Meyer JL, Vaeth JM (eds): Radiotherapy/Chemotherapy Interactions in Cancer Therapy. Front Radiat Ther mcii. Basel, Karger, 1992, vol 26, pp 72-82
Radiation-Chemotherapy Interactions in Limited Small Cell Lung Cancer Robert B. Livingston Division of Oncology, University of Washington, Seattle, Wash., USA
Historical Development of Combined Modality Treatment in SCLC - Sequential Model
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The paradigm chosen by Livingston et al. [ 1] and Holoye and Samuels [2] in their initial use of combined modality therapy for SCLC was that of chemo -+ XRT --> chemo, the `sandwich' approach pioneered with success in the management of pediatric cancers. It was chosen because SCLC, like these tumors, appeared to be both `chemosensitive' and `radiosensitive', using a rapid tumor shrinkage with readily tolerated doses as the criterion for sensitivity. Also, the initial programs of combination chemotherapy all involved the use of agents which can enhance acute radiation effects on normal tissue via their systemic toxicities (as well as, in some cases by specific radiosensitization, called `radiation recall' when seen after completion of the radiotherapy) : these are outlined in table 1. Thus, it was obvious that normal tissue toxicities could be minimized by giving the modalities in sequence, rather than concurrently. Although the results were improved over radiation therapy used alone, in limited SCLC the primary tumor proved to be a common initial site of treatment failure when the `sandwich' approach was employed (table 2). This was perceived as a failure of the local modality, and three reasons were frequently suggested: inadequate field size; inadequate dose; and inherent tumor resistance. The Southwest Oncology Group (SWIG) addressed the issue of field size in a prospective, controlled trial [3]; patients with an initial partial response (PR) to combination chemotherapy were randomized to treatment with a large, `pre-induction' field encompassing all the tumor evident on X-ray before chemotherapy, or to the smaller, `postinduction' treatment volume evident after chemotherapy. There was no survival advantage to the larger volume (although regional recurrences were reduced) and there were more long-term disease-free survivors in the reduced-field group (17 vs. 7% at 2 years). No randomized trial of dose for
Radiation-Chemotherapy Interactions in Limited SCLC
73
Table Ι. `First generation' programs of combination chemotherapy used in combined modality treatment of limited SCLC Regimen
Agents
Normal tissue interactive components with XRT intrathoracic
CAV CMC ± V CMC-VAP POCC
cyclophosphamide, adriamycin (doxorubicin), vincristine cycloposphamide, methotrexate, CCNU (lomustine) ± vincristine (as above) + vincristine, adriamycin, procarbazine procarbazine, oncovin (vincristine), CCNU, cyclophosphamide
brain
adriamycin methotrexate methotrexate, adriamycin —
CCNU, methotrexate CCNU, procarbazine CCNU, procarbazine
Downloaded by: Université de Paris 193.51.85.197 - 1/6/2020 7:38:36 AM
radiation therapy has been conducted. However, in a SWIG trial where there was an investigator's option of 3,000 vs. 4,500 cGy total dose, apparent superiority for the higher dose was demonstrated [4]: 2-year survival was 35 vs. 20%. Retrospective analysis by Cox et al. [5] reached the same conclusion, and most programs of chest irradiation now aim for `cord tolerance' doses delivered by AP-PA fields, followed by a `boost' to the apparent remaining tumor volume to 6,000 cGy in 6 weeks, or its radiobiologic equivalent with higher daily dose and shorter duration. Four major trials of chemotherapy alone versus the combined modalities in sequence were reported in the 1980s. Souhami et al. [6] for the MRC in England studied four cycles of AV-CM (adriamycin plus vincristine, alternating with cyclophosphamide plus methotrexate), or the same program followed by chest irradiation (4,000 cGy in 4 weeks): the results were identical. Similar findings were reported by Osterlind et al. [7] from Denmark, in a study which compared CCM-V (cyclophosphamide, CCNU, methotrexate and vincristine) to CCM-V with sequenced, splitcourse irradiation delivered in weeks 6 and 10 of chemotherapy. Kies et al. [3] for SWIG focussed on patients who achieved complete response (CR) after induction chemotherapy with VMV/VAC (VP-16, methotrexate and vincristine alternating with vincristine, adriamycin and cyclophosphamide). This trial showed no benefit from sequential chest irradiation, and led our group to abandon the `sandwich' model. The fourth study, reported by Perry et al. [8] for the Cancer and Leukemia Group B, did demonstrate a modest advantage at 2 years (25 vs. 15%) for the sequential, combined modality approach vs. CEV (cyclophosphamide, etoposide, vincristine) alone, but in that trial the `sequential' irradiation was delivered concur-
Livingston
74
Table 2. Local failure as a site of initial relapse in combined modality trials for limited small cell lung cancer Study
Ref. No.
Number of patients
Chemotherapy
Radiotherapy
Local failure' %:XRT/no XRT
Sequential SWIG Finsen MRC NCI-C SWIG
1 7 6 36 3
108 145 371 300 153
CAV CMC-V AV/CM CAV/PE VMV/CAV
4,500 cGy, split 4,000 cGy, split 4,000 cGy, continuous 2,500-3,750 cGy, continuous 4,800 cGy, split
50 61/85 28/32 50 56/90
Alternating SEG
13
304
CAV
4,000 cGy, split
36/52
Concurrent CALGB NCI-Navy SWIG Turrisi
8 10 21 23
426 96 154 34
CEV CMC-NAP PEN PE
40/67 26/52 16 0
NCI-Navy
29
18
5,000 cGy, continuous 4,000 cGy, continuous 4,500 cGy, continuous 4,500 c~iy, continuous hyperfractionated 4,500 cGy, continuous hyperfractionated
PE
14
As the initial site of relapse.
rently with the fourth cycle of chemotherapy. The interpretation of this as a positive trial is tempered by the virtually identical median survival and the fact that there was still a 40% local failure rate in the combined modality arm. The Concurrent Model
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The NCI-Navy group and its predecessor at the NCI-VA pioneered the use of concurrent combined modalities in limited SCLC. An analysis of treatment factors leading to prolonged survival led them to conclude that initial, concurrent treatment was superior to sequential treatment, in their nonrandomized experience [9]. This in turn led to a randomized trial in which CMC-VAP (cyclophosphamide, methotrexate and CCNU alternating with vincristine, adriamycin and procarbazine) alone was compared to the same chemotherapy plus initial, concurrent radiotherapy (4,000 cGy in 15 fractions over 3 weeks). To minimize normal tissue toxicity, a shrinking field technique was employed after five and ten treatments, and a posterior spinal cord block was placed after 2,400 cGy. All patients felt to be in CR
Radiation-Chemotherapy Interactions in Limited SCLC
75
received prophylactic cranial irradiation (PCI), given as 2,400 cGy in eight fractions over 2 weeks. The combined therapy produced superior local control of the chest tumor in CR patients (13 vs. 29% chest only failure) and significantly improved survival (median, 15 vs. 11.6 months), but at the price of significantly more myelosuppression, weight loss, esophagitis, and pulmonary dysfunction [ 10]. A second randomized trial which involved concurrent, initial use of a `normal tissue interactive' chemotherapy program was that by Birch et al. [ 11] for the Southeastern Group, which demonstrated greater toxicity in the combined modality arm, identical median survivals, and a marginally greater proportion of long-term survivors in the irradiated group [Greco, personal commun ] Perry et al. [8] found that concurrent initial chest irradiation and CEV was superior to CEV alone, but slightly inferior to the concurrent, delayed approach (20 vs. 25% alive at 2 years) for the two modalites [8]; however, subsequent cycles of chemotherapy were markedly attenuated in the arm receiving immediate chest irradiation. As pointed out by Turrisi [21]; it is uncertain if the poorer results seen in the group given radiotherapy immediately were caused by the physicians' reluctance to continue intensive chemotherapy or by the regimen itself. A final randomized trial with normal tissue interactive chemotherapy, reported by Perez et al. [ 13] for the Southeastern Group, defies simple categorization: it involved delayed administration of chest and brain irradiation, beginning just prior to the third cycle of CAV (cyclophosphamide, adriamycin and vincristine) chemotherapy, versus two cycles of CAV followed by brain irradiation and more chemotherapy. In the group randomized to chest irradiation, an unusual tripartite, alternating split course was used (1,200 cGy in 5 fractions x 3), each time followed the next week by a pulse of CAV. Survival was significantly prolonged by the combined modality approach (median, 60 vs. 49 weeks), with 2-year survivals of 28 and 19%, respectively. The rate of intrathoracic failure was 36 and 52%, while gastrointestinal toxicity appeared comparable. Development of Combined Modalities with Minimal Normal Tissue Interaction
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Even though trials of simultaneous or rapidly alternating combined modalities appeared to offer a modest advantage, concurrent chemotherapy regimens which had major normal tissue interactions with radiation to the chest all produced an increase in toxicity. Not only was there compounding of chemotherapy-related myelosuppression but esophagitis and pneumoni-
Livingston
76
Downloaded by: Université de Paris 193.51.85.197 - 1/6/2020 7:38:36 AM
tis related to radiation therapy were clearly increased in incidence and severity, compared to what would have been expected with radiation alone [10, 11]. The development of cisplatin and etoposide (VP-16) as a two-drug regimen (ΡΕ) allowed the next step forward. Cisplatin is an agent which produces no stomatitis or esophagitis at normal doses, and little myelosuppression. Its dose-limiting toxicities of nephropathy and vomiting can be effectively managed by modern techniques of hydration and antiemetic therapy [ 14, 15], with sensory neuropathy and ototoxicity as remaining serious side effects. Used alone, cisplatin appeared to have modest activity in SCLC [ 16], but combined with etoposide there seemed to be clinical synergism, with CR rates of 50% or greater in limited disease [ 17] and evidence for some lack of cross-resistance with CAV and other `standard' regimens [ 18]. Etoposide at normal doses has myelosuppression as its only common serious side effect. Although cisplatin has some weak radiosensitizing properties [ 19, 20] it is not nearly as potent in this repect as adriamycin, and neither cisplatin nor etoposide have been clinically implicated in `radiation recall' toxicity. In a study reported for the SWIG, McCracken et al. [21] combined PE with vincristine and concurrent, initial chest irradiation at 180 cGy per fraction to a total dose of 4,500 cGy. At the completion of combined modality induction, consolidation chemotherapy was administered with vincristine plus methotrexate/etoposide alternating with adriamycin and cyclophosphamide. Among 154 patients, CR occurred in 56%, with a median survival of 18 months. Most strikingly, 30% survived to 4 years and 25% to 5 years, a result which appears superior to any other reported cooperative group experience (table 3). Pater et al. [22] for NCI Canada have now completed a randomized trial in which PE was administered concurrently with chest irradiation (4,000 cGy in 3 weeks), either with the first cycle of PE or with the third and final PE cycle in a sequence of alternating CAV/PE chemotherapy. The early administration of thoracic irradiation did not compromise chemotherapy, as the dose intensity for each chemotherapy agent was nearly identical in the two arms. The earlier administration of the two modalities appears superior, from analysis yet to be presented fully [Murray, personal commun., 1991]. Table 4 summarizes the normal tissue toxicity within the thorax of 7 combined modality trials in limited SCLC, using a variety of regimens. For chemotherapy programs containing adriamycin and/or methotrexate, it is clear that sequential administration produces less esophagitis, pneumonitis and cardiac toxicity than concurrent administration; the alternating program reported by Perez et al. [ 13] appears intermediate. Remarkably, PEV concurrent with chest irradiation, as reported by McCracken et al. [21], produced less intrathoracic toxicity than the sequential administration of
Radiation-Chemotherapy Interactioπs in Limited SCLC
77
Table 3. Survival in combined modality trials for limited small cell lung cancer Ref. No.
Study
Number of patients
Chemotherapy
Radiotherapy
Survival % at 2 years
Sequential SWIG Finsen
9 7
108 145
CAV CMC-V
MRC
6
371
AV/CM
36 3
300 153
CAV/PE VMV/CAV
4,500 cGy, split
+4,800 cGy, split
20 10 7 15 15 18 23 23
+4,000 cGy, split
19 28
+4,000 cGy, split
NCI-C SWIG
Alternating SEG
Concurrent CALGB
13
8
304
426
+4,000 cGy, continuous 2,500-3,750 cGy, continuous
CAV
CEV +5,000 cGy, continuous
NCI-Navy
10
96
SWIG Turrisi
21 23
154 34
NCI-Navy
26
18
CMC-NAP PEV PE PE
+4,000 cGy, continuous 4,500 cGy, continuous 4,500 cGy, continuous hyperfractionated 4,500 cGy, continuous hyperfractionated
15 20-25 10 28 42 53
5 years
9
Radiation-Chemotherapy Interactions in Limited Small Cell Lung Cancer Robert B. Livingston Division of Oncology, University of Washington, Seattle, Wash., USA
Historical Development of Combined Modality Treatment in SCLC - Sequential Model
Downloaded by: Université de Paris 193.51.85.197 - 1/6/2020 7:38:36 AM
The paradigm chosen by Livingston et al. [ 1] and Holoye and Samuels [2] in their initial use of combined modality therapy for SCLC was that of chemo -+ XRT --> chemo, the `sandwich' approach pioneered with success in the management of pediatric cancers. It was chosen because SCLC, like these tumors, appeared to be both `chemosensitive' and `radiosensitive', using a rapid tumor shrinkage with readily tolerated doses as the criterion for sensitivity. Also, the initial programs of combination chemotherapy all involved the use of agents which can enhance acute radiation effects on normal tissue via their systemic toxicities (as well as, in some cases by specific radiosensitization, called `radiation recall' when seen after completion of the radiotherapy) : these are outlined in table 1. Thus, it was obvious that normal tissue toxicities could be minimized by giving the modalities in sequence, rather than concurrently. Although the results were improved over radiation therapy used alone, in limited SCLC the primary tumor proved to be a common initial site of treatment failure when the `sandwich' approach was employed (table 2). This was perceived as a failure of the local modality, and three reasons were frequently suggested: inadequate field size; inadequate dose; and inherent tumor resistance. The Southwest Oncology Group (SWIG) addressed the issue of field size in a prospective, controlled trial [3]; patients with an initial partial response (PR) to combination chemotherapy were randomized to treatment with a large, `pre-induction' field encompassing all the tumor evident on X-ray before chemotherapy, or to the smaller, `postinduction' treatment volume evident after chemotherapy. There was no survival advantage to the larger volume (although regional recurrences were reduced) and there were more long-term disease-free survivors in the reduced-field group (17 vs. 7% at 2 years). No randomized trial of dose for
Radiation-Chemotherapy Interactions in Limited SCLC
73
Table Ι. `First generation' programs of combination chemotherapy used in combined modality treatment of limited SCLC Regimen
Agents
Normal tissue interactive components with XRT intrathoracic
CAV CMC ± V CMC-VAP POCC
cyclophosphamide, adriamycin (doxorubicin), vincristine cycloposphamide, methotrexate, CCNU (lomustine) ± vincristine (as above) + vincristine, adriamycin, procarbazine procarbazine, oncovin (vincristine), CCNU, cyclophosphamide
brain
adriamycin methotrexate methotrexate, adriamycin —
CCNU, methotrexate CCNU, procarbazine CCNU, procarbazine
Downloaded by: Université de Paris 193.51.85.197 - 1/6/2020 7:38:36 AM
radiation therapy has been conducted. However, in a SWIG trial where there was an investigator's option of 3,000 vs. 4,500 cGy total dose, apparent superiority for the higher dose was demonstrated [4]: 2-year survival was 35 vs. 20%. Retrospective analysis by Cox et al. [5] reached the same conclusion, and most programs of chest irradiation now aim for `cord tolerance' doses delivered by AP-PA fields, followed by a `boost' to the apparent remaining tumor volume to 6,000 cGy in 6 weeks, or its radiobiologic equivalent with higher daily dose and shorter duration. Four major trials of chemotherapy alone versus the combined modalities in sequence were reported in the 1980s. Souhami et al. [6] for the MRC in England studied four cycles of AV-CM (adriamycin plus vincristine, alternating with cyclophosphamide plus methotrexate), or the same program followed by chest irradiation (4,000 cGy in 4 weeks): the results were identical. Similar findings were reported by Osterlind et al. [7] from Denmark, in a study which compared CCM-V (cyclophosphamide, CCNU, methotrexate and vincristine) to CCM-V with sequenced, splitcourse irradiation delivered in weeks 6 and 10 of chemotherapy. Kies et al. [3] for SWIG focussed on patients who achieved complete response (CR) after induction chemotherapy with VMV/VAC (VP-16, methotrexate and vincristine alternating with vincristine, adriamycin and cyclophosphamide). This trial showed no benefit from sequential chest irradiation, and led our group to abandon the `sandwich' model. The fourth study, reported by Perry et al. [8] for the Cancer and Leukemia Group B, did demonstrate a modest advantage at 2 years (25 vs. 15%) for the sequential, combined modality approach vs. CEV (cyclophosphamide, etoposide, vincristine) alone, but in that trial the `sequential' irradiation was delivered concur-
Livingston
74
Table 2. Local failure as a site of initial relapse in combined modality trials for limited small cell lung cancer Study
Ref. No.
Number of patients
Chemotherapy
Radiotherapy
Local failure' %:XRT/no XRT
Sequential SWIG Finsen MRC NCI-C SWIG
1 7 6 36 3
108 145 371 300 153
CAV CMC-V AV/CM CAV/PE VMV/CAV
4,500 cGy, split 4,000 cGy, split 4,000 cGy, continuous 2,500-3,750 cGy, continuous 4,800 cGy, split
50 61/85 28/32 50 56/90
Alternating SEG
13
304
CAV
4,000 cGy, split
36/52
Concurrent CALGB NCI-Navy SWIG Turrisi
8 10 21 23
426 96 154 34
CEV CMC-NAP PEN PE
40/67 26/52 16 0
NCI-Navy
29
18
5,000 cGy, continuous 4,000 cGy, continuous 4,500 cGy, continuous 4,500 c~iy, continuous hyperfractionated 4,500 cGy, continuous hyperfractionated
PE
14
As the initial site of relapse.
rently with the fourth cycle of chemotherapy. The interpretation of this as a positive trial is tempered by the virtually identical median survival and the fact that there was still a 40% local failure rate in the combined modality arm. The Concurrent Model
Downloaded by: Université de Paris 193.51.85.197 - 1/6/2020 7:38:36 AM
The NCI-Navy group and its predecessor at the NCI-VA pioneered the use of concurrent combined modalities in limited SCLC. An analysis of treatment factors leading to prolonged survival led them to conclude that initial, concurrent treatment was superior to sequential treatment, in their nonrandomized experience [9]. This in turn led to a randomized trial in which CMC-VAP (cyclophosphamide, methotrexate and CCNU alternating with vincristine, adriamycin and procarbazine) alone was compared to the same chemotherapy plus initial, concurrent radiotherapy (4,000 cGy in 15 fractions over 3 weeks). To minimize normal tissue toxicity, a shrinking field technique was employed after five and ten treatments, and a posterior spinal cord block was placed after 2,400 cGy. All patients felt to be in CR
Radiation-Chemotherapy Interactions in Limited SCLC
75
received prophylactic cranial irradiation (PCI), given as 2,400 cGy in eight fractions over 2 weeks. The combined therapy produced superior local control of the chest tumor in CR patients (13 vs. 29% chest only failure) and significantly improved survival (median, 15 vs. 11.6 months), but at the price of significantly more myelosuppression, weight loss, esophagitis, and pulmonary dysfunction [ 10]. A second randomized trial which involved concurrent, initial use of a `normal tissue interactive' chemotherapy program was that by Birch et al. [ 11] for the Southeastern Group, which demonstrated greater toxicity in the combined modality arm, identical median survivals, and a marginally greater proportion of long-term survivors in the irradiated group [Greco, personal commun ] Perry et al. [8] found that concurrent initial chest irradiation and CEV was superior to CEV alone, but slightly inferior to the concurrent, delayed approach (20 vs. 25% alive at 2 years) for the two modalites [8]; however, subsequent cycles of chemotherapy were markedly attenuated in the arm receiving immediate chest irradiation. As pointed out by Turrisi [21]; it is uncertain if the poorer results seen in the group given radiotherapy immediately were caused by the physicians' reluctance to continue intensive chemotherapy or by the regimen itself. A final randomized trial with normal tissue interactive chemotherapy, reported by Perez et al. [ 13] for the Southeastern Group, defies simple categorization: it involved delayed administration of chest and brain irradiation, beginning just prior to the third cycle of CAV (cyclophosphamide, adriamycin and vincristine) chemotherapy, versus two cycles of CAV followed by brain irradiation and more chemotherapy. In the group randomized to chest irradiation, an unusual tripartite, alternating split course was used (1,200 cGy in 5 fractions x 3), each time followed the next week by a pulse of CAV. Survival was significantly prolonged by the combined modality approach (median, 60 vs. 49 weeks), with 2-year survivals of 28 and 19%, respectively. The rate of intrathoracic failure was 36 and 52%, while gastrointestinal toxicity appeared comparable. Development of Combined Modalities with Minimal Normal Tissue Interaction
Downloaded by: Université de Paris 193.51.85.197 - 1/6/2020 7:38:36 AM
Even though trials of simultaneous or rapidly alternating combined modalities appeared to offer a modest advantage, concurrent chemotherapy regimens which had major normal tissue interactions with radiation to the chest all produced an increase in toxicity. Not only was there compounding of chemotherapy-related myelosuppression but esophagitis and pneumoni-
Livingston
76
Downloaded by: Université de Paris 193.51.85.197 - 1/6/2020 7:38:36 AM
tis related to radiation therapy were clearly increased in incidence and severity, compared to what would have been expected with radiation alone [10, 11]. The development of cisplatin and etoposide (VP-16) as a two-drug regimen (ΡΕ) allowed the next step forward. Cisplatin is an agent which produces no stomatitis or esophagitis at normal doses, and little myelosuppression. Its dose-limiting toxicities of nephropathy and vomiting can be effectively managed by modern techniques of hydration and antiemetic therapy [ 14, 15], with sensory neuropathy and ototoxicity as remaining serious side effects. Used alone, cisplatin appeared to have modest activity in SCLC [ 16], but combined with etoposide there seemed to be clinical synergism, with CR rates of 50% or greater in limited disease [ 17] and evidence for some lack of cross-resistance with CAV and other `standard' regimens [ 18]. Etoposide at normal doses has myelosuppression as its only common serious side effect. Although cisplatin has some weak radiosensitizing properties [ 19, 20] it is not nearly as potent in this repect as adriamycin, and neither cisplatin nor etoposide have been clinically implicated in `radiation recall' toxicity. In a study reported for the SWIG, McCracken et al. [21] combined PE with vincristine and concurrent, initial chest irradiation at 180 cGy per fraction to a total dose of 4,500 cGy. At the completion of combined modality induction, consolidation chemotherapy was administered with vincristine plus methotrexate/etoposide alternating with adriamycin and cyclophosphamide. Among 154 patients, CR occurred in 56%, with a median survival of 18 months. Most strikingly, 30% survived to 4 years and 25% to 5 years, a result which appears superior to any other reported cooperative group experience (table 3). Pater et al. [22] for NCI Canada have now completed a randomized trial in which PE was administered concurrently with chest irradiation (4,000 cGy in 3 weeks), either with the first cycle of PE or with the third and final PE cycle in a sequence of alternating CAV/PE chemotherapy. The early administration of thoracic irradiation did not compromise chemotherapy, as the dose intensity for each chemotherapy agent was nearly identical in the two arms. The earlier administration of the two modalities appears superior, from analysis yet to be presented fully [Murray, personal commun., 1991]. Table 4 summarizes the normal tissue toxicity within the thorax of 7 combined modality trials in limited SCLC, using a variety of regimens. For chemotherapy programs containing adriamycin and/or methotrexate, it is clear that sequential administration produces less esophagitis, pneumonitis and cardiac toxicity than concurrent administration; the alternating program reported by Perez et al. [ 13] appears intermediate. Remarkably, PEV concurrent with chest irradiation, as reported by McCracken et al. [21], produced less intrathoracic toxicity than the sequential administration of
Radiation-Chemotherapy Interactioπs in Limited SCLC
77
Table 3. Survival in combined modality trials for limited small cell lung cancer Ref. No.
Study
Number of patients
Chemotherapy
Radiotherapy
Survival % at 2 years
Sequential SWIG Finsen
9 7
108 145
CAV CMC-V
MRC
6
371
AV/CM
36 3
300 153
CAV/PE VMV/CAV
4,500 cGy, split
+4,800 cGy, split
20 10 7 15 15 18 23 23
+4,000 cGy, split
19 28
+4,000 cGy, split
NCI-C SWIG
Alternating SEG
Concurrent CALGB
13
8
304
426
+4,000 cGy, continuous 2,500-3,750 cGy, continuous
CAV
CEV +5,000 cGy, continuous
NCI-Navy
10
96
SWIG Turrisi
21 23
154 34
NCI-Navy
26
18
CMC-NAP PEV PE PE
+4,000 cGy, continuous 4,500 cGy, continuous 4,500 cGy, continuous hyperfractionated 4,500 cGy, continuous hyperfractionated
15 20-25 10 28 42 53
5 years
9
