What is the optimal radiation dose and fractionation schedule for good performance status patients with inoperable stage III NSCLC undergoing curative therapy?

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Introduction

Jutta's info icon.png Defining operable and inoperable disease in stage III

The management of Stage III NSCLC has been divided into sections dependent on whether the disease is considered operable or inoperable at the time of diagnosis.

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Stage III NSCLC encompasses a broad spectrum of disease extent from tumour involving a single nodal station identified only postoperatively despite extensive pre-operative staging to involvement of multiple contralateral mediastinal nodes and supraclavicular nodes appreciated on clinical examination. In patients with clinically equivocal involvement, pathological confirmation of nodal status should be made if it will influence management options.

The decision as to operability should be made in a multidisciplinary setting.

Patients with Stage III NSCLC may be deemed inoperable because of patient factors (the patient’s respiratory function or co-morbidities may preclude operative intervention or the patient may choose not to proceed with surgery) or tumour factors (the extent or location of gross disease might make surgical resection technically impossible, for example left sided tumours with mediastinal nodes to the right of the aorta, N3 nodal involvement and most T4 tumours).

In the absence of other factors precluding surgery, patients with N1 disease should be considered for surgery. Patients with confirmed N2 disease should not be treated by surgery as the sole modality, but resectable cases may be considered for a multimodality approach. There is no consensus on the distinction between resectable and unresectable N2 disease. Factors influencing assessment of resectability include nodal size, number of stations involved, extracapsular extension and involvement of the recurrent laryngeal nerve.

Despite improved survival with the concurrent administration of chemotherapy and radiotherapy in stage III NSCLC, loco-regional recurrence rates remain high and survival figures remain low.[1] Attempts to improve loco-regional control and survival include radiation dose escalation using either conventional or altered fractionation schedules.

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Radiation dose

1) Loco-regional control

Evidence exists for a radiation dose-response relationship in NSCLC. The Radiation Therapy Oncology Group (RTOG ) randomised patients with stage II and III disease ( T1-3, N0-2) to either 40Gy total dose given in a split-course (4Gy/day for five days, followed by a two week break and a further 4Gy/day for five days), or a total dose of 40Gy, 50Gy or 60Gy given continuously (2Gy/day).[2] The highest doses resulted in significantly better local control rates, although there was no significant difference in survival. This study established 60Gy in 30f (2Gy/f/day) as the standard RT dose fractionation regimen in the definitive management of stage III disease.

However, the conventional dose of 60Gy is unlikely to control a significant proportion of tumours. At the University of Michigan doses were escalated from 63Gy to 84Gy using 1.8-2Gy fractions given five days a week. The best-fit logistic curve to the outcome data demonstrated that the radiation dose likely to produce 50% local progression-free survival at 30 months was 84.5Gy.[3] This data suggests that much higher biologically effective doses (BED) must be given in order to achieve a tumour control probability of greater than 50%.

2) Survival

Radiation dose has been found to be a significant prognostic factor for overall survival (OS), in addition to locoregional control, in patients with locally advanced or medically inoperable early-stage NSCLC. A prospective dose-escalation trial in patients with stage I-III disease showed a positive relationship between dose and OS, as well as loco-regional tumour control, with RT doses in the rage of 63-103Gy.[4] A retrospective review of 237 patients with stage III NSCLC treated with either RT alone or RT combined with chemotherapy demonstrated that the effect of higher radiation doses on survival was independent of whether chemotherapy was given.[5]

Early phase I/II data suggest that increasing the radiation dose to 74Gy can improve median survival times to 24 months.[6][7][8][9] [10]

Currently, the commonly prescribed dose for definitive RT is 60-70Gy in 1.8-2.0Gy/f.[11]

The role of high dose RT with concurrent chemo was tested in a phase III RCT (RTOG 0617). This trial randomised patients with stage IIIA/B disease to either 60 or 74Gy in conjunction with either carboplatin and paclitaxel or carboplatin, paclitaxel and cetuximab.[12] The trial was designed to detect a median overall survival improvement of seven months in the high dose group. A planned interim analysis after 90 deaths found the high dose radiation therapy group had crossed the futility boundary and this arm has been closed to further accrual.[13] The final analysis found that 74Gy given in 2Gy fractions with concurrent chemotherapy was not better than 60Gy plus concurrent chemotherapy for patients with Stage III NSCLC and might be potentially harmful.[14] The addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival. There was a clinically significant meaningful decline in QOL in the 74Gy at 3 months.[15]

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Radiation dose fractionation schedules

Prolongation of overall treatment time is detrimental to tumour control and survival in NSCLC. Prolongation of time to complete treatment was associated with significantly shortened survival (p=0.016) in four RTOG prospective randomised trials.[10] The loss of survival rate was 1.6% per day of prolongation beyond six weeks.[16] This rate of loss of survival probability in NSCLC is approximately as fast as the loss of local control with treatment prolongation in head and neck tumours. This implies that clonogenic cells continue to proliferate during treatment of NSCLC in a manner similar to those in head and neck cancer.

Thus, both total radiation dose and treatment duration (or overall time) are important in the outcome of radiotherapy in the management of NSCLC. Attempts to improve the outcomes have involved the manipulation of the distribution of radiation dose over time using altered fractionation schedules.

Accelerated radiotherapy delivers the same total dose over a shortened overall treatment time by using multiple daily fractions of standard fraction size. The aim is to reduce the repopulation of tumour cells during a conventional course of radiotherapy, thereby increasing the probability of tumour control for a given total dose. However, normal tissues also have less time to regenerate and thus the potential for acute normal tissue toxicity is increased. This can be overcome by giving multiple fractions per day with a reduced dose/fraction and a sufficient interfraction interval to allow for repair of normal tissues -so called hyperfractionated radiotherapy. A hybrid approach of accelerated fractionation and hyperfractionation is termed accelerated hyperfractioned RT.

Continuous hyperfractionated accelerated radiotherapy (CHART) has been compared with a conventional schedule of radiotherapy in a randomised trial in good performance status patients with inoperable NSCLC.[17][18] The CHART regimen delivered 1.5Gy three times a day for 12 consecutive days to a total dose of 54Gy in 36f. The conventional radiotherapy regimen delivered 2Gy once a day, five days a week to a total dose of 60Gy in 30f. Between 1990 and 1995, 563 patients were recruited of whom 61% had stage IIIA or IIIB disease. Compared with conventional RT, CHART was associated with an absolute improvement in two year survival of 9% (p=0.008). In the subgroup of patients with squamous cell histology, which accounted for 81% of all cases, there was an absolute improvement in two year survival of 13% from 20% to 33% (p=0.0007). This group also demonstrated 25% reduction in the relative risk of local and/or distant disease (p=0.025) and a 24% reduction in the relative risk of metastasis (p=0.043). Severe dysphagia occurred more often in the CHART group than in the conventional group (19% versus 3%) but there were no important differences in short or long-term morbidity.

Subsequently, the CHARTWEL (CHART weekend-less) regimen (60Gy in 40 fractions over 2.5 weeks) was developed to provide dose escalation in an attempt to improve loco-regional control. The CHARTWEL-trial (ARO 97-1) randomsed 406 patients (of whom 83% had Stage IIIA or IIIB disease) to either CHARTWEL or 66Gy in 33 fractions over 6.5 weeks (conventional fractionation). There was no significant difference between the two arms in terms of two year overall survival, disease-free survival or locoregional control. Overall survival in both arms of the CHARTWEL trial was as good as the survival seen in the hyperfractionated arm of CHART.[19]

Altered fractionation radiotherapy schedules have also been combined with chemotherapy. In a randomised Phase III trial conducted by the Eastern Cooperative Oncology Group (ECOG 2597), patients with good performance status and unresectable stage IIIA/B NSCLC received induction chemotherapy followed by either hyperfractionated accelerated RT (HART consisting of 1.5Gy three times a day with two weekend breaks, to a total dose of 57.6Gy) or conventional radiotherapy (64Gy in daily 2 Gy fractions)[20] The study closed prematurely having achieved 40% of its target accrual. The median survival for HART was 20.3 months with two and three year survival figures of 44% and 34% respectively, compared with a median survival of 14.9 months and two and three year survival figures of 24% and 14% for conventional RT. These results did not achieve statistical significance.

Ball et al randomised 204 patients with inoperable stage I-III NSCLC to either one of four treatments using a 2x 2 factorial design: conventional RT (60Gy in 30f in six weeks), accelerated RT (60Gy in 30f in three weeks); or the same regimens with the addition of concurrent chemotherapy. There was no statistically significant difference in survival between treatment arms.[21]

The North Central Cancer Treatment Group (NCCTG) randomised 110 patients with PS ≤1 and stage IIIA/B NSCLC to either standard fractionated RT (60Gy in 30f) or hyperfractionated RT (1.5Gy twice daily to a total dose of 60Gy, with a two week break after the initial 30Gy). The hyperfractionated treatment was given with or without chemotherapy. There was no statistically significant difference in the rates of local recurrence or survival between the arms.[22]

A second NCCTG trial randomised 246 patients with stage III NSCLC and ECOG PS ≤ 1 to either conventional radiotherapy (60Gy in 30 daily fractions) or hyperfractionated RT ( 1.5Gy twice daily to a total dose of 60Gy, with a two week break after the initial 30Gy).[23] In this trial both treatment arms received concurrent chemotherapy. There were no significant differences in time to progression, overall survival or toxicity between the two arms. However, the use of split-course radiotherapy potentially allows for repopulation of tumour clonogens during the treatment break and is therefore deemed a suboptimal mode of RT delivery.

The RTOG 88-08 trial randomised 452 patients with stage III NSCLC, good performance status and <5% weight loss to receive either conventional radiotherapy alone, or sequentially administered chemotherapy and conventional radiotherapy or hyperfractionated RT (1.2Gy bd to a total dose of 69.6Gy).[24] This hyperfractionated RT regimen was derived from a preceding RTOG dose escalation study.[25] Sequential chemo-RT resulted in a statistically significant survival benefit compared with RT alone but there was no significant difference in survival between the sequential chemo-RT and hyperfractionated RT arms (median survival 13.2m versus 12m, two year survival 32% versus 24%, p=0.08 for chemo-RT and chemo-hyperfractionated RT respectively).

The RTOG 94-10 trial randomised patients to sequential chemotherapy and conventional RT (once daily fractions to a total dose of 63Gy) or concurrent chemotherapy and conventional RT (once daily RT to 63Gy) or concurrent chemotherapy and hyperfractionated RT (twice-daily RT to 69.6Gy).[26] Survival was significantly better in the concurrent chemo-RT arm compared with the sequential chemo-RT arm (median survival 17m versus 14.6m, p=0.046) but there was no significant survival difference between the chemo-conventional RT arm and chemo-hyperfractionated RT arm. However, acute toxicity was worst in the concurrent chemo-hyperfractionated RT arm.

In conclusion, there is evidence that CHART is superior to conventionally fractionated RT in patients with stage III NSCLC. However, the pure CHART schedule has not been directly compared with the concurrent administration of chemotherapy and conventionally fractionated RT. Hyperfractionated regimens administered alone or in combination with chemotherapy have not been shown to be superior to concurrently administered chemotherapy and conventionally fractionated RT regimens, although toxicity is increased. Furthermore, hyperfractionated regimens are labour-intensive and difficult to implement when resources are limited. Thus, the administration of once daily, conventionally fractionated RT in combination with chemotherapy is recommended as the standard of care.

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Evidence summary and recommendations

Evidence summary Level References
A radiation dose- response relationship exists for NSCLC

Last reviewed December 2015

II [2]
Radiation dose is a prognostic factor for OS in NSCLC

Last reviewed December 2015

III-2 [4]
The radiation dose used in the definitive management of stage III disease should be at least 60Gy (assuming that dose-volume constraints on organs at risk are met).

Last reviewed December 2015

II [2]
A radiation dose of 74Gy used in the definitive management of stage III disease (with concurrent chemotherapy) is not better than 60Gy and may be potentially harmful.

Last reviewed December 2015

II [14]
Evidence-based recommendationQuestion mark transparent.png Grade
It is recommended that for patients with inoperable stage III NSCLC undergoing curative therapy once daily thoracic radiotherapy to at least 60Gy in 2Gy/f plus chemotherapy is administered.

Last reviewed December 2015

B


Evidence summary Level References
Prolongation of overall treatment time is detrimental to tumour control and survival in NSCLC.

Last reviewed December 2015

III-2 [10]
CHART is associated with a survival advantage compared with conventional radiotherapy alone. This survival advantage was most pronounced in patients with squamous cell histology.

Last reviewed December 2015

II [17], [18]
Accelerated radiotherapy given with chemotherapy, either sequentially or concurrently is not associated with a survival advantage over conventional radiotherapy given with chemotherapy, either sequentially or concurrently.

Last reviewed December 2015

II [21], [20]
Hyperfractionated radiotherapy given either alone or with chemotherapy is not associated with a survival advantage over conventional radiotherapy given either sequentially or concurrently with chemotherapy.

Last reviewed December 2015

II [22], [26], [24], [23]
Evidence-based recommendationQuestion mark transparent.png Grade
For patients with stage III NSCLC who are suitable for curative therapy, but where chemotherapy is contra-indicated or refused, CHART may be used as an alternative to radical conventionally fractionated radiotherapy.

Last reviewed December 2015

B


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References

  1. Mac Manus MP, Hicks RJ, Matthews JP, Wirth A, Rischin D, Ball DL. Metabolic (FDG-PET) response after radical radiotherapy/chemoradiotherapy for non-small cell lung cancer correlates with patterns of failure. Lung Cancer 2005 Jul;49(1):95-108 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15949595.
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  20. 20.0 20.1 Belani CP, Wang W, Johnson DH, Wagner H, Schiller J, Veeder M, et al. Phase III study of the Eastern Cooperative Oncology Group (ECOG 2597): induction chemotherapy followed by either standard thoracic radiotherapy or hyperfractionated accelerated radiotherapy for patients with unresectable stage IIIA and B non-small-cell lung cancer. J Clin Oncol 2005 Jun 1;23(16):3760-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15837967.
  21. 21.0 21.1 Ball D, Bishop J, Smith J, O'Brien P, Davis S, Ryan G, et al. A randomised phase III study of accelerated or standard fraction radiotherapy with or without concurrent carboplatin in inoperable non-small cell lung cancer: final report of an Australian multi-centre trial. Radiother Oncol 1999 Aug;52(2):129-36 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10577698.
  22. 22.0 22.1 Bonner JA, McGinnis WL, Stella PJ, Marschke RF Jr, Sloan JA, Shaw EG, et al. The possible advantage of hyperfractionated thoracic radiotherapy in the treatment of locally advanced nonsmall cell lung carcinoma: results of a North Central Cancer Treatment Group Phase III Study. Cancer 1998 Mar 15;82(6):1037-48 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9506347.
  23. 23.0 23.1 Schild SE, Stella PJ, Geyer SM, Bonner JA, Marks RS, McGinnis WL, et al. Phase III trial comparing chemotherapy plus once-daily or twice-daily radiotherapy in Stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002 Oct 1;54(2):370-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12243810.
  24. 24.0 24.1 Sause W, Kolesar P, Taylor S IV, Johnson D, Livingston R, Komaki R, et al. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 2000 Feb;117(2):358-64 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10669675.
  25. Cox JD, Azarnia N, Byhardt RW, Shin KH, Emami B, Pajak TF. A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non-small-cell lung carcinoma: report of Radiation Therapy Oncology Group 83-11. J Clin Oncol 1990 Sep;8(9):1543-55 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2167952.
  26. 26.0 26.1 Curran W, Scott C, Langer C, Komaki R, Lee JS, Hauseret S et al,. Phase III comparison of sequential v concurrent chemoradiation for patients with unresected stage III non-small cell lung cancer (NSCLC): initial Report of Radiation Therapy Oncology Group (RTOG) 9410. Proc Am Soc Clin Oncol 2000;19:abstr 1891 Abstract available at http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=2&abstractID=201631.

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Appendices

Further resources

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