Deep Inspiration Breath Hold as Primary Strategy for Locally Advanced Lung Cancer Radiotherapy

Background Lung cancer remains a major cause of cancer morbidity and mortality. In Denmark, the incidence has shown a slight, but robust decrease over the last 10 years in males, but the incidence in females continues to increase. The relative survival at 5 years is only 11% for men and 15% for women. While surgery is the treatment of choice in early stage disease, radiotherapy combined with chemotherapy is the only treatment modality with curative potential in patients with locally advanced inoperable non-small cell lung cancer (NSCLC). Unfortunately, the overall survival remains poor and loco-regional disease progression or recurrences are common. Clinical studies have indicated a radiation dose response relationship, suggesting a higher radiation dose would improve local control. However, in a recent randomized phase III trial RTOG0617, of standard-dose (60 Gy) vs. high-dose (74 Gy) concomitant chemo-radiotherapy the overall survival was lowest in the high-dose arm. While toxicity may not be the only explanation to the negative result of RTOG0617, an increased rate of high-grade toxicity in the 74 Gy arm is certainly of major concern: this trial furthermore highlights the limited current understanding of the mechanisms of treatment related toxicities and how they limit our attempts to increase local control.

Radiotherapy-related side effects are severe, yet difficult to assess and quantify. CTC AE is the general golden standard tool for measuring adverse events. However, many patients have heart and lung related comorbidity prior to the radiotherapy and it may be difficult to completely distinguish comorbidity and treatment related toxicity, even if reliable baseline data exist. The symptomatology of pneumonitis correlates poorly with radiological findings and with a decline in lung function. Radiation induced heart toxicity is disputed in this group of patients and not all physiological responses to radiotherapy are fully understood. Serious or even lethal toxicities after high dose radiation therapy are underreported in prospective trials, most likely because the mechanisms and the time span of toxicity was different from the expected. A recent retrospective study13 described a positive correlation between the delivered treatment dose and an increase in lung tissue density after treatment, measured on consecutive follow-up CT scans. No correlation to clinical outcome was made.

In conclusion, the understanding of radiation-induced pulmonary toxicity is still limited. Reliable measures of toxicity are highly warranted in order to perform prospective trials improving the therapeutic outcome of lung cancer patients.

In DIBH radiotherapy, patients hold their breath during imaging for radiotherapy planning and during radiotherapy delivery. DIBH results in profound anatomic changes: tumour motion is minimised, the heart is drawn downward and the lungs are inflated and push the healthy away from the target volume. DIBH is now the standard treatment for patients with mediastinal Hodgkin lymphoma and breast cancer. This technique is simple, cost-efficient and spares the heart and lungs without any detriment to other healthy organs or to the target. However, lung tumours represent an additional challenge as they are mobile: their daily position must be assessed reliably in order to avoid underdosing the tumour and overdosing the healthy lung The investigators recently performed a pilot study based on 17 lung cancer patients, and found that most patients were able to maintain several consecutive deep inspiration breath holds of each 20 seconds throughout the course of radiotherapy. No a correlation between the FEV1 value and the ability to perform DIBH was observed. The range of FEV1 for the 17 patients was 1.2 - 3.2 litres (44-67% of predicted value). The patients were planned in both DIBH and free breathing but treated in free breathing. DIBH plans resulted in a significantly lower lung dose. However, previously it was observed that for some selected patients with multiple targets, DIBH is not the best treatment option. This highlights the importance of a full investigation of the potential benefits and drawbacks of DIBH in lung cancer patients.

The primary aim of INHALE is to investigate the feasibility of delivering safe and precise DIBH lung cancer radiotherapy. The secondary aims of INHALE are to investigate the potential of DIBH lung cancer radiotherapy to reduce treatment toxicity and to explore reliable and logistically manageable toxicity endpoints.