Tumor stage, human papillomavirus and smoking status affect the survival of patients with oropharyngeal cancer: an Italian validation study.

BACKGROUND: Tumor human papillomavirus (HPV) status strongly affects overall survival (OS) of oropharyngeal cancer (OPC) patients. Recently, three groups with different outcomes were identified based on HPV status, smoking history and tumor stage. Our objective was to validate this model using a single-institutional retrospective database. PATIENTS AND METHODS: Patients (n=120) diagnosed with OPC at our institution, treated with concomitant cisplatin plus radiotherapy (RT) (n=64), induction chemotherapy followed by concomitant chemoradiation (n=39) or RT alone (n=17), were stratified in three groups with respect to the risk of death (low 26, intermediate 46 and high 49 patients) according to tumor p16 expression as surrogate of HPV status, pack-years of tobacco smoking and nodal/tumor stage. Group-stratified Kaplan-Meier OS curves were estimated and compared using the log-rank test. RESULTS: The 2-year OS estimates were 100%, 86% and 70%, respectively. The difference between the survival curves was statistically significant (P=0.009). The Harrell's concordance index was 0.70. The calibration plot showed a good concordance between our results and those observed in the original study. CONCLUSIONS: This study validates the risk grouping previously identified. Risk-driven clinical decision making and trial designs will help in better defining the most appropriate treatment in OPC patients.

Consensus guidelines for the management of radiation dermatitis and coexisting acne-like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck.

BACKGROUND: Radiation dermatitis occurs to some degree in most patients receiving radiotherapy, with or without chemotherapy. Patients with squamous cell carcinoma of the head and neck (SCCHN) who receive radiotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab, may develop a characteristic acne-like rash in addition to dermatitis. DESIGN: An advisory board of 11 experienced radiation oncologists, medical oncologists and dermatologists discussed the management options for skin reactions in patients receiving EGFR inhibitors and radiotherapy for SCCHN. Skin toxicity was categorised according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (version 3) grading. RESULTS: Both general and grade-specific approaches for the management of dermatitis in this patient group are presented. It was concluded that where EGFR inhibitor-related acne-like rash and dermatitis coexist within irradiated fields, management should be based on the grade of dermatitis: for grade 1 (or no dermatitis), treatment recommendations for EGFR-related acne-like rash outside irradiated fields should be followed; for grades 2 and above, treatment recommendations for dermatitis were proposed. CONCLUSIONS: This paper presents comprehensive consensus guidelines for the treatment of dermatitis in patients with SCCHN receiving EGFR inhibitors in combination with radiotherapy.

TRIP12 as a mediator of human papillomavirus/p16-related radiation enhancement effects.

Patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) have better responses to radiotherapy and higher overall survival rates than do patients with HPV-negative HNSCC, but the mechanisms underlying this phenomenon are unknown. p16 is used as a surrogate marker for HPV infection. Our goal was to examine the role of p16 in HPV-related favorable treatment outcomes and to investigate the mechanisms by which p16 may regulate radiosensitivity. HNSCC cells and xenografts (HPV/p16-positive and -negative) were used. p16-overexpressing and small hairpin RNA-knockdown cells were generated, and the effect of p16 on radiosensitivity was determined by clonogenic cell survival and tumor growth delay assays. DNA double-strand breaks (DSBs) were assessed by immunofluorescence analysis of 53BP1 foci; DSB levels were determined by neutral comet assay; western blotting was used to evaluate protein changes; changes in protein half-life were tested with a cycloheximide assay; gene expression was examined by real-time polymerase chain reaction; and data from The Cancer Genome Atlas HNSCC project were analyzed. p16 overexpression led to downregulation of TRIP12, which in turn led to increased RNF168 levels, repressed DNA damage repair (DDR), increased 53BP1 foci and enhanced radioresponsiveness. Inhibition of TRIP12 expression further led to radiosensitization, and overexpression of TRIP12 was associated with poor survival in patients with HPV-positive HNSCC. These findings reveal that p16 participates in radiosensitization through influencing DDR and support the rationale of blocking TRIP12 to improve radiotherapy outcomes.

Enhancement of tumor radioresponse in vivo by gemcitabine.

Gemcitabine, 2'2'-difluoro-2'-deoxycytidine, is an inhibitor of DNA synthesis and has been shown previously in vitro and in vivo to enhance the cytotoxic activity of radiation as well as some chemotherapeutic agents. Because gemcitabine has shown clinical activity on its own in several solid tumors traditionally treated with radiotherapy, it was of interest to optimize the combination of gemcitabine and radiation. To determine the optimal gemcitabine dose to combine with irradiation and to determine the effect of gemcitabine on tumor growth, mice bearing SA-NH tumors were treated with 2.5 to 600 mg/kg gemcitabine, and subsequent tumor growth was determined. At low doses, gemcitabine induced transient growth delay, whereas higher doses showed both cytotoxic and cytostatic activity. Flow cytometric, histological, and mitotic analyses of irradiated tumors showed that gemcitabine induced a dose-dependent inhibition of DNA synthesis and induction of apoptosis of cells in S phase. DNA synthesis recovered in cells at the G1-S boundary of the cell cycle in a dose-dependent manner, and a parasynchronous movement of cells through the cell cycle ensued. To determine the optimal schedule for gemcitabine administration in relation to irradiation, tumor-bearing mice were given a single 50 mg/kg dose of gemcitabine at various times before or after irradiation. Gemcitabine enhanced radioresponse in a time-dependent fashion. The highest enhancement factors for tumor growth delay (1.68-2.03) were observed when gemcitabine was administered 24-60 h before irradiation. Although gemcitabine reduced the radiation tumor control dose at all administration times used, the greatest enhancement of tumor radiocurability occurred when gemcitabine was administered 24 h before irradiation (dose modification factor of 1.54). Moreover, gemcitabine decreased the lung metastatic rate in mice with local tumor control from 73% in mice receiving radiation alone to 40% in mice receiving the combination (all combination times included). These results suggest that gemcitabine has strong radioenhancing properties and that the greatest interaction occurs when gemcitabine administration precedes irradiation by 24-72 h. Preliminary studies indicate that normal tissues recover more quickly than tumor tissues from gemcitabine treatment; thus, optimized scheduling of gemcitabine and irradiation may serve to improve the therapeutic ratio of the combination.

Intrinsic radiosensitivity of normal human fibroblasts and lymphocytes after high- and low-dose-rate irradiation.

The existence of heritable radiosensitivity syndromes and clinical observations in radiotherapy patients suggests that human cellular radiosensitivity differs among individuals. We report here an in vitro study of radiosensitivity in 30 fibroblast and 29 lymphocyte cultures obtained from cancer patients and controls. In 25 cases, both fibroblasts and lymphocytes were obtained from the same donors. Fibroblasts were cultured from skin biopsy samples, and peripheral T-cell lymphocytes were cultured from blood. Clonogenic survival assays were performed by using high- and low-dose-rate irradiation; lymphocytes were in G0 phase and fibroblasts in confluent plateau phase. Various end points were calculated and compared (i.e., surviving fraction at 2 Gy, initial slope of the survival curve, and doses resulting in 10 and 1% survival, respectively). Depending on the end point, the coefficient of variation of the survival parameters ranged from 31 to 68% for lymphocytes and 21 to 41% for fibroblasts following high-dose-rate irradiation. Similar ranges were obtained after low-dose-rate irradiation. Variance analysis performed on replicate assays in cultures derived from the same patient showed that variation due to technical or sampling errors was significantly lower than variation between individuals (P = 0.00034 and 0.014 for fibroblasts and lymphocytes, respectively). No correlation was observed between the radiosensitivity of lymphocyte and fibroblast cultures derived from the same donors. We conclude that there is significant variation in normal cell radiosensitivity among individuals. On the other hand, comparisons of lymphocyte and fibroblast radiosensitivities suggest that tissue-specific characteristics, such as differentiation status, may variably modulate radiosensitivity.

Neural and cortical analysis of swallowing and detection of motor imagery of swallow for dysphagia rehabilitation-A review.

Swallowing is an essential function in our daily life; nevertheless, stroke or other neurodegenerative diseases can cause the malfunction of swallowing function, ie, dysphagia. The objectives of this review are to understand the neural and cortical basis of swallowing and tongue, and review the latest techniques on the detection of motor imagery of swallow (MI-SW) and motor imagery of tongue movements (MI-TM), so that a practical system can be developed for the rehabilitation of poststroke dysphagia patients. Specifically, we firstly describe the swallowing process and how the swallowing function is assessed clinically. Secondly, we review the techniques that performed the neural and cortical analysis of swallowing and tongue based on different modalities such as functional magnetic resonance imaging, positron emission tomography, near-infrared spectroscopy (NIRS), and magnetoencephalography. Thirdly, we review the techniques that performed detection and analysis of MI-SW and MI-TM for dysphagia stroke rehabilitation based on electroencephalography (EEG) and NIRS. Finally, discussions on the advantages and limitations of the studies are presented; an example system and future research directions for the rehabilitation of stroke dysphagia patients are suggested.

Combined interferon-alfa, 13-cis-retinoic acid, and alpha-tocopherol in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase II trial.

PURPOSE: Retinoids and interferons (IFNs) have single-agent and synergistic combined effects in modulating cell proliferation, differentiation, and apoptosis in vitro and clinical activity in vivo in the head and neck and other sites. Alpha-tocopherol has chemopreventive activity in the head and neck and may decrease 13-cis-retinoic acid (13-cRA) toxicity. We designed the present phase II adjuvant trial to prevent recurrence or second primary tumors (SPTs) using 13-cRA, IFN-alpha, and alpha-tocopherol in locally advanced-stage head and neck cancer. PATIENTS AND METHODS: After definitive local treatment with surgery, radiotherapy, or both, patients with locally advanced SCCHN were treated with 13-cRA (50 mg/m(2)/d, orally, daily), IFN-alpha (3 x 10(6) IU/m(2), subcutaneous injection, three times a week), and alpha-tocopherol (1,200 IU/d, orally, daily) for 12 months, with a dose modification. Screening for recurrence or SPTs was performed every 3 months. RESULTS: Tumors of 11 (24%) of the 45 treated patients were stage III, and 34 (76%) were stage IV. Thirty-eight (86%) of 44 patients completed the full 12-month treatment (doses modified as needed). Toxicity generally was consistent with previous IFN and 13-cRA reports and included mild to moderate mucocutaneous and flu-like symptoms; occasional significant fatigue (grade 3 in 7% of patients), mild to moderate hypertriglyceridemia in 30% of patients who continued treatment along with antilipid therapy, and mild hematologic side effects. Six patients did not complete the planned treatment because of intolerable toxicity or social problems. At a median 24-months of follow-up, our clinical end point rates were 9% for local/regional recurrence (four patients), 5% for local/regional recurrence and distant metastases (two patients), and 2% for SPT (one patient), which was acute promyelocytic leukemia (ie, not of the upper aerodigestive tract). Median 1- and 2-year rates of overall survival were 98% and 91%, respectively, and of disease-free survival were 91% and 84%, respectively. CONCLUSION: The novel biologic agent combination of IFN-alpha, 13-cRA, and alpha-tocopherol was generally well tolerated and promising as adjuvant therapy for locally advanced squamous cell carcinoma of the head and neck. We are currently conducting a phase III randomized study of this combination (v no treatment) to confirm these phase II study results.

Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma.

PURPOSE: To assess the activity and toxicity profile of combined taxol (paclitaxel), ifosfamide, and platinum (cisplatin) (TIP) in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck. PATIENTS AND METHODS: Recurrent or metastatic head and neck SCC patients received paclitaxel 175 mg/m2 in a 3-hour infusion on day 1; ifosfamide 1,000 mg/m2 in a 2-hour infusion on days 1 through 3; mesna 600 mg/m2 on days 1 through 3; and cisplatin 60 mg/m2 on day 1, repeated every 3 to 4 weeks. All were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic hematopoietic growth factors were not permitted. RESULTS: Fifty-two patients were assessable for response and toxicity; 53 for survival (local-regional recurrence alone in 57% and distant metastasis with or without local-regional recurrence in 43%). Overall response rate was 58% (30 of 52) of patients; complete response rate was 17% (nine of 52) of patients, with six complete responses that continued for a median 15.7+ months. Median follow-up of all patients was 17.7 months. Median survival was 8.8 months (95% confidence interval [CI] 8.1 to 17.5 months). Toxicity was relatively well tolerated and caused no deaths. The most frequent moderate-to-severe toxicity (90% of patients) was transient grades 3 to 4 neutropenia; neutropenic fever occurred in 27%. Grade 3 peripheral neuropathy occurred in three patients, none had grade 4. Grade 3 mucositis occurred in only one patient, none had grade 4. CONCLUSION: TIP had major activity in this setting, with a 58% objective response rate, 17% complete response rate, durable complete responses (six of nine persisting), and relatively well-tolerated toxicity, with no toxic deaths. The activity of TIP, a novel taxol-cisplatin-based regimen, in recurrent or metastatic head and neck SCC should be confirmed in a phase III trial.

Phase I/II trial of radiation with chemotherapy "boost" for advanced squamous cell carcinomas of the head and neck: toxicities and responses.

PURPOSE: Extrapolating from our experience delivering a "boost" field of radiation concurrently with fields treating both gross and subclinical disease at the end of a course of radiation therapy, we developed a regimen to deliver concurrent chemotherapy during the last 2 weeks of a conventionally fractionated course of radiation. PATIENTS AND METHODS: Patients had stage III or IV biopsy-proven squamous cell carcinoma originating from a head and neck mucosal site. The regimen was 70 Gy delivered over 7 weeks with concurrent fluorouracil (5-FU) and cisplatin given daily with each radiation dose during the last 2 weeks. A phase I study was performed to determine the maximum-tolerated dose (MTD) before a phase II study was conducted. RESULTS: The MTD was 400 mg/m(2) per day for 5-FU and 10 mg/m(2) per day for cisplatin. Mucositis persisting more than 6 weeks after therapy was the dose-limiting toxicity. A total of 60 patients were treated on the two phases of the study. Eighteen patients (35%) treated at the MTD developed prolonged mucositis. There were two cases of neutropenic sepsis, including one fatality. The actuarial 2-year rates for overall survival, freedom from relapse, and local control were 62%, 59%, and 80%, respectively. CONCLUSION: Preliminary locoregional control rates seem to be higher than those reported for treatment with radiation alone. Toxicity was also greater than that seen with radiation alone, but the regimen was designed to deliver an intense treatment schedule, which could be completed without significant interruptions, and to obtain high control rates above the clavicles. These end points were achieved.

Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas.

The study investigated whether a relationship exists between the extent of epidermal growth factor receptor (EGFR) expression and in vivo radiocurability of murine tumors. EGFR expression was determined in nine carcinomas (four mammary carcinomas, designated MCa-4, MCa-29, MCa-35, and MCa-K; two squamous cell carcinomas, designated SCC-IV and SCC-VII; an ovarian adenocarcinoma, OCa-I; a hepatocarcinoma, HCa-I; and an adenosquamous carcinoma, ACa-SG) syngeneic to C3Hf/Kam mice using Western blot analysis. These tumors greatly differed in their radioresponse, assessed by TCD50 assay, and in their susceptibility to radiation-induced apoptosis. Likewise, the expression of EGFR greatly varied, by as much as 21-fold, and the magnitude of the EGFR expression positively correlated with increased tumor radioresistance. The levels of EGFR inversely correlated with radiation-induced apoptosis, suggesting that the lack of sensitivity to apoptosis induction was a major mechanism responsible for radioresistance of tumors with high EGFR. This correlation was highly significant only for wild-type p53 carcinomas. Radiation activated EGFR autophosphorylation and increased the activity of protein tyrosine kinase, but only in tumors with high EGFR expression. Thus, EGFR expression was a major determinant of tumor radioresponse in vivo. The pretreatment assessment of EGFR expression could predict radiotherapy outcome and may assist in selecting an effective treatment modality.

Analysis of interleukin-2-activated killer cells of rhesus monkeys: striking resemblance to the human system.

We have found numerous and exquisite homologies between the interleukin-2 (IL-2)-activated killing systems of rhesus monkeys and humans. Lymphocytes with high oncolytic and proliferative activity were generated from peripheral blood, spleen, and bone marrow of monkeys after culture with IL-2. The distribution of lymphocyte subsets in IL-2 cultures closely paralleled that seen in humans, including a decrease in CD4+ and increase in CD8+, CD38+, and CD25+ lymphocytes and an increase in density of CD2 molecules. We also describe three distinct subsets of monkey lymphocytes, CD16+,56-, CD16+,56+"dim", and CD16-,56+"bright", and show that the CD56+"bright" subset is substantially increased (to as high as 79%) after IL-2 activation. Furthermore, as in humans, the cells with oncolytic activity were characterized as CD56+, CD16+/-, and CD8+. This strong homology with humans indicates that the rhesus monkey may be a valuable preclinical model for evaluation of therapeutically relevant biological response modifiers.

Acute side effects and late complications after radiotherapy of localized carcinoma of the prostate.

In the last two decades, many authors have treated prostatic carcinoma by radiation therapy. Accumulated data have been updated, after 10 and 15 years of follow-up. In stage A and B, the reported survival and local control rates after irradiation (20, 22, 30, 34, 35, 39, 42) are as good as in selected patients treated by radical prostatectomy (9, 18, 23). In stage C, the results after irradiation (20, 22, 30, 42) are better than after radical surgery (23, 43). However, patients are nonrandomly selected and the methods of statistical analysis differ. Therefore, a valid comparison cannot be made. The therapeutic ratio is determined by survival and local control, and also by therapy related complications. It is therefore of interest to find out from radiotherapy series if their incidence is related to the treatment technique. Unfortunately, relatively few studies accurately describe treatment technique and complications. Gastro-intestinal radiation injury becomes significant when the dose at the posterior rectal wall is 65-76 Gy and the length of the treated rectum is at least 10 cm. A hot spot of 80-84 Gy needs to be only 2 to 3 cm to increase the risk of late bowel stenosis. Genito-urinary complications are influenced by local extension of the tumor and by previous surgical manipulations. A dose at the prostatic area exceeding 70 Gy should be avoided, as it does not improve local control (22, 35) and apparently increases the risk of late urethral stricture and penile/scrotal edema (12, 39). The dose at the anterior bladder wall correlates with other types of genito-urinary complications. Therefore, the anterior bladder wall should not receive a dose higher than 65 Gy. Incidence of impaired potency after irradiation is usually 30 to 40%, which is much less than after radical surgery. As many data in the literature dealing with radiation treatment of the prostate are still inadequate a more standardized reporting is recommended to make comparison of effectiveness and side effects possible.

Altered fractionation trials in head and neck cancer.

Advancement in radiobiological concepts has led to the development of two classes of new fractionation schedules for the treatment of head and neck cancers. These altered fractionation regimens are referred to as hyperfractionation and accelerated fractionation schedules. Hyperfractionation exploits the difference in fractionation sensitivity between tumors and normal tissues manifesting late morbidity. In contrast, accelerated fractionations attempt to reduce tumor proliferation as a major cause of radiotherapy failure. Although there are many permutations in accelerating radiation treatment, the existing schedules can be conceptually grouped into two categories, pure accelerated fractionations and hybrid accelerated regimens, depending on whether there are concurrent changes in other fractionation parameters. The results of 10 completed phase III clinical trials addressing different types of altered fractionation schedules in head and neck carcinomas are examined and summarized in this review article. The data of trials on hyperfractionation regimens applying 10% to 15% total dose increment over the standard 66 to 70 Gy consistently revealed a 10% to 15% improvement in the local control rate of a subset of intermediate-stage carcinomas without an appreciable increase in the incidence of late complications. The available data on accelerated fractionation regimens showed that tumor clonogen proliferation is a major cause of radiation failure. Completed studies, however, revealed that a 1- to 1.5-week treatment acceleration without total dose reduction achieved by administering 2-Gy fractions 6 times per week or concomitant boost schedule yielded an approximately 15% higher tumor control rate without increasing late toxicity. Shortening the overall time to less than 2 weeks with an associated total dose reduction did not seem to improve tumor control rate, with an exception perhaps for a small subset of patients with laryngeal carcinomas, but might decrease some late normal tissue injury. A weekly dose accumulation rate of 14 Gy or greater, or delivery of 3 fractions of 1.6 Gy/d, with 6 hour intervals, without total dose reduction, was found to increase morbidity beyond the acceptable level. Further treatment refinements building on these findings are being pursued.

Tissue tolerance to reirradiation.

There are increasing requests for delivering a second course of radiation to patients who develop second primary tumors within or close to previous radiotherapy portal or late in-field recurrences. Rational treatment decisions demand rather precise knowledge on long-term recovery of occult radiation injury in various organs. This article summarizes available experimental and clinical data on the effects of reirradiation to the skin, mucosa, gut, lung, spinal cord, brain, heart, bladder, and kidney. The data reveal that, in general, acutely responding tissues recover radiation injury within a few months and, therefore, can tolerate another full course of radiation. For late toxicity endpoints, however, tissues vary considerably in their capacity to recover from occult radiation damage. The heart, bladder, and kidney do not exhibit long-term recovery at all. In contrast, the skin, mucosa, lung, and spinal cord do recover subclinical injury partially to a magnitude dependent on the organ type, size of the initial dose, and, to a lesser extent, the interval between radiation courses. The available clinical data have inspired many radiation oncologists to undertake systematic studies addressing the efficacy and toxicity of reirradiation in various clinical settings. Hopefully, systematic scoring, collection, and analysis of patient outcome will produce quantitative data useful for clinical practice.

An interactive system for point dose optimization.

An interactive system has been developed to aid in determining optimal photon and electron beams and beam weights for radiotherapy treatment planning. Dose constraints at various points are selected and an algorithm searches for a set of beams and weighting factors that satisfy these constraints. In the event that no combination of beam weights satisfies the choice of treatment modalities and dose constraints, the treatment modalities and dose constraints can be modified interactively. The goal of this procedure is different from that of more conventional optimization schemes in which optimal dose values are specified and the optimization algorithm determines the set of beam weights that yields a dose distribution closest to optimal.

Cervical lymph node metastases from occult squamous cell carcinoma: cut down a tree to get an apple?

PURPOSE: To review the value of extended diagnostic work-up procedures and to compare the results of comprehensive or volume-restricted radiotherapy in patients presenting with cervical lymph node metastases from clinically undetectable squamous cell carcinoma. METHODS AND MATERIALS: A systematic review was undertaken of published papers up to May 2000. RESULTS: Positron emission tomography (PET) has an overall staging accuracy of 69%, with a positive predictive value of 56% and negative predictive value of 86%. With negative routine clinical examination and computerized tomography (CT) or magnetic resonance imaging (MRI), PET detected primary tumors in 5-25% of patients, whereas ipsilateral tonsillectomy discovered carcinoma in about 25% of patients. Laser-induced fluorescence imaging with panendoscopy and directed biopsies showed some encouraging preliminary results and warrants further study. All together, the reported mucosal carcinoma emergence rates were 2-13% (median, 9.5%) after comprehensive radiotherapy and 5-44% (median, 8%) after unilateral neck irradiation. The corresponding nodal relapse rates were 8-45% (median, 19%) and 31-63% (median, 51.5%), and 5-year survival rates were 34-63% (median, 50%) and 22-41% (median, 36.5%), respectively. Retrospective single-institution comparisons between comprehensive and unilateral neck radiotherapy did not show apparent differences in outcome. Prognostic determinants for survival are the N stage, number of nodes, extracapsular extension, and histologic grade. No data were found to support the benefit of chemotherapy in this disease. CONCLUSION: Physical examination, CT or MRI, and panendoscopy with biopsies remain the standard work-up for these patients. Routine use of PET or laser-induced fluorescence imaging cannot be firmly advocated based on presently available data. Although combination of nodal dissection with comprehensive radiotherapy yielded most favorable results, its impact on the quality of life should be recognized, and the confounding effects of patient selection for various treatment modalities on therapeutic outcome cannot be ruled out. A randomized trial comparing the therapeutic value of comprehensive vs. volume-limited radiotherapy is being considered.

The tolerance to multiple daily fractionated radiotherapy for the treatment of prostatic and bladder carcinoma: a feasibility study.

A modified fractionation schedule was designed with the purpose of reducing the treatment burden. Three fractions of 2 Gy with four hours interval were given during 5 days. The whole scheme was repeated after a rest period of 4 weeks. This makes it possible to deliver a dose of 60 Gy in 10 treatment days and over a total time of 6 weeks. A total of 30 patients, 22 with prostatic cancer and 8 with invasive bladder carcinoma, have been treated. The feasibility has been found to be very good. Forty-seven percent of the patients had acute morbidity, although it was mild in all patients. One patient had a persistent, another had a transient delayed symptom, and one had a severe late complication. The tolerance to this schedule is better than that observed with conventional fractionation schedules. Together with the drastic reduction of the total treatment days, this multiple daily fractionation (MDF) schedule has already been shown to improve the therapeutic ratio by diminishing the burden on the patients. Longer follow-up necessary for the assessment of the efficacy of this schedule for local tumor control. However, with a follow-up period of 7 to 16 months no recurrence of the prostate cancer in the pelvis has been observed. These results warrant further exploration of the possible benefits of modifications in time-dose-fractionation schedules.

Differences in repopulation kinetics in mouse skin during split course multiple fractions per day (MFD) or daily fractionated irradiations.

The influence of protraction and distribution of irradiation as a function of time on the repopulation kinetics of mouse skin have been evaluated. Twenty fractions have been given either daily for 5 days per week during 4 weeks, or thrice a day to 10 irradiations in 3 days, repeated after a rest period of 19 days, resulting also in an overall time of 4 weeks. The acute skin reaction was scored. It was found that the split course multiple fractions per day (MFD) schedule induced less skin reaction than continuous daily fractionation, which was mainly attributable to recovery of skin damage during the rest period. Therefore, it can be postulated that the repopulation of the surviving clonogenic epidermal cells is less efficient during continuous daily irradiation than during split course MFD schedule given in the same overall treatment time.

The effect of actinomycin D on radiation induced reactions of the lip mucosa of mice.

The interaction of intraperitoneally injected Actinomycin D and irradiation was investigated in the lip mucosa of NMRI mice. In this rapidly proliferating tissue, a semiquantitative assessment of possible modifications of the radiation response by a drug can be done without using lethality as an endpoint. It was shown that a single dose of 0.5 mg/kg drug given at different times between 24 hr prior to and 24 hr after single radiation doses did not effect the rate of development nor the intensity of mucosal radiation damage. With extended time intervals of 2, 3, or 7 days between both single agents, a slight increase of the lip mucosal reaction was measured. Similar results were obtained when 5 daily drug injections of 0.15 mg/kg were administered starting at day 5 after a single radiation exposure. No differences in response could be demonstrated when fractionated irradiations with intervals ranging from 1 to 24 hr were closely combined with either single or repeated drug treatments (0.5 mg/kg in total) as compared to irradiation alone. However, a slight modification of the iso-effect dose was measured when 0.5 mg/kg Actinomycin D was administered at various periods in between 2 radiation doses separated by 10 days. A maximal effect was measured with 5 daily injections of 0.15 mg/kg drug each and given at a time when proliferative capacity was high. With 0.1 mg/kg Actinomycin D per daily injection, no enhancement of the radiation injury was found. Thus, in these circumstances no influence of Actinomycin D on radiosensitivity nor on repair of sublethal damage could be demonstrated. A clear inhibitory effect on lip mucosal repopulation by the drug is evident, but only at high drug doses close to toxic concentrations.

C225 antiepidermal growth factor receptor antibody enhances tumor radiocurability.

PURPOSE: Overexpression of epidermal growth factor receptor (EGFR) has been correlated with tumor resistance to radiation. Blockade of EGFR with C225 anti-EGFR antibody was previously shown to synergistically enhance radiation-induced tumor growth delay. The purpose of this study was to assess whether C225 can increase tumor cure by radiation. METHODS AND MATERIALS: Nude mice bearing 8-mm-diameter A431 tumor xenografts in the hind leg were treated with C225 antibody, graded single doses of local tumor irradiation, or both. C225 was given i.p. at a dose of 1 mg/mouse 6 h before irradiation or 6 h before and 3 plus 6 days after irradiation. Tumor cure was the treatment endpoint assessed by the TCD(50) assay 120 days after treatment. The onset of recurrences of tumors not cured was also determined. RESULTS: C225 antibody increased the antitumor effects of radiation by reducing TCD(50) values and delaying tumor recurrences. Tumor radiocurability was enhanced by a factor of 1.18 by a single dose and by a factor of 1.92 by three doses of C225. Likewise, the appearance of tumor recurrences was delayed by a factor of 1.37 by a single dose and by a factor of 2.13 by three doses of C225. CONCLUSION: The data presented here demonstrate that C225 can increase tumor radiocurability and delay the appearance of recurrences of tumors not cured by radiation treatment.