum IL-2, TNFalpha decreased at borderline statistical significance; the serum levels of leptin did not change significantly. The evaluation of patient subgroups showed that responders/survivors had a pattern superimposable to that of whole patient population, the patients who rapidly progressed and died exhibited no significant changes of these parameters during treatment. The results of the present study suggest that the host immune response, evaluated by several parameters, after IL-2 administration, (e.g. lymphocytosis), are worth further study as potential markers for the major end points of cancer treatment, i.e. OS and QL, in an adequate number of patients.

Primary central nervous system lymphoma 1991-1997: outcome and late adverse effects after combined modality treatment.

This retrospective single-center study assesses the feasibility, therapeutic outcome, and late side effects of combined modality therapy with intravenous methotrexate, whole brain radiotherapy (WBRT), and intravenous cytarabine in patients with primary central nervous system lymphoma (PCNSL). All 28 consecutive patients diagnosed with PCNSL between 1991 and 1997 were scheduled to receive combined modality therapy. Seven of 28 patients did not receive combined modality treatment: 6 patients had WBRT alone because of poor physical condition, and 1 patient died before receiving treatment. Of the remaining 21 patients, 5 received the complete regimen, and 16 received a modified regimen with reduced dose intensity. Fourteen of 21 patients (67%) treated with combined modality therapy had a complete response; 1 had a partial response. Median survival was 11 months in all 28 patients, 23 months in all patients with combined modality treatment, and 41 months in patients receiving the complete regimen. Of 15 examinable patients with a follow-up of 8 months or more, 10 developed severely symptomatic and 5 mildly symptomatic or asymptomatic diffuse white matter changes. Only a small subgroup of all patients with PCNSL appears to be eligible for receiving all parts of the combined modality regimen. Treatment in these patients leads to a marked prolongation of survival. The risk of late side effects is high even with modified, dose intensity-reduced versions of combined modality treatment.

Results and complications of surgery combined with intra-operative radiation therapy for the treatment of locally advanced or recurrent cancers in the pelvis.

Intra-operative radiation therapy (IORT) can benefit patients with pelvic tumors by delivering a high dose of radiation with precise delineation of tumor bed and maximal protection of surrounding normal tissues. The IORT experience has been particularly promising for locally advanced primary or recurrent rectal cancers in which a gross total resection is achieved. However, its potential benefit must be weighed against added toxicity. The main dose-limiting toxicity of pelvic IORT is peripheral neuropathy and ureteral stenosis. We will review the techniques for optimal IORT delivery, the results of the major studies investigating IORT treatment of rectal cancer, and the pelvic complications associated with combining surgery and IORT. A team of surgeons and radiation oncologists providing close multidisciplinary coordination is essential to integrate IORT with combined modality regimens in a safe and effective manner.

Toxicity in head and neck cancer: a review of trends and issues

The quest for improved fractionation and combined modality regimens in head and neck cancer has also yielded progressively higher rates of toxicity. Time compression of dose delivery in accelerated fractionation has produced high rates of severe mucositis including the early stoppage of two randomized trials. The addition of chemotherapy has introduced systemic toxicity and can exacerbate local tissue reactions when used concurrent with radiotherapy. Mucositis is recognized as the principal impediment to efforts at further treatment intensification. The development and utilization of standardized toxicity grading criteria and accepted reporting standards has lagged toxicity production, impeding a full appreciation of the true extent of both acute and late toxicity. Objective data regarding acute and chronic effects on organ function are also sorely lacking. A better characterization of the frequency, severity, and duration of the various toxicities encountered in head and neck cancer will also allow the rational development of toxicity interventions. New methods are needed to summarize the global or aggregate toxicity of a treatment program. Further research into the assessment and analysis of toxicity is not only crucial to improvements in quality of life (QOL), but perhaps, improved rates of disease control as well.

Adjuvant and Neoadjuvant Chemotherapy for Non-Small Cell Lung Cancer: A Time for Reassessment?

Surgical resection has limited success in curing non-small cell lung cancer (NSCLC), particularly among patients with locally advanced disease (stage IIIA). Combined modality regimens, utilizing surgery, radiotherapy, and chemotherapy, have improved response rates, although they have not been shown to significantly impact survival among patients with completely resected stage I and II NSCLC. Future improvements in NSCLC therapy, currently under investigation, are likely to come from newer agents shown to be active in this disease and from alternative schedules, such as neoadjuvant or concurrent combined modality treatments. Neoadjuvant cisplatin-based chemotherapy has already been shown to increase cure rates in stage IIIA NSCLC, from 10 to 15% to 25 to 30%. Newer active agents, such as paclitaxel, vinorelbine, and gemcitabine, may be able to advance the cure rate even further. Radiotherapy, which has been shown to decrease the rate of local recurrence, may play a role as well.

New directions in the treatment of colorectal cancer: a look to the future

Today, adjuvant 5-fluorouracil based therapy is known to significantly reduce the relapse rates and the risks of dying from resected colon cancer; chemotherapy approximately doubles overall survival of advanced colorectal cancer and second line treatment prolongs the survival of patients compared with best supportive care. At the molecular level a number of key genes are often mutated in cancer of the colon and some of these key regulators of apoptosis are discussed (p53 and bcl-2 family of proteins). Dihydropyrimidine dehydrogenase (DPD) activity may be a potential factor controlling fluorouracil (FU) responsiveness at the tumoral level and its importance is stressed. The rationale of combining FU with DPD inhibitors is fairly strong. Ethynyluracil, UFT and S1 pursue this strategy while capecitabine has another the rationale. Drug resistance should be at least partially overcome by combination chemotherapy (FU plus mitomycin, oxaliplatin, irinotecan) and combined modality (FU+RT) regimens. Improved surgical techniques and radiotherapy have substantially decreased local failure rates for rectal cancers. Finally, innovative treatment modalities such as anti-angiogenetic and antimetastatic agents, farnesyl transferase inhibitors, vaccine and gene therapy are in early clinical trials.

Combined-modality therapy in the nonsurgical management of unresectable stage III non-small cell lung cancer.

Combined chemotherapy and radiation for patients with unresectable non-small cell lung cancer has recently been associated with a survival advantage compared with radiation alone; however, despite this apparent improvement in survival, the optimal strategy to combine these two modalities has not yet been defined. Both local tumor control and distant micrometastatic disease remain problems, limiting the curative ability of current combined-modality programs. Over the past year, accelerated radiation schedules have been shown to improve both local tumor control and survival in a selected patient population compared with standard radiotherapy. Some work has centered on the incorporation of novel chemotherapy agents into combined-modality regimens, with encouraging results from phases I and II. Finally, although the benefit for combined-modality therapy has generally been limited to good performance status of patients with minimal weight loss, some data have shown the feasibility of the combined approach in high-risk patient populations. Several ongoing cooperative group phase III trials will help to better define the optimal approach to manage this high-risk patient population.

Induction of growth inhibition and apoptosis in pancreatic cancer cells by auristatin-PE and gemcitabine.

Pancreatic adenocarcinoma is the fifth leading cause of cancer related deaths in the United States. Treatment for this disease has largely been unsuccessful, which may partly be due to insufficient data regarding the molecular mechanisms of chemotherapeutic drugs currently being used as single agents or in combined modality regimens. In this study, we investigated the molecular mechanisms by which auristatin-PE, a newly developed experimental agent, and gemcitabine, a commercially available anti-cancer agent, exert their inhibitory effects on pancreatic cancer cell lines containing wild-type p53 (HPAC) and mutant p53 (PANC-1). Our results showed that auristatin-PE and gemcitabine inhibited cell growth and induced cell cycle arrest in G2/M and S phase, respectively. Auristatin-PE also induced apoptosis in both cell lines. Western blot analysis showed that auristatin-PE up-regulated the expression of wt-p53, p21WAF1 and Bax, and down-regulated Bcl-2 and cyclin B in HPAC cells, while only up-regulation of p21WAF1 and Bax was observed in PANC-1 cells. These results suggest that auristatin-PE may induce apoptosis and p21WAF1 expression through p53-dependent or independent pathways, and that up-regulation of p21WAF1 and Bax and down-regulation of Bcl-2 may be the molecular mechanism through which auristatin-PE inhibits cell growth and induces apoptosis. Furthermore, the up-regulation of p21WAF1 and down-regulation of cyclin B may contribute to the G2/M cell cycle arrest. Combination of auristatin-PE and gemcitabine showed significantly greater inhibition of cell growth and up-regulated expression of p21WAF1 and Bax. From these results, we conclude that the selection of therapeutic agents based on their molecular mechanism may improve therapeutic outcome, and that auristatin-PE may be more effective in the treatment of pancreatic cancer when given in combination with gemcitabine, rather than as a single agent.

Retrospective assessment of quality of life and treatment outcome in patients with Hodgkin's disease from 1969 to 1994

We determined the current quality of life (QoL) of patients with Hodgkin's disease treated at the Innsbruck University Hospital between 1969 and 1994 at a mean time of 9.1±7.0 years after their initial treatment. Further aims of our study were to assess potential differences in objective treatment outcome and QoL between patients treated with chemo-, radio- or combined modality therapy and those enrolled in randomised clinical trials or treated according to standard procedures. The QLQ-C30, a health-related and validated self-report questionnaire developed by the Study Group on Quality of Life of the European Organization for Research and Treatment of Cancer (EORTC) was mailed to a cohort of 194 survivors out of a total of 225 patients with Hodgkin's disease; 126 of them (64.9%) returned the completed questionnaire. The 5- and 10-year overall survival rates for the total group of 225 patients were 94.3% and 84.9%, respectively. Irrespective of stage, higher relapse-free survival rates were observed in patients receiving combined modality treatment ( P=0.025). Five-year relapse-free survival rates were 96.6% for patients enrolled in clinical trials and 82.8% for patients treated outside of randomised studies ( P=0.037 in univariate and P=0.064 in multivariate analysis). Patients treated with combined modality regimens had reduced QoL scores in comparison with those treated with either radiation or chemotherapy alone, but QoL parameters did not differ between patients enrolled in clinical trials and those treated according to standard procedures. Patients with Hodgkin's disease had an excellent long-term prognosis and very high QoL scores a mean of 9.1 years after treatment of their disease. The improved relapse-free survival rates achieved by combined modality regimens must be carefully weighed against the accompanying reduced QoL, since lower relapse rates did not translate into a survival advantage.

2099 A trans-tasman radiation oncology group (TROG) phase 2 study of a simple combined modality regimen using methotrexate and irradiation in primary CNS lymphoma

2099 A trans-tasman radiation oncology group (TROG) phase 2 study of a simple combined modality regimen using methotrexate and irradiation in primary CNS lymphoma

Chimioradiothérapie concomitante des cancers infiltrants de la vessie

Until now, radical cystectomy has been considered the most effective treatment for invasive bladder cancer. However it fails to cure more than 50% of patients and can result in a mediocre quality of life. In an effort to improve cure rates, combined modality regimens have been investigated. Despite the preliminary results of early clinical trials, randomized trials have most often failed to show any benefit from neoadjuvant or adjuvant chemotherapy or radiotherapy. One of the major progress brought by radiotherapy has been the wide use of conservative treatment in several cancer, and in the recent years promising results have been published with concomitant radio-chemotherapy. The use of conservative approach in bladder cancer now appears to be a tangible reality for selected patients, but this combined modality have not yet been tested in randomized trials.

Jasplakinolide: interaction with radiation and hyperthermia in human prostate carcinoma and Lewis lung carcinoma.

Jasplakinolide is a novel natural product anticancer agent which acts by inducing overpolymerization of actin. The aim of the current study was to explore the activity of jasplakinolide with hyperthermia and radiation. The response of human PC-3 and DU-145 prostate carcinoma cells and DU-145 xenografts and the response of the Lewis lung carcinoma to jasplakinolide were studied. Jasplakinolide was cytotoxic toward human prostate carcinoma cells, DU-145, PC-3 and LNCaP in culture, killing 1 log of cells with 0.8, 0.3 and 0.07 microM of drug in 24 h, respectively. The combination of jasplakinolide and hyperthermia resulted in primarily additive cell killing by the two modalities in the three prostate carcinoma lines. In combination with radiation, jasplakinolide produced some diminution in the shoulder of the survival curve of normally oxygenated PC-3 cells and was a radiation sensitizer of hypoxic DU-145 cells and hypoxic PC-3 cells. In vivo, jasplakinolide was an active antitumor agent against the Lewis lung carcinoma and the DU-145 prostate carcinoma xenograft. Jasplakinolide was a radiation sensitizer in the Lewis lung carcinoma. Jasplakinolide was also effective against the systemic Lewis lung carcinoma, decreasing lung metastases. Lung metastases were further decreased when jasplakinolide was administered along with radiation to the subcutaneous primary tumor. In the DU-145 tumor, the effects of jasplakinolide and fractionated radiation for 1 or 2 weeks appeared to be primarily additive. Jasplakinolide is an interesting new anticancer agent for which further study both as an anticancer agent and in combined modality regimens is warranted.

Low rectal cancer: impact of radiation and chemotherapy on surgical treatment.

The aim of this study was to evaluate the impact of combined radiotherapy and chemotherapy (leucovorin and 5-fluorouracil) on the treatment of potentially resectable low rectal cancer using the following end points: 1) toxicity of this combined modality regimen; 2) clinical and pathologic response rate and local control; 3) down-staging of the tumor and its influence on the number of sphincter-saving operations; 4) disease-free interval, patterns of relapse, and overall survival. From 1991 to 1996, 118 patients with potentially resectable cases of histologically proven adenocarcinoma and no distant metastases were enrolled into this protocol. All patients were evaluated by clinical and proctologic examination, abdominal computed tomography, transrectal ultrasound, and chest radiography. Therapy consisted of 5,040 cGy (6 weeks) and concurrent leucovorin (20/mg/m2/day) with bolus doses of 5-fluorouracil administered intravenously at 425 mg/m2/day for three consecutive days on the first and last three days of radiation therapy. After two months, all patients underwent repeat evaluation and biopsy of any suspected residual lesions or scar tissue. Median follow-up was 36 months. Toxicity of chemotherapy regimen was minimum. Thirty-six patients (30.5 percent) were classified as being complete responders. In six of these patients, complete response was confirmed by the absence of tumor in the surgical specimens (3 abdominoperineal resections and 3 proctosigmoidectomies with coloanal anastomosis). In the remaining 30 patients, confirmation of a complete response was made by the absence of symptoms, negative findings on physical examination, and biopsy, transrectal ultrasound, and pelvic computed tomographic test results during follow-up. Eighty-two patients (69.4 percent) were considered incomplete responders. Residual lesions had already been identified during the first examination in 74 patients. In the other eight patients, residual tumor was only identified after 3 to 14 months. All patients underwent surgical treatment, except one patient who refused surgery. Eighty-seven patients underwent 90 surgical procedures: local excision, 9; coloanal anastomosis, 36; abdominoperineal resection, 4; Hartmann's procedure, 1. Isolated local recurrences occurred in five patients (4.3 percent) and combined local and distant failure in eight patients (6.7 percent). Ninety patients are alive and disease-free at a median follow-up of 36 months. Combined up-front chemoradiotherapy was associated with tolerable and acceptable side effects. A significant number of patients had complete disappearance of their tumors (30.5 percent) within a median follow-up of 36 months. This regimen spared 26.2 percent of patients from surgical treatment and allowed sphincter-saving management in 38.1 percent of patients who may have required abdominoperineal resection. Preliminary results of this trial suggests a reduction in the number of local recurrences and reinforces the concept that infiltrative low rectal cancer may be initially treated by chemoradiotherapy.

New Chemotherapeutic Agents for the Treatment of Non-small Cell Lung Cancer: The Japanese Experience

Non-small cell lung cancer (NSCLC) is refractory to systemic chemotherapy, compared with small cell lung cancer. Until recently, only five drugs--cisplatin, vindesine, mitomycin, ifosfamide, and vinblastine--could produce overall response rates of 15% against NSCLC. However, recent efforts have contributed to the development of new drugs with activity against NSCLC, including irinotecan hydrochloride (CPT-11), paclitaxel, docetaxel, vinorelbine, and gemcitabine. Combination chemotherapy against NSCLC using these agents has demonstrated high response rates. In Japan, various combination chemotherapy and combined-modality regimens employing CPT-11 have been evaluated for their efficacy. Randomized controlled trials to establish new state-of-the-art treatments for NSCLC are ongoing.

Radiation Therapy in the Management of Limited Small Cell Lung Cancer: When, Where, and How Much?

Progress in the treatment of patients with small cell lung cancer (SCLC) has come in two phases. In the first phase, SCLC was recognized, even when seemingly localized to the lung and intrathoracic lymph nodes, to be widely metastatic and to require effective systemic therapy from the outset. The development of active chemotherapeutic agents and combinations in the 1970s improved median survival from the 6 months seen with radiotherapy alone to about 1 year. In the second phase has come the recognition that local control of a disease, even one with systemic spread, is necessary for its cure. This has resulted both in a better appreciation of the role of radiation therapy in SCLC treatment and in efforts to optimize combined-modality regimens using radiotherapy and chemotherapy. With current treatment regimens involving concurrent or closely interdigitated administration of cisplatin and etoposide chemotherapy and radiation doses of 45 Gy given over 3 to 5 weeks, median survivals of 20 to 24 months have been reported by many single institutions and confirmed in large cooperative group trials. Issues remaining to be resolved include optimization of radiation dose, volume, and timing; the role of prophylactic cranial irradiation; and how to reduce acute and late toxic reactions of treatment. As we develop more specific therapies based on specific molecular and biological characteristics of SCLC, including its autocrine growth regulation, we will be challenged to integrate these successfully with current radiation and chemotherapeutic approaches.

Applying radiobiological principles to combined modality treatment of head and neck cancer—The time factor

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. 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. 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. 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.