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101 Novel drug radiotherapy combination
$30 Thursday, 1 February 2001
98
oral
Severe late anorectal radiation morbidity following post operative radiotherapy for rectal cancer - Longtime results from a randomized trial L. Lundby, K. Krogh, N. Qvist, P. Gandrup, V. Jense, S. Laurberg, J. Overgaard Aalborg, Odense and Aarhus University Hospital, Denmark. Background & aim: radiation injury of the gastrointestinal tract is a wellknown complication of therapeutic radiation delivered to the abdomen and pelvis. The objective of this study was to evaluate Iong4erm morbidity of adjuvant postoperative radiotherapy on anorectal function in patients with rectal cancer. Patients and methods: 494 patients with rectal cancer participated during 1979-1985 in a randomized multicenter study of anterior resection followed by radiotherapy (+RT), 50 Gy in daily fractions of 2 Gy, versus surgery alone (-RT). There was no long-term difference in survival between the two groups (1). In 1998 there were 84 patients with Iongtime survival without recurrence (2). All the patients were invited to participate in the study. Anorectal function was evaluated in 28 patients. Fifteen patients had received +RT and thirteen -RT. Anorectal function was assessed based on subjective symptoms, sigmoidoscopy, anorectal manometry, anorectal sensation and capacity, anal ultrasound and rectal impedance planimetry. Results: thirteen of the irradiated patients had diarrhea and increased stool frequency. Nine patients suffered from fecal incontinence and seven had to use a pad. Three patients in the -RT group had increased stool frequency and one complained of incontinence. Mucosal atrophy and teiangiectasias assessed by sigmoidoscopy were found in eleven of the +RT patients and in four -RT. The maximum squeeze pressure and rectal capacity were significantly decreased (p=0.03). Rectal impedance planimetry measurements (cross-sectional area-pressure) were significantly different in the two groups (p<0.0001) indicating that the rectum in the +RT group had become rigid and undistensible. Anorectal ultrasound showed no difference in thickness of the anal sphincters between the two groups. Conclusion: adjuvant postoperative radiotherapy after anterior resection causes severe long-term anorectal dysfunction including weakness of the external anal sphincters and stiffness of the rectal wall. Supported by the Danish Cancer Society. Ref. (1) Cancer; 58:22-28, 1986, (2) Lancet; 350: 564, 1997.
CHEMOTHERAPY / RADIOTHERAPY 99
Strategies for drug-radiation combinations L. Peters, D. Rischin Peter Mac Callum Cancer Institute, Melbourne, Australia Rational sequencing and choice of agents for chemo-radiotherapy of advanced head and neck cancer depends on a clear understanding of the underlying strategy or strategies for the use of combined medality treatment. The predominant strategies are: to increase the probability of localregional disease control, to reduce the risk of distant metastasis and to select patients for non-surgical therapy. For the first, chemotherapy is best given concurrently with radiotherapy using agents that sensitise tumor cells to radiation or complement its cytotoxicity eg by targeting hypoxic cells. For the second, chemotherapy should be given sequentially at higher doses and for multiple cycles before and/or after radiotherapy using agents that have the greatest independent action against tumor cells. For the last strategy, the aim should be to give the minimum amount of chemotherapy required to determine chemo-responsiveness using drugs whose action predicts for radiosensitivity. Examples of each of these strategies alone and in combination will be provided by reference to clinical trials undertaken at the Peter MacCallum Cancer Institute for treatment of advanced oropharyngeal, nasopharyngeal and laryngeal cancers. lOO
Acute and late toxicity in chemo-radiation treatment (additive - interactive) P. Olmi 1, L. Cionini2, C. Fallai3, M. Amichetti4, M. Panichi5 V. Torri6 1University of Florence, Department of Radiotherapy, Firenze, Italy 2University of Pisa, Department of Radiotherapy, Pisa, Italy 3University of Florence, Department of Radiotherapy, Firenze, Italy 4Santa Chiara Hospital, Department of Radiotherapy, Trento, Italy 5Research Institute, Milano, Italy
Symposia
During the last few years radiation therapy (RT) with altered fractionation and combination of chemotherapy (CT) and RT have been the most experimented treatment approach in order to obtain better results in tumors with advanced stage and failing mainly with Ioco-regional relapses. Today, many researchers are convinced that the strategy with combination of CT and RT could give the best results, if it were not for the limitation represented by toxicity. Unfortunately, a correct evaluation of combined treatment is not always possible because the majority of studies are single-arm trials and acute and late toxicities are not always reported in detail. Three Italian experiences will be presented focusing on the acute and late toxicity: 1) Bladder Carcinoma: experience of Radiotherapy Dept. of Trento on 56 patients, T2-T4, N0-X, M0 treated with induction chemotherapy x 2 cycles cystoscopy - RT on pelvis 40 Gy + CDDP 70 mg/m 2 on day 1 and 22: if complete response (CR) RT 24 Gy + CDDP; if not CR cystectomy CT-related G3 and 4 acute toxicity due to chemotherapy and RT-related acute and late toxicity will be reported 2) Randomised multicentric study with pre-operative combined radiochemotherapy _+postoperative chemotherapy in locally advanced rectum cancer : 614 recruited patients subdivided in arm A ( 288 pts) and in arm B (315 pts), classified as B2, B3 (unknown in 38 cases) according to Astler & Coller classification. 544 pts underwent to treatment. Toxicity will be analysed in relation to number of cycles given preoperatively (less than the 2 planned cycles), treatment breaks (both for chemotherapy and radiotherapy), types of surgery after the first part of treatment and related complications; the toxicity of cases who underwent to post-operative chemotherapy (315 cases) will be reported separately. 3) Loco-regionally advanced carcinoma of the oropharynx: conventional radiotherapy versus accelerated hyperfractionated radiotherapy vs. concomitant radio-chemotherapy: a multicentric randomised trial: 192 recruited pts, subdivided in three arms, stage III and IV, with the exclusion of T1 N1 and T2N1 lesions. We will analyse the acute and late toxicity of three arms. In the above mentioned studies the toxicity was scored according to RTOG and/or WHO scale. 101
Novel drug radiotherapy combination F. Eschweae Institut Gustave Roussy, Department of Radiotherapy, Villejuif, France The combination of chemotherapy and radiation has constituted since 40 years one of the main subject of research in oncology. The exact place of neoadjuvant or concomitant chemo-radiotherapy is not fully elucidated as the biological mechanismes of the combination. The main drugs used in the combination of CT-and RT are often ancient (5Fu, Cisplatin, Carboplatin, Hydroxyurea, Mitomycine, Etoposide, etc...) and lead to different biological mechanisms explaining the results obtained in clinic as inhibition of repairs of damage, cytokinetic effects depending on the phase in the cell cycle or of the hypoxycity of the tumour. Enhancement of oxygenation increased apoptosis, or pharmacomodulation of drug concentration (inside the cell) by ionizing radiation are among the main potential interactions. The gains have usually come at the cost of an increasing rate of morbidity needing agressive supportive care, more recently other agents such as taxanes, topoisomerase inhibitors (I and II) as topotecan, hypoxic cell cytotoxic drugs as tirapazamine or porphyromicin and radiosensitizing agents (not directly cytotoxic) are under investigation ; among them fluodarabin and gemcitabin have shown interesting preliminary results, even if the mechanisms for interaction between gemcitabin and ionizing radiation have yet to be fully elucitated with probably several mechanisms as for fludarabin. The utilisation of angiostatin angiogenesis inhibitor) have shown in animal models a synergistic activity when combined with radiotherapy and the role of angiogenesis inhibitor combined with radiotherapy is one of the major new possibilities in the treatment of cancers. 102
Effect of chemotherapy on survival of patients with HNSCC J. Bourhi& J.P. Pignon Institut Gustave Roussy, Villejuif, France on behalf of the MACH-NC collaborative group. The effect of chemotherapy on survival of patients with a carcinoma of the oropharynx oral cavity, larynx and hypopharynx was assessed in 3 metaanalyses based on the collection of updated patient data from randomized trials performed between 1965 and 1993. The first meta-analysis included 63 trials (10850 patients randomized), comparing Ioco-regional treatment versus the same Ioco-regional treatment + chemotherapy. The pooled relative risk of death was 0.90 (95% confidence interval (CI) = 0.85-0.94, P < 0.0001) which translated in an absolute survival benefit of 4% at 2 and 5 years in favour of chemothera-
98
oral
Severe late anorectal radiation morbidity following post operative radiotherapy for rectal cancer - Longtime results from a randomized trial L. Lundby, K. Krogh, N. Qvist, P. Gandrup, V. Jense, S. Laurberg, J. Overgaard Aalborg, Odense and Aarhus University Hospital, Denmark. Background & aim: radiation injury of the gastrointestinal tract is a wellknown complication of therapeutic radiation delivered to the abdomen and pelvis. The objective of this study was to evaluate Iong4erm morbidity of adjuvant postoperative radiotherapy on anorectal function in patients with rectal cancer. Patients and methods: 494 patients with rectal cancer participated during 1979-1985 in a randomized multicenter study of anterior resection followed by radiotherapy (+RT), 50 Gy in daily fractions of 2 Gy, versus surgery alone (-RT). There was no long-term difference in survival between the two groups (1). In 1998 there were 84 patients with Iongtime survival without recurrence (2). All the patients were invited to participate in the study. Anorectal function was evaluated in 28 patients. Fifteen patients had received +RT and thirteen -RT. Anorectal function was assessed based on subjective symptoms, sigmoidoscopy, anorectal manometry, anorectal sensation and capacity, anal ultrasound and rectal impedance planimetry. Results: thirteen of the irradiated patients had diarrhea and increased stool frequency. Nine patients suffered from fecal incontinence and seven had to use a pad. Three patients in the -RT group had increased stool frequency and one complained of incontinence. Mucosal atrophy and teiangiectasias assessed by sigmoidoscopy were found in eleven of the +RT patients and in four -RT. The maximum squeeze pressure and rectal capacity were significantly decreased (p=0.03). Rectal impedance planimetry measurements (cross-sectional area-pressure) were significantly different in the two groups (p<0.0001) indicating that the rectum in the +RT group had become rigid and undistensible. Anorectal ultrasound showed no difference in thickness of the anal sphincters between the two groups. Conclusion: adjuvant postoperative radiotherapy after anterior resection causes severe long-term anorectal dysfunction including weakness of the external anal sphincters and stiffness of the rectal wall. Supported by the Danish Cancer Society. Ref. (1) Cancer; 58:22-28, 1986, (2) Lancet; 350: 564, 1997.
CHEMOTHERAPY / RADIOTHERAPY 99
Strategies for drug-radiation combinations L. Peters, D. Rischin Peter Mac Callum Cancer Institute, Melbourne, Australia Rational sequencing and choice of agents for chemo-radiotherapy of advanced head and neck cancer depends on a clear understanding of the underlying strategy or strategies for the use of combined medality treatment. The predominant strategies are: to increase the probability of localregional disease control, to reduce the risk of distant metastasis and to select patients for non-surgical therapy. For the first, chemotherapy is best given concurrently with radiotherapy using agents that sensitise tumor cells to radiation or complement its cytotoxicity eg by targeting hypoxic cells. For the second, chemotherapy should be given sequentially at higher doses and for multiple cycles before and/or after radiotherapy using agents that have the greatest independent action against tumor cells. For the last strategy, the aim should be to give the minimum amount of chemotherapy required to determine chemo-responsiveness using drugs whose action predicts for radiosensitivity. Examples of each of these strategies alone and in combination will be provided by reference to clinical trials undertaken at the Peter MacCallum Cancer Institute for treatment of advanced oropharyngeal, nasopharyngeal and laryngeal cancers. lOO
Acute and late toxicity in chemo-radiation treatment (additive - interactive) P. Olmi 1, L. Cionini2, C. Fallai3, M. Amichetti4, M. Panichi5 V. Torri6 1University of Florence, Department of Radiotherapy, Firenze, Italy 2University of Pisa, Department of Radiotherapy, Pisa, Italy 3University of Florence, Department of Radiotherapy, Firenze, Italy 4Santa Chiara Hospital, Department of Radiotherapy, Trento, Italy 5Research Institute, Milano, Italy
Symposia
During the last few years radiation therapy (RT) with altered fractionation and combination of chemotherapy (CT) and RT have been the most experimented treatment approach in order to obtain better results in tumors with advanced stage and failing mainly with Ioco-regional relapses. Today, many researchers are convinced that the strategy with combination of CT and RT could give the best results, if it were not for the limitation represented by toxicity. Unfortunately, a correct evaluation of combined treatment is not always possible because the majority of studies are single-arm trials and acute and late toxicities are not always reported in detail. Three Italian experiences will be presented focusing on the acute and late toxicity: 1) Bladder Carcinoma: experience of Radiotherapy Dept. of Trento on 56 patients, T2-T4, N0-X, M0 treated with induction chemotherapy x 2 cycles cystoscopy - RT on pelvis 40 Gy + CDDP 70 mg/m 2 on day 1 and 22: if complete response (CR) RT 24 Gy + CDDP; if not CR cystectomy CT-related G3 and 4 acute toxicity due to chemotherapy and RT-related acute and late toxicity will be reported 2) Randomised multicentric study with pre-operative combined radiochemotherapy _+postoperative chemotherapy in locally advanced rectum cancer : 614 recruited patients subdivided in arm A ( 288 pts) and in arm B (315 pts), classified as B2, B3 (unknown in 38 cases) according to Astler & Coller classification. 544 pts underwent to treatment. Toxicity will be analysed in relation to number of cycles given preoperatively (less than the 2 planned cycles), treatment breaks (both for chemotherapy and radiotherapy), types of surgery after the first part of treatment and related complications; the toxicity of cases who underwent to post-operative chemotherapy (315 cases) will be reported separately. 3) Loco-regionally advanced carcinoma of the oropharynx: conventional radiotherapy versus accelerated hyperfractionated radiotherapy vs. concomitant radio-chemotherapy: a multicentric randomised trial: 192 recruited pts, subdivided in three arms, stage III and IV, with the exclusion of T1 N1 and T2N1 lesions. We will analyse the acute and late toxicity of three arms. In the above mentioned studies the toxicity was scored according to RTOG and/or WHO scale. 101
Novel drug radiotherapy combination F. Eschweae Institut Gustave Roussy, Department of Radiotherapy, Villejuif, France The combination of chemotherapy and radiation has constituted since 40 years one of the main subject of research in oncology. The exact place of neoadjuvant or concomitant chemo-radiotherapy is not fully elucidated as the biological mechanismes of the combination. The main drugs used in the combination of CT-and RT are often ancient (5Fu, Cisplatin, Carboplatin, Hydroxyurea, Mitomycine, Etoposide, etc...) and lead to different biological mechanisms explaining the results obtained in clinic as inhibition of repairs of damage, cytokinetic effects depending on the phase in the cell cycle or of the hypoxycity of the tumour. Enhancement of oxygenation increased apoptosis, or pharmacomodulation of drug concentration (inside the cell) by ionizing radiation are among the main potential interactions. The gains have usually come at the cost of an increasing rate of morbidity needing agressive supportive care, more recently other agents such as taxanes, topoisomerase inhibitors (I and II) as topotecan, hypoxic cell cytotoxic drugs as tirapazamine or porphyromicin and radiosensitizing agents (not directly cytotoxic) are under investigation ; among them fluodarabin and gemcitabin have shown interesting preliminary results, even if the mechanisms for interaction between gemcitabin and ionizing radiation have yet to be fully elucitated with probably several mechanisms as for fludarabin. The utilisation of angiostatin angiogenesis inhibitor) have shown in animal models a synergistic activity when combined with radiotherapy and the role of angiogenesis inhibitor combined with radiotherapy is one of the major new possibilities in the treatment of cancers. 102
Effect of chemotherapy on survival of patients with HNSCC J. Bourhi& J.P. Pignon Institut Gustave Roussy, Villejuif, France on behalf of the MACH-NC collaborative group. The effect of chemotherapy on survival of patients with a carcinoma of the oropharynx oral cavity, larynx and hypopharynx was assessed in 3 metaanalyses based on the collection of updated patient data from randomized trials performed between 1965 and 1993. The first meta-analysis included 63 trials (10850 patients randomized), comparing Ioco-regional treatment versus the same Ioco-regional treatment + chemotherapy. The pooled relative risk of death was 0.90 (95% confidence interval (CI) = 0.85-0.94, P < 0.0001) which translated in an absolute survival benefit of 4% at 2 and 5 years in favour of chemothera-