Inoperable Tumors

Stage I/II Non–Small Cell Lung Cancer

The standard of care for a patient with operable early-stage lung cancer remains lobectomy or pneumonectomy with mediastinal lymph node dissection. However, a significant percentage of these patients cannot tolerate invasive procedures because of the comorbidities prevalent in patients with lung cancer, such as chronic obstructive pulmonary disease and poor cardiovascular health. Historically, the standard therapeutic approach for these patients has been conventionally fractionated definitive radiotherapy alone, with daily fractions delivered over a period of 6 to 8 weeks.¹⁶² More recently, a hypofractionated approach with delivery of a small number of large fractions over a short period of time has gained acceptance. This approach has most commonly been referred to as stereotactic body radiation therapy (SBRT), although recently there has been a move to rename this approach stereotactic ablative radiotherapy (SABR) to emphasize its distinct radiobiology.¹⁶³

Conventionally Fractionated External-Beam Radiotherapy

The RTOG performed a multi-institutional dose escalation study for inoperable NSCLC using three-dimensional conformal radiotherapy (3D-CRT). Patients with small, early-stage tumors were escalated to doses as high as 83.8Gy with acceptable toxicity. The 1-year local control rate for patients treated to this dose was 76%.¹⁶⁴ Hayman et al.¹⁶⁵ performed an adaptive dose escalation trial allowing safe delivery of doses up to 102.9 Gy to small peripheral tumors.¹⁶⁵ However, the OS rates for patients with medically inoperable early-stage NSCLC remain poor when compared to surgery. The 5-year survival for patients treated with definitive radiotherapy range from 10% to 30% and are approximately one-half that reported in surgical series^166–169 (Table 51.6). Several possible explanations exist for this disparity in outcomes, including the poorer overall health of the medically inoperable patient and the fact that most of these patients are clinically, rather than surgically, staged. An additional limitation is the maximum dose that can be delivered to the tumor through conventionally fractionated external-beam radiotherapy (EBRT) utilizing currently available techniques. Based on fundamental radiobiologic principles, Fletcher¹⁷⁰predicted that using conventional fraction sizes of 1.8 to 2 Gy, doses of 100 Gy or higher might be required for the sterilization of most NSCLC tumors. These doses are not routinely achievable with conventionally fractionated radiotherapy in the medically inoperable patient without excessive toxicity.

TABLE 51.6. Outcome by Radiation Therapy Dose and Treatment Volume for Patients with Early-Stage Non–Small Cell Lung Cancer

Stereotactic Body Radiotherapy

SBRT refers to the delivery of large doses of radiation to a small treatment volume, usually employing multiple beams, using a small number of fractions (usually five fractions or less). It has been known for quite some time that this approach is remarkably effective at tumor sterilization, presumably due to greater radiobiologic efficacy.¹⁷¹ This treatment approach was initially put to clinical use over a half-century ago by a Swedish neurosurgeon, Lars Leksell, for the treatment of intracranial metastases.¹⁷²However, unlike the cranial vault, the lung is a highly mobile structure. Thus, application of SBRT in lung cancer was impractical until advanced imaging treatment delivery techniques were developed (Fig. 51.4).

FIGURE 51.4. Stereotactic body radiation therapy (SBRT) in stage I non–small cell lung carcinoma (NSCLC).

The patient was diagnosed as having T1N0M0 right upper lobe NSCLC and was treated with SBRT. A: Pretreatment tumor volume. B: Treatment plan with dose color-wash C: CT showing response 6 weeks after treatment.

A phase I dose escalation trial enrolled patients with T1–2 N0 NSCLC, stratified into three dose escalation groups based on T-stage and size (T1, T2 <5 cm, and T2 5–7 cm). This trial reported a maximally tolerated dose for T2 tumors >5 cm of 22 Gy × 3 and was not reached at 20 Gy × 3 for T1 tumors or at 22 Gy × 3 for T2 tumors <5 cm.¹⁷³ There was a loose association between total delivered dose and likelihood of local failure, with 9 of 10 local failures observed in patients treated to the lower dose levels (<16 Gy × 3). Based on these results, this group moved forward with a phase II trial, utilizing the dose levels identified in the phase I trial. They were able to duplicate the excellent local control results in this expanded cohort of 70 patients. With a median follow-up of 17.5 months, the local control rate was 95%. However, with such large fraction sizes (of approximately 20 Gy), the group also identified an association between tumor location and toxicity, with severe toxicity occurring at a median of 10.5 months in 17% of those patients with peripheral lesions versus 46% with central lesions.¹⁷⁴ Preliminary data from other institutions suggest that early, central lesions can be treated safely and effectively using a lower dose per fraction (e.g., 7 to 12 Gy).¹⁷⁵ To this end, the RTOG has recently opened a phase I dose escalation trial for patients with centrally located, medically inoperable stage I NSCLC.

Several other institutions have published their experience applying SBRT to early (primarily peripheral) lung cancer with a variety of dose fractionation and prescription schemes (Table 51.7). The initial data appear promising with 80% to 100% local control, 40% to 100% 2- to 3-year survival, and 0% to 4% grade 3 toxicity, although in general the median follow-up for these studies is relatively short.^176–182Timmerman et al.¹⁷⁴ reported the results of RTOG 0236, a phase II trial of SBRT in medically inoperable patients with T1 or T2 tumors treated to 54 Gy in three 18-Gy fractions. In this study, 59 patients were enrolled, with 55 patients having evaluable disease. At a median follow-up of 34 months, they reported a 3-year primary tumor control rate of 97.6% and a 3-year primary tumor and involved lobe (local) control rate of 90.6%. Two patients experienced regional failure; the locoregional control rate was 87.2%. Eleven patients experienced distant recurrence with a 3-year rate of distant failure of 22.1%. The rates for disease-free survival and OS at 3 years were 48.3% and 55.8%, respectively. The median OS was 48.1 months. Protocol-specific treatment-related grade 3 adverse events were reported in 7 patients; grade 4 adverse events were reported in 2 patients. No grade 5 adverse events were reported. The RTOG (RTOG 0618) initiated a phase II study of SBRT in operable patients with early-stage NSCLC, and, together with the ACOSOG, a randomized trial of SBRT versus sublobar resection for high-risk early-stage NSCLC. SBRT, with its advantage of patient convenience and promising local control results, has largely replaced conventionally fractionated radiotherapy as the standard approach in the medically inoperable patient.

TABLE 51.7. Outcome for Patients with Early-Stage Non–Small Cell Lung Cancer Receiving Stereotactic Body Radiation Therapy

Stage III Non–Small Cell Lung Cancer

Definitive Radiotherapy

The majority of patients with inoperable locally advanced NSCLC will receive definitive thoracic radiotherapy as a part of their treatment strategy. The rationale for definitive radiotherapy in patients with inoperable NSCLC is to provide intrathoracic control of disease. Kubota et al.¹⁸³ performed a prospective randomized trial in 63 patients with stage III NSCLC comparing chemotherapy alone to chemotherapy plus thoracic radiotherapy. The survival rate in the thoracic radiotherapy group was 58% at 1 year, 36% at 2 years, and 29% at 3 years, compared with 66%, 9%, and 3% at 1, 2, and 3 years, respectively, in the chemotherapy-alone group. The investigators concluded that thoracic radiotherapy “significantly increases the number of long-term survivors as compared with chemotherapy alone and that radiotherapy to bulky disease in the thorax is an important part of combined modality therapy, and a necessary part of further studies in locally advanced disease.” At present, definitive thoracic radiotherapy is part of the standard therapeutic approach for patients with unresectable locally advanced NSCLC. However, because of high local failure rates and the significant toxicity associated with this treatment, the optimal dose, treatment volume, and optimal integration scheme with chemotherapy remain to be defined.

Dose and Fractionation with Radiotherapy Alone

The RTOG launched a prospective randomized trial in 1973 to determine the most effective dose and fractionation schedule in patients with inoperable NSCLC. In the initial report of RTOG 7301, 365 patients with T1-3, N0-2, M0 unresectable NSCLC were randomized to one of four treatment regimens: 40 Gy given in a split course of 20 Gy in five fractions in 1 week, a 2-week rest, and then an additional 20 Gy in 1 week; or 40 Gy, 50 Gy, or 60 Gy given in 2 Gy per fraction continuous course 5 days per week. The split-course group had the poorest survival: 10% at 2 years.¹⁸⁴ The incidence of tumor recurrence in the irradiated volume was 58% for the patients receiving 40 Gy continuous course, 53% for those treated with 40 Gy split course, 49% with 50 Gy continuous irradiation, and 35% in the patients receiving 60 Gy.¹⁸⁵ There were no differences in 5-year survival rates between the four arms. However, based on the differences in local tumor control and short-term survival, this study established 60 Gy as the standard of care.

Motivated by these results, the RTOG moved to explore methods of escalating radiation dose while maintaining the therapeutic ratio through altered fractionation schedules or improved treatment delivery techniques. RTOG 8311 was a randomized phase I/II trial that delivered thoracic radiation at a dose of 1.2 Gy with twice daily fractions escalating from a starting point of 60.0 Gy to 79.2 Gy. A total of 848 patients were enrolled and analyzed for outcome. No significant differences in the risks of acute or late effects in normal tissues were found in the five arms. In a subset analysis of good performance status patients (stage III, Karnofsky performance scale [KPS] ≥70, <6% weight loss), there was a dose response identified for survival with 69.6 Gy yielding improved survival over the lower-dose arms (p = .02). There were no differences in survival among the three high-dose arms; therefore, 69.6 Gy became the standard altered fractionation regimen for subsequent RTOG trials.¹⁸⁶

The development of 3D-CRT in the early 1990s allowed the radiation oncologist to increase the dose distribution to the tumor while restricting the dose to surrounding critical normal structures.¹⁸⁷ This approach had immediate applications in the treatment of NSCLC, and preliminary data suggested that 3D-CRT might allow for safe escalation of dose to the tumor bed.¹⁸⁸ However, it is unclear whether this approach to dose escalation can be broadly applied to all lung cancer patients. Bradley et al.¹⁸⁹ examined 207 patients with inoperable NSCLC and demonstrated by multivariate analysis that GTV was strongly predictive of overall and cause-specific survival, suggesting that large-volume disease might require escalated doses of radiotherapy, if feasible without significantly increased toxicity risk.¹⁸⁹ Rengan et al.¹⁹⁰examined the value of dose escalation in patients with large-volume stage III disease and found that even in patients with large tumor volumes, local failure rates were significantly reduced when treated to ≥64 Gy. Taken together, these data suggest that dose escalation can be achieved safely in locally advanced NSCLC via novel fractionation or treatment delivery approaches.

Volume of Radiation with Definitive Radiotherapy: Involved-Field Versus Elective Nodal Irradiation in Inoperable Stage III Non–Small Cell Lung Cancer

In the era of two-dimensional (2D) radiation therapy for NSCLC, it was customary to include the elective nodal basin in the radiation portals for any patient receiving curative intent radiotherapy, regardless of stage. There is ample evidence that the elective nodal basins can be safely omitted in stage I NSCLC, as there is low risk of nodal failure after IFRT either with conventionally fractionated radiotherapy or SBRT in this setting in patients who have undergone modern clinical staging.^191,192 The rationale for IFRT in locally advanced disease is to allow for safe dose escalation. Although there are limited data to suggest that escalating radiation dose could improve local control and that this approach would be feasible in locally advanced NSCLC, this increased dose is associated with an increased risk of radiation toxicity when larger treatment volumes are employed.¹⁹⁰ One technique for facilitating dose escalation while maintaining the therapeutic ratio is to utilize IFRT; this approach has been widely adopted. However, there is clear evidence to suggest that the untreated nodal basin may harbor occult disease. Surgical studies report that 10% to 35% of patients with clinically node negative NSCLC have evidence of occult mediastinal metastasis on lymph node dissection.¹⁹³ Additionally, although ¹⁸FDG-PET/CT has become an indispensible tool for noninvasive staging of the mediastinum, studies have shown that FDG-PET may carry up to a 25% false-negative rate in lymph nodes <1 cm in the short axis.⁶⁹ Therefore, some have argued that while IFRT may allow for dose escalation, this may come at the expense of clinical outcome in this disease.¹⁹⁴

Motivated by this concern, several studies have examined the rate of elective nodal failure in patients treated with IFRT and have shown this to be a relatively rare event.¹⁹⁵ In a study of 524 inoperable patients treated with IFRT, Rosenzweig et al.¹⁹⁶ reported a 2-year elective nodal control rate of 92.4%. Kepka et al.¹⁹⁷ studied 207 unresectable patients, staged without ¹⁸FDG-PET and treated with elective nodal irradiation (ENI). This study reported a 2-year elective nodal control rate of 88%. In a separate study, Kepka et al.¹⁹⁸ performed a comparative analysis of IFRT, limited ENI, and extended ENI and reported that substantial incidental radiation dose was delivered to the elective nodal basins even with IFRT; the median dose delivered to these areas ranged from 18 Gy to 45 Gy, depending on the location of the primary tumor and involved nodes as well as the technique employed. Further, there was no significant difference in dose delivered to much of the elective nodal basin between extended and limited ENI. In the only prospective study of ENI versus IFRT, Yuan et al.¹⁹⁹ demonstrated an increase in local control with IFRT of 8% and 15% at 2 and 5 years, respectively. This increase, however, was only statistically significant at the 5-year time point. Additionally, Yuan et al.¹⁹⁹ demonstrated an improved OS rate at 2 years with IFRT (39.4% vs. 25.6%, p = .048) and significantly higher pneumonitis rates in patients treated with ENI (29% vs. 17%, p = .044). Although interesting, this study has been criticized for the imbalances in several factors, including the radiation dose delivered (68 to 74 Gy for IFRT vs. 60 to 64 Gy for ENI) and V₂₀ between the two arms, making attribution of the results observed solely to IFRT or ENI problematic. In a recently published single-institution retrospective cohort comparison of patients receiving definitive 3D-CRT for locally advanced NSCLC, Fernandes et al.²⁰⁰ analyzed 108 consecutive patients treated with either ENI or IFRT. The median follow-up time for survivors was 18.9 months. The median dose for patients treated with IFRT was 69.9 Gy versus 63.6 Gy for ENI. In a multivariable logistic regression analysis, patients treated with IFRT demonstrated a significantly lower risk of high-grade esophagitis (odds ratio 0.31, p = .036). There was a suggestion of improved 2-year local control with IFRT (59.6% IFRT vs. 39.2% ENI); however, this was not significant (p = .23). There were no significant differences in elective nodal control (84.3% vs. 84.3%), distant control (52.7 IFRT vs. 47.7% ENI), and OS (43.7% IFRT vs. 40.1% ENI) rates between ENI and IFRT. The authors concluded that IFRT had a favorable therapeutic ratio compared with ENI owing to reduced acute toxicity. Taken together, these data suggest that IFRT can be employed in patients with locally advanced NSCLC without risk of significant compromise in clinical outcome.

Combined Modality Therapy for Inoperable Stage III Non–Small Cell Lung Cancer

Sequential Chemoradiotherapy

Although dose escalation was achievable and appeared to be associated with improvements in local control in locally advanced NSCLC, the dominant pattern of failure in these patients is through distant dissemination in about 75% to 80% of patients.¹⁸⁵ To address the issue of systemic disease in locally advanced cases, the CALGB initiated a phase III randomized trial of 155 patients with unresectable stage III NSCLC with excellent performance status and minimal weight loss to either radiotherapy alone to 60 Gy or to induction chemotherapy with cisplatin (100 mg/m² given intravenously on days 1 and 29) and vinblastine (5 mg/m² given intravenously on days 1, 8, 15, 22, and 29) followed by radiotherapy to 60 Gy. Median survival was improved with induction chemotherapy to 13.7 months versus 9.6 months with radiotherapy alone (p = .0066). The 5-year survival was improved from 6% to 17% with induction chemotherapy.²⁰¹ A subsequent intergroup trial was launched randomizing 490 patients with inoperable locally advanced NSCLC to one of the following regimens: (a) standard radiation therapy to 60 Gy, (b) induction chemotherapy followed by standard radiation therapy to 60 Gy, and (c) twice-daily radiation therapy to 69.6 Gy as 1.2 Gy given twice daily. Median survival was improved to 13.8 months with induction chemotherapy compared to 11.4 months with standard radiotherapy and 12.3 months with hyperfractionated radiotherapy (p = .03).²⁰² A third prospective randomized trial reported by Le Chevalier et al.¹³⁶ examined a total of 325 patients with unresectable locally advanced NSCLC who were randomized to either radiotherapy alone to 65 Gy delivered in a split course in 26 fractions over 45 days or 3 monthly cycles of VCPC therapy: vindesine, 1.5 mg/m² on days 1 and 2; lomustine, 50 mg/m² on day 2 and 25 mg/m² on day 3; cisplatin, 100 mg/m² on day 2; and cyclophosphamide, 200 mg/m² on days 2 through 4 followed by radiotherapy to 65 Gy in 26 fractions delivered in a split-course fashion over 45 days starting 2 to 3 weeks after the third cycle of chemotherapy. The 2-year survival rate was 14% in patients receiving radiotherapy alone and 21% in the chemoradiotherapy group (P = .08). The distant metastasis rate was significantly lower in patients receiving induction chemotherapy, with the relative risk of metastasis twofold higher in the radiotherapy-alone arm compared to the chemoradiotherapy group (p<.001). Overall, these trials established the role of chemotherapy, in addition to radiation, in the management of inoperable stage III NSCLC (Table 51.8).

TABLE 51.8. Sequential Chemotherapy Versus Radiation Therapy Alone for Locally Advanced Non–Small Cell Lung Cancer

Concurrent Chemoradiotherapy

The EORTC performed a phase III randomized trial comparing concurrent cisplatin-based chemoradiation to radiotherapy alone and demonstrated a clear survival benefit to this approach.¹³⁸ Of note, there was no difference in rate of distant metastases; thus, the authors concluded that the benefit in OS was attributable to an improvement in local control secondary to enhanced radiosensitization of the tumor by low-dose cisplatin. A meta-analysis performed in 2010 to examine the value of concurrent chemotherapy in definitive management of NSCLC by O'Rourke et al.²⁰³ included 19 randomized studies with a total of 2,728 patients with NSCLC (stages I through III), who were randomized to receive either concurrent chemoradiotherapy or radiotherapy alone. Concurrent chemotherapy significantly reduced overall risk of death (HR 0.71) and improved overall PFS at any site (HR 0.69). However, this clinical benefit came at the expense of increased acute toxicity, especially severe esophagitis with concurrent treatment (RR 4.96).

Concurrent Versus Sequential Chemoradiotherapy

Initial phase II trials suggested that concurrent chemoradiotherapy might be an even more effective treatment than sequential chemoradiotherapy.²⁰⁴ Therefore, Furuse et al.²⁰⁵ performed a phase III randomized trial comparing concurrent chemoradiotherapy with mitomycin, vindesine, and cisplatin (MVP) to sequential chemotherapy and radiation therapy. They demonstrated a statistically significant survival advantage to the concurrent approach (median survival of 16.5 months vs. 13.3 months and 5-year survival of 15.8% vs. 8.9%). RTOG 9410 compared two different concurrent regimens (cisplatin and vinblastine with conventional radiotherapy, arm 1, or cisplatin and oral etoposide with hyperfractionated radiotherapy, arm 2) with a “standard” sequential regimen of cisplatin followed by conventional radiotherapy (arm 3). Comparing arm 1 to arm 3 (as per the study design), median survival times improved significantly (17 vs. 14.6 months), as did 5-year survival (15% vs. 10%) with an increase in acute grade 3 through grade 5 nonhematologic toxicities.^206,207 The survival in arm 2 was not significantly better than arm 1, although this intensive regimen was associated with much higher esophageal toxicity. Fournel et al.²⁰⁸ reported the results of a smaller randomized trial that did not show a statistically significant survival advantage for concurrent chemoradiotherapy, with a median survival of 14 months with sequential chemoradiotherapy versus 16 months with concurrent chemoradiotherapy (p = .24). Nevertheless, a consistent trend favoring concurrent chemoradiotherapy in median, 2-, 3-, and 4-year survival rates was observed.²⁰⁸ More recently, a meta-analysis performed by Auperin et al.²⁰⁹analyzed data from six clinical trials involving 1,205 patients. The median follow-up was 6 years. They observed a significant benefit favoring concurrent over sequential chemotherapy and radiotherapy with respect to OS (HR 0.84, p = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. PFS was also improved with concurrent chemoradiotherapy (HR 0.90, p = .07). Concurrent chemoradiotherapy decreased locoregional progression (HR 0.77, p = .01), although not distant progression. Again, this improvement in locoregional control came at the expense of greater acute toxicity for the patient receiving concurrent chemoradiotherapy, with an increase in acute esophageal toxicity (grades 3 and 4) from 4% to 18% with a relative risk of 4.9 (p <.001).²⁰⁹

Because of the increased toxicity with concurrent chemoradiation, especially acute esophagitis, there are often treatment delays that are potentially detrimental in terms of radiobiologic efficacy. Cox et al.²¹⁰examined the impact of prolonged treatment time in stage III NSCLC treated with radiotherapy alone and documented an association with decreased locoregional control and 5-year survival (15% vs. 0%). To determine whether treatment time had a similar impact in the setting of concurrent chemoradiation, Machtay et al.²¹¹ performed a retrospective study of three prospective RTOG trials (RTOG 9106, 9204, and 9410), all of which included good performance status stage III NSCLC patients treated with cisplatin-based concurrent chemoradiotherapy. The authors defined “short” treatment time as finishing treatment within 5 days of the projected end date. They found that “long” treatment time was significantly associated with acute esophagitis. They also found a nonsignificant trend toward improvement in median survival in the “short” (19.5 months) versus “long” treatment time (14.8 months). This study, although retrospective, indicated that even with concurrent chemoradiation, there could be a detrimental effect on survival with delayed treatment time.²¹¹ Thus, appropriate patient selection and maneuvers to minimize toxicity are increasingly important to minimize the likelihood of treatment delays that can compromise the efficacy of concurrent therapy.

In summary, these data strongly support concurrent chemoradiotherapy as the standard approach for patients with good performance status and minimal weight loss. This therapeutic strategy results in improved OS, likely driven by an improvement in locoregional control in patients with locally advanced NSCLC. Of note, this comes at the expense of greater toxicity to the patient, and therefore patient selection is critical when using this approach.

Cytotoxic Platforms for Concurrent Chemoradiotherapy in Locally Advanced Non–Small Cell Lung Cancer

The management of patients with locally advanced NSCLC remains a therapeutic challenge. The era of combined modality therapy was ushered in by Dillman et al.²⁰¹ when the CALGB demonstrated superior survival for chemotherapy with vinblastine and cisplatin followed by definitive radiation (XRT) versus radiation alone. The benefits of sequential chemotherapy followed by radiation were reinforced by subsequent trials by the RTOG and in France.^{212–213,214} In fit patients with minimal weight loss (<5% to 10% from baseline) and intact performance status (ECOG performance status 0 to 1), concurrent chemoradiation with a platinum-based combination has demonstrated clear superiority to radiation alone and to sequential chemotherapy followed by radiation.^{138,205,207,208,215,216} A meta-analysis by Auperin²¹⁷reinforced this observation, demonstrating a 5% absolute increase in long-term survival. Multiple studies in this arena have confirmed 4- to 5-year survival rates of 10% to 20%, which are clearly better than the 5% to 7% observed with XRT alone in this setting^{205,207,208,217,218–219,220,221} (Table 51.9). In the absence of significant comorbidity, hearing loss, or renal compromise in patients who can readily tolerate an acute fluid load, cisplatin-based therapy is considered the standard of care. Most North American clinicians have opted for the EP combination. Unlike limited SCLC, where cisplatin is dosed at 60 mg/m²every 3 weeks and etoposide at 80 to 120 mg/m² daily × 3 both during and after radiation, an alternative dose and schedule is generally used.²²² There are abundant data from the SWOG and RTOG for a schedule that was ultimately phase III tested in RTOG 9309 and later by the Hoosier Oncology Group: cisplatin 50 mg/m² days 1 and 8, 29 and 36; and etoposide 50 mg/m² intravenously days 1 through 5 and days 19 through 33.^{139,140,223,224} This schedule, while inconvenient, is tried and tested and usually safe. Ideally, radiation to a minimum total dose of 60 Gy is given concurrently day 1 with chemotherapy.

TABLE 51.9. Concurrent Chemoradiotherapy for Stage III Non–Small Cell Lung Cancer

In frailer patients or older patients, and in those with significant comorbidity including renal insufficiency (creatinines of 1.5 to 3.0), hearing loss, congestive heart failure, or severe COPD, a carboplatin combination is clearly better tolerated compared to cisplatin, and paclitaxel is often substituted for etoposide. Pilot trials by Belani²²⁵ and Choy²²⁶ clearly demonstrated the safety and efficacy of carboplatin (area under the concentration-time curve [AUC] 2 weekly) and paclitaxel (45 to 50 mg/m² weekly) both initiated day 1 of thoracic radiation, followed by two cycles of full-dose “consolidative” chemotherapy once radiation is completed.^227,228 Conventionally, during the consolidation phase, carboplatin AUC 6 and paclitaxel 200 mg/m² are administered for two cycles at 3-week intervals. This regimen has become the platform for multiple cooperative group phase II and phase III trials, most notably RTOG 0617.

Many have argued that carboplatin-based therapy is inferior to cisplatin in the treatment of locally advanced NSCLC. However, recent data from Japan in a combined modality trial (West Japan Oncology Group Trial WJTOG 0105) evaluating various concurrent chemoradiation regimens failed to show superiority for cisplatin over carboplatin in the context of concurrent chemoradiation.²²¹ Investigators led by Nobuyuki Yamamoto compared their erstwhile standard of MVP to weekly carboplatin in combination with either irinotecan or paclitaxel during XRT; in each arm, those without disease progression or untoward toxicity went on to receive two cycles of full-dose chemotherapy during the “consolidation” period using the same agents administered during XRT. The paclitaxel-carboplatin regimen resulted in less toxicity, fewer dose reductions or omissions, and equivalent if not superior survival at 5 years: 19.5% versus 17.5% for MVP and 17.8% for irinotecan-carboplatin. In fairness, this study also compared second-generation to third-generation chemotherapy; to date, this study is the only phase III trial to attempt to address the platinum question, which arises continually in the clinic.

    Updated by Ramesh Rengan (11/22/2013) There is also recent data to suggest that the toxicity profile with carboplatin-paclitaxel may be distinct from that observed with EP. Palma et al. performed an individual patient meta-analysis to identify predictors for radiation pneumonitis after concurrent chemoradiotherapy and found that elderly patients receiving carboplatin-paclitaxel chemotherapy were at highest risk. (Palma DA, Senan S, Tsujino K, et al., Int J Radiat Oncol Biol Phys. 2013 Feb 1;85:444-50 [PMID: 22682812])

There are additional data to suggest that third-generation regimens are superior to second-generation therapy. Segawa et al.²¹⁸ form the Okayama Lung Cancer Study Group in Japan that demonstrated therapeutic superiority for docetaxel in combination with cisplatin compared with MVP in combination with XRT. An ongoing, pharmaceutical-based, randomized phase III trial in the context of chemoradiation is comparing pemetrexed-cisplatin (another third-generation regimen) followed by single-agent pemetrexed during the consolidation period to EP during XRT followed by investigator's choice during the consolidation period.²²⁹

In patients with baseline V20s (percentage of normal lung that will receive >20 Gy) >35% or in those with borderline pulmonary function or other comorbidities, many clinicians consider administration of chemotherapy first for two or even three cycles, followed by radiation alone or concurrent chemoradiation if there has been sufficient tumor shrinkage to allow a more reasonable radiotherapy treatment field. In those with minimal or no tumor shrinkage using this approach, some investigators omit concurrent chemotherapy during XRT to avoid untoward toxicity, proceeding with XRT alone. These patients are often much more symptomatic than those with smaller-volume tumors, with postobstructive symptoms including wheezing, pneumonitis, and hypoxia, and often have compromised performance status. However, the one study to isolate the role of induction therapy prior to concurrent chemoradiation with paclitaxel and carboplatin failed to show a survival advantage compared to concurrent chemoradiation alone.²²⁰

Toxicity mitigation is another major challenge that has been inadequately addressed. Both acute esophagitis and long-term pneumonitis and pulmonary fibrosis are common complications of combined-modality therapy. A recent meta-analysis by Auperin et al.²¹⁷ demonstrated a sixfold increase in short-term esophagitis, grade 3 or worse (18% vs. 3%) in those receiving concurrent chemoradiation as opposed to asynchronous or sequential chemotherapy and radiation. A phase III study evaluating amifostine as an esophageal protectant failed to show a significant reduction in esophagitis rates, as determined by objective measures, compared to a control arm that did not feature this agent²⁶; however, a subsequent analysis based on patient-reported outcomes suggested a modest benefit with reduction in pain and weight loss.^114,230 There is continued interest in evaluating mucosal protectants, including palifermin and other agents, although to date, no prospective randomized phase III trial has demonstrated a palliative benefit. Consequently, the approach to in-field toxicity has generally been reactive rather than pre-emptive. Newer technologies including proton beam may help to reduce the severity and duration of acute and late esophageal and pulmonary effects. This is currently under investigation.

Consolidative Chemotherapy

Consolidative chemotherapy remains highly controversial. A SWOG trial using the EP/XRT regimen as a platform investigated the role of consolidation docetaxel in stage IIIB patients, yielding a 5-year survival rate of nearly 30%, which is virtually unprecedented in the realm of locally advanced NSCLC.¹³⁹ However, in a phase III randomized Hoosier Oncology Group trial, docetaxel consolidation failed to yield a survival advantage compared to standard “observation” in patients who had completed concurrent chemoradiation with EP, in part because the reference arm “outperformed” its historic controls.²²⁴ These results were disappointing. However, there was a borderline significant imbalance in baseline pulmonary function favoring the control arm: nearly 60% of patients on the arm featuring no consolidation had an FEV1 ≥2 L, compared to slightly >40% in the investigational arm. Similarly, empiric use of gefitinib as maintenance therapy in a SWOG trial led to a paradoxical survival decrement compared to placebo after completion of docetaxel consolidation.²³¹ Hence, based on these trials, there is no proven role for consolidative chemotherapy in patients who have already received systemically dosed chemotherapy during thoracic XRT. In those who receive a radiosensitizing schedule of chemotherapy during XRT, the general consensus favors at least two cycles of full-dose chemotherapy after chemoradiation is completed. Despite the disappointments with docetaxel and empiric gefitinib in this setting, the role of consolidation or maintenance therapy after chemoradiation remains an open question.

Targeted Agents in Locally Advanced Disease

There are no data as yet to support the empiric use of EGFRs, TKIs, EGFR monoclonal antibodies (MAbs), or angiogenesis inhibitors either during or after chemoradiation. The CALGB mounted a randomized phase II trial of concurrent radiation and chemotherapy with carboplatin and pemetrexed followed by “consolidative” pemetrexed with or without cetuximab.²³² The latter did not appear to exacerbate typical in-field toxicities, nor did it yield a significant improvement in long-term survival. The RTOG separately spearheaded a phase II study evaluating cetuximab in combination with standard thoracic radiotherapy and weekly paclitaxel-carboplatin, demonstrating feasibility as well a promising median survival approaching 2 years.²³³ The phase III trial comparing higher dose XRT (74 Gy) to standard dose (60 Gy) was amended early on to address the role of cetuximab in a 2 × 2 design. Although the component of the trial testing higher versus standard dose XRT was closed because of futility, the C225 question remains open and RTOG 0617 continues to accrue; enrollment completed in November of 2011 and results are eagerly awaited. In higher-risk patients with >5% weight loss or compromised performance status, the CALGB is evaluating induction therapy with nab-paclitaxel and carboplatin followed by concurrent XRT and erlotinib. A previous, analogous phase II CALGB study in higher-risk patients evaluating induction carboplatin and paclitaxel followed by concurrent XRT and gefitinib yielded a median OS of 19 months.²³⁴ Attempts to integrate bevacizumab into the combined-modality approach have been unsuccessful, with adverse events including tracheoesophageal fistulas and pulmonary hemorrhages.^235,236

Dose Escalation with Concurrent Chemoradiotherapy

Although concurrent chemoradiotherapy has emerged as the standard therapeutic approach for fit patients with unresectable locally advanced disease, this has come at the cost of increased toxicity to the patient. It is therefore unclear whether dose escalation in the setting of concurrent chemotherapy will provide meaningful clinical benefit. The Lineberger Comprehensive Cancer Center group reported the results of a single-institution phase I dose escalation study with concurrent chemoradiation. They performed a stepwise escalation of thoracic radiation dose from 60 to 74 Gy in conjunction with paclitaxel-carboplatin without a clinically significant increase in toxicity.²³⁷ The median survival of 24 months and 5-year survival of 25% in this study were promising, although patient numbers are small. In 2006, the RTOG opened a 2 × 2 phase III randomized trial to simultaneously examine the question of 60 Gy versus 74 Gy and concurrent chemoradiotherapy with or without cetuximab for patients with inoperable stage III NSCLC. After a planned interim analysis, the high-dose radiation therapy (74 Gy) arms of RTOG 0617 were closed to accrual effective June 17, 2011. In a communication to all RTOG trial investigators, Bradley²³⁸ stated that the “high dose arms crossed a futility boundary, meaning that high dose radiation therapy cannot result in a survival benefit with further accrual or follow up of patients on these 2 arms.” At the 2011 American Society of Therapeutic Radiology and Oncology (ASTRO) annual meeting, the initial results of this trial were presented, actually demonstrating a statistically significant detriment to survival with 74 Gy (p = .02). The interim analysis did not identify patient safety concerns and gave no indication of a statistical difference in high-grade toxicity between arms, nor any clear explanation for the observed decrement in survival. Regardless, the 74-Gy arm for this trial has been closed and 60 Gy remains the standard dose in all RTOG lung cancer trials going forward.²³⁹

Superior Sulcus Tumors and Pancoast's Syndrome

SSTs were first described in 1838 and the characteristic accompanying neurologic symptoms in 1932 by Dr. Henry Pancoast.²⁴⁰ The most common tumors of the superior sulcus are bronchogenic, primarily squamous cell, followed by adenocarcinoma, and less likely small cell. SSTs account for <5% of all lung cancer.²⁴¹

Signs and Symptoms

The most common symptom among patients with SST is pain in the shoulder, which may radiate down the arm. This can be attributable to direct tumor invasion of the parietal pleura, vertebral body, ribs one through three, or the brachial plexus (Fig. 51.5). Pain radiating down the ulnar aspect of the arm past the elbow indicates involvement of the T1 nerve root, whereas extension to the fourth and fifth digits indicates involvement of the C8 nerve root or more distally the ulnar nerve. There may be weakness or atrophy of the intrinsic muscles of the hand. SSTs that invade the neural foramina may cause spinal cord compression, which can ultimately occur in up to 25% of patients. Involvement of the stellate ganglion may manifest as Horner's syndrome: the triad of ptosis, papillary miosis, and facial anhidrosis. Irritation or compression of the adjacent sympathetic chain may cause ipsilateral flushing and sweating of the face or reflex sympathetic dystrophy, a regional syndrome of burning neuropathic pain. Pancoast's syndrome is a constellation of signs and symptoms including shoulder/arm pain, Horner's syndrome, and unilateral upper extremity weakness.

FIGURE 51.5. A 51-year-old former smoker presented with right shoulder pain and right-sided Horner's syndrome and was found to have an adenocarcinoma in the right superior sulcus.

A: Coronal view with gross tumor volume (GTV) contoured. B:An axial view with GTV contoured. A 4-cm tumor is seen invading the mediastinum with displacement of the trachea. He underwent a staging evaluation including mediastinoscopy and was staged as T4N0M0. C: Sagittal view with GTV contoured showing vertebral body impingement. The patient was treated with radiotherapy with concurrent cisplatin and etoposide to 50 Gy and underwent resection with negative margins.

Diagnosis and Staging

SSTs are staged in the same way that SCLC and NSCLC are staged elsewhere in the thorax. For patients without metastatic disease, it is important to assess resectability. Surgery typically involves lobectomy with en bloc resection of the chest wall, which may be accompanied by resection of portions of the parasympathetic chain, stellate ganglion, lower trunks of the brachial plexus, subclavian artery, and portions of vertebral bodies.

Management

Determining the feasibility of resection is a critical decision point in the management of NSCLC SSTs. Because of the apical location of the tumor, invasion of the brachial plexus, vertebral bodies, and subclavian vessels is not uncommon and may eliminate surgical resection as an option, depending on the extent of invasion. In addition to CT, PET, and bone scan, MRI is useful in documenting the extent of involvement of the brachial plexus, spinal nerve roots, vertebral bodies, and subclavian vessels and is more sensitive than CT for this purpose.²⁴² Small cell SSTs in patient with good performance status are treated with concurrent chemoradiotherapy for limited-stage disease or chemotherapy for extensive-stage disease.

Multimodality Therapy for Superior Sulcus Tumors

Several large retrospective series and prospective trials have investigated outcomes of multimodality treatment of SSTs. SWOG 9416/Intergroup 0160 included 110 patients with T3-4, N0-1 SSTs. All patients were treated with two cycles of EP with radiotherapy (45 Gy in 25 fractions), followed by surgery within 3 to 5 weeks, and then two further cycles of chemotherapy.²⁴³ The study included patients with apical tumors and Pancoast's syndrome, or SSTs with chest wall invasion, or involvement of the vertebrae or subclavian vessels. In this study, 88 patients (80%) underwent surgery, and 83 (76%) had complete resection. The 5-year OS was 44%. As well, 61 resected patients (56%) had a pathologic complete response to induction therapy, and their 5-year survival was significantly better at 54%. A Japan Clinical Oncology Group (JCOG) study enrolled 76 patients and used induction mitomycin, vindesine, and cisplatin with 45 Gy in 27 fractions (split course) followed by surgery.²⁴⁴ The study included patients with SSTs, staged T3-4, N0-1, and nonbulky N2 disease; 76% of patients underwent resection, and 68% had complete resection. The 5-year OS was 56%. A single-institution French study enrolled 107 patients with SSTs in a prospective trial of induction chemoradiotherapy.²⁴⁵ The study excluded those with bulky N2 or N3 disease. All patients received EP concurrently with radiotherapy to 45 Gy; 72 patients underwent resection; unresectable patients received an additional 25 Gy. The 3-year OS was 40%.

In patients who are resectable at diagnosis, surgery may be offered as initial therapy. A prospective trial at the University of Texas MD Anderson Cancer Center enrolled 32 patients with resectable or marginally resectable SSTs.²⁴⁶ All patients had gross total resection initially; 28% had microscopic residual disease. Postoperatively, patients were treated with radiotherapy to 60 Gy in 1.2-Gy fractions (for negative margins) or 64.8 Gy in 1.2-Gy fractions (for positive margins) with concurrent EP. The 5-year locoregional control was 76%, and 5-year OS was 50%.

    Updated by Ramesh Rengan (11/22/2013) The long-term results of this trial were recently updated showing the 10-year locoregional control to remain excellent at 76% and the 10-year OS to be 45%. (Gomez DR, Cox JD, Roth JA, et al., Cancer. 2012 Jan 15;118:444-51 [PMID: 21713767])

Chemoradiotherapy

Retrospective evidence suggests that patients who undergo surgery have better local control and survival than those treated with radiation therapy, although such data is subject to significant selection bias.²⁴⁷Patients with unresectable localized SSTs and those with stage III disease and bulky N2 (or N3) lymph nodes should be treated with definitive chemotherapy and radiation. Early studies of radiotherapy alone for SSTs show acceptable local control and survival. In a series of 32 patients treated with definitive radiation, 91% of patients with pain reported relief, and 75% of patients with Horner's syndrome had symptomatic improvement.²⁴⁸ The addition of concurrent chemotherapy improves local control and survival in patients with stage III NSCLC—an observation that has led to the widespread use of concurrent therapy in SSTs. Small series in patients with SSTs appear to support this. A retrospective analysis from the Netherlands examined the outcome of patients treated with chemoradiotherapy.²⁴⁹ In this study, 49 patients with stage II or III SST received 66 Gy with daily cisplatin (6 mg/m²); 19 patients had sufficient response to undergo resection, and in these patients there was a 53% pathologic complete response rate. The 5-year OS was 18% in patients who received chemoradiotherapy and 33% in patients who were able to undergo surgery.

I want to emphasize that lymphomas are relatively rare diseases. There are many randomized trials that have influenced practice. However many of the cases we see do not have randomized trials that support good data for making decisions and so there are different opinions especially when there are few data. I want to tell the importance of experience in our rationale approach. This helps us in treating patients and often there is no right answers. You see some differences between the cases. The opinions from the panel will be important. Some cases are a little more challenging but they have been selected to represent cases that you might see in your practice.

This issue will be a little more focused on NHL and we mention the audience texting. One of the things that we try to do this year and prior years is to show cases of recent publications.

This is what you should be able to do after this session so I will not read this.

This is a patient that I recently saw. He is a 53 old male presenting with a right groin mass. He was referred by his primary care physician to a surgeon who performed a laparoscopic hernia repair but after the procedure he still had a mass. So he underwent a CT scan which showed a confluent nodal mass of the inguinal – sacral region on the right of 3.7 cm in greatest dimension.

He then underwent an excisional nodal biopsy which revealed a grade 2 follicular lymphoma. He underwent a PET CT scan which showed no other abnormal areas of FDG uptake. There was a post – op uptake in the surgical bed. He had a negative BM biopsy. He was then seen by a local oncologist who recommended observing him. At that time he was referred to us for a second opinion.

The first question is what you would recommend in this situation. Would you choose observation as suggested or CHOP chemotherapy or chemotherapy and radiation therapy, IFRT, involved field and adjacent nodal group RT.

So 73% voted for IFRT.

So anyone in the panel wants to comment?

IF is a term undergoing evaluation and re – examination. There is a group of RO who have a great interest in lymphoma. They try to define the appropriate definitions in different scenarios. They adopted the term involved site radiation which implies for the most part irradiation of the initially involved LN regions with appropriate extension to define the CTV and the PTV depending upon clinical circumstances and trying to move away from the terminology involved field which suggests rather regimented designed fields based on anatomic orders that may not be completely appropriate.

For example, in this case if you say involved field you would just treat the inguinal femoral area and stop at the inguinal ligament. Another panelist would treat into the iliac area so my choice would be four and a half. While treating I would not go to the bifurcation but I would treat a little bit more that just the inguinal femoral area.

The next question is what dose do you use. None, 2 x 2 Gy, 24 Gy, 30 Gy, 36 Gy.

The majority voted for 30 Gy, close to 73%.

I want to comment on that dose range.

My answer would be number 4 in a case where RT is curative and intense. We have been describing 30 Gy in 20 fractions. My answer is that there is too much difference between number 3 and number 4 really. We have been restricting boom boom for this case. It is extremely effective.

We do have a study for this. There is a phase III trial from Great Britain for indolent lymphomas.

You mean the 24 Gy compared to 40 - 44 Gy. They really do not look at 30 Gy but I agree that 24 Gy is effective as 40 - 44 Gy.

I can comment on that. Actually we do believe this. At MD Anderson we started and we enrolled other centers to join us and the way we do it is we give 24 Gy plus minus Rituximab. I can comment on the reason why we added Rituxmab to it. Basically the definitive impulse is 24 Gy.

I think that the guidelines from the national lymphoma radiation oncology group will come out as 24 - 30 Gy range.

So the patient received 30 Gy and here is the field. In the clinic we quickly changed this treatment plan. Here is the other field on the axial.

Would you include the external iliac LN?

The inguinal nodes are very interior so you could use a wedge are for example but we were concerned about the external iliac chain. With the dose we use we go AP PA sometimes wedging a little bit anteriorly. Because of some concernes about the distal external iliac nodes. We did include the external iliac chain. The other thing we do is we use double blocking. Is there any question about testing the field under the normal block. So instead of 3 and a half we got a 3% dose. So we put the anal c blocking.

Why I like this case. We have the forward case. It is quite shocking how often our medical oncologist refers to us these patients, who received either Rituximab alone or a recommendation for nothing. I want to go back and look at the historical data and this is from Stanford. We all know the original report of 177 patients with stage I and II as shown with median follow up of almost 8 years. The OS and RFS are listed but even in 20 years the RFS is 40%. Most of the recurrences are early within the first 5 years.

This is the study you are referring to looking at randomized doses of RT. This was a larger study which included both aggressive and indolent lymphomas. Patients were randomized to 24 Gy vs 40 - 45 Gy without any difference in the overall response rate, complete response rate, PFS, OS.

This is a paper that we did from the NCCN database at Dana Farber. There are 7 academic medical centers who were part of the database. We looked across all the centers. How many patients with grade I and II follicular lymphoma received RT which is a level 1 recommendation by the guideline panel.

Here you can see there are 100 patients with stage I that we identified within the database. There is a significant variation among the different centers. You can see that less than 25% received RT alone. There is a fair number of patients who were observed. Perhaps some of these patients had intra abdominal disease or disease that was not easily accessible. We found that it is interesting and worth funny now.

There is a recent study that came out. A vary large study from the SEER database looking at more questions. You can see how many patients with localized grade 1 and 2 follicular lymphoma received RT. This data look quite similar. This is from SEER but we saw the academic medical centers. In that fewer than 40% of patients across multiple decades received RT.

This is the lymphoma specific survival from that study. You can see it is a very large study with 6400 patients. 2200 patients received RT, 4300 did not. There was a significant benefit both in terms of LSS and OS in this particular study.

So here we do a multivariate analysis including a number of factors for DFS and OS. You can see that age in stage I vs II were predictive but the radiotherapy on the bottom was highly predictive and the DFS was very significant as well as OS.

This are data that were presented at Lugano this year from Princess Margaret. It is a very large series of 700 patients with stage I and II follicular lymphoma treated with 20 Gy with a long median follow up of over 10 years. About 182 patients received combined modality therapy. The majority of them received R - CHOP based therapy. patients to receive chemotherapy were more likely to have stage II grade III high LDH or bulky disease. But in the group 526 patients received RT alone. When you look at the outcome they really look very good. The median dose is about 30 Gy.

The vast majority of patients had a complete response. The 10 year relapse rate was 50%, which fitted better than the original data from Stanford. The local and marginal recurrence rate are very low. The 10 year OS for the patients who received RT alone is 65% in the combined modality therapy group. It was not better than 66%. The lymphoma SS was similar across both groups at 80%. Very low grade of transformation for this follow up at 5.9%. For the patients who recurred (288 patients) only less than half required chemotherapy at 10 years post diagnosis suggesting that this means a distinct biology for the patient with more advanced follicular lymphoma.

So there are a couple of questions. One is when we give 24 Gy vs 30 Gy I think that some of these decisions are based on the fact that the disease was excised completely or if there is large disease even at an early stage. It depends a little bit on when the radiation oncologist had his training. Those who were trained long ago tend to give higher doses.

There is also a question about the definition of IFRT. Inguinal lymphomas are treated up to the SI joints. I think we do not use this trick for IFRT any more. I think we adjust the fields a little bit.

Using RT alone for treating a patients like this I would extend my field at least 5 cm proximally from where the disease was based on PET or CT or both or physical exam. In this scenario of combined modality therapy then I do not worry about those extensions as much. I would treat more tighter fields but when you use radiation alone you have to put wider margins.

In the trial they gave 24 Gy in 2 Gy fractions. I think there is no difference between this and 30 Gy in 1.5 Gy fractions.

I want to ask my own question. We never advocate aggressive surgery. Sometimes patients come with 1 or 2 neck LN that were removed completely and the post op staging shows no evidence of abnormal LN at CT or PET. Are you more open to discussion about observation in that scenario?

I would not. I think there is the risk of recurrence in this area. It is the neck area and you are concerned about several functions. You can drop the dose below 24 Gy in that setting.

I would not agree with observation for a simple reason: many times you would see patients with very small LN, very low SUV under PET scan. But if you are lucky enough to do an excisional biopsy on them they look non specific by radiological definition but then they come back with follicular lymphoma. This comes accordingly to what dr Haffty was saying. When you use radiation, not everything you see or you do not see on your imaging means it is or it is not there. Therefore yes we do involved sites but then we do a more careful look to include that area with more generous margins because I am chasing those small LN that look so unassuming on imaging. So the short answer is that you have to treat.

We presented a case 3 or 4 years back, that was similar. Things have changed so I want to present this case. It is a little bit unusual but many of the people in the audience see cases like this in their practice. RT makes a big impact on the outcome.

This was a 72 year old man that we saw with a 10 year history of rhinoplasty and obstructive sleep apnea. He then developed nasal fullness. CT revealed the soft tissue mass in the left nasal cavity. There was no biopsy at the time. He was treated with antibiotics and the symptoms resolved. Then 6 months later he developed worsening of the nasal fullness, occasional epistaxis, increasing discharge. He had an ENT exam at that time under anesthesia that revealed a diffuse inflammatory process of the left nasal wall. There was a very friable inflammatory pseudo mass with fluid that was excised. This pseudo tumor appeared to extend to the nasal floor. The entire lesion was not excised.

Pathology revealed an extranodal NK T cell lymphoma nasal type. The Ki 67 was up to 70% in some areas. PET CT and contrast CT one week post surgery revealed node disease outside of the nasal area. The PET was mildly positive at the surgical site.

He repeated an ENT exam 2 months later and it was normal. There was a delay because of surgical complications. At the ENT exam nothing appeared abnormal. We obtained a MRI at that time because we wanted to have an idea of the extent of this disease.

We should recommend RT alone 45 Gy, 54 Gy, CHOP followed by radiation, radiation 45 Gy followed by chemo, radiation 54 Gy followed by ChT.

Many studies that were published so far showed that ChT and typically CHOP is not effective in NK cell lymphoma. That is why recently we reversed the sequence and we started with radiation followed by ChT. There are 2 studies coming from the canadians and the japanese that actually use concomitant ChT and RT. So based on that actually we just started a prospective study at MDA using 54 Gy and concurrent ChT. Yes it is toxic but then this is a disease that is locally advanced. If it has to come back it does it locally so your local treatment is probably the most important thing.

In terms of ChT CHOP is well expressed at MDR genes that may pumps the ChT. I think that newer regimens using MTX or L asparaginase are important. In addition there have been studies looking at checking EBV viral loads before you treat a patient. They can be predictive of distant recurrence. That makes thinking about it. Absolutely the radiation needs to come early or you loose your local control and it is a really morbid disease.

We had the CT to evaluate the lesion. We used IMRT for this case. We also have a terrific neuro radiologist that will comment. We have covered anything suspicious. This is the lateral view.

I have another comment. Imaging is important. That is why you have to use all the imaging available to you. For instance we use the PET scan that will show the activity which sometimes could be inflammatory or could be disease. Then we use the MRI for the soft tissue and then we use an enhanced contrast CT for the bony invasion. The 3 of them will be fused most of the time with the planning CT. The main reason is that you have to have a very low threshold to include any area that looks suspicious into your field. Most of the data that comes from the asian countries actually included all the sinus. I would think that the reason why we do that is not that we have to include all the sinus is maybe that they had not enough imaging ability to figure out what to include and what not. That is why the local control was high when they included all the sinus.

This was difficult in this case because we had only one study that was really helpful at the time we were doing this. But I agree with the concept of multiple image fusion.

When a sinus cavity has been filled then we cover the whole sinus. So if the tumor is perforated to the bone medial wall but the maxillary sinus is not completely filled we will assume that it is contaminated and treat that as CTV. We do not treat all the sinus unless there is some evidence that the sinus wall is penetrated.

I want to show you a couple of views because this case involves the medial wall, the orbit or the lacrimal gland or the duct. In this case it is more central but you have to be very careful of the total dose and the dose you give the optic nerve and the retina. In this case we were lucky so we just had a little bit of the left eye orbit. I show you a couple of pictures.

We had some discussion a few minutes ago about the 3 different regimens that are used. There si a number of publications using these various regimens. I think the problem is CHOP plus RT is not very good. The data show sandwich regimens.

In this case since it was a 72 year old patient we did not feel good to give chemo at the same time. We gave RT and then chemo.

I think that at ASCO 2013 there was a phase III trial on this disease. It compared CHOP vs a more aggressive chemo regimen. I think it is the second at the bottom. It suffered from the fact that they put RT at the end of the treatment so it was not a perfect study. There was a dramatic survival advantage for the more aggressive chemo not - CHOP. So I think there are data that endorse the fact that it is good not to use CHOP.

Most of the studies that use concurrent CRT ended up while breaking the radiation course which we do not like at all or ending short of 40 Gy which again we do not recommend. One has to use the mentality of HN when treating this disease and go through it and afford the side effects because if you really finish at least at 50.4 Gy with no interruption it is good.

There was a lot of discussion about that particularly there were abstract at ASCO. I think a lot of people knows it is difficult to lead the radiation to the end. There was not a OS benefit. It was a regimen the no one really uses. It has a little bit of PFS in the original study but it was not statistically significant. I think people will be disappointed by the results of the study.

There was a survival advantage. People were very surprised that the study was presented because no one felt that the radiation should go to the end and it was giving a bad message.

There was very very little advantage in PFS in the intense arm locally. I agree with you.

I had a slide here. There is a study from China on 84 patients with nasal NK T cell lymphoma. Most patients got combined modality. The chemo was CHOP for almost all the patients. It showed significant advantage giving radiation before ChT and a significant advantage in terms of DFS and OS using doses of 54 Gy or above vs dose less than 54 Gy. I think in terms of RT you want to make sure that you give an enough high dose.

Do you have any comment about 45 - 54 Gy?

We give 54 - 55 Gy. Before that data came out we would give 45. We occasionally saw recurrences in 3 or 4 years. That was a disaster.

I give 50.4 Gy. I think the NCCN guidelines say 50.4 - 54 Gy.

If I have the sinus filled I am doubtful that there is disease in it. Maybe there is thickening or inflammation. I paint the dose because I am using IMRT to give 54 Gy to the area of low suspicion. Then I go up to the definitive dose where I know there is the disease.

There is a very nice review on Blood this year. How I treat NK T cell lymphoma; it is about the radiation dose.

I want to present a case of mantle cell lymphoma. It is in 2 parts, an advanced stage and an early stage I will start with a 70 year old patient. It is a stage IV mantle cell lymphoma. In 2007 he had multiple previous therapies. He underwent he regimen that is used at MDA, the leukemia like regimen that they used for mantle cell lymphoma. He got into remission for quite some time then he came back with a relapse. He was treated with Rituximab then he relapsed then he came back, he was treated with Rituximab, then he came back with a relapse. Then they used hyperfractionated Ciclophosphamide. Then he presented to me with troubled swallowing because of the mass that you can see in his throat. Since he was pancitopenic with a low bone marrow reserve I treated him with radiation. The question is what would you recommend observation, additional ChT, RT 2 Gy x 2F, RT 20 Gy, RT 40 Gy.

The majority chose 20 Gy. This is what I did. The patient is completely cleared. Then he presented again.

Sometimes mantle cell lymphoma is very radiosensitive. I would give 4 Gy in this setting.

I just finished treating a patient with 4 Gy and he had a CR.

I learnt over the years. Mantle cell lymphoma was such a new disease to us. I kept on dropping. Now sometimes I give 4 Gy, 8 Gy and you have a nice local control.

Then he presented again with that mass in the back. You can see it on the PET scan. I gave him again 20 Gy. He went into remission. You can see on the PET scan it went away after 20 Gy. He presented again with a mass you can see in the orbit and in the nasal area. I started treating him and after 8 Gy his eye is completely open. So in these years I went on dropping the dose. I am a big believer that mantle cell lymphoma is extremely radiosensitive. You do not need to use a high dose.

We know from multiple publications for example form MSCKK that there is a high response rate. They investigated 21 patients, 38 sites. The overall response rate was 100%. There was a complete response in 64% of them. The average time to response was 20 days which is what you usually see. They immediately melts when you give the radiation. The median dose was 30 Gy, with a range between 10 to 45 Gy. Now at MSKCC they use a lower dose.

At this meeting something similar was presented form the MSKCC. They presented a paper with 41 patients and 68 sites. The response was a CR in 57 sites which is 83%. PR in 8 sites. The RT dose ranged between 20 and 40 Gy. I am more convinced now to drop the dose to lower than 20 Gy.

I will also present a 60 year old gentleman who was diagnosed of a stage I mantle cell lymphoma of a high left cervical node. The PET scan did not reveal any disease as well. The bone marrow biopsy was negative. The question to the audience is would you do ChT alone, ChT and RT to 20 Gy, CRT 30 Gy, RT alone 20 Gy, RT alone 30 Gy, RT alone 40 Gy.

Did you investigate the GI tract?

It is part of the classic investigation as you do an endoscopy and a colonoscopy.

The majority would give ChT and RT 20 Gy. I think the opinion is divided when it comes to stage I - II. There are people who believe that RT alone would be fine. The majority in some centers would go with ChT without consolidation with RT. I would like to hear your opinion.

The algorithm we follow is to give combined modality therapy and we turn away probably with R - CHOP or something similar followed by radiation. I would give 30 Gy in this setting even though it is a radiosensitive lymphoma. In combined modality 20 Gy is as good as 30 Gy so I give 30 Gy.

We do the same. We use R CHOP. Now we use BR which is better than R CHOP.

It is the same combined modality with involved field 30 Gy.

I wanted to show you this study we submitted to ASH. It is form multiple centers around the world. We collected all the cases with mantle cell lymphoma stage I and II. The take home message was that radiation is effective in combined modality but in some instances also when you give RT alone it would lead to the same outcome.

Did you do any mutivariate analysis. One may think that there is some selection bias in those who got combined modality.

Sure. The selection bias was the reason why we ended up examining the cases that came to the RT department. Now we are collecting all the cases that come just to the door of the institution and how they were distributed. That is what we are doing right now. specifically for the selection bias.

30 Gy. I think we have a consensus on that.

Some cases with RT alone had very good 5 year DFS.

I think the message that we want to give the audience is mantle cell lymphoma is a forgotten disease for the radiation oncologist. It is extremely sensitive to radiation especially when the medical oncologist is out of options or he can not give ChT alone. I think that maybe there are 2 MCL. That is my personal opinion. There is the MCL that is aggressive like leukemia. There is the MCL that keeps on coming back for many years. For this latter one I think that the role of local treatment with RT becomes relevant.

I think there are some correlatives that we know like the KI67 fraction. It is very predictive of biological behavior. Those who have KI67 p deletion tend to have very aggressive disease. There is a number of other correlatives that are coming out. They may be predictive and help you to pick up patients. The BTK inhibitor is coming out early next year. It will change the way we treat MCL.

When stage I or II MCL present in the HN area for some reason they do better than when they present in the rest of the body. We ended up with that.

Despite those good results you see for RT alone I would be uncomfortable treating a patient with MCL with RT alone. I would prefer combined modality.

It strucks me that we do not see a lot of these cases because most of the times they are stage III or IV when they present. So you have a disease that is systemic. It takes a lot of effort to show that there is a subgroup of patients that are curable with local treatment. I agree that you may gain something using systemic therapy as well.

I think we should discriminate that there is a subgroup that present with HN disease such as the eye or the NP. Honestly they behave completely differently than your regular MCL that comes with blood involvement.

You have to follow these patients for a very long time. We had a patient that we treated 10 years ago. He recurred with systemic disease. We thought it was one of these cases. It was a BOT. He got combined modality 10 years later. Now he has very aggressive disease everywhere.

My conclusions were that MCL is very sensitive to radiation. Low dose radiation can achieve a CR (20 - 24 Gy). In my practice I would use 8 - 10 Gy. It is an effective and tolerable treatment for palliative reasons. It could be used also in combined modality if you have early stage patients.

I would include 4 Gy on that list of low doses that can achieve a CR. When I prescribe 20 Gy over 2 weeks and I see the patient at the end of 1 week, even quite big LN can be completely gone. The point is do I have to go on.

We have 2 minutes.

One of the questions for this case is what about R CHOP followed by high dose ChT. I think it is a question more for stage III IV. I will be interested in the panel thought about BMT for this disease.

We looked at the NCCN patients data base and compared patients who got Tarceva and ASCT. There were differences in PFS but there are a number of randomized studies including those from the nordic group. There are randomized studies from France. They suggest that ASCT probably improve PFS. It is unlikely that it results in long term cure so maybe there is a small subset of patients with low KI67. I think that novel drugs (Abrutinib) are promising. Maybe there are data from Germany in old patients with CHOP and R in maintenance. Those studies look really good and one wonders if maintenance R or some type of maintenance maybe equivalent to high dose ChT and ASCT as rescue. Those studies are not really well done.

There is something that you see potentially. At PMH patients with MCL are treated with a protocol using R CHOP and a TBI containing ASCT regimen.

We still do it for our patients.

There are a couple of questions. Can IMRT lead to underdosing of important regions. All data come from large field era. The second question is how much extension. We discussed some of the concerns about using multiple scans to fuse treating any area that looks suspicious at all because I think we are aware that the price that you pay using IMRT is the rapid fall off at the edge of the field. The extension question is a little complicated because I think it depends on how close your normal structures are. I think that if you are in an area where you are not worried about with high doses I think that you can use more expansion than you would in other areas.

Using IMRT for this case is almost a must. I would give 54 Gy. We are in a fortunate position as you can keep the mean dose to salivary gland less than 24 Gy where patients treated to 70 Gy for SCC can not achieve it. You really can reduce the morbidity substantially. You can use the chiasm dose less than 50 Gy. The merits of IMRT in this case are far away the concerns.

About the N case the survival is 60 months.

I present the case of a 46 year old female presenting with a large mediastinal mass showed on CT scans. She is found to have a PMBCL stage IIa with an elevated LDH.

Which is the optimal ChT.

Do we really need to go to 8 cycles of R CHOP.

In the era of PET if you do not have a CR after 6 cycles you do not have to go to 8 ones.

The NCCN panel says to go to 8. You do not know how much disease is left, the most part is cured. In this disease RT is effective if you use R CHOP.

There are no randomized trials about the optimal ChT. There are 2 controversies, one is about the addiction of R. The other is about the dose dense so called third generation protocol. The question is if they are more effective than for example R CHOP 21. These is one retrospective study that compared patients with this disease treated with CHOP versus third generation protocol. The inferior DFS on that curve is with R CHOP. The 80% DFS is what has been seen with the dose dense protocol.

Here there are other retrospective studies comparing CHOP with third generation protocols. If you look at the middle column you see RFS and EFS. The CHOP regimen is inferior. This led many people to conclude that TGP are preferable. However many people in the room also recalled that this was the same argument that was made for DBLCL again base on retrospective data. That was disproven in a randomized trial.

The other issue is if or not R may be better. This are data from the NIH shown some time ago. On the left there is the dose adjusted EPOCH and on the right are the EFS and OS when R is added. You can see the improvement when you add R.

With R CHOP and RT the EFS is 75 - 80%.

This regimen received a lot of attention over the last year and so what I want to do is update you about this. Dose - adjusted EPOCH plus R is a combination of agents that are listed on the top. With each cycle the dose is increased depending on the neutrophil count. It depends on the dose adjusted components of the regimen.

This regimen is more difficult to give. R CHOP is given one day to an out patients. Dose adjusted R EPOCH is 5 days. There is a 4 day continuous infusion of adria etoposide vincristine and R at the end. Many patients can go home with the pump but it is not easy and you drive people to be neutropenic. With vincristine you have a lot of neuropathies.

A phase II study was published in the NEJM early this year. Patients were accrued in a 10 year period. In 10 years they enrolled 51 patients. 65% had mediastinal bulk, 70% has elevated LDH. They received 6 - 8 cycles of the regimen with GF support. The small prints says that 2 patients received RT due to a poor response. The results were compared with 16 patients in a retrospective study form a separate center.

These are the graphs of EFS and OS in the NEJM. The EFS and the outcome are excellent with an EFS of 93% and a OS of 97%. They do not show the numbers at risk. We do not really know how many people has a 10 year follow up or the CI.

In this disease the relapses are exclusively in the first year. There may be late toxicity.

One patient died of AML. Hospitalization occurred during 13% of cycles. The number of patients hospitalized is not reported.

In the JCO they published that they had 74 pts hospitalized. 4 pts had toxicity within 6 weeks from administering ChT. So it is 4 out of 64, which is 3%. They do not report the non hematologic toxicity. They say it was similar to the prior reports. You see this line there is no decline in the ejection fraction.

Many pts get a glucose intolerance due to vincristine. A lot of people need a dose reduction. There is a presumption that giving a CI of adriamycin is safer so you can push the dose. We do not have data to support that. We will see a late toxicity. Most were young patients so they had a dose escalation.

They have to be PMBLC. They must not be grey zone L. At past Lugano when they presented data on grey zone L they said that adjusted dose of EPOCH are not as successful. They can not do it without RT. I am not sure how you can differentiate PMBLCL versus grey zone L.

The other institution that had cases in this paper was stanford. They were consecutive cases acquired in a short period of time. Until few years ago we were treating with R VEACOBP B plus RT routinely. In the last 3 years we treated pts with R ECPOCH. The stanford data were similar to the NCI.

People with SVC syndrome are not to be treated. The pathology is a major issue.

A single institution study should be placed in an appropriate context. No mention is made about fertility with Cyclophosphamide dose escalated. It is too soon to make conclusions about cardiac toxicity. The assumption that patients with this disease who receive RT are prone to second malignancy and cardiac toxicity needs to be substantiated.

There are some contrary findings. There is a similar study of patients receiving third generation ChT R. The EFS is 84% not as good as it was in the NEJM paper.

Our pt receives 6 cycles of R CHOP and had a PR. At the PET CT there is some residual avidity. My oncologist did the wrong thing and gave 2 more cycles of R CHOP and it worked. So we have now a CR on PET.

Should the pt receive RT? For observation there are no randomized data.

The role of RT was evaluated in retrospective series. RT improves the complete response rate. This is a series where CR went from 42% to 95%.

We have retrospective studies which compare pts who receive RT or not after a CR based on an institutional preference. There was an improvement in EFS among the pts who received RT so the EFS was 90% as compared to 75% among the pts treated with ChT alone (CHOP or R CHOP).

We have a study of pts who received a very aggressive ChT including ASCT. About half pts received local RT. When a multivariate analysis was done that included an adjustment for ChT response, stage and other RF, the addition of RT was associated with improvement in PFS. When the analysis was limited to pts who achieved the first line of ChT again pts who received RT did better than those receiving ChT alone.

The conclusions are that there is a small randomized study reporting a good outcome after dose adjusted ECPOCH with low use of RT. There re other studies that do not report EFS as high as shown in the NEJM paper. There is no clear comparative data, no randomized data of R CHOP versus intense ChT. The same level of data suggests a better outcome with IFRT. 30 - 36 Gy is the standard dose.

There is a randomized trial in which the use of RT is the primary study question. Pts who had a CR to ChT are randomized to RT or not. It is an institutional preference as to which ChT regimen is used.

Dose adjusted EPOCH is a very hard regimen. You need to have medical oncologists who are used to give it. It is hard to have a clear cut PMLCBL where R EPOCH can be used. We end up with biopsy proven disease after 6 cycles of R EPOCH. There is no magic in any ChT regimen.

The NCCN guidelines say that if you give R CHOP you need to give RT. You can omit RT if you have a PET CR but we need some randomized data.

When do you give RT for bulky L in stage I II. I give it all the time.

The unfolder trial randomized pts to R CHOP alone or R CHOP with RT on site of bulky and extra nodal disease. The no RT arm was closed at a interim analysis because the EFS was going to be better with combined modality.

Bony involvement at Lugano was statistically significant for DFS and OS.

This is a 13 year old girl with left inguinal adenopathy. They began to grow. Biopsy showed L.

Diagnosis: nodular LP hodgkin. LP cells. RS cells.

PET CT. Excisional biopsy. Progressive transformation of germinal centers.

She has stage I nodular LP.

58% IF 25 - 30 Gy.

It is hard to give pelvic RT to a 13 year old pt for fertility impair. ChT alone is a reasonable option.

ABVD does not work very well in this case. R CHOP is better.

The pt was places on a prospective trial seeking to clarify ChT and RT in nodular LP. As the inguinal node was resected the protocol for this pt was observation.

The concept of this protocol was based largely on reports form europe. They had 58 children with limited stage LP hodgkin. 88% had complete resection with surgery. OS was 100%. PFS was 57% at 4 years.

3 years later the pt had a LN in the left inguinal area. A PET CT showed disease. An excisional biopsy showed recurrence.

Oophoropexy plus IF received most consent.

Among the pts who relapsed the next step in the protocol was 3 cycles of AVPC. If a pt does not get CR he receives RT 20 Gy.

She received ChT alone.

There is a german study about R alone in stage I with good early results.

We use MRI simulation.